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Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer’s and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink

For peer review only Journal: BMJ Open

Manuscript ID bmjopen-2016-012044

Article Type: Protocol

Date Submitted by the Author: 23-Mar-2016

Complete List of Authors: Walker, Venexia; University of Bristol Davies, Neil; University of Bristol Jones, Tim; NIHR CLAHRC West Kehoe, Patrick; University of Bristol Martin, Richard; University of Bristol

Primary Subject Pharmacology and therapeutics Heading:

Secondary Subject Heading: Neurology, Epidemiology

Dementia < NEUROLOGY, Parkinson-s disease < NEUROLOGY, Motor Keywords:

neurone disease < NEUROLOGY, EPIDEMIOLOGY, THERAPEUTICS http://bmjopen.bmj.com/

on September 25, 2021 by guest. Protected copyright.

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1 2 3 TITLE 4 5 Can commonly prescribed drugs be repurposed for the prevention or treatment of 6 Alzheimer’s and other neurodegenerative diseases? Protocol for an observational cohort 7 study in the UK Clinical Practice Research Datalink 8 9 10 CO-AUTHORS 11 1, 2 1, 2 3 4 1, 2 12 Venexia M Walker , Neil M Davies , Tim Jones , Patrick G Kehoe , Richard M Martin 13 14 1 School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom 15 2 MRC UniversityFor of Bristol peer Integrative reviewEpidemiology Unit, Bristol,only United Kingdom 16 3 NIHR CLAHRC West, Bristol, United Kingdom 17 4 Dementia Research Group, School of Clinical Sciences, University of Bristol, Bristol, 18 19 United Kingdom 20 21 CORRESPONDING AUTHOR 22 23 Venexia M Walker 24 25 Address: School of Social and Community Medicine, University of Bristol, Oakfield House, 26 Oakfield Grove, Bristol, BS8 2BN 27 28 29 Email: [email protected] 30 31 Telephone: +441173310128 32 33 KEYWORDS

34 http://bmjopen.bmj.com/ 35 Alzheimer’s disease, Neurodegenerative Disease, Drug Repurposing, Clinical Practice 36 Research Datalink, Pharmacoepidemiology 37 38 39 WORD COUNT 40 41 42 3569 words excluding title page, abstract, references, figures and tables. on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 ABSTRACT 4 5 Introduction: Current treatments for Alzheimer’s and other neurodegenerative diseases have 6 only limited effectiveness meaning there is an urgent need for new medications that could 7 influence disease incidence and progression. We will investigate the potential of a selection 8 9 of commonly prescribed drugs, as a more efficient and cost-effective method of identifying 10 new drugs for the prevention or treatment of Alzheimer’s disease, non-Alzheimer’s disease 11 dementias, Parkinson’s disease and amyotrophic lateral sclerosis. Our research will focus on 12 drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all 13 of which have previously been identified as potentially cerebroprotective and have variable 14 levels of pre-clinical evidence that suggest they may have beneficial effects for various 15 aspects of dementiaFor pathology. peer Methods review and analysis: We will only conduct a hypothesis testing 16 observational cohort study using data from the Clinical Practice Research Datalink (CPRD). 17 Our analysis will consider four statistical methods, which have different approaches for 18 19 modelling confounding. These are multivariable adjusted Cox regression; propensity matched 20 regression; instrumental variable analysis; and marginal structural models. We will also use 21 an intention-to-treat analysis, whereby we will define all exposures based on the first 22 prescription observed in the database so that the target parameter is comparable to that 23 estimated by a randomised controlled trial. Ethics and dissemination: This protocol has 24 been approved by the CPRD’s Independent Scientific Advisory Committee (ISAC). We will 25 publish the results of the study as open-access peer-reviewed publications and disseminate 26 findings through national and international conferences as are appropriate. 27 28 29 STRENGTHS AND LIMITATIONS OF THIS STUDY 30 31 • This study will involve a large sample of data and has considerable power to detect 32 even relatively small effects, even under highly conservative Bonferroni corrections. 33 For example, the sample to assess the progression of dementia contains 105,471

34 patients and has a minimum detectable hazard ratio of 0.931. http://bmjopen.bmj.com/ 35 • We plan to use four different statistical methods in our analysis, which have different 36 approaches for modelling confounding. By doing this, we will be able to assess the 37 38 merits of each method in the given situation in order to minimize confounding. 39 • Dementia is a heterogeneous outcome, and electronic codes used to define cases in 40 primary care may not be as accurate as cases in clinical cohorts. We will undertake 41 sensitivity analyses to explore how this may affect our results. 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 INTRODUCTION 4 5 Rationale 6 7 Alzheimer’s disease is a progressive disease affecting brain function and independent living, 8 9 and eventually requires full-time care. There are only a few treatments that temporarily help 10 symptoms such as memory loss; however, these eventually become ineffective as the 11 underlying disease progresses unabated. Part of the difficulty of treating Alzheimer’s disease 12 is that it involves the activation of many destructive processes in the brain, each of which is 13 likely to need simultaneous treatment if the progression of the disease is to be halted. 14 15 For this reason,For there is urgentpeer need for newreview evidence about medications only that could influence 16 the incidence and progression of Alzheimer’s disease. One promising approach is to 17 investigate drug repositioning[1], which offers a time- and cost-effective alternative to 18 19 traditional drug development. A recent consensus study of dementia experts identified a 20 short-list of individual and classes of prescribed drugs that may be repurposed as novel 21 treatments for dementia.[2] The short-list included compounds used to treat hypertension, 22 hypercholesterolemia and type 2 diabetes, all of which can be classed as having 23 ‘cerebroprotective’ properties and have variable levels of pre-clinical evidence that suggest 24 they may have beneficial effects for various aspects of dementia pathology. However as yet 25 there is limited pharmacoepidemiological data to support their effects in human populations. 26 Therefore, we plan to investigate whether these existing medications could be repurposed to 27 prevent or treat Alzheimer’s disease. 28 29 30 Furthermore, the overlap of different forms of neurodegenerative disease would suggest that 31 there may be scope to translate existing or newly identified interventions for testing in 32 neurodegenerative diseases where similarities exist. Thus we will start by examining the most 33 common form of neurodegenerative disease - Alzheimer’s disease.[3,4] We will then

34 investigate whether the drug candidates could also be repurposed to treat or prevent other http://bmjopen.bmj.com/ 35 neurodegenerative diseases – these will include other non-Alzheimer’s disease dementias (i.e. 36 the group for dementias in which Alzheimer’s disease is not thought to play a part), 37 Parkinson’s disease and amyotrophic lateral sclerosis. Collectively these findings will allow 38 39 the prioritisation of drugs to be tested as repurposed treatments in clinical trials of 40 Alzheimer’s and other neurodegenerative diseases in the future. 41 42 Objectives on September 25, 2021 by guest. Protected copyright. 43 44 To investigate whether commonly prescribed medications, previously identified as potentially 45 cerebroprotective, are associated with the incidence or progression of neurodegenerative 46 disease. 47

48 49 We will focus on the following medications: 50 a. Treatments for hypertension 51 b. Treatments for hypercholesterolemia 52 c. Treatments for type 2 diabetes 53 54 Along with the following neurodegenerative diseases: 55 a. Alzheimer’s disease (AD) 56 b. Non-Alzheimer’s disease dementias (NADD) 57 c. Parkinson’s disease (PD) 58 d. Amyotrophic lateral sclerosis (ALS) 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 METHODS AND ANALYSIS 4 5 Study Design 6

7 8 We will conduct a hypothesis testing observational cohort study of neurodegenerative disease 9 incidence and progression, using data from the Clinical Practice Research Datalink (CPRD). 10 11 Participants 12 13 We will include men and women older than 40 years, with at least 12 consecutive months of 14 records classified as ‘acceptable’ by the CPRD from all “up to standard” practices.[5] 15 Patients registeredFor at a practicepeer less than review 365 days before their only 40th birthday, or those with a 16 th 17 first record of one of the index drug classes of interest before their 40 birthday will be 18 excluded. This will ensure high quality assessment of baseline data and possible confounders. 19 20 Sample Selection 21 22 We will investigate the incidence and progression of Alzheimer’s disease, non-Alzheimer’s 23 disease dementias, Parkinson’s disease and amyotrophic lateral sclerosis. Our investigations 24 25 into the incidence will focus on treatments which are reported to be cerebroprotective and are 26 currently prescribed for hypertension[6], hypercholesterolaemia[7,8] and type 2 diabetes[9]. 27 For each treatment, we will conduct two analyses. The first will compare treated to untreated 28 individuals with similar indications – this is cohort A. The second will compare the outcomes 29 of individuals given different sub-classes of specific medications – this is cohort B. We will 30 also investigate progression using a third cohort, cohort C. Progression will be defined as the 31 post-diagnosis survival of a patient. For each neurodegenerative disease group of interest, we 32 will determine the effects on progression of the three possible new treatments. In cohort C, 33 exposure will be defined in two ways: i) using patients being prescribed these drugs at the

To investigate To investigate on September 25, 2021 by guest. Protected copyright. incidence by comparing 43 incidence by comparing progression by Purpose the different drug 44 treated and untreated comparing treated and subclasses of each 45 individuals. untreated individuals. 46 treatment. 47 There will be three There will be three There will be three 48 Number of cohorts of this type, one cohorts of this type, one cohorts of this type, one 49 cohorts for each of dementia for each treatment of for each treatment of 50 required (AD or NADD), PD 51 interest. interest. and ALS. 52 53 Treatments for Treatments for Treatments for hypertension, hypertension, hypertension, 54 Exposures 55 hypercholesterolaemia hypercholesterolaemia hypercholesterolaemia, 56 and type 2 diabetes. and type 2 diabetes. and type 2 diabetes. 57 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Date at first risk of the 4 condition the treatment 5 Start of is used for or date of Date of first Date of first diagnosis 6 follow-up first diagnosis of the prescription of a of neurodegenerative 7 (index date) condition itself if there treatment of interest. disease of interest. 8 9 was no preceding 10 period ‘at risk’. 11 Diagnosis of Diagnosis of 12 Outcome neurodegenerative neurodegenerative Death. 13 disease of interest. disease of interest. 14 Individuals prescribed 15 For peer reviewboth treatment and only Individuals with less Individuals with less 16 control medications at 17 Exclusion than 12 consecutive than 12 consecutive the same time or with 18 Criteria months of records prior months of records prior less than 12 consecutive 19 to cohort entry. to cohort entry. 20 months of records prior 21 to cohort entry. 22 Conventional Conventional Conventional 23 regression, propensity regression, propensity regression, propensity 24 Statistical score regression, score regression, score regression and 25 Analysis instrumental variable instrumental variable 26 marginal structural analysis and marginal analysis and marginal 27 models. 28 structural models. structural models. 29 30 Cohort A 31 32 For each treatment, we will create a cohort of patients who are diagnosed with the condition 33 the treatment is used for or ‘at risk’ of that condition. This will be determined by the

34 indications and test results described in Table 2. We will split each cohort into ‘exposed’ and http://bmjopen.bmj.com/ 35 ‘unexposed’ groups. The ‘exposed’ group will consist of patients who received a treatment of 36 37 interest within 6 months of initial diagnosis of the condition for which the treatment is being 38 given (the ‘indication’ for treatment). The ‘unexposed’ group will consist of all others in the 39 cohort. Patients will be identified as having received a treatment of interest by product codes 40 (see Supplementary Files 3-5). Therefore, in this analysis, we will compare an ‘exposed’ 41 group of individuals who were prescribed the treatment to an ‘unexposed’ group of 42 individuals who received similar test results (i.e. were ‘at risk’ of or diagnosed with the on September 25, 2021 by guest. Protected copyright. 43 indication for treatment), but did not receive the treatment, as illustrated in Figure 1. The aim 44 of this approach is to address confounding by indication that could cause bias if the 45 ‘unexposed’ group is drawn from the full population, whom are likely to be healthier. It will 46 47 also allow us to minimise excluded immortal time bias as patients will be followed from a 48 consistent index date (date first at risk or date of first diagnosis of the condition itself if there 49 was no preceding period at risk). 50 51 Follow up for cohort A will start on the first date a patient is diagnosed with the condition the 52 treatment is used for or ‘at risk’ of that condition (See Table 2 and Supplementary Files 3-5.) 53 Follow-up will end with the earliest of a relevant neurodegenerative disease diagnosis, death, 54 or censoring due to the end of registration at a CPRD general practice. 55 56 57 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Table 2: The cohorts of type A, one for each treatment of interest. 4 Cohort Entry Criteria 5 Patients who are ‘at risk’ of hypertension as indicated by one of the 6 following: 7 8 • Medical code indicating a diagnosis of ‘at risk’ of hypertension 9 • Recorded systolic blood pressure test result between 120-139 mmHg 10 • Recorded diastolic blood pressure test result between 80-89 mmHg 11 12 Treatments for In the case of no period ‘at risk’, patients who have hypertension as 13 hypertension indicated by one of the following: 14 • Medical code indicating a diagnosis of hypertension 15 For peer review only 16 • Product code indicating treatment for hypertension 17 • Recorded systolic blood pressure test result of 140 mmHg or more 18 • Recorded diastolic blood pressure test result of 90 mmHg or more 19 20 See Supplementary File 3 for code lists relating to hypertension. 21 Patients who are ‘at risk’ of hypercholesterolaemia as indicated by one of 22 the following: 23 24 • Medical code indicating a diagnosis of ‘at risk’ of hypercholesterolaemia 25 • Recorded test result where total cholesterol level is between 4-5 mmol/L 26 • Recorded test result where LDL level is between 2-3 mmol/L 27 Treatments for 28 In the case of no period ‘at risk’, patients who have hypercholesterolaemia Hypercholest- 29 as indicated by one of the following: 30 erolaemia 31 • Medical code indicating a diagnosis of hypercholesterolaemia 32 • Product code indicating treatment for hypercholesterolaemia 33 • Recorded test result where total cholesterol level exceeds 5 mmol/L

34 • Recorded test result where LDL level exceeds 3 mmol/L http://bmjopen.bmj.com/ 35 36 See Supplementary File 4 for code lists relating to hypercholesterolaemia. 37 Patients who are ‘at risk’ of type 2 diabetes as indicated by a medical code. 38 39 40 In the case of no period ‘at risk’, patients who have type 2 diabetes as 41 indicated by one of the following: 42

• Medical code indicating a diagnosis of type 2 diabetes on September 25, 2021 by guest. Protected copyright. 43 • Product code indicating treatment for type 2 diabetes 44 Medical code indicating a diagnosis of unspecified diabetes, first received Treatments for • 45 over the age of 40 46 type 2 diabetes 47 • Product code indicating treatment with insulin, first received over the age 48 of 40 49 50 This assumes that patients treated with insulin or receiving a diagnosis of 51 unspecified diabetes after the age of 40 have type 2 diabetes. Patients with a 52 recorded diagnosis of type 1 diabetes at any age will be excluded. See 53 Supplementary File 5 for code lists relating to type 2 diabetes. 54 55 56 57 58 59 60 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Cohort B 4 5 In this analysis we will compare different drug sub-classes that exist for a given treatment 6 (listed in Table 3). To do this, we will create a cohort of all patients who were prescribed a 7 treatment and categorise them by the drug sub-class they initially received. This will allow us 8 9 to compare the outcomes for each of the resulting sub-groups. For each treatment, we have 10 defined the most frequently prescribed sub-class as the control (indicated in Table 3). In the 11 primary analysis of this cohort we will exclude patients initially prescribed the control sub- 12 class if they receive another sub-class of the same treatment at the same time, however we do 13 not expect this to be a common. We will explore the outcomes of individuals prescribed 14 multiple sub-classes, other than that specified above, in a sensitivity analysis. 15 For peer review only 16 Follow-up for cohort B will start on the date of first eligible prescription as determined by a 17 product code (see the treatment code lists in Supplementary Files 3-5). Follow-up will end 18 19 with the earliest of a relevant neurodegenerative disease diagnosis, death, or censoring due to 20 the end of registration at a CPRD general practice. 21 22 Table 3: The drug sub-classes of interest for each treatment group with the control 23 treatments indicated. 24 Treatments for hypertension 25 • Beta-adrenoceptor blocking drugs (control) 26 27 • Angiotensin-converting enzyme inhibitors 28 • Thiazides and related diuretics 29 • Calcium channel blockers 30 • Loop diuretics 31 • Alpha-adrenoceptor blocking drugs 32 • Centrally acting antihypertensive drugs 33 • Angiotensin-II receptor antagonists 34 http://bmjopen.bmj.com/ 35 • Vasodilator antihypertensive drugs 36 • Potassium-sparing diuretics and aldosterone antagonists 37 Treatments for hypercholesterolaemia 38 • Statins (control) 39 • Fibrates 40 41 • Bile acid sequestrants 42 • Omega-3 fatty acid compounds on September 25, 2021 by guest. Protected copyright. 43 • Ezetimibe 44 • Nicotinic acid group 45 Treatments for type 2 diabetes 46 47 • Biguanides (control) 48 • Sulphonylureas 49 • Other antidiabetic drugs 50 51 Cohort C 52 53 For each neurodegenerative disease group of interest, we will create a cohort of individuals 54 with a read code indicating this outcome (see Supplementary File 1) or a product code 55 56 indicating they received treatment for the outcome (see Supplementary File 2). These cohorts 57 will be used to investigate the associations of neurodegenerative disease progression with 58 exposure to one of the three treatment groups of interest: treatments for hypertension, 59 60 5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

17 18 Exposures 19 20 For our primary analysis we will define all exposures based on the first prescription observed 21 in the database.[10] This is so that the target parameter estimated in the observational study 22 will be comparable to that estimated by a randomised controlled trial (RCT). Analogous to an 23 intention-to-treat analysis in a RCT, patients initially prescribed an active treatment 24 medication (exposed), but later stop that medication or switch to a control drug (unexposed), 25 will be allocated to treatment (i.e. classified as exposed, irrespective of what happens in the 26 future) and vice-versa. First time prescriptions of the medications of interest (treatment and 27 28 control) will be defined as people who received at least one prescription of the product but 29 who had no use of a related product during the 12 months before the start of follow-up. The 30 prescriptions will be defined by the therapy file in the CPRD, which records the date each 31 prescription was issued, the quantity of drug prescribed and the dosage. Patients initially 32 receiving more than one prescription of a drug of interest will be included in our analysis in a 33 group representing the specific combination of drugs they receive. The effects of treatment

34 switching will be explored using marginal structural models. http://bmjopen.bmj.com/ 35 36 Outcomes 37 38 39 For incidence, we will identify the neurodegenerative disease outcomes (Alzheimer’s disease, 40 non-Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) by the first 41 record of a relevant read code (see Supplementary File 1) or the first record of a product code 42

indicating treatment for the neurodegenerative disease (see Supplementary File 2). For both on September 25, 2021 by guest. Protected copyright. 43 incidence and progression, we will identify deaths using linked Office of National Statistics 44 (ONS) data. 45 46 Covariates 47 48 49 We will match all covariates on date of birth, sex, year of index date and years of recorded 50 history in the database before the index date. The covariates we will include in our analyses 51 are: body mass index, smoking status, alcohol consumption, a postcode-based measure of 52 socioeconomic position, previous history of coronary-artery disease, previous coronary- 53 bypass surgery and cerebrovascular disease including stroke. We will also control for other 54 major chronic illness (including cancer, arthritis) using the Charlson index [11,12] and for 55 consultation rate, calculated by dividing the total number of clinic visits prior to the index 56 57 date by the length of each patient's follow-up. If there are missing data in the covariates we 58 will consider using multiple imputation. 59 60 6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Data Sources 4 5 The main data source for this project is the CPRD. Cause-specific mortality from linked ONS 6 data are more accurate than CPRD data on mortality from general practices.[13] Therefore, 7 we will use the ONS data to identify date and cause of death and test our hypotheses relating 8 9 to mortality using data from linked practices only. We will also be using the Index of 10 Multiple Deprivation (IMD) in order to define socioeconomic position, which is listed as a 11 covariate in our analysis. 12 13 Study Size 14 15 The table belowFor (Table 4)peer details our estimates review of the cohort sizeonly with the minimum sample 16 size and detectable hazard ratio (alpha=0.05, beta=0.80) for the Cox regression analysis of 17 18 cohorts B and C. The minimum detectable hazard ratio is taken to be the detectable hazard 19 ratio for the smallest exposed group tested against the control group. The minimum sample 20 size is the sum of patients in the smallest exposed group and the control group. It is difficult 21 to provide such details for cohort A due to its novel design that includes patients who are ‘at 22 risk’ of the condition the treatment is used for. We can however consider the cohort size 23 estimates for cohort B to be conservative estimates for cohort A as all patients in cohort B are 24 included in cohort A by definition. Further details concerning the sample size and detectable 25 hazard ratios (alpha=0.05, beta=0.80) for specific comparisons within cohorts B and C can be 26 found in Supplementary Files 6 and 7. This study will involve a large sample of data and has 27 28 considerable power to detect even relatively small effects. Therefore, our statistical power 29 will be more than adequate to test all of our proposed hypotheses, even under highly 30 conservative Bonferroni corrections. 31 32 Table 4: The cohort size with the minimum sample size and detectable hazard ratio 33 (alpha=0.05, beta=0.80) for the Cox regression analysis of cohorts B and C. Further

34 details provided in Supplementary Files 6 and 7. http://bmjopen.bmj.com/ 35 Minimum 36 Minimum Cohort Start of Follow Up Cohort Size Detectable 37 Sample Size 38 Hazard Ratio Treatment for 39 1,018,519 269,808 0.968 40 hypertension 41 Treatment for 42 B 808,687 788,479 0.844 hypercholesterolaemia on September 25, 2021 by guest. Protected copyright. 43 Treatment for 200,800 158,775 0.943 44 type 2 diabetes 45 Diagnosis of dementia 46 105,471 0.931 47 (AD and NADD) Diagnosis of Parkinson’s 48 C 20,686 0.870 49 disease 50 Diagnosis of 2,227 0.600 51 ALS 52 53 54 55 56 57 58 59 60 7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Bias 4 5 There are three main sources of bias in our results: ascertainment bias, collider bias and 6 immortal time bias. To overcome ascertainment bias, we will control for consultation rate in 7 our analyses because people who have more chronic conditions such as hypertension, 8 diabetes or renal insufficiency may have higher rates of consultation, which may also increase 9 10 the opportunity for recording other diagnoses such as dementia. Collider bias could occur if 11 we conditioned on events that happened as a result of the prescription the patient was issued. 12 To prevent this form of bias from affecting our results, we will define each covariate using 13 data inputted prior to the index date.[14] Finally, we will minimise the risk of immortal time 14 bias in two ways. Firstly, to prevent misclassified immortal time, we will define exposures 15 based on theFor first prescription peer observed review in the database[10] only and use an intention-to-treat 16 analysis. Secondly, to minimise immortal time, we will follow-up patients (exposed and 17 unexposed) from a consistent index date. This will be a test result or a read code indicating 18 19 diagnosis where possible[15] however, to capture all relevant patients, we will allow those 20 receiving treatment without a recorded diagnosis to be included. 21 22 Confounding 23 24 We have identified two key sources of confounding in our study: confounding by indication 25 and time dependent confounding. To address the former, we will use four different statistical 26 methods, which have different approaches for modelling confounding. Through examination 27 28 of these approaches, we hope to highlight any uncontrolled confounding that may be leading 29 to false conclusions about drug effect. We will also account for confounding by indication in 30 the construction of our cohorts. Consider cohort A, where we compare ‘exposed’ and 31 ‘unexposed’ groups of individuals. Drawing the ‘unexposed’ group from the full population 32 can introduce bias as they are likely to be in better health. We will avoid this by defining 33 cohort entry on the basis of first test or recording of a relevant read code so the ‘exposed’ and

34 ‘unexposed’ groups will have more in common. In addition to this, we will address time http://bmjopen.bmj.com/ 35 dependent confounding in our study. This will be done by using marginal structural models, 36 which can allow for time dependent confounding and treatment switching between products. 37 38 39 Missing Data 40 41 We will investigate the extent of missing data in our exposures, outcomes and covariates and 42 use multiple imputation to impute missing data where appropriate.[16–18] on September 25, 2021 by guest. Protected copyright. 43 44 45 Multiple Testing 46 47 We will account for multiple testing using permutation analysis where appropriate. A portion 48 of the data included in this project was previously used in a study investigating the 49 association of alpha-adrenoceptor blocking drugs and angiotensin-II receptor antagonists with 50 Alzheimer’s disease and non-Alzheimer’s disease dementias.[19] We anticipate the overlap 51 between our study and this previous study to be around 4% for each of cohorts A and B and 52 9% for cohort C. We acknowledge that this might be a concern for multiple testing however 53 wish to highlight that the analyses conducted in this study will differ from those used before. 54 55 56 57 58 59 60 8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Statistical Methods 4 5 We will use four statistical approaches in our study – they are: multivariable adjusted Cox 6 regression, propensity matched regression, instrumental variable analysis and marginal 7 structural models. We are committed to presenting the findings from all our analyses, 8 9 irrespective of the direction of findings, and will handle discrepancies between them by 10 assessing the merits of each method in the given situation. 11 12 We will be using an intention to treat analysis in our primary analysis. The reasons for this 13 are two-fold. First, whilst there are theoretical statistical models for estimating the effects of 14 treatment switching such as marginal structural models, these methods require the strong 15 assumption thatFor there are peer no unmeasured review confounders. Second, only to our knowledge there are no 16 instrumental variable methods for estimating the effects of treatment switching. We will 17 investigate treatment switching using marginal structural models in a secondary analysis. All 18 19 of the methods we will use for this study are summarised below. 20 21 Multivariable adjusted Cox regression 22 23 In our first analyses, a conventional observational analysis, we will estimate the hazard ratios 24 of incidence and survival using Cox-proportional hazards models. Both analyses will use the 25 actual prescriptions issued to the patients.[20] We will report these associations adjusted for 26 basic confounders (age and gender), and results adjusted for all measured covariates 27 described previously. We will also perform tests of the proportional hazards assumption. 28 29 30 Propensity matched regression 31 32 In our second analysis we will construct a sample of patients balanced on covariates and risk 33 factors using a propensity score.[21–24] We will construct propensity scores using a logistic

34 regression of the actual treatment received on the covariates described above. Therefore, each http://bmjopen.bmj.com/ 35 participant’s propensity score will be their conditional probability (odds) of receiving 36 treatment or not (Cohort types A and C), or receiving treatment versus control therapy 37 (Cohort type B). We will match each patient receiving one treatment to another patient 38 39 receiving the control treatment with the closest propensity score on a ratio of 1:1 using a 40 nearest neighbour algorithm with no replacement, and matching will be restricted to the 41 common support region. Patients outside the common support region are those prescribed the 42 treatment therapy with propensity scores higher than any patient prescribed the control on September 25, 2021 by guest. Protected copyright. 43 treatment and vice versa. We will estimate odds-ratios and hazard ratios of the outcomes 44 using the propensity score matched sample using logistic and Cox-regressions. 45 46 Instrumental variable analysis 47 48 49 In our third analysis, we will estimate the effects i) treatment or no treatment, and ii) the 50 specific sub-class of medication prescribed using physicians’ prescribing preferences as 51 instruments for the prescriptions the GPs issue to their patients. We cannot directly measure 52 the physicians’ preferences; therefore, we will use the prescriptions they issued to their 53 previous patients as a proxy for their preferences. For example, if the instrument were based 54 on just one previous prescription, physicians who previously prescribed the treatment therapy 55 would be categorised as a “treatment” prescriber otherwise they would be categorised as 56 “control”. As with our previous studies we will use seven prior prescriptions to improve the 57 strength of the instruments.[25–27] Using multiple prior prescriptions will maximise power. 58 59 60 9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 We will report risk differences in the outcomes using additive structural mean models 4 estimated via the generalised method of moments.[28–30] We will categorise each of the 5 adverse event outcomes as occurring within 3, 6, 9, 12, 24 and 48 months of index date. 6 Methods for estimating survival models using instrumental variables are not well developed. 7 Therefore we will explore potential instrumental variable survival models in a secondary 8 9 analysis.[31] 10 11 Marginal structural models 12 13 In our fourth analysis, we will estimate the effects of each treatment using marginal structural 14 models.[32] We will use these models to account for time dependent confounding and 15 treatment switching.For We peer will construct inversereview probability weights only for each treatment based 16 on the patients’ observed characteristics such as: gender, age, comorbidities and concurrent 17 treatments. We will use these models to estimate the odds and hazard ratios of disease 18 19 incidence and progression. 20 21 ETHICS 22 23 This protocol has been approved by the CPRD’s Independent Scientific Advisory Committee 24 (ISAC). Although this study does not directly involve patients, the topic of identifying new 25 repurposable drug candidates for neurodegenerative diseases is becoming widely supported 26 by patient and user groups from various communities. In the event that we progress any drug 27 candidates identified from this study into a formal clinical trial, then we will consult with 28 29 relevant representatives in the design of that study. We have direct experience of this from 30 the currently underway NIHR funded RADAR trial, the case for which was supported by 31 work undertaken as part of a previous study using CPRD data [ISAC protocol 08_101]. 32 33 DISSEMINATION

34 http://bmjopen.bmj.com/ 35 We will publish the results of the study as open-access peer-reviewed publications. We will 36 disseminate findings through national and international conferences as are appropriate. 37 Depending on the findings we would also explore additional options for focussed 38 39 dissemination within appropriate communities, e.g. via an Alzheimer’s Society dissemination 40 grant. 41 42 CONTRIBUTORSHIP STATEMENT on September 25, 2021 by guest. Protected copyright. 43 44 VMW, NMD, PGK, and RMM contributed to planning the analysis. TJ provided the 45 feasibility numbers and refined the cohort definitions. VMW drafted this protocol and all 46 others edited and revised the manuscript. PGK and RMM were responsible for securing the 47 funding. 48 49 50 FUNDING STATEMENT 51 52 This project is supported by a generous donation from the Perros Trust, obtained through the 53 University of Bristol Campaigns and Alumni Office. This project is also supported by the 54 MRC Integrative Epidemiology Unit at the University of Bristol. The MRC Integrative 55 Epidemiology Unit is supported by the Medical Research Council and the University of 56 Bristol [MC_UU_12013/9]. NMD is supported by the Economics and Social Research 57 Council (ESRC) via a Future Research Leaders Fellowship [ES/N000757/1]. PGK has a 58 59 60 10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Professorship supported by the Sigmund Gestetner Foundation. TJ is supported by the 4 National Institute for Health Research (NIHR) Collaboration for Leadership in Applied 5 Health Research and Care (CLAHRC) West at University Hospitals Bristol NHS Foundation 6 Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, 7 the NIHR or the Department of Health. 8 9 10 COMPETING INTERESTS STATEMENT 11 12 PGK is the principal investigator on a non-commercial NIHR-funded clinical trial of losartan 13 in Alzheimer’s disease [ISRCTN 93682878, EudraCT 2012-003641-15]. 14 15 REFERENCESFor peer review only 16 17 1 Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for 18 19 existing drugs. Nat Rev Drug Discov 2004;3:673–83. doi:10.1038/nrd1468 20 21 2 Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev 22 Drug Discov 2012;11:833–46. doi:10.1038/nrd3869 23 24 3 Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus 25 study. The Lancet 2005;366:2112–7. doi:10.1016/S0140-6736(05)67889-0 26 27 4 Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of 28 dementia in individuals aged 65 years and older from three geographical areas of 29 England: results of the Cognitive Function and Ageing Study I and II. The Lancet 30 2013;382:1405–12. doi:10.1016/S0140-6736(13)61570-6 31 32 5 Herrett E, Gallagher AM, Bhaskaran K, et al. Data Resource Profile: Clinical Practice 33 Research Datalink (CPRD). Int J Epidemiol 2015;44:827–36. doi:10.1093/ije/dyv098

34 http://bmjopen.bmj.com/ 35 36 6 Unger T. Comparing the cerebroprotective properties of antihypertensive drugs in terms 37 of their effects on angiotensin. Nat Clin Pract Nephrol 2008;4:12–3. 38 doi:10.1038/ncpneph0672 39 40 7 Asahi M, Thomas S, Yoshimura S, et al. Protective Effects of Statins after Embolic Focal 41 Cerebral Ischemia in Endothelial Nitric Oxide Synthase Knockout Mice. J Cereb Blood 42 Flow Metab Off J Int Soc Cereb Blood Flow Metab 2005;25:722–9. on September 25, 2021 by guest. Protected copyright. 43 doi:10.1038/sj.jcbfm.9600070 44 45 8 Huxley RR, Hawkins MH, Humphries SE, et al. Risk of Fatal Stroke in Patients With 46 Treated Familial Hypercholesterolemia A Prospective Registry Study. Stroke 47 48 2003;34:22–5. doi:10.1161/01.STR.0000047123.14312.3E 49 50 9 Liu Y, Tang G, Li Y, et al. Metformin attenuates blood-brain barrier disruption in mice 51 following middle cerebral artery occlusion. J Neuroinflammation 2014;11. 52 doi:10.1186/s12974-014-0177-4 53 54 10 Hernán MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized 55 experiments: an application to postmenopausal hormone therapy and coronary heart 56 disease. Epidemiol Camb Mass 2008;19:766–79. doi:10.1097/EDE.0b013e3181875e61 57 58 59 60 11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 11 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic 4 comorbidity in longitudinal studies: development and validation. J Chronic Dis 5 1987;40:373–83. 6 7 12 Khan NF, Perera R, Harper S, et al. Adaptation and validation of the Charlson Index for 8 Read/OXMIS coded databases. BMC Fam Pract 2010;11:1. doi:10.1186/1471-2296-11-1 9 10 13 Thomas KH, Davies N, Metcalfe C, et al. Validation of Suicide and Self-harm records in 11 12 the Clinical Practice Research Datalink. Br J Clin Pharmacol Published Online First: 6 13 December 2012. doi:10.1111/bcp.12059 14 15 14 Cole SR,For Platt RW, peer Schisterman EF,review et al. Illustrating biasonly due to conditioning on a 16 collider. Int J Epidemiol 2009;39:417–20. doi:10.1093/ije/dyp334 17 18 15 Suissa S, Azoulay L. Metformin and the Risk of Cancer: Time-related biases in 19 observational studies. Diabetes Care 2012;35:2665–73. doi:10.2337/dc12-0788 20 21 16 Royston P. Multiple imputation of missing values: Further update of ice, with an 22 emphasis on categorical variables. Stata J 2009;9:466–77. 23 24 17 Sterne JAC, White IR, Carlin JB, et al. Multiple imputation for missing data in 25 epidemiological and clinical research: potential and pitfalls. BMJ 2009;338:b2393– 26 27 b2393. doi:10.1136/bmj.b2393 28 29 18 White IR, Kalaitzaki E, Thompson SG. Allowing for missing outcome data and 30 incomplete uptake of randomised interventions, with application to an Internet-based 31 alcohol trial. Stat Med 2011;30:3192–207. doi:10.1002/sim.4360 32 33 19 Davies NM, Kehoe PG, Ben-Shlomo Y, et al. Associations of anti-hypertensive

34 treatments with Alzheimer’s disease, vascular dementia, and other dementias. J http://bmjopen.bmj.com/ 35 Alzheimers Dis 2011;26:699. 36 37 20 Kirkwood BR. Essential medical statistics. 2nd ed. Malden, Mass: : Blackwell Science 38 2003. 39 40 21 Glynn R, Schneeweiss S, Stürmer T. Indications for propensity scores and review of their 41 42 use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 2006;98:253–9. on September 25, 2021 by guest. Protected copyright. 43 44 22 Leuven E, Sianesi B. PSMATCH2: Stata module to perform full Mahalanobis and 45 propensity score matching, common support graphing, and covariate imbalance testing. 46 Stat Softw Compon Published Online First: 47 2012.http://ideas.repec.org/c/boc/bocode/s432001.html (accessed 13 May2013). 48 49 23 Rosenbaum PR, Rubin DB. Constructing a Control Group Using Multivariate Matched 50 Sampling Methods That Incorporate the Propensity Score. Am Stat 1985;39:33. 51 doi:10.2307/2683903 52 53 24 Rosenbaum PR, Rubin DB. The Central Role of the Propensity Score in Observational 54 Studies for Causal Effects. Biometrika 1983;70:41. doi:10.2307/2335942 55 56 57 25 Davies NM, Davey Smith G, Windmeijer F, et al. COX-2 Selective Nonsteroidal Anti- 58 inflammatory Drugs and Risk of Gastrointestinal Tract Complications and Myocardial 59 60 12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Infarction: An Instrumental Variable Analysis. Epidemiology 2013;24:352–62. 4 doi:10.1097/EDE.0b013e318289e024 5 6 26 Thomas KH, Martin RM, Davies NM, et al. Smoking cessation treatment and risk of 7 depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective 8 cohort study. BMJ 2013;347:f5704–f5704. doi:10.1136/bmj.f5704 9 10 27 Davies NM, Gunnell D, Thomas KH, et al. Physicians’ prescribing preferences were a 11 12 potential instrument for patients’ actual prescriptions of antidepressants. J Clin Epidemiol 13 Published Online First: September 2013. doi:10.1016/j.jclinepi.2013.06.008 14 15 28 Clarke PS,For Windmeijer peer F. Instrumental review Variable Estimators only for Binary Outcomes. J Am 16 Stat Assoc 2012;107:1638–52. doi:10.1080/01621459.2012.734171 17 18 29 Hansen L, Singleton K. Generalized instrumental variables estimation of nonlinear 19 rational expectations models. Econometrica 1982;50:1269–86. 20 21 30 Clarke PS, Windmeijer F. Identification of causal effects on binary outcomes using 22 structural mean models. Biostatistics 2010;11:756–70. doi:10.1093/biostatistics/kxq024 23 24 31 Tchetgen Tchetgen EJ, Walter S, Vansteelandt S, et al. Instrumental Variable Estimation 25 in a Survival Context. Epidemiol Camb Mass Published Online First: 16 February 2015. 26 27 doi:10.1097/EDE.0000000000000262 28 29 32 Hernán MA, Brumback B, Robins JM. Marginal Structural Models to Estimate the Joint 30 Causal Effect of Nonrandomized Treatments. J Am Stat Assoc 2001;96:440–8. 31 doi:10.1198/016214501753168154 32 33 33 Levesque LE, Hanley JA, Kezouh A, et al. Problem of immortal time bias in cohort

34 studies: example using statins for preventing progression of diabetes. Br Med J http://bmjopen.bmj.com/ 35 2010;340:b5087–b5087. doi:10.1136/bmj.b5087 36 37 34 Suissa S. Immortal time bias in pharmacoepidemiology. Am J Epidemiol 2008;167:492– 38 9. 39 40 41 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 152 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Figure 1: The cohort construction for cohort type A, designed to eliminate immortal 4 time bias. For those without a period ‘at risk’, cohort entry will occur when they are 5 diagnosed with the condition. 6 7 Figure 1 – Mono Image.tif 8 9 10 A patient will enter the cohort for a given treatment when they first become ‘at risk’ of the 11 condition the treatment is used for or, in the case of no period ‘at risk’, when they are first 12 diagnosed with the condition (see Table 2). We define cohort entry in this way to avoid 13 excluded immortal time bias that can occur when cohort entry is determined by treatment 14 variation over time.[33,34] Immortal time is the period during follow-up when the outcome 15 cannot occur.For For example, peer suppose we review started following the onlytreated patients in our cohort 16 from the date of their first prescription and the untreated patients from a matched date. This 17 18 would make it impossible for the treated patients to have an outcome prior to their first 19 prescription. Consequently, patients in this group would all have a period before treatment, 20 when an event could not occur. This period is their immortal time, and it must be correctly 21 attributed to the ‘unexposed’ group i.e. if they have an event prior to the first prescription, 22 they should be allocated to the ‘unexposed’ group. To do this, patients in the ‘exposed’ and 23 ‘unexposed’ groups must be followed-up and compared from the same start date. In this 24 cohort we are minimizing excluded immortal time by following patients from either a test 25 result or diagnosis where possible. In order to capture all relevant patients, we will allow 26 those receiving treatment without a recorded diagnosis to be included as it is assumed 27 28 treatment suggests a diagnosis. 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 152 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 The cohort construction for cohort type A, designed to eliminate immortal time bias. For those without a 23 period ‘at risk’, cohort entry will occur when they are diagnosed with the condition. 24 Figure 1 25 158x71mm (300 x 300 DPI) 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 152

1 2 Medical code list: possible Alzheimer's disease

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 E00..00 Senile and presenile organic psychotic conditions 6 E00..11 Senile dementia 7 E00..12 Senile/presenile dementia 8 E000.00 Uncomplicated senile dementia 9 10 E001.00 Presenile dementia 11 E001000 Uncomplicated presenile dementia 12 E001100 Presenile dementia with delirium 13 14 E001200 Presenile dementia with paranoia 15 E001300 Presenile dementia with depression 16 E001z00 Presenile dementia NOS 17 For peer review only E002.00 Senile dementia with depressive or paranoid features 18 19 E002000 Senile dementia with paranoia 20 E002100 Senile dementia with depression 21 E002z00 Senile dementia with depressive or paranoid features NOS 22 23 E003.00 Senile dementia with delirium 24 E00z.00 Senile or presenile psychoses NOS 25 Eu02z11 [X] Presenile dementia NOS 26 Eu02z12 [X] Presenile psychosis NOS 27 28 Eu02z14 [X] Senile dementia NOS 29 Eu02z15 [X] Senile psychosis NOS 30 Eu02z16 [X] Senile dementia, depressed or paranoid type 31 32 Eu05700 [X]Mild cognitive disorder 33 F11z.11 Cerebral atrophy 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: probable Alzheimer's disease

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 Eu00.00 [X]Dementia in Alzheimer's disease 6 Eu00000 [X]Dementia in Alzheimer's disease with early onset 7 Eu00011 [X]Presenile dementia,Alzheimer's type 8 Eu00012 [X]Primary degen dementia, Alzheimer's type, presenile onset 9 10 Eu00013 [X]Alzheimer's disease type 2 11 Eu00100 [X]Dementia in Alzheimer's disease with late onset 12 Eu00111 [X]Alzheimer's disease type 1 13 14 Eu00112 [X]Senile dementia,Alzheimer's type 15 Eu00113 [X]Primary degen dementia of Alzheimer's type, senile onset 16 Eu00200 [X]Dementia in Alzheimer's dis, atypical or mixed type 17 For peer review only Eu00z00 [X]Dementia in Alzheimer's disease, unspecified 18 19 Eu00z11 [X]Alzheimer's dementia unspec 20 F110.00 Alzheimer's disease 21 F110000 Alzheimer's disease with early onset 22 23 F110100 Alzheimer's disease with late onset 24 Fyu3000 [X]Other Alzheimer's disease 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: non-specific dementia (non Alzheimer's disease dementias)

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6AB..00 Dementia annual review 6 9hD0.00 Excepted from dementia quality indicators: Patient unsuitabl 7 9hD1.00 Excepted from dementia quality indicators: Informed dissent 8 E00y.00 Other senile and presenile organic psychoses 9 10 E041.00 Dementia in conditions EC 11 Eu02.00 [X]Dementia in other diseases classified elsewhere 12 Eu02y00 [X]Dementia in other specified diseases classif elsewhere 13 14 Eu02z00 [X] Unspecified dementia 15 Eu02z13 [X] Primary degenerative dementia NOS 16 F112.00 Senile degeneration of brain 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: other dementia (non Alzheimer's disease dementias)

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 8BPa.00 Antipsychotic drug therapy for dementia 6 E02y100 Drug-induced dementia 7 Eu01111 [X]Predominantly cortical dementia 8 Eu02000 [X]Dementia in Pick's disease 9 10 Eu02100 [X]Dementia in Creutzfeldt-Jakob disease 11 Eu02200 [X]Dementia in Huntington's disease 12 Eu02300 [X]Dementia in Parkinson's disease 13 14 Eu02400 [X]Dementia in human immunodef virus [HIV] disease 15 Eu02500 [X]Lewy body dementia 16 Eu04100 [X]Delirium superimposed on dementia 17 For peer review only F111.00 Pick's disease 18 19 F116.00 Lewy body disease 20 F11x200 Cerebral degeneration due to cerebrovascular disease 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: vascular dementia (non Alzheimer's disease dementias)

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 E004.00 Arteriosclerotic dementia 6 E004.11 Multi infarct dementia 7 E004000 Uncomplicated arteriosclerotic dementia 8 E004100 Arteriosclerotic dementia with delirium 9 10 E004200 Arteriosclerotic dementia with paranoia 11 E004300 Arteriosclerotic dementia with depression 12 E004z00 Arteriosclerotic dementia NOS 13 14 Eu01.00 [X]Vascular dementia 15 Eu01.11 [X]Arteriosclerotic dementia 16 Eu01000 [X]Vascular dementia of acute onset 17 For peer review only Eu01100 [X]Multi-infarct dementia 18 19 Eu01200 [X]Subcortical vascular dementia 20 Eu01300 [X]Mixed cortical and subcortical vascular dementia 21 Eu01y00 [X]Other vascular dementia 22 23 Eu01z00 [X]Vascular dementia, unspecified 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: amyotrophic lateral sclerosis

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 7Q04100 Amyotrophic lateral sclerosis drugs Band 1 6 F152.00 Motor neurone disease 7 F152000 Amyotrophic lateral sclerosis 8 F152z00 Motor neurone disease NOS 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: Parkinson's disease

3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 F12..00 Parkinson's disease 6 F12z.00 Parkinson's disease NOS 7 8 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for Alzheimer's disease

3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 2930 Donepezil 5mg tablets 6 2931 Donepezil 10mg tablets 7 4597 Rivastigmine 1.5mg capsules 8 5247 Aricept 10mg tablets (Eisai Ltd) 9 10 5334 Reminyl 12mg tablets (Shire Pharmaceuticals Ltd) 11 5400 Aricept 5mg tablets (Eisai Ltd) 12 5616 Exelon 6mg capsules (Novartis Pharmaceuticals UK Ltd) 13 14 6225 Memantine 10mg tablets 15 7329 Galantamine 20mg/5ml oral solution sugar free 16 7361 Galantamine 24mg modified-release capsules 17 For peer review only 9786 Rivastigmine 6mg capsules 18 19 9854 Reminyl 4mg tablets (Shire Pharmaceuticals Ltd) 20 9966 Ebixa 5mg/pump actuation oral solution (Lundbeck Ltd) 21 10187 Galantamine 4mg tablets 22 23 10255 Galantamine 8mg modified-release capsules 24 11546 Exelon 1.5mg capsules (Novartis Pharmaceuticals UK Ltd) 25 11635 Galantamine 12mg tablets 26 11654 Galantamine 8mg tablets 27 28 11716 Exelon 3mg capsules (Novartis Pharmaceuticals UK Ltd) 29 11751 Rivastigmine 3mg capsules 30 11752 Rivastigmine 4.5mg capsules 31 32 11827 Rivastigmine 2mg/ml oral solution sugar free 33 11837 Memantine 10mg/ml oral solution sugar free 34 14309 Galantamine 16mg modified-release capsules 35 18062 Reminyl 8mg tablets (Shire Pharmaceuticals Ltd) 36 37 18556 Exelon 2mg/ml oral solution (Novartis Pharmaceuticals UK Ltd) 38 18587 Reminyl XL 8mg capsules (Shire Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 18800 Ebixa 10mg tablets (Lundbeck Ltd) 40 41 20140 Reminyl XL 16mg capsules (Shire Pharmaceuticals Ltd) 42 20404 Exelon 4.5mg capsules (Novartis Pharmaceuticals UK Ltd) 43 24088 Reminyl XL 24mg capsules (Shire Pharmaceuticals Ltd) 44 29288 Reminyl 4mg/ml oral solution (Shire Pharmaceuticals Ltd) 45 46 35088 Donepezil 10mg orodispersible tablets sugar free 47 35179 Donepezil 5mg orodispersible tablets sugar free on September 25, 2021 by guest. Protected copyright. 48 36848 Aricept Evess 5mg orodispersible tablets (Eisai Ltd) 49 50 36976 Rivastigmine 4.6mg/24hours transdermal patches 51 37132 Rivastigmine 9.5mg/24hours transdermal patches 52 37188 Aricept Evess 10mg orodispersible tablets (Eisai Ltd) 53 37444 Exelon 4.6mg/24hours transdermal patches (Novartis Pharmaceuticals UK Ltd) 54 55 37957 Exelon 9.5mg/24hours transdermal patches (Novartis Pharmaceuticals UK Ltd) 56 38976 Memantine 5mg+10mg+15mg+20mg Tablet 57 39240 Memantine 20mg tablets 58 59 39362 Ebixa tablets treatment initiation pack (Lundbeck Ltd) 60 39363 Ebixa 20mg tablets (Lundbeck Ltd) 48015 Galsya XL 24mg capsules (Consilient Health Ltd) 48482 Galsya XL 8mg capsules (Consilient Health Ltd)

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1 2 53842 Aricept 5mg tablets (Waymade Healthcare Plc) 3 53882 Rivastigmine 2mg/ml oral solution BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 55720 Gatalin XL 24mg capsules (Aspire Pharma Ltd) 6 55928 Exelon 4.5mg capsules (Waymade Healthcare Plc) 7 56600 Donepezil 5mg tablets (Zentiva) 8 56709 Gatalin XL 16mg capsules (Aspire Pharma Ltd) 9 10 56771 Rivastigmine 3mg capsules (Dr Reddy's Laboratories (UK) Ltd) 11 57139 Ebixa 10mg tablets (DE Pharmaceuticals) 12 57171 Erastig 9.5mg/24hours transdermal patches (Teva UK Ltd) 13 14 57627 Erastig 4.6mg/24hours transdermal patches (Teva UK Ltd) 15 58709 Donepezil 10mg tablets (A A H Pharmaceuticals Ltd) 16 58780 Voleze 9.5mg/24hours transdermal patches (Focus Pharmaceuticals Ltd) 17 For peer review only 58947 Donepezil 10mg tablets (Accord Healthcare Ltd) 18 19 59871 Donepezil 10mg/5ml oral suspension 20 60107 Donepezil 5mg tablets (Alliance Healthcare (Distribution) Ltd) 21 60493 Galantex XL 24mg capsules (Creo Pharma Ltd) 22 23 60723 Rivastigmine 6mg capsules (Waymade Healthcare Plc) 24 61385 Nemdatine 10mg tablets (Actavis UK Ltd) 25 61476 Acumor XL 24mg capsules (Generics (UK) Ltd) 26 61618 Nemdatine 20mg tablets (Actavis UK Ltd) 27 28 61921 Luventa XL 24mg capsules (Fontus Health Ltd) 29 62164 Alzest 9.5mg/24hours transdermal patches (Dr Reddy's Laboratories (UK) Ltd) 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for amyotrophic lateral sclerosis

3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 3975 Riluzole 50mg tablets 6 18838 Rilutek 50mg tablets (Sanofi) 7 8 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for Parkinson's disease

3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 514 Cabergoline 500microgram tablets 6 546 Sinemet 110 Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 7 758 Entacapone 200mg tablets 8 772 Ropinirole 1mg tablets 9 10 811 Pramipexole 88microgram tablets 11 1853 Half sinemet cr 25mg+100mg Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 12 2074 Sinemet 275 Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 13 14 2279 Bromocriptine 2.5mg tablets 15 2464 Pergolide 250microgram tablets 16 2465 Madopar CR capsules (Roche Products Ltd) 17 For peer review only 2466 Madopar 100mg/25mg capsules (Roche Products Ltd) 18 19 2467 Selegiline 5mg tablets 20 2534 Sinemet plus Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 21 2739 Sinemet 62.5 Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 22 23 2829 Sinemet CR 50mg+200mg Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 24 3562 Madopar 50mg/12.5mg capsules (Roche Products Ltd) 25 3640 Selegiline 10mg tablets 26 3641 Levodopa with benserazide 100mg + 25mg Capsule 27 28 3642 Co-beneldopa 25mg/100mg capsules 29 3910 Madopar 50mg/12.5mg dispersible tablets (Roche Products Ltd) 30 4146 Pergolide 50microgram tablets 31 32 4300 Bromocriptine 5mg capsules 33 4581 Dostinex 500microgram tablets (Pfizer Ltd) 34 4866 Co-careldopa 12.5mg/50mg tablets 35 4941 Pergolide 1mg tablets 36 37 4975 Bromocriptine 1mg tablets 38 5233 Selegiline 10mg/5ml oral solution http://bmjopen.bmj.com/ 39 5248 Co-beneldopa 25mg/100mg modified-release capsules 40 41 5310 Co-careldopa 25mg/250mg tablets 42 5339 Amantadine 100mg capsules 43 5389 Cabergoline 1mg tablets 44 5406 Cabergoline 2mg tablets 45 46 5464 Co-beneldopa 12.5mg/50mg capsules 47 5487 Apomorphine 2mg sublingual tablets sugar free on September 25, 2021 by guest. Protected copyright. 48 5535 Apomorphine 3mg sublingual tablets sugar free 49 50 5575 Uprima 2mg sublingual tablets (Abbott Laboratories Ltd) 51 5665 Uprima 3mg sublingual tablets (Abbott Laboratories Ltd) 52 5673 Co-beneldopa 25mg/100mg dispersible tablets sugar free 53 5674 Ropinirole 250microgram tablets 54 55 5675 Co-careldopa 25mg/100mg modified-release tablets 56 5766 Pramipexole 180microgram tablets 57 5869 Madopar 100mg/25mg dispersible tablets (Roche Products Ltd) 58 59 5909 Pramipexole 700microgram tablets 60 6012 Ropinirole 250micrograms with 500micrograms with 1mg tablet 6016 Cabergoline 4mg tablets 6035 Amantadine 50mg/5ml oral solution sugar free

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1 2 6122 Ropinirole 5mg tablets 3 6143 Ropinirole 500micrograms with 1mg with 2mg tablet BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6156 Co-careldopa 25mg/100mg tablets 6 7040 Rasagiline 1mg tablets 7 7051 Selegiline 1.25mg oral lyophilisates sugar free 8 7246 Co-careldopa 50mg/200mg modified-release tablets 9 10 7256 Madopar 200mg/50mg capsules (Roche Products Ltd) 11 7339 Mirapexin 0.18mg tablets (Boehringer Ingelheim Ltd) 12 7386 Stalevo 150mg/37.5mg/200mg tablets (Orion Pharma (UK) Ltd) 13 14 7386 Stalevo 150mg/37.5mg/200mg tablets (Orion Pharma (UK) Ltd) 15 7428 Symmetrel 100mg capsules (Alliance Pharmaceuticals Ltd) 16 7879 Levodopa with benserazide 200mg + 50mg Capsule 17 For peer review only 8407 Levodopa with benserazide 50mg + 12.5mg Capsule 18 19 8408 Levodopa with benserazide 50mg + 12.5mg Dispersible tablet 20 8426 Eldepryl 5mg tablets (Orion Pharma (UK) Ltd) 21 9283 Co-careldopa 10mg/100mg tablets 22 23 9327 Tolcapone 100mg tablets 24 9333 Parlodel 2.5mg Tablet (Novartis Pharmaceuticals UK Ltd) 25 9512 Co-beneldopa 50mg/200mg capsules 26 9701 Apomorphine 10mg/ml injection 27 28 9799 Ropinirole 2mg tablets 29 10142 Stalevo 100mg/25mg/200mg tablets (Orion Pharma (UK) Ltd) 30 10142 Stalevo 100mg/25mg/200mg tablets (Orion Pharma (UK) Ltd) 31 32 11235 Co-beneldopa 12.5mg/50mg dispersible tablets sugar free 33 11277 Pergolide Starter Pack (Pergolide 50 micrograms tablet with Pergolide 250 micrograms tablet) 81 tablets 34 11541 Cabaser 1mg tablets (Pfizer Ltd) 35 11586 Zelapar 1.25mg oral lyophilisates (Teva UK Ltd) 36 37 12057 Bromocriptine 10mg capsules 38 12481 Levodopa 125mg Capsule http://bmjopen.bmj.com/ 39 12762 ReQuip 250microgram tablets (GlaxoSmithKline UK Ltd) 40 41 13403 Parlodel 1mg Tablet (Novartis Pharmaceuticals UK Ltd) 42 13515 Parlodel 5mg Capsule (Novartis Pharmaceuticals UK Ltd) 43 13736 Celance 250microgram tablets (Eli Lilly and Company Ltd) 44 13793 Celance 1mg tablets (Eli Lilly and Company Ltd) 45 46 14140 Cabaser 4mg tablets (Pfizer Ltd) 47 14342 Ropinirole 500microgram tablets on September 25, 2021 by guest. Protected copyright. 48 14914 Rotigotine 2mg/24hours transdermal patches 49 50 14915 Rotigotine 6mg/24hours transdermal patches 51 14916 Stalevo 50mg/12.5mg/200mg tablets (Orion Pharma (UK) Ltd) 52 14916 Stalevo 50mg/12.5mg/200mg tablets (Orion Pharma (UK) Ltd) 53 14934 ReQuip 1mg tablets (GlaxoSmithKline UK Ltd) 54 55 14935 Apomorphine 50mg/10ml solution for infusion pre-filled syringes 56 16224 Eldepryl 10mg tablets (Orion Pharma (UK) Ltd) 57 16617 Mirapexin 0.088mg tablets (Boehringer Ingelheim Ltd) 58 59 16780 Levodopa 500mg tablets 60 16817 Benserazide 50mg with Levodopa 200mg capsules 16861 Levodopa with benserazide 100mg + 25mg Dispersible tablet 16933 Mirapexin 0.7mg tablets (Boehringer Ingelheim Ltd)

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1 2 16970 Levodopa with benserazide 100mg + 25mg Modified-release capsule 3 17053 Rotigotine 4mg/24hours transdermal patches BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 17058 Adartrel 250microgram tablets (GlaxoSmithKline UK Ltd) 6 17066 Adartrel 500microgram tablets (GlaxoSmithKline UK Ltd) 7 17443 Cabaser 2mg tablets (Pfizer Ltd) 8 17619 ReQuip 2mg tablets (GlaxoSmithKline UK Ltd) 9 10 17622 ReQuip 5mg tablets (GlaxoSmithKline UK Ltd) 11 18346 Levodopa 250mg Capsule 12 18566 APO-go PFS 50mg/10ml solution for infusion pre-filled syringes (Britannia Pharmaceuticals Ltd) 13 14 18715 Brocadopa 125mg Capsule (Yamanouchi Pharma Ltd) 15 18891 Adartrel 2mg tablets (GlaxoSmithKline UK Ltd) 16 19267 Apo-go 10mg/ml Injection (Britannia Pharmaceuticals Ltd) 17 For peer review only 19492 Neupro 2mg/24hours transdermal patches (UCB Pharma Ltd) 18 19 19498 Neupro 4mg/24hours transdermal patches (UCB Pharma Ltd) 20 19505 Neupro 6mg/24hours transdermal patches (UCB Pharma Ltd) 21 19592 Larodopa 500mg Tablet (Cambridge Laboratories Ltd) 22 23 20023 Celance 50microgram tablets (Eli Lilly and Company Ltd) 24 20211 Britaject 10mg/ml Subcutaneous injection (Britannia Pharmaceuticals Ltd) 25 20651 Comtess 200mg tablets (Orion Pharma (UK) Ltd) 26 21118 Tasmar fc 100mg Tablet (Roche Products Ltd) 27 28 21361 Parlodel 10mg Capsule (Novartis Pharmaceuticals UK Ltd) 29 21745 Symmetrel 50mg/5ml syrup (Alliance Pharmaceuticals Ltd) 30 21793 Azilect 1mg tablets (Teva UK Ltd) 31 32 22602 Rotigotine 2mg/24hr with 4mg/24hr with 6mg/24hr with 8mg/24hr patch 33 22604 Rotigotine 8mg/24hours transdermal patches 34 22675 Tolcapone fc 200mg Tablet 35 23293 Neupro 8mg/24hours transdermal patches (UCB Pharma Ltd) 36 37 24528 Brocadopa 500mg Capsule (Yamanouchi Pharma Ltd) 38 25288 Co-careldopa 10mg/100mg tablets (Teva UK Ltd) http://bmjopen.bmj.com/ 39 25298 Eldepryl 10mg/5ml syrup (Orion Pharma (UK) Ltd) 40 41 25844 Levodopa 500mg Capsule 42 25890 Lysovir 100mg capsules (Alliance Pharmaceuticals Ltd) 43 26041 Tasmar 100mg tablets (Meda Pharmaceuticals Ltd) 44 26257 Centrapryl 5mg Tablet (Opus Pharmaceuticals Ltd) 45 46 27302 Brocadopa 250mg Capsule (Yamanouchi Pharma Ltd) 47 27649 Benserazide 12.5mg with levodopa 50mg capsules on September 25, 2021 by guest. Protected copyright. 48 27738 Stilline 10mg Tablet (Berk Pharmaceuticals Ltd) 49 50 28590 Vivapryl 5mg Tablet (Viatris Pharmaceuticals Ltd) 51 29846 Vivapryl 10mg Tablet (Viatris Pharmaceuticals Ltd) 52 31268 Co-careldopa 25mg/250mg tablets (Teva UK Ltd) 53 31356 Tasmar fc 200mg Tablet (Roche Products Ltd) 54 55 31682 Benserazide 12.5mg with Levodopa 50mg dispersible tablets 56 32003 Benserazide 25mg with Levodopa 100mg dispersible tablet 57 32067 Bromocriptine 2.5mg Tablet (Generics (UK) Ltd) 58 59 33133 Apomorphine 50mg/5ml solution for injection ampoules 60 33541 Co-careldopa 5mg/20mg/1ml intestinal gel 100ml cassette 33781 Apomorphine 20mg/2ml solution for injection ampoules 34123 Selegiline 5mg tablets (IVAX Pharmaceuticals UK Ltd)

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1 2 34132 Bromocriptine 2.5mg tablets (A A H Pharmaceuticals Ltd) 3 34219 Bromocriptine 2.5mg Tablet (Berk Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 34250 Selegiline 10mg tablets (IVAX Pharmaceuticals UK Ltd) 6 35255 Apomorphine 30mg/3ml solution for injection pre-filled disposable devices 7 35407 Benserazide 25mg with levodopa 100mg capsules 8 35939 APO-go 50mg/5ml solution for injection ampoules (Britannia Pharmaceuticals Ltd) 9 10 36038 APO-go PEN 30mg/3ml solution for injection (Britannia Pharmaceuticals Ltd) 11 37489 Benserazide 25mg with Levodopa 100mg modified-release capsules 12 37635 Pramipexole 350microgram tablets 13 14 37984 Mirapexin 0.35mg tablets (Boehringer Ingelheim Ltd) 15 38151 Ropinirole 8mg modified-release tablets 16 38199 APO-go 20mg/2ml solution for injection ampoules (Britannia Pharmaceuticals Ltd) 17 For peer review only 38245 Ropinirole 2mg modified-release tablets 18 19 38249 Ropinirole 4mg modified-release tablets 20 38250 ReQuip XL 4mg tablets (GlaxoSmithKline UK Ltd) 21 38251 ReQuip XL 2mg tablets (GlaxoSmithKline UK Ltd) 22 23 38256 ReQuip XL 8mg tablets (GlaxoSmithKline UK Ltd) 24 38357 Stalevo 200mg/50mg/200mg tablets (Orion Pharma (UK) Ltd) 25 38357 Stalevo 200mg/50mg/200mg tablets (Orion Pharma (UK) Ltd) 26 39348 Caramet 50mg/200mg CR tablets (Teva UK Ltd) 27 28 40039 Parlodel 2.5mg tablets (Meda Pharmaceuticals Ltd) 29 40235 Selegiline 5mg tablets (Niche Generics Ltd) 30 40306 Stalevo 75mg/18.75mg/200mg tablets (Orion Pharma (UK) Ltd) 31 32 40306 Stalevo 75mg/18.75mg/200mg tablets (Orion Pharma (UK) Ltd) 33 40418 Stilline 5mg Tablet (Berk Pharmaceuticals Ltd) 34 40452 Caramet 25mg/100mg CR tablets (Teva UK Ltd) 35 40568 Stalevo 125mg/31.25mg/200mg tablets (Orion Pharma (UK) Ltd) 36 37 40568 Stalevo 125mg/31.25mg/200mg tablets (Orion Pharma (UK) Ltd) 38 40866 Rotigotine 1mg/24hours transdermal patches http://bmjopen.bmj.com/ 39 40947 Parlodel 5mg capsules (Meda Pharmaceuticals Ltd) 40 41 41091 Co-careldopa 25mg/100mg/5ml oral suspension 42 41147 Neupro 1mg/24hours transdermal patches (UCB Pharma Ltd) 43 41219 Pramipexole 260microgram modified-release tablets 44 41242 Pramipexole 3.15mg modified-release tablets 45 46 41243 Pramipexole 1.05mg modified-release tablets 47 41265 Pramipexole 520microgram modified-release tablets on September 25, 2021 by guest. Protected copyright. 48 41272 Pramipexole 2.1mg modified-release tablets 49 50 41309 Rotigotine 3mg/24hours transdermal patches 51 41350 Mirapexin 2.1mg modified-release tablets (Boehringer Ingelheim Ltd) 52 41358 Mirapexin 0.52mg modified-release tablets (Boehringer Ingelheim Ltd) 53 41359 Mirapexin 0.26mg modified-release tablets (Boehringer Ingelheim Ltd) 54 55 41360 Mirapexin 1.05mg modified-release tablets (Boehringer Ingelheim Ltd) 56 41370 Co-careldopa 25mg/100mg/5ml oral solution 57 41464 Ropinirole 250microgram tablets (Zentiva) 58 59 41484 Mirapexin 3.15mg modified-release tablets (Boehringer Ingelheim Ltd) 60 41707 Selegiline 10mg tablets (Teva UK Ltd) 41804 Parlodel 1mg tablets (Meda Pharmaceuticals Ltd) 42041 Sinemet 12.5mg/50mg tablets (Merck Sharp & Dohme Ltd)

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1 2 42147 Sinemet Plus 25mg/100mg tablets (Merck Sharp & Dohme Ltd) 3 42172 Half Sinemet CR 25mg/100mg tablets (Merck Sharp & Dohme Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 42215 Co-careldopa 25mg/100mg tablets (Teva UK Ltd) 6 42255 Sinemet CR 50mg/200mg tablets (Merck Sharp & Dohme Ltd) 7 42262 Sinemet 25mg/250mg tablets (Merck Sharp & Dohme Ltd) 8 42293 Sinemet 10mg/100mg tablets (Merck Sharp & Dohme Ltd) 9 10 42649 Neupro 3mg/24hours transdermal patches (UCB Pharma Ltd) 11 42808 Selegiline 10mg tablets (Niche Generics Ltd) 12 43033 Tilolec 200mg/50mg modified-release tablets (Tillomed Laboratories Ltd) 13 14 43631 Co-careldopa 50mg/200mg modified-release tablets (A A H Pharmaceuticals Ltd) 15 43718 Lecado 25mg+100mg Modified-release tablet (Sandoz Ltd) 16 43855 Lecado 50mg+200mg Modified-release tablet (Sandoz Ltd) 17 For peer review only 44486 Pramipexole 1.57mg modified-release tablets 18 19 44566 Mirapexin 1.57mg modified-release tablets (Boehringer Ingelheim Ltd) 20 44649 Pramipexole 2.62mg modified-release tablets 21 44750 Mirapexin 2.62mg modified-release tablets (Boehringer Ingelheim Ltd) 22 23 45303 Ropinirole 2mg tablets (Generics (UK) Ltd) 24 45761 Duodopa intestinal gel 100ml cassette (AbbVie Ltd) 25 46660 Neliprax 0.35mg tablets (Aspire Pharma Ltd) 26 47248 Stalevo 175mg/43.75mg/200mg tablets (Orion Pharma (UK) Ltd) 27 28 47248 Stalevo 175mg/43.75mg/200mg tablets (Orion Pharma (UK) Ltd) 29 47730 Pramipexole 88microgram tablets (Actavis UK Ltd) 30 47762 Spiroco XL 2mg tablets (Teva UK Ltd) 31 32 47763 Spiroco XL 8mg tablets (Teva UK Ltd) 33 48075 Spiroco XL 4mg tablets (Teva UK Ltd) 34 49481 Sinemet Plus 25mg/100mg tablets (Waymade Healthcare Plc) 35 50289 Mirapexin 0.088mg tablets (Waymade Healthcare Plc) 36 37 51023 Sinemet 10mg/100mg tablets (Lexon (UK) Ltd) 38 52376 Ralnea XL 2mg tablets (Consilient Health Ltd) http://bmjopen.bmj.com/ 39 52694 Sinemet Plus 25mg/100mg tablets (DE Pharmaceuticals) 40 41 53299 Sinemet 25mg/250mg tablets (Mawdsley-Brooks & Company Ltd) 42 53526 Half Sinemet CR 25mg/100mg tablets (DE Pharmaceuticals) 43 53837 Ropinirole 1mg tablets (A A H Pharmaceuticals Ltd) 44 54469 Pramipexole 88microgram tablets (Sigma Pharmaceuticals Plc) 45 46 55508 Co-careldopa 6.25mg/25mg/5ml oral suspension 47 55876 Pergolide 50microgram tablets (A A H Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 48 56261 Stalevo 100mg/25mg/200mg tablets (Lexon (UK) Ltd) 49 50 56261 Stalevo 100mg/25mg/200mg tablets (Lexon (UK) Ltd) 51 56442 Bromocriptine 2.5mg tablets (Kent Pharmaceuticals Ltd) 52 56507 Sinemet 10mg/100mg tablets (Sigma Pharmaceuticals Plc) 53 57082 Co-careldopa 10mg/100mg tablets (A A H Pharmaceuticals Ltd) 54 55 57511 ReQuip XL 2mg tablets (DE Pharmaceuticals) 56 57518 Neupro 8mg/24hours transdermal patches (Mawdsley-Brooks & Company Ltd) 57 57586 Sinemet 25mg/250mg tablets (Dowelhurst Ltd) 58 59 57635 Co-beneldopa 12.5mg/50mg capsules (Teva UK Ltd) 60 57652 Ropinirole 1mg tablets (Waymade Healthcare Plc) 58776 Pramipexole 88microgram tablets (A A H Pharmaceuticals Ltd) 58831 Raponer XL 8mg tablets (Actavis UK Ltd)

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1 2 59192 Ropinirole 250microgram tablets (A A H Pharmaceuticals Ltd) 3 59833 Ralnea XL 8mg tablets (Consilient Health Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 59980 Repinex XL 8mg tablets (Aspire Pharma Ltd) 6 59997 Repinex XL 2mg tablets (Aspire Pharma Ltd) 7 60818 Pramipexole 88microgram tablets (Generics (UK) Ltd) 8 61452 ReQuip 2mg tablets (DE Pharmaceuticals) 9 10 61511 Raponer XL 2mg tablets (Actavis UK Ltd) 11 61512 Raponer XL 4mg tablets (Actavis UK Ltd) 12 62274 Oprymea 0.52mg modified-release tablets (Consilient Health Ltd) 13 14 62435 Co-careldopa 12.5mg/50mg/5ml oral suspension 15 62482 Sastravi 100mg/25mg/200mg tablets (Actavis UK Ltd) 16 62482 Sastravi 100mg/25mg/200mg tablets (Actavis UK Ltd) 17 For peer review only 62543 Sastravi 150mg/37.5mg/200mg tablets (Actavis UK Ltd) 18 19 62543 Sastravi 150mg/37.5mg/200mg tablets (Actavis UK Ltd) 20 62652 Bromocriptine 2.5mg Tablet (Approved Prescription Services Ltd) 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: 'at risk' of hypertension

3 Read Code Read Code BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 1JD..00 Suspected hypertension 6 662Q.00 Borderline blood pressure 7 68B4.00 Risk factors present at hypertension screen 8 R1y2.00 [D]Raised blood pressure reading 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: hypertension

3 Read Code Read Code BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 662O.00 On treatment for hypertension 6 7Q01.00 High cost hypertension drugs 7 7Q01y00 Other specified high cost hypertension drugs 8 G20..00 Essential hypertension 9 10 G20..11 High blood pressure 11 G20..12 Primary hypertension 12 G200.00 Malignant essential hypertension 13 14 G201.00 Benign essential hypertension 15 G202.00 Systolic hypertension 16 G203.00 Diastolic hypertension 17 For peer review only G20z.00 Essential hypertension NOS 18 19 G20z.11 Hypertension NOS 20 G25..00 Stage 1 hypertension (NICE - Nat Ins for Hth Clin Excl 2011) 21 G25..11 Stage 1 hypertension 22 23 G26..00 Severe hypertension (Nat Inst for Health Clinical Ex 2011) 24 G26..11 Severe hypertension 25 G28..00 Stage 2 hypertension (NICE - Nat Ins for Hth Clin Excl 2011) 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for hypertension 3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 2 Bendroflumethiazide 2.5mg tablets 6 5 Atenolol 50mg tablets 7 8 6 Furosemide 40mg tablets 9 24 Atenolol 100mg tablets 10 26 Atenolol 25mg tablets 11 12 29 Amlodipine besilate 5mg tablets 13 55 Furosemide 20mg tablets 14 56 Co-amilofruse 5mg/40mg tablets 15 16 58 Bendroflumethiazide 5mg tablets 17 65 Lisinopril 10mg tabletsFor peer review only 18 69 Lisinopril 20mg tablets 19 20 71 Amlodipine besilate 10mg tablets 21 78 Lisinopril 5mg tablets 22 23 80 Ramipril 5mg capsules 24 82 Ramipril 10mg capsules 25 97 Perindopril erbumine 4mg tablets 26 27 119 Doxazosin 1mg tablets 28 147 Ramipril 1.25mg capsules 29 193 Co-amilofruse 2.5mg/20mg tablets 30 31 196 Enalapril 5mg tablets 32 197 Atenolol 5mg/10ml solution for injection ampoules 33 34 211 Frumil 40mg+5mg Tablet (Helios Healthcare Ltd) 35 219 Diltiazem 120mg modified-release tablets 36 220 Propranolol 5mg/5ml oral solution 37 38 269 Nifedipine 5mg capsules http://bmjopen.bmj.com/ 39 277 Lisinopril 2.5mg tablets 40 297 Propranolol 10mg tablets 41 42 338 Clonidine 25microgram tablets 43 348 Moduretic Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 44 45 410 Nifedipine 10mg modified-release tablets 46 445 Prazosin 1mg tablets and Prazosin 500microgram tablets on September 25, 2021 by guest. Protected copyright. 47 448 Enalapril 2.5mg tablets 48 49 452 Nifedipine 10mg capsules 50 460 Flomax MR 400microgram capsules (Astellas Pharma Ltd) 51 472 Bisoprolol 5mg tablets 52 53 491 Felodipine 2.5mg modified-release tablets 54 493 Doxazosin 2mg tablets 55 56 501 Felodipine 5mg modified-release tablets 57 504 Hydralazine 20mg powder for solution for injection ampoules 58 517 Adizem sr 120mg Modified-release capsule (Napp Pharmaceuticals Ltd) 59 60 520 Losartan 25mg tablets 529 Candesartan 2mg tablets 531 Candesartan 4mg tablets

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1 2 536 Tildiem la 200mg Modified-release capsule (Sanofi) 3 541 Adalat LA 20 tablets (Bayer Plc) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 542 Hydrochlorothiazide 25mg tablets 6 562 Furosemide 10mg/ml Injection 7 8 568 Felodipine 10mg modified-release tablets 9 573 Hydralazine 25mg tablets 10 575 Valsartan 40mg capsules 11 12 581 Atenolol 50mg with Chlortalidone 12.5mg tablets 13 582 Doxazosin 4mg modified-release tablets 14 591 Prazosin 1mg tablets 15 16 593 Perindopril erbumine 2mg tablets 17 594 Bisoprolol 2.5mg tabletsFor peer review only 18 599 Bisoprolol 1.25mg tablets 19 20 605 Chlortalidone 50mg tablets 21 624 Losartan 100mg tablets 22 23 633 Fosinopril 10mg tablets 24 634 Tamsulosin 400microgram modified-release capsules 25 636 Diltiazem 60mg modified-release capsules 26 27 654 Ramipril 2.5/5mg/10mg capsule 28 662 Adalat 5mg capsules (Bayer Plc) 29 692 Spironolactone 25mg tablets 30 31 700 Vera-Til SR 120mg tablets (Tillomed Laboratories Ltd) 32 707 Propranolol 40mg tablets 33 34 708 Spironolactone 50mg tablets 35 709 Ramipril 2.5mg capsules 36 726 Prazosin 2mg tablets 37 38 729 Amlodipine maleate 5mg tablets http://bmjopen.bmj.com/ 39 737 Nifedipine 20mg modified-release capsules 40 739 Metoprolol 50mg tablets 41 42 749 Amlodipine 5mg tablets 43 751 Nebivolol 5mg tablets 44 45 753 Metoprolol 100mg tablets 46 755 Cardura XL 4mg tablets (Pfizer Ltd) on September 25, 2021 by guest. Protected copyright. 47 756 Ramipril 10mg tablets 48 49 761 Ramipril 1.25mg tablets 50 764 Co-Diovan 80mg/12.5mg tablets (Novartis Pharmaceuticals UK Ltd) 51 769 Propranolol 80mg modified-release capsules 52 53 786 Sotalol 40mg tablets 54 787 Spironolactone 100mg capsule 55 56 793 Adizem xl 240mg Capsule (Napp Pharmaceuticals Ltd) 57 814 Bumetanide 1mg tablets 58 817 Carvedilol 3.125mg tablets 59 60 822 Bisoprolol 1.5mg/5ml oral suspension 828 Irbesartan 75mg tablets 923 Co-amilozide 5mg/50mg tablets

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1 2 924 Co-amilozide 2.5mg/25mg tablets 3 939 Tildiem Retard 90mg tablets (Sanofi) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 940 Propranolol 80mg tablets 6 1006 Half Inderal LA 80mg capsules (AstraZeneca UK Ltd) 7 8 1021 Innozide 20mg/12.5mg tablets (Merck Sharp & Dohme Ltd) 9 1048 Inderal 80mg tablets (AstraZeneca UK Ltd) 10 1050 Inderal 40mg tablets (AstraZeneca UK Ltd) 11 12 1060 Amiloride 5mg tablets 13 1118 Verapamil 40mg tablets 14 1120 Verapamil 80mg tablets 15 16 1121 Captopril 12.5mg tablets 17 1124 Tenoretic 100mg/25mg tablets (AstraZeneca UK Ltd)For peer review only 18 1125 Navidrex -k Tablet (Novartis Pharmaceuticals UK Ltd) 19 20 1130 Viazem XL 300mg capsules (Thornton & Ross Ltd) 21 1143 Captopril 25mg tablets 22 23 1144 Capoten 25mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 24 1170 Cyclopenthiazide 500microgram tablets 25 1209 Neo-Naclex 5mg tablets (Mercury Pharma Group Ltd) 26 27 1211 Bendroflumethiazide 2.5mg / Potassium chloride 630mg (potassium 8.4mmol) modified- 28 release tablets 29 1213 Neo-Naclex-K modified-release tablets (Mercury Pharma Group Ltd) 30 31 1251 Moduret 25 tablets (Merck Sharp & Dohme Ltd) 32 1262 Nifedipine 12 20mg Modified-release tablet 33 1288 Tenoret 50mg/12.5mg tablets (AstraZeneca UK Ltd) 34 35 1289 Tildiem Retard 120mg tablets (Sanofi) 36 1290 Bisoprolol 10mg tablets 37 38 1292 Hypovase 1mg tablets (Pfizer Ltd) http://bmjopen.bmj.com/ 39 1293 Irbesartan 150mg tablets 40 1294 Doxazosin 4mg tablets 41 42 1295 Labetalol 400mg tablets 43 1296 Hydralazine 50mg tablets 44 1297 Aldactide 50 tablets (Pfizer Ltd) 45 46 1298 Verapamil 240mg modified-release tablets 47 1299 Enalapril 10mg tablets on September 25, 2021 by guest. Protected copyright. 48 1300 Nifensar xl 20mg Modified-release tablet (Rhone-Poulenc Rorer Ltd) 49 50 1301 Frumil ls 20mg+2.5mg Tablet (Helios Healthcare Ltd) 51 1333 Oxprenolol 40mg tablets 52 53 1334 Oxprenolol 160mg modified-release tablets 54 1369 Furosemide with amiloride 40mg+5mg Tablet 55 1448 Propranolol 160mg modified-release capsules 56 57 1449 Nifedipine 24 30mg Modified-release tablet 58 1455 Prazosin 500microgram tablets 59 1520 Capozide 25mg/50mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 60 1529 Posicor 50mg Tablet (Roche Products Ltd) 1538 Diltiazem 60mg tablets

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1 2 1572 Sotalol 80mg tablets 3 1574 Verapamil 120mg modified-release capsules BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 1597 Labetalol 100mg tablets 6 1684 Beta-Adalat modified-release capsules (Bayer Plc) 7 8 1686 Diltiazem 90mg modified-release capsules 9 1707 Methyldopa 250mg tablets 10 1721 Dyazide 50mg/25mg tablets (AMCo) 11 12 1747 Verapamil 120mg tablets 13 1748 Cordilox 120mg tablets (IVAX Pharmaceuticals UK Ltd) 14 1780 Losartan 50mg tablets 15 16 1788 Atenolol 100mg with Chlortalidone 25mg tablets 17 1807 Captopril 50mg tabletsFor peer review only 18 1836 Diltiazem 60mg modified-release tablets 19 20 1854 Adalat la 30mg Tablet (Bayer Plc) 21 1904 Enalapril 20mg tablets 22 23 1995 Diltiazem 12hr 120mg modified-release capsules 24 2001 Aldactide 25 tablets (Pfizer Ltd) 25 2002 Amiloride 5mg / hydrochlorothiazide 50mg tablets 26 27 2046 Navidrex 500microgram tablets (AMCo) 28 2104 Rauwiloid 2mg Tablet (3M Health Care Ltd) 29 2117 Doralese Tiltab 20mg tablets (Chemidex Pharma Ltd) 30 31 2142 Spironolactone 100mg tablets 32 2179 Triamterene 50mg capsules 33 34 2255 Navispare 2.5mg/250microgram tablets (AMCo) 35 2280 Adalat retard 10mg tablets (Bayer Plc) 36 2343 Adalat retard 20mg tablets (Bayer Plc) 37 38 2345 Hytrin BPH tablets starter pack (AMCo) http://bmjopen.bmj.com/ 39 2346 Hytrin 5mg Tablet (Abbott Laboratories Ltd) 40 2347 Hytrin 10mg Tablet (Abbott Laboratories Ltd) 41 42 2348 Hytrin bph 10mg Tablet (Amdipharm Plc) 43 2361 Trasicor 80mg Tablet (Novartis Pharmaceuticals UK Ltd) 44 45 2362 Apresoline 25mg tablets (AMCo) 46 2389 Aldactone 25mg tablets (Pfizer Ltd) on September 25, 2021 by guest. Protected copyright. 47 2414 Inderal 10mg tablets (AstraZeneca UK Ltd) 48 49 2432 Tenormin LS 50mg tablets (AstraZeneca UK Ltd) 50 2453 Diltiazem 60mg modified-release capsules 51 2493 Burinex A 5mg/1mg tablets (LEO Pharma) 52 53 2495 Bumetanide with Amiloride tablets 54 2499 Nadolol 80mg tablets 55 56 2521 Adalat 10mg capsules (Bayer Plc) 57 2528 Slozem 120mg capsules (Merck Serono Ltd) 58 2587 Tenormin 100mg tablets (AstraZeneca UK Ltd) 59 60 2590 Tenormin 25mg tablets (AstraZeneca UK Ltd) 2592 Viazem XL 120mg capsules (Thornton & Ross Ltd) 2605 Nifedipine 10mg modified-release capsules

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1 2 2612 Indapamide 2.5mg tablets 3 2629 Carvedilol 12.5mg tablets BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 2663 Diltiazem 240mg modified-release capsules 6 2680 Apresoline 50mg Tablet (Sovereign Medical Ltd) 7 8 2686 Dilzem xl mr 240mg Modified-release capsule (Elan Pharma) 9 2746 Coracten SR 10mg capsules (UCB Pharma Ltd) 10 2772 Lasoride 5mg/40mg tablets (Sanofi) 11 12 2775 Labetalol 200mg tablets 13 2780 Oxprenolol 80mg tablets 14 2788 Burinex 1mg tablets (LEO Pharma) 15 16 2811 Adizem sr 180mg Modified-release capsule (Napp Pharmaceuticals Ltd) 17 2816 Indoramin 20mg tabletsFor peer review only 18 2833 CYCLOPENTHIAZIDE -K tablets 19 20 2878 Clonidine 100microgram tablets 21 2888 Tildiem 60mg modified-release tablets (Sanofi) 22 23 2926 Nicardipine 20mg capsules 24 2961 Frusene 50mg/40mg tablets (Orion Pharma (UK) Ltd) 25 2967 Minoxidil 5mg tablets 26 27 2968 Minoxidil 10mg tablets 28 2970 Minoxidil 2.5mg tablets 29 2971 Irbesartan 300mg tablets 30 31 2979 Centyl k Tablet (Edwin Burgess Ltd) 32 2982 Zestoretic 20- 20mg+12.5mg Tablet (AstraZeneca UK Ltd) 33 34 3005 Inderal LA 160mg capsules (AstraZeneca UK Ltd) 35 3049 Methyldopa 125mg tablets 36 3050 Furosemide with triamterene 40mgwith50mg Tablet 37 38 3054 Hygroton 100mg Tablet (Alliance Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 3056 Natrilix SR 1.5mg tablets (Servier Laboratories Ltd) 40 3057 Securon 120mg tablets (Abbott Laboratories Ltd) 41 42 3061 Diltiazem 12hr 180mg modified-release capsules 43 3069 Acepril 25mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 44 45 3070 Methyldopa 500mg tablets 46 3087 Propranolol 40mg/5ml oral solution sugar free on September 25, 2021 by guest. Protected copyright. 47 3118 Adizem sr 90mg Modified-release capsule (Napp Pharmaceuticals Ltd) 48 49 3167 Propranolol 160mg tablets 50 3203 Capozide LS Tablet (E R Squibb and Sons Ltd) 51 3221 Lacidipine 4mg tablets 52 53 3222 Valsartan 80mg capsules 54 3248 Furosemide 500mg tablets 55 56 3287 Furosemide 1mg/ml Oral solution 57 3293 Moduretic Oral solution (Bristol-Myers Squibb Pharmaceuticals Ltd) 58 3302 Cardene SR 30mg capsules (Astellas Pharma Ltd) 59 60 3310 Capoten 12.5mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 3342 Securon SR 240mg tablets (Abbott Laboratories Ltd) 3343 Half Securon SR 120mg tablets (Abbott Laboratories Ltd)

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1 2 3344 Betaloc 100mg tablets (AstraZeneca UK Ltd) 3 3370 Dilzem xl mr 120mg Modified-release capsule (Elan Pharma) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 3470 Terazosin 1mg tablets 6 3474 Betaloc-SA 200mg tablets (AstraZeneca UK Ltd) 7 8 3516 Oxprenolol 20mg tablets 9 3517 Hydrochlorothiazide 50mg tablets 10 3526 Amiloride with atenolol with hydrochlorothiazide capsules 11 12 3548 Chlortalidone 100mg tablets 13 3588 Monocor 5mg tablets (Wyeth Pharmaceuticals) 14 3676 Dilzem xl mr 180mg Modified-release capsule (Elan Pharma) 15 16 3691 Sotalol 160mg with hydrochlorothiazide 25mg tablet 17 3701 Amiloride 2.5mg / hydrochlorothiazide 25mg tabletsFor peer review only 18 3711 Adipine MR 20 tablets (Chiesi Ltd) 19 20 3712 Coracten XL 30mg capsules (UCB Pharma Ltd) 21 3715 Prazosin 5mg tablets 22 23 3720 Zestril 2.5mg tablets (AstraZeneca UK Ltd) 24 3748 Oxprenolol 160mg Tablet 25 3793 Co-amilofruse 10mg/80mg tablets 26 27 3827 Propanix 40mg Tablet (Ashbourne Pharmaceuticals Ltd) 28 3839 Capoten 50mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 29 3917 Istin 5mg tablets (Pfizer Ltd) 30 31 3923 Terazosin BPH starter pack 7x1mg with 14x2mg with 7x5mg 32 3924 Terazosin 5mg tablets 33 34 3929 Quinapril 10mg tablets 35 3930 Nifedipine 60mg modified-release tablets 36 3931 Posicor 100mg Tablet (Roche Products Ltd) 37 38 3943 Verapamil 240mg modified-release capsules http://bmjopen.bmj.com/ 39 3997 Hygroton 50mg tablets (Alliance Pharmaceuticals Ltd) 40 4004 Sotacor 80mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 41 42 4025 Slow-Trasicor 160mg tablets (AMCo) 43 4034 Amiloride 5mg / hydrochlorothiazide 50mg/5ml solution 44 45 4044 Diurexan 20mg tablets (Meda Pharmaceuticals Ltd) 46 4068 Dytac 50mg capsules (AMCo) on September 25, 2021 by guest. Protected copyright. 47 4103 Trandolapril 1mg capsules 48 49 4111 Hypovase 500microgram tablets (Pfizer Ltd) 50 4155 Amias 2mg tablets (Takeda UK Ltd) 51 4161 Spiroctan 25mg Tablet (Roche Products Ltd) 52 53 4182 Lasix 5mg/5ml oral solution (Borg Medicare) 54 4211 Furosemide with amiloride 20mg+2.5mg Tablet 55 56 4215 Catapres 100microgram tablets (Boehringer Ingelheim Ltd) 57 4226 Cozaar 25mg tablets (Merck Sharp & Dohme Ltd) 58 4227 Adalat la 60mg Tablet (Bayer Plc) 59 60 4239 Adipine MR 10 tablets (Chiesi Ltd) 4258 Lasix 20mg/2ml solution for injection ampoules (Sanofi) 4265 Celectol 200mg Tablet (Pantheon Healthcare Ltd)

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1 2 4308 Dilzem sr 90mg Capsule (Elan Pharma) 3 4332 Metolazone 5mg tablets BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 4334 Metolazone 500microgram low dose Tablet 6 4374 Debrisoquine 20mg tablets 7 8 4406 Decaserpyl plus Tablet (Roussel Laboratories Ltd) 9 4408 Slozem 240mg capsules (Merck Serono Ltd) 10 4410 Carvedilol 6.25mg tablets 11 12 4429 Trasidrex modified-release tablets (Mercury Pharma Group Ltd) 13 4449 Cardura 1mg tablets (Pfizer Ltd) 14 4540 Cozaar-Comp 50mg/12.5mg tablets (Merck Sharp & Dohme Ltd) 15 16 4542 Atenolol 50mg / Nifedipine 20mg modified-release capsules 17 4571 Staril 10mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd)For peer review only 18 4588 Visken 5mg Tablet (Sovereign Medical Ltd) 19 20 4605 Moducren tablets (Merck Sharp & Dohme Ltd) 21 4635 Diltiazem 200mg modified-release capsules 22 23 4637 Terazosin 2mg tablets 24 4645 Valsartan 160mg capsules 25 4661 Spironolactone 50mg / Furosemide 20mg capsules 26 27 4685 Amias 4mg tablets (Takeda UK Ltd) 28 4694 Terazosin 2mg tablets and Terazosin 1mg tablets 29 4705 Furosemide 20mg/2ml Injection 30 31 4725 Labetalol 50mg tablets 32 4732 Diltiazem 90mg modified-release tablets 33 34 4741 Candesartan 16mg tablets 35 4771 Emcor LS 5mg tablets (Merck Serono Ltd) 36 4796 Inderetic 80mg/2.5mg capsules (AstraZeneca UK Ltd) 37 38 4802 Cardura 2mg tablets (Pfizer Ltd) http://bmjopen.bmj.com/ 39 4808 Diltiazem 240mg modified-release capsules 40 4818 Candesartan 8mg tablets 41 42 4852 Adizem sr 120mg Modified-release tablet (Napp Pharmaceuticals Ltd) 43 4856 Coracten SR 20mg capsules (UCB Pharma Ltd) 44 45 4873 Fru-Co 5mg/40mg tablets (Teva UK Ltd) 46 4875 Terazosin 10mg tablets on September 25, 2021 by guest. Protected copyright. 47 4923 Diltiazem 24hr 180mg modified-release capsules 48 49 4939 Coracten XL 60mg capsules (UCB Pharma Ltd) 50 4960 Aldactone 50mg tablets (Pfizer Ltd) 51 4983 Atenolol with amiloride and hydrochlorothiazide capsules 52 53 4993 Moxonidine 200microgram tablets 54 5013 Amias 8mg tablets (Takeda UK Ltd) 55 56 5047 Trandolapril 2mg capsules 57 5054 Angitil SR 180 capsules (Chiesi Ltd) 58 5112 Indapamide 1.5mg modified-release tablets 59 60 5117 Amias 16mg tablets (Takeda UK Ltd) 5158 Lacidipine 2mg tablets 5159 Quinapril 20mg tablets

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1 2 5162 Nifedipine 30mg modified-release capsules 3 5181 Angiopine MR 20mg tablets (Ashbourne Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 5183 Hypovase 2mg tablets (Pfizer Ltd) 6 5189 Enalapril 20mg / Hydrochlorothiazide 12.5mg tablets 7 8 5194 Dilzem sr 120mg Capsule (Elan Pharma) 9 5218 Bumetanide 1mg/5ml oral solution sugar free 10 5220 Furosemide with amiloride 80mg+10mg Tablet 11 12 5234 Slozem 180mg capsules (Merck Serono Ltd) 13 5249 Furosemide 50mg/5ml oral solution sugar free 14 5275 Tritace 2.5mg capsules (Sanofi) 15 16 5277 Fortipine LA 40 tablets (AMCo) 17 5284 Pindolol 5mg tabletsFor peer review only 18 5289 Clonidine 250microgram modified-release capsules 19 20 5296 Tildiem la 300mg Modified-release capsule (Sanofi) 21 5326 Diltiazem 24hr 300mg modified-release capsules 22 23 5330 Corgaretic 40mg tablets (Sanofi-Synthelabo Ltd) 24 5337 Hytrin bph 5mg Tablet (Amdipharm Plc) 25 5348 Diltiazem 300mg modified-release capsules 26 27 5416 Co-triamterzide 50mg/25mg tablets 28 5477 Nicardipine 30mg modified-release capsules 29 5478 Propranolol 10mg/5ml oral solution sugar free 30 31 5496 Doxazosin 8mg modified-release tablets 32 5513 Dilzem sr 60mg Capsule (Elan Pharma) 33 34 5570 Zanidip 10mg tablets (Recordati Pharmaceuticals Ltd) 35 5593 Lercanidipine 10mg tablets 36 5612 Coversyl 2mg tablets (Servier Laboratories Ltd) 37 38 5618 Cardura XL 8mg tablets (Pfizer Ltd) http://bmjopen.bmj.com/ 39 5713 Bisoprolol 7.5mg tablets 40 5721 Co-tenidone 100mg/25mg tablets 41 42 5723 Cozaar 50mg tablets (Merck Sharp & Dohme Ltd) 43 5727 Amiloride 2.5mg / Cyclopenthiazide 250microgram tablets 44 45 5728 Furosemide 40mg/5ml oral solution sugar free 46 5735 Tritace 5mg capsules (Sanofi) on September 25, 2021 by guest. Protected copyright. 47 5800 Coversyl 4mg tablets (Servier Laboratories Ltd) 48 49 5806 Tensipine MR 20 tablets (Thornton & Ross Ltd) 50 5815 Indoramin 25mg tablets 51 5858 Beta-Cardone 40mg tablets (Focus Pharmaceuticals Ltd) 52 53 5861 Fosinopril 20mg tablets 54 5868 Frusol 20mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 55 56 5914 Istin 10mg tablets (Pfizer Ltd) 57 5968 Monocor 10mg tablets (Wyeth Pharmaceuticals) 58 5988 Telmisartan 40mg tablets 59 60 6008 Omnic 400microgram Modified-release capsule (Paines & Byrne Ltd) 6066 Atenolol 25mg/5ml oral solution sugar free 6078 Perindopril erbumine 8mg tablets

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1 2 6118 Furosemide 20mg/5ml oral solution sugar free 3 6200 Tritace titration pack capsules (Sanofi) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6207 Tadalafil 20mg tablets 6 6217 Olmesartan medoxomil 10mg tablets 7 8 6243 Telmisartan 20mg tablets 9 6261 Tritace 1.25mg tablets (Sanofi) 10 6285 Olmesartan medoxomil 20mg tablets 11 12 6288 Ramipril 5mg tablets 13 6309 Adizem xl 300mg Capsule (Napp Pharmaceuticals Ltd) 14 6314 Ramipril 2.5mg tablets 15 16 6351 Olmesartan medoxomil 40mg tablets 17 6359 Zestoretic 10- 10mg+12.5mg Tablet (AstraZeneca UK Ltd)For peer review only 18 6362 Tritace 5mg tablets (Sanofi) 19 20 6364 Tritace 2.5mg tablets (Sanofi) 21 6408 Tanatril 5mg tablets (Chiesi Ltd) 22 23 6437 Losartan 50mg / Hydrochlorothiazide 12.5mg tablets 24 6468 Lisinopril 20mg / Hydrochlorothiazide 12.5mg tablets 25 6477 Amlodipine maleate 10mg tablets 26 27 6510 Univer 120mg modified-release capsules (Teva UK Ltd) 28 6518 Diovan 160mg capsules (Novartis Pharmaceuticals UK Ltd) 29 6694 Clonidine 300microgram tablets 30 31 6751 Beta-Cardone 80mg tablets (Focus Pharmaceuticals Ltd) 32 6765 Quinapril 5mg tablets 33 34 6786 Lisinopril 10mg / Hydrochlorothiazide 12.5mg tablets 35 6794 Perindopril erbumine 4mg / Indapamide 1.25mg tablets 36 6806 Zestril 10mg tablets (AstraZeneca UK Ltd) 37 38 6807 Zestril 5mg tablets (AstraZeneca UK Ltd) http://bmjopen.bmj.com/ 39 6815 Spironolactone 50mg/5ml oral suspension sugar free 40 6816 Chlorothiazide 250mg/5ml oral suspension 41 42 6856 Amlodipine 10mg tablets 43 6877 Co-Diovan 160mg/12.5mg tablets (Novartis Pharmaceuticals UK Ltd) 44 45 6939 Eprosartan 300mg tablets 46 7043 Candesartan 32mg tablets on September 25, 2021 by guest. Protected copyright. 47 7049 Carvedilol 25mg tablets 48 49 7056 Tamsulosin 400microgram modified-release tablets 50 7066 Metoprolol 100mg / Hydrochlorothiazide 12.5mg tablets 51 7091 Bisoprolol 3.75mg tablets 52 53 7136 Dytide capsules (Mercury Pharma Group Ltd) 54 7174 Moxonidine 400microgram tablets 55 56 7280 Plendil 10mg modified-release tablets (AstraZeneca UK Ltd) 57 7314 Accupro 5mg tablets (Pfizer Ltd) 58 7338 Aprovel 75mg tablets (Sanofi) 59 60 7351 Bendroflumethiazide 2.5mg/5ml oral suspension 7398 Viazem XL 360mg capsules (Thornton & Ross Ltd) 7416 Aldomet 50mg/ml Injection (Merck Sharp & Dohme Ltd)

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1 2 7419 Trandolapril 500microgram capsules 3 7429 Tenormin 5mg/10ml solution for injection ampoules (AstraZeneca UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 7441 Lasilactone 20mg/50mg capsules (Sanofi) 6 7474 Trasicor 20mg Tablet (Novartis Pharmaceuticals UK Ltd) 7 8 7528 Nebilet 5mg tablets (A. Menarini Farmaceutica Internazionale SRL) 9 7541 Nifopress Retard 20mg tablets (AMCo) 10 7543 Kalten capsules (M & A Pharmachem Ltd) 11 12 7547 Doxadura 2mg tablets (Discovery Pharmaceuticals Ltd) 13 7549 Doxadura 1mg tablets (Discovery Pharmaceuticals Ltd) 14 7553 Bisoprolol 5mg/5ml oral suspension 15 16 7562 Cardene 30mg capsules (Astellas Pharma Ltd) 17 7606 Lasix 40mg tablets (Sanofi)For peer review only 18 7618 Xipamide 20mg tablets 19 20 7620 Acebutolol 400mg tablets 21 7626 Aldomet 250mg Tablet (Merck Sharp & Dohme Ltd) 22 23 7641 Natrilix 2.5mg tablets (Servier Laboratories Ltd) 24 7642 Aldomet 500mg Tablet (Merck Sharp & Dohme Ltd) 25 7681 Synadrin 60mg Tablet (Hoechst UK Ltd) 26 27 7698 Aprinox 5mg tablets (Amdipharm Plc) 28 7709 Arelix 6mg Capsule (Hoechst Marion Roussel) 29 7740 Triamterene 50mg / Benzthiazide 25mg capsules 30 31 7759 Phenoxybenzamine 10mg capsules 32 7799 Lasix 20mg tablets (Borg Medicare) 33 34 7806 Bumetanide 5mg tablets 35 7852 Blocadren 10mg Tablet (Merck Sharp & Dohme Ltd) 36 7853 Timolol 10mg tablets 37 38 7911 Declinax 10mg Tablet (Roche Products Ltd) http://bmjopen.bmj.com/ 39 7922 Ismelin 10mg Tablet (Sovereign Medical Ltd) 40 7923 Guanethidine 10mg Tablet 41 42 7952 Aldactone 100mg tablets (Pfizer Ltd) 43 7961 Spironolactone 50mg with hydroflumethiazide 50mg tablet 44 45 7974 Celiprolol 400mg tablets 46 7991 Spiroctan 100mg Capsule (Roche Products Ltd) on September 25, 2021 by guest. Protected copyright. 47 8023 Sectral 400mg tablets (Sanofi) 48 49 8025 Gopten 1mg capsules (Abbott Laboratories Ltd) 50 8026 Gopten 2mg capsules (Abbott Laboratories Ltd) 51 8033 Aldomet 125mg Tablet (Merck Sharp & Dohme Ltd) 52 53 8052 Torasemide 5mg tablets 54 8058 Normetic Tablet (Abbott Laboratories Ltd) 55 56 8061 Sotalol 80mg with hydrochlorothiazide 12.5mg tablet 57 8068 Metoprolol 200mg modified-release tablets 58 8071 Betaloc 50mg tablets (AstraZeneca UK Ltd) 59 60 8076 Hytrin tablets starter pack (AMCo) 8077 Hytrin 2mg Tablet (Abbott Laboratories Ltd) 8086 Cardura 4mg Tablet (Pfizer Ltd)

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1 2 8105 Innovace 20mg tablets (Merck Sharp & Dohme Ltd) 3 8106 Innovace 2.5mg tablets (Merck Sharp & Dohme Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 8113 Acebutolol 200mg capsules 6 8147 Lopresoretic Tablet (Novartis Pharmaceuticals UK Ltd) 7 8 8172 Acebutolol 100mg capsules 9 8189 Secadrex 200mg/12.5mg tablets (Sanofi) 10 8198 Hypovase 5mg Tablet (Pfizer Ltd) 11 12 8201 Nicardipine 30mg capsules 13 8213 Nifedipine 24 20mg Modified-release tablet 14 8257 Prescal 2.5mg tablets (Novartis Pharmaceuticals UK Ltd) 15 16 8262 Celiprolol 200mg tablets 17 8268 Zestril 20mg tablets (AstraZeneca UK Ltd)For peer review only 18 8290 Trasicor 40mg Tablet (Novartis Pharmaceuticals UK Ltd) 19 20 8296 Catapres PL Perlongets 250microgram capsules (Boehringer Ingelheim Ltd) 21 8303 Tenavoid Tablet (Edwin Burgess Ltd) 22 23 8310 Isradipine 2.5mg tablets 24 8331 Inderal 160mg Tablet (AstraZeneca UK Ltd) 25 8342 Declinax 20mg Tablet (Roche Products Ltd) 26 27 8369 Inderex 160mg/5mg modified-release capsules (AstraZeneca UK Ltd) 28 8464 Meprobamate with bendroflumethiazide Tablet 29 8521 Spironolactone 25mg with hydroflumethiazide 25mg tablet 30 31 8524 Securon 40mg Tablet (Abbott Laboratories Ltd) 32 8526 Aprinox 2.5mg tablets (AMCo) 33 34 8555 Sectral 200mg capsules (Sanofi) 35 8558 Adizem xl 120mg Capsule (Napp Pharmaceuticals Ltd) 36 8602 Metenix 5mg tablets (Sanofi) 37 38 8623 Prestim Tablet (ICN Pharmaceuticals France S.A.) http://bmjopen.bmj.com/ 39 8642 Tenif 50mg/20mg modified-release capsules (AstraZeneca UK Ltd) 40 8673 Oxprenolol with cyclopenthiazide 160mg+0.25mg Modified-release tablet 41 42 8707 Trandate 200mg tablets (Focus Pharmaceuticals Ltd) 43 8759 Verapamil hcl 120mg modified release tablets 44 45 8800 Innovace 5mg tablets (Merck Sharp & Dohme Ltd) 46 8807 Trandate 400mg tablets (Focus Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 8830 Innovace 10mg tablets (Merck Sharp & Dohme Ltd) 48 49 8836 Chlorothiazide 500mg tablets 50 8863 Hypovase benign prostatic hyperplasia 1mg Tablet (Pfizer Ltd) 51 8884 Cordilox 40mg tablets (IVAX Pharmaceuticals UK Ltd) 52 53 8891 Hygroton -k Tablet (Novartis Pharmaceuticals UK Ltd) 54 8897 Triam-Co 50mg/25mg tablets (IVAX Pharmaceuticals UK Ltd) 55 56 8935 Nadolol 40mg tablets 57 8942 Dibenyline 10mg capsules (Mercury Pharma Group Ltd) 58 8945 Univer 240mg modified-release capsules (Teva UK Ltd) 59 60 8975 Verapamil 180mg modified-release capsules 8978 Propanix 160mg Modified-release capsule (Ashbourne Pharmaceuticals Ltd) 8987 Propranolol 160mg modified-release / Bendroflumethiazide 5mg capsules

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1 2 9016 Trandate 100mg tablets (Focus Pharmaceuticals Ltd) 3 9019 Indoramin 50mg Tablet BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 9143 Viskaldix tablets (AMCo) 6 9178 Atenolol 25mg / Bendroflumethiazide 1.25mg capsules 7 8 9185 Propranolol 80mg/5ml oral solution 9 9196 Aprovel 150mg tablets (Sanofi) 10 9223 Triamterene with hydrochlorothiazide 50mg + 25mg Tablet 11 12 9225 Methyldopa 250mg Capsule 13 9240 Adizem xl 180mg Capsule (Napp Pharmaceuticals Ltd) 14 9269 Nifedipine 40mg modified-release tablets 15 16 9273 Trandate 50mg tablets (Focus Pharmaceuticals Ltd) 17 9292 Sotalol 160mg tabletsFor peer review only 18 9334 Plendil 2.5mg modified-release tablets (AstraZeneca UK Ltd) 19 20 9374 Adizem 60mg Modified-release tablet (Napp Pharmaceuticals Ltd) 21 9386 Nicardipine 45mg modified-release capsules 22 23 9410 Angitil SR 120 capsules (Chiesi Ltd) 24 9431 Frusemek 40mg+5mg Tablet (Approved Prescription Services Ltd) 25 9437 Plendil 5mg modified-release tablets (AstraZeneca UK Ltd) 26 27 9456 Amiloride 5mg / furosemide 40mg tablets 28 9463 Loniten 5mg tablets (Pfizer Ltd) 29 9485 Hypolar Retard 20 tablets (Sandoz Ltd) 30 31 9553 Slofedipine XL 60 tablets (Zentiva) 32 9569 Verapamil 120mg modified-release tablets 33 34 9573 Slofedipine XL 30mg tablets (Zentiva) 35 9646 Tritace 1.25mg capsules (Aventis Pharma) 36 9670 Motens 4mg tablets (GlaxoSmithKline UK Ltd) 37 38 9680 Frusol 40mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 9693 Tritace 10mg capsules (Sanofi) 40 9697 Loniten 2.5mg tablets (Pfizer Ltd) 41 42 9708 Diltiazem 24hr 120mg modified-release capsules 43 9723 Calcicard CR 90mg tablets (Teva UK Ltd) 44 45 9731 Quinapril 40mg tablets 46 9745 Teveten 300mg tablets (Abbott Healthcare Products Ltd) on September 25, 2021 by guest. Protected copyright. 47 9749 Physiotens 400microgram tablets (Abbott Healthcare Products Ltd) 48 49 9750 Nifedipine 60mg modified-release capsules 50 9764 Carace 20 Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 51 9783 Co-tenidone 50mg/12.5mg tablets 52 53 9876 Physiotens 300microgram tablets (Abbott Healthcare Products Ltd) 54 9915 Tritace 10mg tablets (Sanofi) 55 56 9935 Amiloride 5mg/5ml oral solution sugar free 57 9948 Trandolapril 4mg capsules 58 10066 Torem 5mg tablets (Meda Pharmaceuticals Ltd) 59 60 10088 Doxadura 4mg tablets (Discovery Pharmaceuticals Ltd) 10134 Flomaxtra XL 400microgram tablets (Astellas Pharma Ltd) 10135 Nifedipress mr 10mg Modified-release tablet (Sandoz Ltd)

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1 2 10136 Nifedipress MR 20 tablets (Dexcel-Pharma Ltd) 3 10153 Felendil xl 5mg Modified-release tablet (Ratiopharm UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 10191 Atenix 50 tablets (Ashbourne Pharmaceuticals Ltd) 6 10214 Spironolactone 5mg/5ml oral suspension sugar free 7 8 10246 Adipine XL 60mg tablets (Chiesi Ltd) 9 10251 Eplerenone 25mg tablets 10 10253 Moxonidine 300microgram tablets 11 12 10267 Adizem-XL 200mg capsules (Napp Pharmaceuticals Ltd) 13 10316 CoAprovel 150mg/12.5mg tablets (Sanofi) 14 10323 Losartan 100mg / Hydrochlorothiazide 25mg tablets 15 16 10392 Lasix 500mg tablets (Sanofi) 17 10422 Lasix 50mg/5ml Injection (Hoechst UK Ltd)For peer review only 18 10429 Lopresor 50mg Tablet (Novartis Pharmaceuticals UK Ltd) 19 20 10595 Nimotop 30mg tablets (Bayer Plc) 21 10627 Co-Betaloc tablets (Pfizer Ltd) 22 23 10688 Verapamil 160mg tablets 24 10713 Decaserpyl 5mg Tablet (Roussel Laboratories Ltd) 25 10714 Methoserpidine 5mg Tablet 26 27 10716 Corgard 80mg tablets (Sanofi) 28 10777 Trasicor 160mg Tablet (Novartis Pharmaceuticals UK Ltd) 29 10832 Securon 80mg Tablet (Abbott Laboratories Ltd) 30 31 10879 Bethanidine sulphate 10mg tablets 32 10882 Carace 2.5mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 33 34 10892 Emcor 10mg tablets (Merck Serono Ltd) 35 10902 Captopril 50mg with Hydrochlorothiazide 25mg tablets 36 11133 Hydrochlorothiazide with captopril 25mg with 50mg Tablet 37 38 11156 Spirolone 25mg Tablet (Berk Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 11177 Physiotens 200microgram tablets (Abbott Healthcare Products Ltd) 40 11197 Innovace melt 5mg Wafer (Merck Sharp & Dohme Ltd) 41 42 11223 Angitil SR 90 capsules (Chiesi Ltd) 43 11251 Diovan 40mg capsules (Novartis Pharmaceuticals UK Ltd) 44 45 11252 Diovan 80mg capsules (Novartis Pharmaceuticals UK Ltd) 46 11265 Triamterene 50mg / Furosemide 40mg tablets on September 25, 2021 by guest. Protected copyright. 47 11268 Torem 2.5mg tablets (Meda Pharmaceuticals Ltd) 48 49 11338 Bendroflumethiazide 5mg with Nadolol 40mg tablets 50 11348 Aprovel 300mg tablets (Sanofi) 51 11351 Co-zidocapt 25mg/50mg tablets 52 53 11380 Sotacor 160mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 54 11384 Co-flumactone 50mg/50mg tablets 55 56 11394 Baratol 25mg Tablet (Shire Pharmaceuticals Ltd) 57 11448 Irbesartan 150mg / Hydrochlorothiazide 12.5mg tablets 58 11469 Irbesartan 300mg / Hydrochlorothiazide 12.5mg tablets 59 60 11487 Torasemide 2.5mg tablets 11512 Nifedipress MR 10 tablets (Dexcel-Pharma Ltd) 11519 Spironolactone 25mg/5ml oral suspension sugar free

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1 2 11526 CoAprovel 300mg/12.5mg tablets (Sanofi) 3 11547 Nimodipine 30mg tablets BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 11561 Co-zidocapt 12.5mg/25mg tablets 6 11567 Ramipril 5mg with felodipine 5mg modified-release tablet 7 8 11641 Captopril 25mg with Hydrochlorothiazide 12.5mg tablets 9 11711 Propranolol 50mg/5ml oral solution 10 11769 Calchan MR 20 tablets (Ranbaxy (UK) Ltd) 11 12 11770 Dilzem SR 60 capsules (Teva UK Ltd) 13 11777 Verapamil 40mg/5ml oral solution sugar free 14 11793 Metoprolol 50mg/5ml oral suspension 15 16 11864 Valsartan 160mg / Hydrochlorothiazide 12.5mg tablets 17 11922 Diltiazem 60mg/5ml oral suspensionFor peer review only 18 11937 Ramipril 2.5mg/5ml oral suspension 19 20 11943 Cardene 20mg capsules (Astellas Pharma Ltd) 21 11965 Ramipril 2.5mg with felodipine 2.5mg modified-release tablet 22 23 11966 Motens 2mg tablets (GlaxoSmithKline UK Ltd) 24 11972 Vertab SR 240 tablets (Chiesi Ltd) 25 11973 Calcicard CR 120mg tablets (Teva UK Ltd) 26 27 11983 Perindopril erbumine 4mg/5ml oral suspension 28 11987 Lisinopril 5mg/5ml oral solution 29 12037 Betim 10mg Tablet (ICN Pharmaceuticals France S.A.) 30 31 12054 Propranolol 80mg / Bendroflumethiazide 2.5mg capsules 32 12104 Cordilox 160mg tablets (IVAX Pharmaceuticals UK Ltd) 33 34 12110 Hydroflumethiazide 50mg Tablet 35 12141 Betaxolol 20mg tablets 36 12226 Burinex 1mg/5ml Oral solution (LEO Pharma) 37 38 12294 Burinex 5mg tablets (LEO Pharma) http://bmjopen.bmj.com/ 39 12296 Sectral 100mg capsules (Sanofi) 40 12313 Carace 20mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 41 42 12318 Lasix 250mg/25ml Injection (Hoechst Marion Roussel) 43 12354 Etacrynic 50mg tablets 44 45 12360 Nephril 1mg Tablet (Pfizer Ltd) 46 12367 Piretanide 6mg capsule on September 25, 2021 by guest. Protected copyright. 47 12392 Univer 180mg modified-release capsules (Teva UK Ltd) 48 49 12411 Cilazapril 500microgram tablets 50 12412 Cilazapril 2.5mg tablets 51 12440 Hydrosaluric 25mg tablets (Merck Sharp & Dohme Ltd) 52 53 12456 Sotazide Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 54 12495 Berkolol 10mg Tablet (Berk Pharmaceuticals Ltd) 55 56 12517 Timolol maleate with bendroflumethiazide 20mg + 5mg Tablet 57 12518 Hypovase tablets B.D. starter pack (Pfizer Ltd) 58 12519 Kerlone 20mg tablets (Sanofi-Synthelabo Ltd) 59 60 12545 Phentolamine 10mg/1ml solution for injection ampoules 12546 Kalspare Tablet (Dominion Pharma) 12547 Triamterene 50mg / Chlortalidone 50mg tablets

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1 2 12574 Cilazapril 1mg tablets 3 12606 Nifelease 20mg Modified-release tablet (Eastern Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 12613 Unipine xl 30mg Modified-release tablet (Genus Pharmaceuticals Ltd) 6 12639 Diltiazem HCl 90mg Modified-release tablet (Actavis UK Ltd) 7 8 12651 Timolol 10mg / Bendroflumethiazide 2.5mg tablets 9 12705 Angiozem CR 90mg tablets (Ashbourne Pharmaceuticals Ltd) 10 12815 Tanatril 10mg tablets (Chiesi Ltd) 11 12 12836 Eprosartan 600mg tablets 13 12858 Imidapril 10mg tablets 14 12874 Telmisartan 80mg tablets 15 16 12875 Cardene SR 45mg capsules (Astellas Pharma Ltd) 17 12926 Polythiazide 1mg tabletsFor peer review only 18 12946 Spironolactone 10mg/5ml oral suspension sugar free 19 20 13026 Cilazapril 5mg tablets 21 13027 Viazem XL 240mg capsules (Thornton & Ross Ltd) 22 23 13033 Angitil XL 240 capsules (Chiesi Ltd) 24 13051 Sotalol 200mg tablets 25 13075 Dilzem XL 180 capsules (Teva UK Ltd) 26 27 13123 Eprosartan 400mg tablets 28 13127 Dilzem XL 240 capsules (Teva UK Ltd) 29 13139 Adipine XL 30mg tablets (Chiesi Ltd) 30 31 13240 Dilzem XL 120 capsules (Teva UK Ltd) 32 13243 Lercanidipine 20mg tablets 33 34 13246 Chlorothiazide 150mg/5ml oral suspension 35 13251 Vera-Til SR 240mg tablets (Tillomed Laboratories Ltd) 36 13264 Spironolactone 15mg/5ml oral suspension 37 38 13302 Dilzem SR 90 capsules (Teva UK Ltd) http://bmjopen.bmj.com/ 39 13317 Apresoline 20mg powder for solution for injection ampoules (AMCo) 40 13352 Midamor 5mg Tablet (MSD Thomas Morson Pharmaceuticals) 41 42 13363 Esidrex 50mg Tablet (Novartis Pharmaceuticals UK Ltd) 43 13379 Ismelin 25mg Tablet (Sovereign Medical Ltd) 44 45 13394 Tenormin 25mg/5ml syrup (AstraZeneca UK Ltd) 46 13410 Angiozem 60mg modified-release tablets (Ashbourne Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 13415 Corgard 40mg tablets (Sanofi-Synthelabo Ltd) 48 49 13435 Frumil Forte 10mg/80mg tablets (Sanofi) 50 13487 Beta-Cardone 200mg tablets (Focus Pharmaceuticals Ltd) 51 13499 Lopresor 100mg Tablet (Novartis Pharmaceuticals UK Ltd) 52 53 13525 Hydrenox 50mg Tablet (Knoll Ltd) 54 13526 Atenix Co 100 tablets (Ashbourne Pharmaceuticals Ltd) 55 56 13589 Staril 20mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 57 13610 Alphavase 2 tablets (Ashbourne Pharmaceuticals Ltd) 58 13672 Angiopine MR 10mg tablets (Ashbourne Pharmaceuticals Ltd) 59 60 13699 Angiopine la 40mg Tablet (Ashbourne Pharmaceuticals Ltd) 13755 Enalapril 10mg wafer 13821 Micardis 40mg tablets (Boehringer Ingelheim Ltd)

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1 2 13856 Verapress MR 240mg tablets (Actavis UK Ltd) 3 13871 Co-prenozide 160mg/0.25mg modified-release tablets BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 13926 Diltiazem 360mg modified-release capsules 6 13965 Cordilox MR 240mg tablets (Teva UK Ltd) 7 8 14030 Cardicor 2.5mg tablets (Merck Serono Ltd) 9 14057 Pindolol 10mg / Clopamide 5mg tablets 10 14058 Cardicor 1.25mg tablets (Merck Serono Ltd) 11 12 14109 Spironolactone 100mg/5ml oral solution sugar free 13 14117 Eucardic 3.125mg tablets (Roche Products Ltd) 14 14126 Acebutolol 200mg / Hydrochlorothiazide 12.5mg tablets 15 16 14144 Inspra 25mg tablets (Pfizer Ltd) 17 14146 Eucardic 6.25mg tablets (Roche Products Ltd)For peer review only 18 14228 Coversyl Plus tablets (Servier Laboratories Ltd) 19 20 14283 Valsartan 160mg / Hydrochlorothiazide 25mg tablets 21 14300 Zanidip 20mg tablets (Recordati Pharmaceuticals Ltd) 22 23 14305 Vascalpha 10mg modified-release tablets (Actavis UK Ltd) 24 14387 Carace 5mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 25 14390 Aldomet 250mg/5ml Liquid (Merck Sharp & Dohme Ltd) 26 27 14438 Corgaretic 80mg tablets (Sanofi-Synthelabo Ltd) 28 14442 Esbatal 50mg Tablet (Wellcome Medical Division) 29 14477 Accupro 10mg tablets (Pfizer Ltd) 30 31 14478 Accupro 20mg tablets (Pfizer Ltd) 32 14495 Loniten 10mg tablets (Pfizer Ltd) 33 34 14502 Metoprolol 5mg/5ml solution for injection ampoules 35 14552 Propanix 10mg Tablet (Ashbourne Pharmaceuticals Ltd) 36 14587 Amiloride 5mg / Bumetanide 1mg tablets 37 38 14673 Pindolol 15mg tablets http://bmjopen.bmj.com/ 39 14738 Hydrochlorothiazide with losartan 12.5mg with 50mg Tablet 40 14761 Frusid 40mg tablets (Dr Reddy's Laboratories (UK) Ltd) 41 42 14808 Bedranol SR 80mg capsules (Sandoz Ltd) 43 14837 Frusol 50mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 44 45 14861 Calchan MR 10 tablets (Ranbaxy (UK) Ltd) 46 14870 Telmisartan 40mg / Hydrochlorothiazide 12.5mg tablets on September 25, 2021 by guest. Protected copyright. 47 14932 Tabphyn MR 400microgram capsules (ProStrakan Ltd) 48 49 14943 Valsartan 40mg tablets 50 14960 Coversyl 8mg tablets (Servier Laboratories Ltd) 51 14965 Cozaar 100mg tablets (Merck Sharp & Dohme Ltd) 52 53 14983 Olmetec 10mg tablets (Daiichi Sankyo UK Ltd) 54 15031 Accuretic 12.5mg/10mg tablets (Pfizer Ltd) 55 56 15042 Tolerzide Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 57 15052 Spiroctan 50mg Tablet (Roche Products Ltd) 58 15085 Innovace Titration pack (Merck Sharp & Dohme Ltd) 59 60 15096 Accupro 40mg tablets (Pfizer Ltd) 15108 Quinapril 10mg / Hydrochlorothiazide 12.5mg tablets 15117 Nifedipine with atenolol 20mg + 50mg Capsule

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1 2 15121 Moexipril 7.5mg tablets 3 15127 Hydrochlorothiazide with triamterene 25mgwith50mg Tablet BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 15135 Hydrochlorothiazide with captopril 12.5mg with 25mg Tablet 6 15176 Totamol 50mg Tablet (C P Pharmaceuticals Ltd) 7 8 15221 Dilcardia xl 180mg Modified-release capsule (Generics (UK) Ltd) 9 15288 Angitil XL 300 capsules (Chiesi Ltd) 10 15341 Burinex 0.5mg/ml Injection (LEO Pharma) 11 12 15457 Baycaron 25mg Tablet (Bayer Plc) 13 15488 Metoprolol tartrate with chlortalidone Tablet 14 15493 Reserpine with hydrochlorothiazide tablet 15 16 15605 Cilazapril 250micrograms tablets 17 15619 Half-betadur cr 80mg Capsule (Monmouth Pharmaceuticals Ltd)For peer review only 18 15652 Mibefradil 50mg Tablet 19 20 15715 Genalat retard 20mg Modified-release tablet (Wyeth Pharmaceuticals) 21 15730 Totamol 100mg Tablet (C P Pharmaceuticals Ltd) 22 23 15811 Co-flumactone 25mg/25mg tablets 24 15874 Amiloride 2.5mg / furosemide 20mg tablets 25 15958 Captopril 2mg tablets 26 27 16038 Dilzem SR 120 capsules (Teva UK Ltd) 28 16060 Valsartan 80mg / Hydrochlorothiazide 12.5mg tablets 29 16073 Nifedipress MR 10 tablets (Teva UK Ltd) 30 31 16161 Telmisartan 80mg / Hydrochlorothiazide 12.5mg tablets 32 16162 Amlodipine 5mg/5ml oral suspension 33 34 16196 Vascace 5mg tablets (Roche Products Ltd) 35 16197 Vascace 2.5mg tablets (Roche Products Ltd) 36 16198 Baratol 50mg Tablet (Shire Pharmaceuticals Ltd) 37 38 16201 Hytrin bph 2mg Tablet (Amdipharm Plc) http://bmjopen.bmj.com/ 39 16206 Froop 40mg tablets (Ashbourne Pharmaceuticals Ltd) 40 16212 Vascace 1mg tablets (Roche Products Ltd) 41 42 16248 Clonidine 150micrograms/1ml solution for injection ampoules 43 16285 Teveten 400mg tablets (Abbott Healthcare Products Ltd) 44 45 16328 Verapress MR 240mg tablets (Dexcel-Pharma Ltd) 46 16371 Teveten 600mg tablets (Abbott Healthcare Products Ltd) on September 25, 2021 by guest. Protected copyright. 47 16498 Kalspare tablets (DHP Healthcare Ltd) 48 49 16531 Eplerenone 50mg tablets 50 16632 Hydrosaluric 50mg tablets (Merck Sharp & Dohme Ltd) 51 16645 Labrocol 400mg Tablet (Lagap) 52 53 16677 Cordilox 80mg tablets (IVAX Pharmaceuticals UK Ltd) 54 16701 Carace 10mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 55 56 16708 Enalapril titration pack 57 16710 Gopten 500microgram capsules (Abbott Laboratories Ltd) 58 16776 Celectol 400mg Tablet (Pantheon Healthcare Ltd) 59 60 16786 Chlortalidone 25mg with Atenolol 100mg tablets 16850 Angiozem CR 120mg tablets (Ashbourne Pharmaceuticals Ltd) 16924 Imidapril 5mg tablets

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1 2 17006 Triapin 5mg/5mg modified-release tablets (Sanofi) 3 17082 Syprol 5mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 17120 Moexipril 15mg tablets 6 17122 Isoprenaline 200micrograms/1ml solution for injection ampoules 7 8 17143 Mefruside 25mg Tablet 9 17149 Monozide 10 tablets (Wyeth Pharmaceuticals) 10 17252 Esidrex 25mg Tablet (Novartis Pharmaceuticals UK Ltd) 11 12 17291 Guanethidine 25mg Tablet 13 17322 Atenix 25 tablets (Ashbourne Pharmaceuticals Ltd) 14 17325 Cardilate MR 10mg tablets (Teva UK Ltd) 15 16 17338 Nifedotard 20 mr 20mg Modified-release tablet (Galen Ltd) 17 17342 Nivaten retard 10mg Modified-release tablet (Actavis UK Ltd)For peer review only 18 17406 Zemtard 180 XL capsules (Galen Ltd) 19 20 17425 Zemtard 120 XL capsules (Galen Ltd) 21 17448 Nifedipress mr 10mg Modified-release tablet (Sterwin Medicines) 22 23 17462 Bisoprolol 10mg / Hydrochlorothiazide 6.25mg tablets 24 17474 Felodipine 5mg modified-release / Ramipril 5mg tablets 25 17492 Zemtard 300 XL capsules (Galen Ltd) 26 27 17545 Micardis 80mg tablets (Boehringer Ingelheim Ltd) 28 17557 Felotens XL 5mg tablets (Thornton & Ross Ltd) 29 17561 Bendroflumethiazide 2.5mg / Potassium chloride 573mg (potassium 7.7mmol) modified- 30 31 release tablets 32 17566 Felotens XL 10mg tablets (Thornton & Ross Ltd) 33 17586 Slozem 300mg capsules (Merck Serono Ltd) 34 35 17599 Verapress MR 240mg tablets (Sandoz Ltd) 36 17615 Cardicor 5mg tablets (Merck Serono Ltd) 37 38 17624 Captopril 5mg/5ml oral suspension http://bmjopen.bmj.com/ 39 17633 Captopril 3mg/5ml oral solution 40 17640 Amlostin 5mg tablets (Discovery Pharmaceuticals Ltd) 41 42 17655 Carace 10 Tablet (Bristol-Myers Squibb Pharmaceuticals Ltd) 43 17666 Viazem XL 180mg capsules (Thornton & Ross Ltd) 44 17679 Sotalol 10mg/ml injection 45 46 17686 Micardis 20mg tablets (Boehringer Ingelheim Ltd) 47 17689 MicardisPlus 80mg/12.5mg tablets (Boehringer Ingelheim Ltd) on September 25, 2021 by guest. Protected copyright. 48 17720 Saluric 500mg Tablet (Merck Sharp & Dohme Ltd) 49 50 17783 Spiroprop Tablet (Pharmacia Ltd) 51 17902 Spirolone 100mg Tablet (Berk Pharmaceuticals Ltd) 52 53 17950 Spirolone 50mg Tablet (Berk Pharmaceuticals Ltd) 54 18038 Nisoldipine 20mg modified-release tablets 55 18096 Torasemide 10mg tablets 56 57 18185 Cardicor 7.5mg tablets (Merck Serono Ltd) 58 18200 Olmesartan medoxomil 20mg / Hydrochlorothiazide 12.5mg tablets 59 18202 MicardisPlus 40mg/12.5mg tablets (Boehringer Ingelheim Ltd) 60 18219 Imidapril 20mg tablets 18223 Trandolapril with verapamil 2mg + 180mg Modified-release capsule

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1 2 18247 Esbatal 10mg Tablet (Wellcome Medical Division) 3 18252 Metalpha 250mg Tablet (Ashbourne Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 18263 Acezide 25mg/50mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 6 18267 Enduron 5mg Tablet (Abbott Laboratories Ltd) 7 8 18269 Acepril 12.5mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 9 18287 Co-Betaloc SA tablets (Pfizer Ltd) 10 18325 Acepril 50mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 11 12 18332 Aridil 20mg+2.5mg Tablet (C P Pharmaceuticals Ltd) 13 18361 Amilmaxco 5mg/50mg tablets (Ashbourne Pharmaceuticals Ltd) 14 18379 Dilcardia SR 90mg capsules (Generics (UK) Ltd) 15 16 18403 Diltiazem HCl 180mg Modified-release capsule (Hillcross Pharmaceuticals Ltd) 17 18404 Diltiazem 60mg modified-release capsules (A A H Pharmaceuticals Ltd)For peer review only 18 18414 Eucardic 12.5mg tablets (Roche Products Ltd) 19 20 18497 Amiloride 10mg / furosemide 80mg tablets 21 18606 Diltiazem and hydrochlorothiazide 150mg+12.5mg modified-release capsules 22 23 18650 Edecrin 50mg Tablet (Merck Sharp & Dohme Ltd) 24 18716 Dryptal 10mg/ml Injection (Berk Pharmaceuticals Ltd) 25 18726 Triamaxco 50mg/25mg tablets (Ashbourne Pharmaceuticals Ltd) 26 27 18733 Co-amilozide 5mg with 50mg/ml oral solution 28 18743 Tenben 25mg/1.25mg capsules (Galen Ltd) 29 18830 Disogram SR 90mg capsules (Ranbaxy (UK) Ltd) 30 31 18834 Disogram SR 60mg capsules (Ranbaxy (UK) Ltd) 32 18852 Disogram SR 120mg capsules (Ranbaxy (UK) Ltd) 33 34 18861 Hydralazine 10mg/5ml oral suspension 35 18874 Disogram SR 180mg capsules (Ranbaxy (UK) Ltd) 36 18903 Olmesartan medoxomil 20mg / Hydrochlorothiazide 25mg tablets 37 38 18910 Olmetec 20mg tablets (Daiichi Sankyo UK Ltd) http://bmjopen.bmj.com/ 39 18950 Totamol 25mg Tablet (C P Pharmaceuticals Ltd) 40 18973 Centyl 2.5mg Tablet (Edwin Burgess Ltd) 41 42 18975 Calcicard 60mg Tablet (3M Health Care Ltd) 43 18983 Brinaldix k Effervescent tablet (Berk Pharmaceuticals Ltd) 44 45 19013 Clinium 120mg Tablet (LEO Pharma) 46 19055 Chlortalidone 12.5mg with Atenolol 50mg tablets on September 25, 2021 by guest. Protected copyright. 47 19056 Furosemide 50mg/5ml sugar free Oral solution (Rosemont Pharmaceuticals Ltd) 48 49 19129 Syscor MR 10 tablets (Forest Laboratories UK Ltd) 50 19142 Bendroflumethiazide 2.5mg with Timolol maleate 10mg tablets 51 19170 Tensipine MR 10 tablets (Thornton & Ross Ltd) 52 53 19172 Atenolol 25mg tablets (IVAX Pharmaceuticals UK Ltd) 54 19175 Verapamil 40mg tablets (IVAX Pharmaceuticals UK Ltd) 55 56 19178 Bisoprolol 10mg tablets (Ranbaxy (UK) Ltd) 57 19182 Atenolol 50mg tablets (IVAX Pharmaceuticals UK Ltd) 58 19191 Atenolol 100mg tablets (Teva UK Ltd) 59 60 19192 Furosemide 40mg Tablet (M & A Pharmachem Ltd) 19193 Doxazosin 2mg tablets (Teva UK Ltd) 19194 Furosemide 20mg tablets (Teva UK Ltd)

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1 2 19195 Spironolactone 50mg Tablet (Wyeth Pharmaceuticals) 3 19198 Lisinopril 20mg tablets (Teva UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 19200 Bisoprolol 5mg tablets (IVAX Pharmaceuticals UK Ltd) 6 19202 Carvedilol 6.25mg tablets (Teva UK Ltd) 7 8 19204 Lisinopril 5mg tablets (Teva UK Ltd) 9 19208 Enalapril 10mg tablets (Actavis UK Ltd) 10 19216 Doxazosin 4mg tablets (IVAX Pharmaceuticals UK Ltd) 11 12 19223 Lisinopril 10mg tablets (Teva UK Ltd) 13 19258 Furosemide 50mg/5ml solution for injection ampoules 14 19300 Bumetanide 2mg/4ml solution for injection ampoules 15 16 19325 Cordilox 2.5mg/ml Injection (IVAX Pharmaceuticals UK Ltd) 17 19352 Xuret 0.5mg Tablet (Galen Ltd)For peer review only 18 19426 Disogram SR 240mg capsules (Ranbaxy (UK) Ltd) 19 20 19437 Eucardic 25mg tablets (Roche Products Ltd) 21 19440 Disogram SR 300mg capsules (Ranbaxy (UK) Ltd) 22 23 19457 Ranvera MR 240mg tablets (Ranbaxy (UK) Ltd) 24 19459 Verapamil 240mg modified-release tablets (A A H Pharmaceuticals Ltd) 25 19690 Verapamil 180mg modified-release / Trandolapril 2mg capsules 26 27 19823 Alphavase 5 tablets (Ashbourne Pharmaceuticals Ltd) 28 19853 Cardicor 3.75mg tablets (Merck Serono Ltd) 29 19858 Cardicor 10mg tablets (Merck Serono Ltd) 30 31 19890 Hydrochlorothiazide with amiloride 25mgwith2.5mg Tablet 32 19892 Serpasil -esidrex Tablet (Novartis Pharmaceuticals UK Ltd) 33 34 19998 Trandate 100mg/20ml solution for injection ampoules (Focus Pharmaceuticals Ltd) 35 20012 Visken 15mg Tablet (Sovereign Medical Ltd) 36 20057 Methyclothiazide 5mg Tablet 37 38 20066 Amil-Co 5mg/50mg tablets (IVAX Pharmaceuticals UK Ltd) http://bmjopen.bmj.com/ 39 20082 Lopresor SR 200mg tablets (Recordati Pharmaceuticals Ltd) 40 20093 Metoprolol 200mg modified-release / Hydrochlorothiazide 25mg tablets 41 42 20117 Olmetec 40mg tablets (Daiichi Sankyo UK Ltd) 43 20169 Practolol 2mg/ml injection 44 45 20188 Enalapril 2.5mg wafer 46 20257 Cardilate MR 20mg tablets (IVAX Pharmaceuticals UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 20311 Nifedipress mr 20mg Modified-release tablet (Generics (UK) Ltd) 48 49 20369 Doxazosin 1mg/5ml oral suspension 50 20426 Centyl k 2.5mg+7.7mmol Tablet (Edwin Burgess Ltd) 51 20431 Centyl K modified-release tablets (LEO Pharma) 52 53 20459 Felendil xl 10mg Modified-release tablet (Ratiopharm UK Ltd) 54 20468 Half Beta-Prograne 80mg modified-release capsules (Tillomed Laboratories Ltd) 55 56 20502 Atenix 100 tablets (Ashbourne Pharmaceuticals Ltd) 57 20538 Frumax 40mg Tablet (Ashbourne Pharmaceuticals Ltd) 58 20579 Tarka modified-release capsules (Abbott Laboratories Ltd) 59 60 20591 Nifedipress MR 20 tablets (Teva UK Ltd) 20642 Bi-carzem sr 60mg Modified-release capsule (Tillomed Laboratories Ltd) 20656 Serpasil 250microgram Tablet (Novartis Pharmaceuticals UK Ltd)

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1 2 20690 Reserpine 250micrograms tablet 3 20728 Atenamin 25mg Tablet (OPD Pharm) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 20849 Tensopril 12.5mg tablets (Teva UK Ltd) 6 20878 Angiopine 10 capsules (Ashbourne Pharmaceuticals Ltd) 7 8 20890 Zemtard 240 XL capsules (Galen Ltd) 9 20975 Lisinopril 7.5mg/5ml oral suspension 10 21025 Prestim forte Tablet (LEO Pharma) 11 12 21053 Vascace 500microgram tablets (Roche Products Ltd) 13 21133 Atenamin 50mg Tablet (OPD Pharm) 14 21145 Dilcardia SR 60mg capsules (Generics (UK) Ltd) 15 16 21162 Felodipine 2.5mg modified-release / Ramipril 2.5mg tablets 17 21182 Hydrochlorothiazide with timolol and amiloride 25mg with 10mg with 2.5mg TabletFor peer review only 18 21216 Hypolar Retard 10mg tablets (Sandoz Ltd) 19 20 21231 Caralpha 20mg/12.5mg tablets (Actavis UK Ltd) 21 21245 Nifedipress mr 10mg Modified-release tablet (Actavis UK Ltd) 22 23 21346 Hydromet Tablet (MSD Thomas Morson Pharmaceuticals) 24 21423 Cozaar-Comp 100mg/25mg tablets (Merck Sharp & Dohme Ltd) 25 21502 Serpasil 100microgram Tablet (Novartis Pharmaceuticals UK Ltd) 26 27 21763 Diltiazem 60mg modified-release tablets (A A H Pharmaceuticals Ltd) 28 21773 Diltiazem HCl 60mg Tablet (Generics (UK) Ltd) 29 21778 Diltiazem 60mg modified-release tablets (Teva UK Ltd) 30 31 21795 Retalzem 60 modified-release tablets (Kent Pharmaceuticals Ltd) 32 21803 Berkozide 2.5mg Tablet (Berk Pharmaceuticals Ltd) 33 34 21838 Propanix 80mg Tablet (Ashbourne Pharmaceuticals Ltd) 35 21839 Berkolol 80mg Tablet (Berk Pharmaceuticals Ltd) 36 21849 Dryptal 40mg Tablet (Berk Pharmaceuticals Ltd) 37 38 21866 Berkolol 40mg Tablet (Berk Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 21867 Berkozide 5mg Tablet (Berk Pharmaceuticals Ltd) 40 21872 Angiopine 5mg Capsule (Ashbourne Pharmaceuticals Ltd) 41 42 21873 Atenix Co 50 tablets (Ashbourne Pharmaceuticals Ltd) 43 21885 Oxyprenix SR 160mg tablets 44 45 21886 Nifedipress MR 20 tablets (Actavis UK Ltd) 46 21905 Bipranix 10mg tablets (Ashbourne Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 21911 Spirospare 25mg Tablet (Ashbourne Pharmaceuticals Ltd) 48 49 21918 Optil 60mg modified-release tablets (Opus Pharmaceuticals Ltd) 50 21938 Froop Co 5mg/40mg tablets (Ashbourne Pharmaceuticals Ltd) 51 21943 Kaplon 12.5mg tablets (Teva UK Ltd) 52 53 21966 Bipranix 5mg tablets (Ashbourne Pharmaceuticals Ltd) 54 22019 Calanif 10mg Capsule (Berk Pharmaceuticals Ltd) 55 56 22142 Calcilat 10mg Capsule (Eastern Pharmaceuticals Ltd) 57 22208 Half propanix la 80mg Modified-release capsule (Ashbourne Pharmaceuticals Ltd) 58 22217 Nimodrel 10mg modified-release tablet (Opus Pharmaceuticals Ltd) 59 60 22241 Mibefradil 100mg Tablet 22439 Ednyt 20mg Tablet (Dominion Pharma) 22454 Demser 250mg Capsule (Merck Sharp & Dohme Ltd)

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1 2 22619 Britiazim 60mg Modified-release tablet (Thames Laboratories Ltd) 3 22658 Torem 10mg tablets (Meda Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 22696 Slofedipine 20mg tablets (Sterwin Medicines) 6 22708 Enalapril 5mg wafer 7 8 22793 Labrocol 200mg Tablet (Lagap) 9 22826 Securon 160mg Tablet (Abbott Laboratories Ltd) 10 22839 Clopamide with Potassium effervescent tablets 11 12 22853 Reserpine 100micrograms tablet 13 22912 Bendroflumethiazide 2.5mg with Propanolol 80mg capsules 14 22923 Hydrochlorothiazide with amiloride 50mg with 5mg Tablet 15 16 23010 Rogitine 10mg/1ml solution for injection ampoules (Alliance Pharmaceuticals Ltd) 17 23091 Spirospare 100 tablets (Ashbourne Pharmaceuticals Ltd)For peer review only 18 23131 Bendroflumethiazide 5mg with Propanolol 160mg modified-release capsules 19 20 23134 Nadolol 40mg / Bendroflumethiazide 5mg tablets 21 23233 Bi-carzem sr 90mg Modified-release capsule (Tillomed Laboratories Ltd) 22 23 23252 Pralenal 10 tablets (Opus Pharmaceuticals Ltd) 24 23326 Betadur cr 160mg Modified-release capsule (Monmouth Pharmaceuticals Ltd) 25 23345 Hypercal 2mg Tablet (Carlton Laboratories) 26 27 23380 Catapres 300microgram tablets (Boehringer Ingelheim Ltd) 28 23427 Bendroflumethiazide 5mg tablets (A A H Pharmaceuticals Ltd) 29 23456 Hydrochlorothiazide with valsartan 25mg with 160mg Tablet 30 31 23459 Hypovase benign prostatic hyperplasia 2mg Tablet (Pfizer Ltd) 32 23478 Tensopril 50mg tablets (Teva UK Ltd) 33 34 23505 Adizem xl plus 150mg+12.5mg Modified-release capsule (Napp Pharmaceuticals Ltd) 35 23587 Sloprolol 160mg Capsule (C P Pharmaceuticals Ltd) 36 23642 Vascace 0.25mg Tablet (Roche Products Ltd) 37 38 23733 Optil sr 90mg Modified-release capsule (Opus Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 23736 Hypolar XL 30 tablets (Sandoz Ltd) 40 23761 Methyldopa 250mg/5ml oral suspension 41 42 23805 Nisoldipine 10mg modified-release tablets 43 23823 Nisoldipine 30mg modified-release tablets 44 45 23872 Berkatens 40mg Tablet (Berk Pharmaceuticals Ltd) 46 24008 Vasetic Tablet (Shire Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 24041 Enalapril 20mg wafer 48 49 24083 Bisoprolol 5mg tablets (Teva UK Ltd) 50 24094 Trasicor 40mg tablets (Amdipharm Plc) 51 24189 Neo-bendromax 2.5mg Tablet (Ashbourne Pharmaceuticals Ltd) 52 53 24190 Neo-bendromax 5mg Tablet (Ashbourne Pharmaceuticals Ltd) 54 24191 Antipressan 50mg tablets (Teva UK Ltd) 55 56 24195 Antipressan 100mg tablets (Teva UK Ltd) 57 24196 Dopamet 250mg Tablet (Berk Pharmaceuticals Ltd) 58 24218 Berkolol 160mg Tablet (Berk Pharmaceuticals Ltd) 59 60 24228 Nimodrel 20mg modified-release tablet (Opus Pharmaceuticals Ltd) 24268 Hydrochlorothiazide with valsartan 12.5mg with 80mg Tablet 24280 Totaretic 100mg+25mg Tablet (C P Pharmaceuticals Ltd)

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1 2 24359 Diovan 40mg tablets (Novartis Pharmaceuticals UK Ltd) 3 24365 Cardioplen XL 5mg tablets (Chiesi Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 24366 Cardioplen XL 10mg tablets (Chiesi Ltd) 6 24369 Petyme 400microgram MR capsules (Teva UK Ltd) 7 8 24461 Betaloc I.V. 5mg/5ml solution for injection ampoules (AstraZeneca UK Ltd) 9 24482 Captomex 50mg tablets (Actavis UK Ltd) 10 24484 Hydrochlorothiazide with valsartan 12.5mg with 160mg Tablet 11 12 24632 Hydrochlorothiazide with losartan 25mg with 100mg Tablet 13 24635 Sotacor 10mg/ml Injection (Bristol-Myers Squibb Pharmaceuticals Ltd) 14 24832 Lasipressin Tablet (Hoechst UK Ltd) 15 16 24835 Min-i-jet furosemide 10mg/ml Injection (Celltech Pharma Europe Ltd) 17 24893 Amilospare Tablet (Ashbourne Pharmaceuticals Ltd)For peer review only 18 25047 Hypovase benign prostatic hyperplasia 500microgram Tablet (Pfizer Ltd) 19 20 25059 Berkatens 80mg Tablet (Berk Pharmaceuticals Ltd) 21 25132 Nifopress MR 20mg tablets (Teva UK Ltd) 22 23 25275 Metalpha 500mg Tablet (Ashbourne Pharmaceuticals Ltd) 24 25289 Dopamet 500mg Tablet (Berk Pharmaceuticals Ltd) 25 25334 Furosemide 500mg tablets (A A H Pharmaceuticals Ltd) 26 27 25359 Rapranol SR 160mg capsules (Ranbaxy (UK) Ltd) 28 25363 Prestim tablets (Meda Pharmaceuticals Ltd) 29 25367 Rapranol SR 80mg capsules (Ranbaxy (UK) Ltd) 30 31 25382 Co-Diovan 160mg/25mg tablets (Novartis Pharmaceuticals UK Ltd) 32 25393 Decaserpyl 10mg Tablet (Roussel Laboratories Ltd) 33 34 25462 Clopamide 5mg with Pindolol 10mg tablets 35 25487 Cascor 2mg tablets (Ranbaxy (UK) Ltd) 36 25494 Diatensec 50mg Tablet (Pharmacia Ltd) 37 38 25500 Hypertane 50 Tablet (Schwarz Pharma Ltd) http://bmjopen.bmj.com/ 39 25505 Spiro-co 50mg+50mg Tablet (IVAX Pharmaceuticals UK Ltd) 40 25551 Cascor 4mg tablets (Ranbaxy (UK) Ltd) 41 42 25572 Felogen XL 5mg tablets (Generics (UK) Ltd) 43 25644 Apsolox 80mg Tablet (Approved Prescription Services Ltd) 44 45 25645 Seominal Tablet (Sterling-Winthrop) 46 25646 Nivaten retard 20mg Modified-release tablet (Actavis UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 25717 Furosemide 40mg tablets (Generics (UK) Ltd) 48 49 25730 Timolol maleate with amiloride and hydrochlorothiazide Tablet 50 25777 Dilcardia SR 120mg capsules (Generics (UK) Ltd) 51 25919 Nifedipine 20mg modified-release tablets (A A H Pharmaceuticals Ltd) 52 53 25965 Co-amilofruse 2.5mg/20mg tablets (Wockhardt UK Ltd) 54 25998 Captomex 12.5mg tablets (Actavis UK Ltd) 55 56 26211 Antipressan 25mg tablets (Teva UK Ltd) 57 26217 Berkamil 5mg Tablet (Berk Pharmaceuticals Ltd) 58 26219 Zida-co 5mg+50mg Tablet (Opus Pharmaceuticals Ltd) 59 60 26220 Delvas Tablet (Berk Pharmaceuticals Ltd) 26228 Propanix LA 160mg Modified-release capsule (Ashbourne Pharmaceuticals Ltd) 26229 Beta-Prograne 160mg modified-release capsules (Tillomed Laboratories Ltd)

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1 2 26237 Alphavase 500microgram Tablet (Ashbourne Pharmaceuticals Ltd) 3 26238 Alphavase 1 tablets (Ashbourne Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 26248 Tenchlor 100mg/25mg tablets (Teva UK Ltd) 6 26252 Berkatens 160mg Tablet (Berk Pharmaceuticals Ltd) 7 8 26255 Lopranol la 160mg Capsule (Opus Pharmaceuticals Ltd) 9 26256 Opumide 2.5mg Tablet (Opus Pharmaceuticals Ltd) 10 26265 Calanif 5mg Capsule (Berk Pharmaceuticals Ltd) 11 12 26267 Optil sr 120mg Modified-release capsule (Opus Pharmaceuticals Ltd) 13 26269 Optil sr 180mg Modified-release capsule (Opus Pharmaceuticals Ltd) 14 26270 Optil xl 300mg Modified-release capsule (Opus Pharmaceuticals Ltd) 15 16 26275 Nindaxa 2.5 tablets (Ashbourne Pharmaceuticals Ltd) 17 26292 Diuresal 40mg Tablet (Lagap)For peer review only 18 26309 Optil xl 240mg Modified-release capsule (Opus Pharmaceuticals Ltd) 19 20 26337 Cabren 10mg modified-release tablets (Teva UK Ltd) 21 26460 Dilcardia xl 240mg Modified-release capsule (Generics (UK) Ltd) 22 23 26463 Zemret xl 240mg Capsule (Neo Laboratories Ltd) 24 26529 Furosemide with penbutolol Tablet 25 26674 Verapamil 5mg/2ml solution for injection ampoules 26 27 26693 Hypovase benign prostatic hyperplasia bd BD Starter pack (Pfizer Ltd) 28 26741 Totaretic 50mg+12.5mg Tablet (C P Pharmaceuticals Ltd) 29 26759 Zildil SR 60mg capsules (Chanelle Medical UK Ltd) 30 31 26774 Nifedipine 10mg/5ml Oral suspension 32 26895 Syprol 10mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 33 34 26919 Methyldopa 50mg/ml Injection 35 26995 Kaplon 25mg tablets (Teva UK Ltd) 36 27135 Diltiazem sr 90mg Capsule (Hillcross Pharmaceuticals Ltd) 37 38 27136 Diltiazem 90mg modified-release tablets (A A H Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 27137 Sildenafil 20mg tablets 40 27256 Bendroflumethiazide 2.5mg tablets (Wockhardt UK Ltd) 41 42 27295 Securon IV 5mg/2ml solution for injection ampoules (Abbott Laboratories Ltd) 43 27357 Oxprenolol 40mg Tablet (Actavis UK Ltd) 44 45 27401 Kenzem SR 90mg capsules (Kent Pharmaceuticals Ltd) 46 27403 Omnic MR 400microgram capsules (Astellas Pharma Ltd) on September 25, 2021 by guest. Protected copyright. 47 27447 Furosemide 40mg tablets (Wockhardt UK Ltd) 48 49 27520 Olmetec Plus 20mg/25mg tablets (Daiichi Sankyo UK Ltd) 50 27685 Diltiazem HCl 300mg Capsule (PLIVA Pharma Ltd) 51 27689 Bendroflumethiazide 2.5mg tablets (IVAX Pharmaceuticals UK Ltd) 52 53 27690 Furosemide 40mg tablets (A A H Pharmaceuticals Ltd) 54 27696 Furosemide 40mg tablets (Kent Pharmaceuticals Ltd) 55 56 27700 Propranolol 40mg tablets (Actavis UK Ltd) 57 27719 Metoros ls 95mg Tablet (Geigy Pharmaceuticals) 58 27727 Sotalol 2mg/ml injection 59 60 27871 Innovace melt 10mg Wafer (Merck Sharp & Dohme Ltd) 27926 Furosemide 20mg tablets (Generics (UK) Ltd) 27946 Nadolol 80mg / Bendroflumethiazide 5mg tablets

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1 2 27957 Natramid 2.5mg Tablet (Trinity Pharmaceuticals Ltd) 3 27964 Apsolol 40mg Tablet (Approved Prescription Services Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 28048 Angilol 10mg Tablet (DDSA Pharmaceuticals Ltd) 6 28127 Enalapril 2.5mg tablets (Teva UK Ltd) 7 8 28128 Propranolol 80mg Modified-release capsule (Actavis UK Ltd) 9 28129 Co-amilofruse 5mg/40mg tablets (Teva UK Ltd) 10 28157 Kalspare ls Tablet (Dominion Pharma) 11 12 28177 Hydrochlorothiazide with atenolol and amiloride Capsule 13 28438 Triapin 2.5mg/2.5mg modified-release tablets (Sanofi) 14 28441 Pamsvax XL 400microgram capsules (Actavis UK Ltd) 15 16 28486 Captopril 6.25mg/5ml oral suspension 17 28586 Lopace 5mg capsules (Discovery Pharmaceuticals Ltd)For peer review only 18 28676 Bethanidine sulphate 50mg tablets 19 20 28688 Nifedipine 10mg modified-release tablets (A A H Pharmaceuticals Ltd) 21 28700 Cartrol 10mg Tablet (Novartis Consumer Health UK Ltd) 22 23 28721 Neofel XL 5mg tablets (Kent Pharmaceuticals Ltd) 24 28724 Perdix 7.5mg tablets (UCB Pharma Ltd) 25 28725 Perdix 15mg tablets (UCB Pharma Ltd) 26 27 28738 Methyldopa with hydrochlorothiazide Tablet 28 28788 Half propatard la 80mg Modified-release capsule (Galen Ltd) 29 28820 Captomex 25mg tablets (Actavis UK Ltd) 30 31 28843 Verapamil hc 80mg Tablet (Celltech Pharma Europe Ltd) 32 28844 Berkatens 120mg Tablet (Berk Pharmaceuticals Ltd) 33 34 28902 Odrik 2mg capsules (Aventis Pharma) 35 28949 Bi-carzem sr 120mg Modified-release capsule (Tillomed Laboratories Ltd) 36 28996 Bedranol SR 160mg capsules (Sandoz Ltd) 37 38 29044 Neofel XL 10mg tablets (Kent Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 29130 Gopten 4mg capsules (Abbott Laboratories Ltd) 40 29145 Felendil xl 2.5mg Modified-release tablet (Ratiopharm UK Ltd) 41 42 29180 Trasicor 80mg tablets (Amdipharm Plc) 43 29187 Methoserpidine 10mg Tablet 44 45 29230 Slow-pren 160mg Tablet (IVAX Pharmaceuticals UK Ltd) 46 29368 Atenolol 25mg tablets (Teva UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 29397 Spiretic 100mg Tablet (DDSA Pharmaceuticals Ltd) 48 49 29398 Atenamin 100mg Tablet (OPD Pharm) 50 29427 Hydrochlorothiazide with metoprolol tartrate 12.5mg with 100mg tablet 51 29443 Bendogen 10mg Tablet (Lagap) 52 53 29529 Hydroflumethiazide with spironolactone 25mg+25mg Tablet 54 29530 Innovace melt 2.5mg Wafer (Merck Sharp & Dohme Ltd) 55 56 29560 Bosentan 62.5mg tablets 57 29561 Bosentan 125mg tablets 58 29570 Dopamet 125mg Tablet (Berk Pharmaceuticals Ltd) 59 60 29610 Betim 10mg tablets (Meda Pharmaceuticals Ltd) 29627 Lopace 2.5mg capsules (Discovery Pharmaceuticals Ltd) 29634 Olmetec Plus 20mg/12.5mg tablets (Daiichi Sankyo UK Ltd)

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1 2 29637 Verapress MR 240mg tablets (Teva UK Ltd) 3 29676 Calazem 60mg Modified-release tablet (Berk Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 29694 Inspra 50mg tablets (Pfizer Ltd) 6 29696 Methoserpidine with benzthiazide Tablet 7 8 29762 Mepranix 50mg Tablet (Ashbourne Pharmaceuticals Ltd) 9 29763 Propanix 160mg Tablet (Ashbourne Pharmaceuticals Ltd) 10 29780 Furosemide 20mg Tablet (C P Pharmaceuticals Ltd) 11 12 29827 Carteolol HCl 10mg tablets 13 29991 Centyl 5mg Tablet (Edwin Burgess Ltd) 14 29998 Metoros 190mg Tablet (Novartis Pharmaceuticals UK Ltd) 15 16 30039 Tensopril 25mg tablets (Teva UK Ltd) 17 30127 Ismelin 10mg/ml Injection (Sovereign Medical Ltd)For peer review only 18 30129 Abicol Tablet (Knoll Ltd) 19 20 30197 Diltiazem 120mg modified-release capsules 21 30199 Nifedipine 30mg modified-release tablets 22 23 30242 Diltiazem 180mg modified-release capsules 24 30272 Benthiazide with Triamterene capsules 25 30293 Catapres 150micrograms/1ml solution for injection ampoules (Boehringer Ingelheim Ltd) 26 27 30400 Mepranix 100mg Tablet (Ashbourne Pharmaceuticals Ltd) 28 30462 Ethimil MR 240mg tablets (Genus Pharmaceuticals Ltd) 29 30473 Coroday MR 20mg tablets (Generics (UK) Ltd) 30 31 30519 Amiloride with timolol with hydrochlorothiazide tablets 32 30557 Felogen XL 10mg tablets (Generics (UK) Ltd) 33 34 30625 Furosemide 20mg tablets (A A H Pharmaceuticals Ltd) 35 30636 Vasaten 50mg Tablet (Shire Pharmaceuticals Ltd) 36 30691 Hypercal b Tablet (Carlton Laboratories) 37 38 30758 Lidoflazine 120mg Tablet http://bmjopen.bmj.com/ 39 30770 Labetalol 200mg tablets (A A H Pharmaceuticals Ltd) 40 30773 Co-amilofruse 5mg+40mg Tablet (Berk Pharmaceuticals Ltd) 41 42 30875 Furosemide 250mg/25ml solution for injection ampoules 43 30913 Betinex 1mg Tablet (Berk Pharmaceuticals Ltd) 44 45 30915 Cabren 2.5mg modified-release tablets (Teva UK Ltd) 46 30921 Lisinopril 2.5mg tablets (Teva UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 30967 Revatio 20mg tablets (Pfizer Ltd) 48 49 30991 Cabren 5mg modified-release tablets (Teva UK Ltd) 50 31072 Amias 32mg tablets (Takeda UK Ltd) 51 31080 Guanethidine 10mg/1ml solution for injection ampoules 52 53 31109 Prosurin XL 400microgram capsules (Generics (UK) Ltd) 54 31131 Spiro-co 25mg+25mg Tablet (IVAX Pharmaceuticals UK Ltd) 55 56 31150 Co-amilozide 5mg/50mg tablets (IVAX Pharmaceuticals UK Ltd) 57 31214 Propranolol 80mg tablets (Generics (UK) Ltd) 58 31219 Spironolactone 100mg tablets (A A H Pharmaceuticals Ltd) 59 60 31220 Hydralazine 25mg tablets (A A H Pharmaceuticals Ltd) 31307 Odrik 500microgram capsules (Aventis Pharma) 31336 Syscor MR 30 tablets (Forest Laboratories UK Ltd)

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1 2 31337 Syscor MR 20 tablets (Forest Laboratories UK Ltd) 3 31375 Amilamont 5mg/5ml oral solution sugar free (Rosemont Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 31470 Tenchlor 50mg/12.5mg tablets (Teva UK Ltd) 6 31489 Bi-carzem xl 240mg Capsule (Tillomed Laboratories Ltd) 7 8 31490 Zolvera 40mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 9 31529 Spironolactone 25mg tablets (Teva UK Ltd) 10 31536 Atenolol 25mg tablets (Kent Pharmaceuticals Ltd) 11 12 31548 Furosemide 20mg tablets (Actavis UK Ltd) 13 31587 Innovace melt 20mg Wafer (Merck Sharp & Dohme Ltd) 14 31670 Bendroflumethiazide 2.5mg tablets (Teva UK Ltd) 15 16 31676 Diltiazem HCl 120mg Modified-release tablet (Actavis UK Ltd) 17 31708 Co-tenidone 50mg/12.5mg tablets (Actavis UK Ltd)For peer review only 18 31711 Verapamil 80mg tablets (A A H Pharmaceuticals Ltd) 19 20 31716 Enalapril 20mg tablets (Actavis UK Ltd) 21 31737 Zildil SR 120mg capsules (Chanelle Medical UK Ltd) 22 23 31761 Amlostin 10mg tablets (Discovery Pharmaceuticals Ltd) 24 31773 Co-amilofruse 5mg/40mg tablets (Wockhardt UK Ltd) 25 31776 Propranolol 40mg tablets (Generics (UK) Ltd) 26 27 31810 Odrik 1mg capsules (Aventis Pharma) 28 31820 Bendroflumethiazide 5mg tablets (Wockhardt UK Ltd) 29 31833 Angilol 80mg Tablet (DDSA Pharmaceuticals Ltd) 30 31 31932 Bumetanide 1mg tablets (C P Pharmaceuticals Ltd) 32 31934 Atenolol 100mg tablets (IVAX Pharmaceuticals UK Ltd) 33 34 32002 Etacrynic 50mg/vial injection 35 32048 Kaplon 50mg tablets (Teva UK Ltd) 36 32089 Diltiazem HCl 120mg Modified-release capsule (Hillcross Pharmaceuticals Ltd) 37 38 32091 Bumetanide 1mg tablets (A A H Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 32094 Co-tenidone 50mg/12.5mg tablets (A A H Pharmaceuticals Ltd) 40 32114 Bisoprolol 5mg tablets (Generics (UK) Ltd) 41 42 32162 Propranolol 80mg Modified-release capsule (Lagap) 43 32166 Capto-co 25mg+50mg Tablet (IVAX Pharmaceuticals UK Ltd) 44 45 32241 Enalapril 10mg tablets (A A H Pharmaceuticals Ltd) 46 32262 Diltiazem HCl 60mg Tablet (C P Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 32267 Diazoxide 300mg/20ml solution for injection ampoules 48 49 32277 Furosemide 80mg/8ml solution for injection pre-filled syringes 50 32514 Ecopace 25mg tablets (AMCo) 51 32552 Congescor 2.5mg tablets (Tillomed Laboratories Ltd) 52 53 32560 Tanatril 20mg tablets (Chiesi Ltd) 54 32590 Verapamil 40mg tablets (Generics (UK) Ltd) 55 56 32595 Amlodipine 5mg tablets (A A H Pharmaceuticals Ltd) 57 32597 Lisinopril 10mg tablets (Sandoz Ltd) 58 32630 Vivacor 10mg tablets (Lexon (UK) Ltd) 59 60 32658 Dilcardia xl 120mg Modified-release capsule (Generics (UK) Ltd) 32787 Visken 15mg tablets (AMCo) 32836 Metoprolol 50mg tablets (Generics (UK) Ltd)

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1 2 32837 Spironolactone 50mg tablets (Teva UK Ltd) 3 32857 Ramipril 1.25mg capsules (Teva UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 32870 Diltiazem 60mg modified-release tablets (Sterwin Medicines) 6 32896 Furosemide 40mg tablets (Ranbaxy (UK) Ltd) 7 8 32913 Methyldopa 250mg tablets (Actavis UK Ltd) 9 32917 Amlodipine 5mg tablets (IVAX Pharmaceuticals UK Ltd) 10 32918 Furosemide 20mg tablets (Sandoz Ltd) 11 12 32922 Felodipine 10mg Modified-release tablet (Sandoz Ltd) 13 32934 Lopace 10mg capsules (Discovery Pharmaceuticals Ltd) 14 33025 Nimodrel XL 30mg tablets (Zurich Pharmaceuticals) 15 16 33057 Ednyt 5mg Tablet (Dominion Pharma) 17 33078 Enalapril 20mg tablets (A A H Pharmaceuticals Ltd)For peer review only 18 33079 Atenolol 100mg tablets (Generics (UK) Ltd) 19 20 33083 Indapamide 2.5mg tablets (Teva UK Ltd) 21 33085 Atenolol 100mg tablets (A A H Pharmaceuticals Ltd) 22 23 33091 Felodipine 10mg modified-release tablets (A A H Pharmaceuticals Ltd) 24 33092 Atenolol 50mg tablets (A A H Pharmaceuticals Ltd) 25 33093 Clonidine 25microgram tablets (Sandoz Ltd) 26 27 33094 Doxazosin 2mg tablets (Generics (UK) Ltd) 28 33095 Perindopril erbumine 4mg tablets (A A H Pharmaceuticals Ltd) 29 33184 Atenolol 100mg tablets (Wockhardt UK Ltd) 30 31 33322 Moxonidine 200microgram tablets (Sandoz Ltd) 32 33336 Captopril 5mg/5ml Oral suspension (Eldon Laboratories) 33 34 33353 Lisinopril 20mg / Hydrochlorothiazide 12.5mg tablets (Teva UK Ltd) 35 33374 Carvedilol 12.5mg tablets (Genus Pharmaceuticals Ltd) 36 33376 Probeta LA 160mg Capsule (Trinity Pharmaceuticals Ltd) 37 38 33415 Bendroflumethiazide 2.5mg tablets (Generics (UK) Ltd) http://bmjopen.bmj.com/ 39 33471 Verapamil 40mg tablets (Actavis UK Ltd) 40 33527 Co-amilofruse 5mg/40mg tablets (Generics (UK) Ltd) 41 42 33569 Oxprenolol sr 160mg Modified-release tablet (Hillcross Pharmaceuticals Ltd) 43 33602 Slo-Pro 160mg capsules (Generics (UK) Ltd) 44 45 33644 Propranolol 80mg tablets (A A H Pharmaceuticals Ltd) 46 33646 Captopril 12.5mg Tablet (Generics (UK) Ltd) on September 25, 2021 by guest. Protected copyright. 47 33650 Atenolol 50mg tablets (Generics (UK) Ltd) 48 49 33651 Bendroflumethiazide 2.5mg tablets (A A H Pharmaceuticals Ltd) 50 33657 Atenolol 25mg tablets (A A H Pharmaceuticals Ltd) 51 33658 Co-amilofruse 5mg/40mg tablets (A A H Pharmaceuticals Ltd) 52 53 33659 Hydrochlorothiazide with metoprolol tartrate 25mg with 200mg Modified-release tablet 54 33724 Diuril 250mg/5ml oral suspension (Imported (United States)) 55 56 33788 Metirosine 250mg Capsule 57 33811 Ramipril 2.5mg capsules (Ranbaxy (UK) Ltd) 58 33836 Apsolol 160mg Tablet (Approved Prescription Services Ltd) 59 60 33837 Amiloride 5mg tablets (A A H Pharmaceuticals Ltd) 33839 Bisoprolol 10mg tablets (Actavis UK Ltd) 33850 Atenolol 50mg tablets (Actavis UK Ltd)

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1 2 33894 Ramipril 10mg capsules (Teva UK Ltd) 3 33909 Congescor 1.25mg tablets (Tillomed Laboratories Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 33932 Parmid XL 5mg tablets (Sandoz Ltd) 6 33977 Lisinopril 10mg tablets (Generics (UK) Ltd) 7 8 34006 Furosemide 40mg tablets (Actavis UK Ltd) 9 34012 Co-tenidone 100mg/25mg tablets (IVAX Pharmaceuticals UK Ltd) 10 34034 Co-tenidone 50mg/12.5mg tablets (IVAX Pharmaceuticals UK Ltd) 11 12 34059 Bendroflumethiazide 2.5mg tablets (Actavis UK Ltd) 13 34080 Stronazon 400microgram MR capsules (Actavis UK Ltd) 14 34092 Metoprolol 100mg tablets (Teva UK Ltd) 15 16 34093 Amlodipine 10mg tablets (A A H Pharmaceuticals Ltd) 17 34094 Metoprolol 50mg tablets (A A H Pharmaceuticals Ltd)For peer review only 18 34101 Nifedipine mr 20mg Modified-release tablet (IVAX Pharmaceuticals UK Ltd) 19 20 34115 Nifedipine 60mg Modified-release tablet 21 34124 Bendroflumethiazide 5mg tablets (Actavis UK Ltd) 22 23 34125 Metoprolol 100mg tablets (A A H Pharmaceuticals Ltd) 24 34146 Nifedipine mr 10mg Modified-release tablet (IVAX Pharmaceuticals UK Ltd) 25 34171 Labetalol 100mg Tablet (C P Pharmaceuticals Ltd) 26 27 34177 Labetalol 100mg tablets (A A H Pharmaceuticals Ltd) 28 34185 Propranolol LA 80mg Modified-release capsule (Approved Prescription Services Ltd) 29 34187 Nifedipine 10mg Modified-release tablet (Generics (UK) Ltd) 30 31 34188 Labetalol 200mg Tablet (Celltech Pharma Europe Ltd) 32 34208 Propranolol SR 160mg Modified-release capsule (C P Pharmaceuticals Ltd) 33 34 34214 Propranolol 160mg tablets (Actavis UK Ltd) 35 34247 Nifedipine 10mg Capsule (Berk Pharmaceuticals Ltd) 36 34265 Atenolol 50mg tablets (Sandoz Ltd) 37 38 34280 Co-amilofruse 2.5mg/20mg tablets (Sandoz Ltd) http://bmjopen.bmj.com/ 39 34296 Spironolactone 25mg tablets (A A H Pharmaceuticals Ltd) 40 34324 Amiloride 5mg tablets (Teva UK Ltd) 41 42 34342 Doxazosin 1mg tablets (Teva UK Ltd) 43 34347 Spironolactone 25mg tablets (Actavis UK Ltd) 44 45 34357 Ramipril 10mg capsules (Genus Pharmaceuticals Ltd) 46 34365 Atenolol 50mg tablets (Teva UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 34367 Co-amilozide 2.5mg/25mg tablets (Wockhardt UK Ltd) 48 49 34371 Sotalol 40mg tablets (A A H Pharmaceuticals Ltd) 50 34374 Furosemide 40mg tablets (Teva UK Ltd) 51 34377 Diltiazem HCl 90mg Modified-release capsule (Hillcross Pharmaceuticals Ltd) 52 53 34378 Propranolol 10mg tablets (A A H Pharmaceuticals Ltd) 54 34382 Ramipril 5mg capsules (Zentiva) 55 56 34390 Ramipril 5mg capsules (Genus Pharmaceuticals Ltd) 57 34400 Enalapril 5mg Tablet (Dowelhurst Ltd) 58 34407 Metoprolol 50mg tablets (Teva UK Ltd) 59 60 34412 Ramipril 5mg capsules (Teva UK Ltd) 34429 Ramipril 5mg capsules (Generics (UK) Ltd) 34430 Metoprolol 50mg tablets (Actavis UK Ltd)

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1 2 34431 Ramipril 2.5mg capsules (Zentiva) 3 34432 Ramipril 2.5mg capsules (Genus Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 34443 Atenolol 50mg tablets (Wockhardt UK Ltd) 6 34449 Co-tenidone 50mg/12.5mg tablets (Generics (UK) Ltd) 7 8 34453 Enalapril 20mg tablets (Generics (UK) Ltd) 9 34471 Lisinopril 5mg tablets (Generics (UK) Ltd) 10 34475 Diltiazem HCl 90mg Modified-release tablet (IVAX Pharmaceuticals UK Ltd) 11 12 34490 Ramipril 2.5mg capsules (Teva UK Ltd) 13 34492 Atenolol 25mg tablets (Generics (UK) Ltd) 14 34501 Carvedilol 12.5mg tablets (Actavis UK Ltd) 15 16 34505 Ramipril 2.5mg capsules (Sandoz Ltd) 17 34509 Metoprolol 100mg tablets (Generics (UK) Ltd)For peer review only 18 34520 Sotalol 80mg tablets (Generics (UK) Ltd) 19 20 34522 Nifedipine 5mg capsules (A A H Pharmaceuticals Ltd) 21 34528 Ramipril 2.5mg capsules (A A H Pharmaceuticals Ltd) 22 23 34539 Ramipril 5mg capsules (Sandoz Ltd) 24 34540 Ramipril 5mg capsules (A A H Pharmaceuticals Ltd) 25 34544 Captopril 12.5mg Tablet (IVAX Pharmaceuticals UK Ltd) 26 27 34551 Indapamide 2.5mg tablets (Generics (UK) Ltd) 28 34553 Doxazosin 4mg tablets (Generics (UK) Ltd) 29 34557 Furosemide 40mg tablets (IVAX Pharmaceuticals UK Ltd) 30 31 34562 Captopril 25mg Tablet (IVAX Pharmaceuticals UK Ltd) 32 34567 Ramipril 2.5mg capsules (Generics (UK) Ltd) 33 34 34575 Atenolol 25mg tablets (Wockhardt UK Ltd) 35 34581 Diltiazem HCl 60mg Modified-release tablet (Kent Pharmaceuticals Ltd) 36 34583 Ramipril 10mg Capsule (Dexcel-Pharma Ltd) 37 38 34584 Metoprolol 50mg tablets (IVAX Pharmaceuticals UK Ltd) http://bmjopen.bmj.com/ 39 34585 Atenolol 25mg tablets (Sandoz Ltd) 40 34589 Ramipril 5mg Capsule (Dexcel-Pharma Ltd) 41 42 34600 Sotalol 40mg tablets (Teva UK Ltd) 43 34601 Doxazosin 1mg tablets (Generics (UK) Ltd) 44 45 34602 Bendroflumethiazide 2.5mg tablets (Sovereign Medical Ltd) 46 34607 Nifedipine 5mg capsules (IVAX Pharmaceuticals UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 34613 Bumetanide 5mg tablets (Teva UK Ltd) 48 49 34622 Co-amilofruse 10mg/80mg tablets (Wockhardt UK Ltd) 50 34625 Doxazosin 2mg tablets (A A H Pharmaceuticals Ltd) 51 34640 Sotalol 40mg Tablet (Tillomed Laboratories Ltd) 52 53 34651 Ramipril 10mg capsules (Generics (UK) Ltd) 54 34652 Ramipril 5mg Capsule (Sovereign Medical Ltd) 55 56 34657 Ramipril 10mg capsules (Zentiva) 57 34690 Sotalol 80mg tablets (Sandoz Ltd) 58 34695 Atenolol 50mg tablets (Kent Pharmaceuticals Ltd) 59 60 34696 Lisinopril 20mg tablets (Generics (UK) Ltd) 34698 Ramipril 1.25mg capsules (Zentiva) 34710 Ramipril 10mg capsules (Sandoz Ltd)

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1 2 34712 Enalapril 20mg tablets (Kent Pharmaceuticals Ltd) 3 34715 Doxazosin 1mg tablets (A A H Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 34719 Captopril 50mg Tablet (Generics (UK) Ltd) 6 34732 Ramipril 2.5mg Capsule (Dexcel-Pharma Ltd) 7 8 34740 Carvedilol 6.25mg tablets (Actavis UK Ltd) 9 34741 Carvedilol 3.125mg tablets (IVAX Pharmaceuticals UK Ltd) 10 34750 Amiloride 5mg tablets (Actavis UK Ltd) 11 12 34754 Atenolol 100mg tablets (Sandoz Ltd) 13 34768 Enalapril 20mg tablets (IVAX Pharmaceuticals UK Ltd) 14 34783 Propranolol 10mg tablets (Actavis UK Ltd) 15 16 34798 Enalapril 20mg tablets (Sandoz Ltd) 17 34799 Lisinopril 20mg tablets (Zentiva)For peer review only 18 34803 Bendroflumethiazide 2.5mg Tablet (Regent Laboratories Ltd) 19 20 34804 Propranolol 10mg tablets (Teva UK Ltd) 21 34821 Bisoprolol 10mg tablets (Generics (UK) Ltd) 22 23 34824 Diltiazem HCl 120mg Modified-release tablet (IVAX Pharmaceuticals UK Ltd) 24 34825 Co-tenidone 50mg/12.5mg tablets (Teva UK Ltd) 25 34854 Metoprolol 100mg tablets (Actavis UK Ltd) 26 27 34867 Propranolol 80mg Capsule (IVAX Pharmaceuticals UK Ltd) 28 34868 Propranolol 40mg tablets (Teva UK Ltd) 29 34877 Ramipril 10mg Capsule (Sovereign Medical Ltd) 30 31 34882 Atenolol 50mg Tablet (Berk Pharmaceuticals Ltd) 32 34884 Propranolol 160mg Modified-release capsule (Sandoz Ltd) 33 34 34890 Metoprolol 50mg Tablet (Berk Pharmaceuticals Ltd) 35 34893 Ramipril 10mg Capsule (IVAX Pharmaceuticals UK Ltd) 36 34899 Co-tenidone 100mg/25mg tablets (A A H Pharmaceuticals Ltd) 37 38 34908 Spironolactone 25mg tablets (IVAX Pharmaceuticals UK Ltd) http://bmjopen.bmj.com/ 39 34925 Metoprolol 50mg tablets (Sandoz Ltd) 40 34934 Bumetanide 1mg tablets (Generics (UK) Ltd) 41 42 34936 Captopril 25mg Tablet (Lagap) 43 34937 Captopril 50mg Tablet (IVAX Pharmaceuticals UK Ltd) 44 45 34943 Ramipril 10mg capsules (A A H Pharmaceuticals Ltd) 46 34945 Propranolol 160mg Modified-release capsule (Lagap) on September 25, 2021 by guest. Protected copyright. 47 34949 Propranolol 160mg Modified-release capsule (Actavis UK Ltd) 48 49 34952 Enalapril 10mg tablets (Generics (UK) Ltd) 50 34953 Enalapril 20mg tablets (Zentiva) 51 34959 Verapamil 40mg tablets (A A H Pharmaceuticals Ltd) 52 53 34963 Bisoprolol 5mg tablets (Actavis UK Ltd) 54 34975 Nifedipine 5mg capsules (Teva UK Ltd) 55 56 34976 Atenolol 25mg tablets (Tillomed Laboratories Ltd) 57 35007 Ramipril 10mg/5ml oral suspension 58 35054 Celectol 200mg tablets (Zentiva) 59 60 35058 Diffundox XL 400microgram capsules (Zentiva) 35062 Trasicor 20mg tablets (Amdipharm Plc) 35084 Vascalpha 5mg modified-release tablets (Actavis UK Ltd)

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1 2 35096 Exforge 10mg/160mg tablets (Novartis Pharmaceuticals UK Ltd) 3 35162 Furosemide 20mg/2ml solution for injection ampoules BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 35173 Valsartan 160mg with amlodipine 5mg tablets 6 35174 Valsartan 80mg with amlodipine 5mg tablets 7 8 35189 Amlodipine 10mg / Valsartan 160mg tablets 9 35192 Sildenafil 10mg/5ml oral solution 10 35196 CoAprovel 300mg/25mg tablets (Sanofi) 11 12 35272 Doxadura XL 4mg tablets (Discovery Pharmaceuticals Ltd) 13 35302 Captopril 12.5mg/5ml oral suspension 14 35304 Valsartan 160mg with amlodipine 10mg tablets 15 16 35312 Bazetham MR 400microgram capsules (Teva UK Ltd) 17 35317 Exforge 5mg/80mg tablets (Novartis Pharmaceuticals UK Ltd)For peer review only 18 35329 Amlodipine 5mg / Valsartan 80mg tablets 19 20 35343 Amlodipine 5mg / Valsartan 160mg tablets 21 35380 Hydrochlorothiazide with olmesartan medoxomil 12.5mg with 20mg tablet 22 23 35466 Alphacard MR 400microgram capsules (Ratiopharm UK Ltd) 24 35481 Irbesartan 300mg / Hydrochlorothiazide 25mg tablets 25 35592 Cardioplen XL 2.5mg tablets (Chiesi Ltd) 26 27 35603 Doxazosin 4mg/5ml oral suspension 28 35646 Neozipine XL 60mg tablets (Kent Pharmaceuticals Ltd) 29 35695 Visken 5mg tablets (AMCo) 30 31 35696 Kenzem SR 120mg capsules (Kent Pharmaceuticals Ltd) 32 35697 Exforge 5mg/160mg tablets (Novartis Pharmaceuticals UK Ltd) 33 34 35710 Sotalol 25mg/5ml oral suspension 35 35729 Verapamil 80mg tablets (Teva UK Ltd) 36 35731 Perindopril erbumine 8mg tablets (A A H Pharmaceuticals Ltd) 37 38 35778 Labrocol 100mg Tablet (Lagap) http://bmjopen.bmj.com/ 39 35789 Spironolactone 25mg Tablet (Celltech Pharma Europe Ltd) 40 35794 Enalapril 5mg tablets (A A H Pharmaceuticals Ltd) 41 42 35925 Contiflo XL 400microgram capsules (Ranbaxy (UK) Ltd) 43 35938 Propranolol 80mg modified-release capsules (A A H Pharmaceuticals Ltd) 44 45 35940 Celectol 400mg tablets (Zentiva) 46 36023 Cardozin xl 4mg Tablet (Hillcross Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 36190 Furosemide 5mg/5ml oral solution sugar free 48 49 36202 Amlodipine 10mg tablets (Actavis UK Ltd) 50 36261 Atenolol 50mg tablets (Tillomed Laboratories Ltd) 51 36282 Morvesin XL 400microgram capsules (Sandoz Ltd) 52 53 36519 Esidrex -k Tablet (Novartis Pharmaceuticals UK Ltd) 54 36576 Propranolol 10mg tablets (Generics (UK) Ltd) 55 56 36583 Zemret xl 180mg Capsule (Neo Laboratories Ltd) 57 36603 Propranolol SR 160mg Modified-release capsule (Hillcross Pharmaceuticals Ltd) 58 36612 Sodium nitroprusside 50mg powder for solution for infusion vials 59 60 36620 Parmid XL 10mg tablets (Sandoz Ltd) 36629 Aliskiren 150mg tablets 36649 Hytrin 2mg tablets (AMCo)

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1 2 36664 Zemret xl 300mg Capsule (Neo Laboratories Ltd) 3 36740 Slocinx XL 4mg tablets (Zentiva) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 36742 Captopril 2mg/5ml oral suspension 6 36753 Ednyt 10mg Tablet (Dominion Pharma) 7 8 36767 Bumetanide 1mg tablets (IVAX Pharmaceuticals UK Ltd) 9 36780 Hytrin 5mg tablets (AMCo) 10 36878 Rasilez 150mg tablets (Novartis Pharmaceuticals UK Ltd) 11 12 36879 Rasilez 300mg tablets (Novartis Pharmaceuticals UK Ltd) 13 36909 Aliskiren 300mg tablets 14 36939 Irbesartan 300mg/5ml oral suspension 15 16 37025 Nifedipine 20mg modified-release tablets 17 37080 Enalapril 5mg/5ml oral solutionFor peer review only 18 37085 Sitaxentan 100mg tablets 19 20 37087 Enalapril 5mg/5ml oral suspension 21 37118 Bisoprolol 2.5mg tablets (A A H Pharmaceuticals Ltd) 22 23 37184 Valni XL 30mg tablets (Zentiva) 24 37243 Cardozin xl 4mg Tablet (Teva UK Ltd) 25 37294 Triamterene with chlortalidone 50mg + 25mg Tablet 26 27 37428 Hytrin 10mg tablets (AMCo) 28 37530 Neozipine XL 30mg tablets (Kent Pharmaceuticals Ltd) 29 37573 Valsartan 320mg tablets 30 31 37650 Losartan 100mg / Hydrochlorothiazide 12.5mg tablets 32 37655 Captopril 25mg tablets (Teva UK Ltd) 33 34 37710 Lisinopril 10mg / Hydrochlorothiazide 12.5mg tablets (Teva UK Ltd) 35 37725 Co-tenidone 100mg/25mg tablets (Generics (UK) Ltd) 36 37726 Nifedipine 100mg/5ml oral suspension 37 38 37747 Cozaar-Comp 100mg/12.5mg tablets (Merck Sharp & Dohme Ltd) http://bmjopen.bmj.com/ 39 37774 Kenzem SR 60mg capsules (Kent Pharmaceuticals Ltd) 40 37778 Lisinopril 5mg/5ml oral suspension 41 42 37837 Bisoprolol 2.5mg Tablet (Teva UK Ltd) 43 37897 Felotens XL 2.5mg tablets (Thornton & Ross Ltd) 44 45 37908 Coversyl Arginine Plus 5mg/1.25mg tablets (Servier Laboratories Ltd) 46 37930 Perindopril arginine 5mg tablets on September 25, 2021 by guest. Protected copyright. 47 37964 Perindopril arginine 2.5mg tablets 48 49 37965 Coversyl Arginine 5mg tablets (Servier Laboratories Ltd) 50 37971 Perindopril arginine 10mg tablets 51 37978 Perindopril arginine 5mg / Indapamide 1.25mg tablets 52 53 38026 Coversyl Arginine 10mg tablets (Servier Laboratories Ltd) 54 38034 Coversyl Arginine 2.5mg tablets (Servier Laboratories Ltd) 55 56 38066 Diltiazem HCl 60mg Modified-release tablet (Lagap) 57 38107 Nifedipine sr 30mg Tablet (Hillcross Pharmaceuticals Ltd) 58 38285 Perindopril erbumine 4mg tablets (Teva UK Ltd) 59 60 38308 Ramipril 2.5/5mg/10mg tablet 38367 Hydrochlorothiazide with losartan 12.5mg with 100mg Tablet 38370 Labetalol 100mg/20ml solution for injection ampoules

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1 2 38395 Valsartan 80mg tablets 3 38433 Propranolol 50mg/5ml Oral solution (Rosemont Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 38434 Keloc SR 10mg tablets (Teva UK Ltd) 6 38459 Telmisartan 80mg / Hydrochlorothiazide 25mg tablets 7 8 38461 Cardozin XL 4mg tablets (Arrow Generics Ltd) 9 38510 Perindopril erbumine 4mg tablets (Apotex UK Ltd) 10 38545 Tildiem LA 200 capsules (Sanofi) 11 12 38632 Adizem-SR 90mg capsules (Napp Pharmaceuticals Ltd) 13 38634 Adizem-XL 300mg capsules (Napp Pharmaceuticals Ltd) 14 38818 Adizem-SR 120mg capsules (Napp Pharmaceuticals Ltd) 15 16 38831 Adizem-SR 180mg capsules (Napp Pharmaceuticals Ltd) 17 38854 Quinapril 20mg/5ml oral solutionFor peer review only 18 38855 Adizem-XL 180mg capsules (Napp Pharmaceuticals Ltd) 19 20 38865 Adizem-XL 120mg capsules (Napp Pharmaceuticals Ltd) 21 38876 Tildiem LA 300 capsules (Sanofi) 22 23 38882 Adizem-XL 240mg capsules (Napp Pharmaceuticals Ltd) 24 38889 MicardisPlus 80mg/25mg tablets (Boehringer Ingelheim Ltd) 25 38899 Quinil 10mg tablets (Tillomed Laboratories Ltd) 26 27 38901 Frumil LS 20mg/2.5mg tablets (Sanofi) 28 38964 Adizem-SR 120mg tablets (Napp Pharmaceuticals Ltd) 29 38991 Bisoprolol 7.5mg tablets (A A H Pharmaceuticals Ltd) 30 31 38995 Zestoretic 20 tablets (AstraZeneca UK Ltd) 32 39009 Verapamil 40mg tablets (Teva UK Ltd) 33 34 39021 Hydrochlorothiazide with olmesartan medoxomil 25mg with 20mg tablet 35 39137 Zestoretic 10 tablets (AstraZeneca UK Ltd) 36 39147 Carace 20 Plus tablets (Merck Sharp & Dohme Ltd) 37 38 39171 Bi-Carzem SR 60mg capsules (Tillomed Laboratories Ltd) http://bmjopen.bmj.com/ 39 39199 Diovan 320mg tablets (Novartis Pharmaceuticals UK Ltd) 40 39227 Capozide LS 12.5mg/25mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 41 42 39233 Propranolol 80mg modified-release capsules (Teva UK Ltd) 43 39242 Carace 10 Plus tablets (Merck Sharp & Dohme Ltd) 44 45 39298 Bi-Carzem SR 90mg capsules (Tillomed Laboratories Ltd) 46 39355 Tritace 10mg Tablet (Sterwin Medicines) on September 25, 2021 by guest. Protected copyright. 47 39357 Neofel XL 2.5mg tablets (Kent Pharmaceuticals Ltd) 48 49 39421 Tritace titration pack tablets (Sanofi) 50 39423 Sotalol 80mg tablets (A A H Pharmaceuticals Ltd) 51 39447 Varbim XL 1.5mg tablets (Teva UK Ltd) 52 53 39512 Captopril 25mg/5ml oral suspension 54 39602 Bumetanide 1mg tablets (Actavis UK Ltd) 55 56 39646 Bisoprolol 0.625mg/5ml oral solution 57 39786 Olmesartan medoxomil 10mg/5ml oral suspension 58 39800 Valni XL 60mg tablets (Zentiva) 59 60 39804 Amlodipine 5mg tablets (Dr Reddy's Laboratories (UK) Ltd) 39807 Frumil 40mg/5mg tablets (Sanofi) 39846 Vivacor 5mg tablets (Lexon (UK) Ltd)

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1 2 39914 Amlodipine 5mg tablets (Teva UK Ltd) 3 39944 Losartan 12.5mg tablets BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 39984 Sevikar 20mg/5mg tablets (Daiichi Sankyo UK Ltd) 6 40074 Nifedipine 20mg Capsule 7 8 40149 Bendroflumethiazide 5mg tablets (IVAX Pharmaceuticals UK Ltd) 9 40167 Metoprolol 100mg tablets (IVAX Pharmaceuticals UK Ltd) 10 40190 Torasemide iv 20mg/4ml Intravenous injection 11 12 40240 Labetalol 400mg tablets (A A H Pharmaceuticals Ltd) 13 40241 Propranolol LA 160mg Capsule (Approved Prescription Services Ltd) 14 40247 Furosemide 10mg/ml Injection (Martindale Pharmaceuticals Ltd) 15 16 40256 Baratol 25mg tablets (Amdipharm Plc) 17 40310 Moxonidine 200microgram tablets (Teva UK Ltd)For peer review only 18 40316 Olmesartan medoxomil 20mg / Amlodipine 5mg tablets 19 20 40355 Quinil 5mg tablets (Tillomed Laboratories Ltd) 21 40384 Ramipril 10mg tablets (A A H Pharmaceuticals Ltd) 22 23 40405 Verapamil 120mg tablets (Teva UK Ltd) 24 40421 Bendogen 50mg Tablet (Lagap) 25 40527 Ambrisentan 10mg tablets 26 27 40528 Ambrisentan 5mg tablets 28 40571 Cozaar 12.5mg tablets (Merck Sharp & Dohme Ltd) 29 40633 Vascalpha 5mg modified-release tablets (Almus Pharmaceuticals Ltd) 30 31 40639 Olmesartan medoxomil 40mg / Amlodipine 5mg tablets 32 40668 Olmesartan medoxomil 40mg / Amlodipine 10mg tablets 33 34 40678 Doxazosin 4mg tablets (Teva UK Ltd) 35 40711 Losartan 2.5mg/ml oral suspension sugar free 36 40738 Torem iv 10mg/2ml Intravenous injection (Boehringer Mannheim UK Ltd) 37 38 40761 Nebivolol 2.5mg tablets http://bmjopen.bmj.com/ 39 40810 Phenoxybenzamine 10mg/5ml oral suspension 40 40886 Bendroflumethiazide 2.5mg tablets (Almus Pharmaceuticals Ltd) 41 42 40891 Doxazosin 2mg tablets (IVAX Pharmaceuticals UK Ltd) 43 40898 Torasemide 5mg tablets (A A H Pharmaceuticals Ltd) 44 45 40899 Thelin 100mg tablets (Pfizer Ltd) 46 40907 Indapamide 2.5mg tablets (Genus Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 41074 Spironolactone 25mg tablets (Almus Pharmaceuticals Ltd) 48 49 41203 Sevikar 40mg/10mg tablets (Daiichi Sankyo UK Ltd) 50 41205 Sevikar 40mg/5mg tablets (Daiichi Sankyo UK Ltd) 51 41232 Cozaar 2.5mg/ml oral suspension (Merck Sharp & Dohme Ltd) 52 53 41292 Furosemide 20mg tablets (Wockhardt UK Ltd) 54 41405 Furosemide 500mg tablets (Teva UK Ltd) 55 56 41417 Enalapril 2.5mg tablets (A A H Pharmaceuticals Ltd) 57 41489 Bi-Carzem SR 120mg capsules (Tillomed Laboratories Ltd) 58 41517 Bendroflumethiazide 5mg tablets (Teva UK Ltd) 59 60 41522 Lisopress 20mg tablets (Teva UK Ltd) 41532 Lisopress 5mg tablets (Teva UK Ltd) 41533 Co-amilofruse 2.5mg/20mg tablets (Teva UK Ltd)

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1 2 41538 Lisopress 2.5mg tablets (Teva UK Ltd) 3 41543 Doxazosin 1mg tablets (IVAX Pharmaceuticals UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 41555 Propranolol 40mg tablets (A A H Pharmaceuticals Ltd) 6 41556 Co-amilozide 5mg/50mg tablets (Teva UK Ltd) 7 8 41572 Co-tenidone 100mg/25mg tablets (Teva UK Ltd) 9 41573 Lisopress 10mg tablets (Teva UK Ltd) 10 41586 Verapamil 80mg tablets (Actavis UK Ltd) 11 12 41591 Bisoprolol 10mg tablets (Teva UK Ltd) 13 41592 Spironolactone 100mg tablets (Actavis UK Ltd) 14 41617 Captopril 25mg tablets (Actavis UK Ltd) 15 16 41630 Amiloride 5mg Tablet (IVAX Pharmaceuticals UK Ltd) 17 41633 Captopril 12.5mg tablets (Actavis UK Ltd)For peer review only 18 41635 Diltiazem 60mg modified-release tablets (IVAX Pharmaceuticals UK Ltd) 19 20 41639 Hydralazine 50mg tablets (Actavis UK Ltd) 21 41651 Prazosin 500microgram Tablet (Approved Prescription Services Ltd) 22 23 41652 Prazosin 500microgram tablets (A A H Pharmaceuticals Ltd) 24 41660 Spironolactone 100mg tablets (Teva UK Ltd) 25 41661 Methyldopa 250mg Tablet (C P Pharmaceuticals Ltd) 26 27 41679 Verapamil 80mg tablets (IVAX Pharmaceuticals UK Ltd) 28 41693 Verapamil 120mg tablets (Generics (UK) Ltd) 29 41694 Enalapril 2.5mg tablets (IVAX Pharmaceuticals UK Ltd) 30 31 41706 Spironolactone 50mg tablets (IVAX Pharmaceuticals UK Ltd) 32 41719 Co-amilofruse 5mg/40mg tablets (Actavis UK Ltd) 33 34 41721 Prazosin 1mg tablets (A A H Pharmaceuticals Ltd) 35 41740 Celiprolol 200mg tablets (Teva UK Ltd) 36 41743 Captopril 50mg tablets (Teva UK Ltd) 37 38 41746 Enalapril 10mg tablets (Sandoz Ltd) http://bmjopen.bmj.com/ 39 41827 Labetalol 100mg tablets (Generics (UK) Ltd) 40 41828 Furosemide 500mg tablets (Actavis UK Ltd) 41 42 41861 Tensaid XL 1.5mg tablets (Generics (UK) Ltd) 43 41885 Ethibide XL 1.5mg tablets (Genus Pharmaceuticals Ltd) 44 45 41979 Adipine la 30mg Modified-release tablet (Chiesi Ltd) 46 42081 Tritace 1.25mg Tablet (Sterwin Medicines) on September 25, 2021 by guest. Protected copyright. 47 42142 Moduretic 5mg/50mg tablets (Merck Sharp & Dohme Ltd) 48 49 42152 Syprol 50mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 50 42210 Amlodipine 10mg tablets (Zentiva) 51 42285 Quinil 40mg tablets (Tillomed Laboratories Ltd) 52 53 42388 Furosemide 40mg/5ml oral solution sugar free (Focus Pharmaceuticals Ltd) 54 42462 Kirtacap mr 400microgram Capsule (Consilient Health Ltd) 55 56 42488 Furosemide 40mg/5ml oral solution sugar free (A A H Pharmaceuticals Ltd) 57 42625 Vera-Til SR 120mg tablets (Actavis UK Ltd) 58 42723 Pralenal 5 tablets (Opus Pharmaceuticals Ltd) 59 60 42731 Diltiazem sr 120mg Capsule (Hillcross Pharmaceuticals Ltd) 42795 Celiprolol 200mg tablets (Generics (UK) Ltd) 42804 Diltiazem HCl 180mg Capsule (PLIVA Pharma Ltd)

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1 2 42819 Diltiazem xl 240mg Capsule (Hillcross Pharmaceuticals Ltd) 3 42894 Enalapril 10mg tablets (Teva UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 42901 Enalapril 5mg tablets (Teva UK Ltd) 6 42902 Enalapril 20mg tablets (Teva UK Ltd) 7 8 42906 Indapamide 2.5mg tablets (Niche Generics Ltd) 9 42908 Enalapril 5mg tablets (IVAX Pharmaceuticals UK Ltd) 10 42912 Nifedipine 10mg capsules (Teva UK Ltd) 11 12 42936 Flomax Relief MR 400microgram capsules (Boehringer Ingelheim Self-Medication Division) 13 43012 Perindopril erbumine oral solution 14 43184 Mapemid XL 1.5mg tablets (Teva UK Ltd) 15 16 43222 Valni 20 Retard tablets (Tillomed Laboratories Ltd) 17 43251 Bisoprolol 1.25mg tablets (Generics (UK) Ltd)For peer review only 18 43322 Olmesartan medoxomil 40mg / Hydrochlorothiazide 12.5mg tablets 19 20 43394 Pinefeld XL 10mg tablets (Tillomed Laboratories Ltd) 21 43410 Nifedipine extra 60mg Modified-release tablet 22 23 43411 Enalapril 5mg tablets (Sandoz Ltd) 24 43412 Lisinopril 2.5mg tablets (A A H Pharmaceuticals Ltd) 25 43413 Lisinopril 20mg tablets (A A H Pharmaceuticals Ltd) 26 27 43416 Lisinopril 10mg tablets (A A H Pharmaceuticals Ltd) 28 43418 Lisinopril 5mg tablets (A A H Pharmaceuticals Ltd) 29 43430 Diltiazem 120mg modified-release tablets (A A H Pharmaceuticals Ltd) 30 31 43432 Captopril 6.25mg tablets 32 43470 Amlodipine 5mg tablets (Wockhardt UK Ltd) 33 34 43500 Hydralazine 25mg tablets (Actavis UK Ltd) 35 43507 Captopril 25mg Tablet (Generics (UK) Ltd) 36 43508 Co-amilofruse 5mg/40mg tablets (Sandoz Ltd) 37 38 43511 Nifedipine 10mg capsules (A A H Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 43512 Felodipine 5mg modified-release tablets (A A H Pharmaceuticals Ltd) 40 43514 Spironolactone 50mg tablets (A A H Pharmaceuticals Ltd) 41 42 43515 Nifedipine 10mg capsules (Actavis UK Ltd) 43 43516 Indapamide 2.5mg tablets (Actavis UK Ltd) 44 45 43523 Amiloride 5mg tablets (Generics (UK) Ltd) 46 43525 Propranolol 10mg tablets (IVAX Pharmaceuticals UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 43531 Moxonidine 400microgram tablets (Sandoz Ltd) 48 49 43547 Prazosin 500microgram tablets (IVAX Pharmaceuticals UK Ltd) 50 43549 Sotalol 40mg tablets (IVAX Pharmaceuticals UK Ltd) 51 43563 Enalapril 2.5mg tablets (Zentiva) 52 53 43564 Bisoprolol 5mg Tablet (PLIVA Pharma Ltd) 54 43566 Lisinopril 2.5mg tablets (Sandoz Ltd) 55 56 43649 Captopril 25mg tablets (A A H Pharmaceuticals Ltd) 57 43695 Colixil XL 4mg tablets (Sandoz Ltd) 58 43753 Adalat LA 30 tablets (Bayer Plc) 59 60 43790 Vascalpha 10mg modified-release tablets (Almus Pharmaceuticals Ltd) 43813 Perindopril erbumine 2mg tablets (Actavis UK Ltd) 43818 Adalat LA 60 tablets (Bayer Plc)

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1 2 43879 Vera-Til SR 240mg tablets (Actavis UK Ltd) 3 43880 Amlodipine 5mg tablets (Almus Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 43915 Olmetec Plus 40mg/12.5mg tablets (Daiichi Sankyo UK Ltd) 6 43988 Aldomet 250mg tablets (Aspen Pharma Trading Ltd) 7 8 43989 Aldomet 500mg tablets (Aspen Pharma Trading Ltd) 9 44000 Bisoprolol 2.5mg/5ml oral suspension 10 44083 Labetalol 200mg tablets (Actavis UK Ltd) 11 12 44168 Indipam XL 1.5mg tablets (Actavis UK Ltd) 13 44192 Zemret 240 XL capsules (Tillomed Laboratories Ltd) 14 44254 Amiloride 5.67mg tablets 15 16 44527 Captopril 5mg/ml oral solution sugar free 17 44553 Pinexel PR 400microgram capsules (Wockhardt UK Ltd)For peer review only 18 44657 Ednyt 2.5mg Tablet (Dominion Pharma) 19 20 44778 Valsartan 160mg tablets 21 44808 Nebivolol 2.5mg tablets (A A H Pharmaceuticals Ltd) 22 23 44858 Atenolol 25mg tablets (Actavis UK Ltd) 24 44859 Felodipine sr 5mg Tablet (Approved Prescription Services Ltd) 25 44887 Bi-carzem xl 300mg Capsule (Tillomed Laboratories Ltd) 26 27 45040 Larbex XL 4mg tablets (Teva UK Ltd) 28 45051 Verapamil hc 240mg Modified-release tablet (Actavis UK Ltd) 29 45070 Amlodipine 10mg/5ml oral suspension 30 31 45078 Spironolactone 25mg/5ml Oral solution sugar free (Rosemont Pharmaceuticals Ltd) 32 45217 Enalapril 5mg tablets (Kent Pharmaceuticals Ltd) 33 34 45228 Captopril capsules 35 45250 Labetalol 400mg tablets (Sandoz Ltd) 36 45264 Ramipril 1.25mg capsules (Actavis UK Ltd) 37 38 45265 Doxazosin sr 4mg Tablet (Generics (UK) Ltd) http://bmjopen.bmj.com/ 39 45279 Amlodipine 5mg tablets (Sandoz Ltd) 40 45289 Metoprolol tartrate Oral solution 41 42 45292 Nicardipine 30mg capsules (A A H Pharmaceuticals Ltd) 43 45297 Propranolol 40mg tablets (IVAX Pharmaceuticals UK Ltd) 44 45 45300 Lisinopril 10mg tablets (Actavis UK Ltd) 46 45305 Bumetanide 1mg tablets (Teva UK Ltd) on September 25, 2021 by guest. Protected copyright. 47 45308 Verapamil 240mg modified-release tablets (Generics (UK) Ltd) 48 49 45309 Acebutolol 400mg tablets (A A H Pharmaceuticals Ltd) 50 45319 Perindopril erbumine 2mg tablets (A A H Pharmaceuticals Ltd) 51 45324 Lisinopril 20mg tablets (Actavis UK Ltd) 52 53 45328 Doxazosin 1mg tablets (Sandoz Ltd) 54 45337 Lisinopril 5mg tablets (Actavis UK Ltd) 55 56 45340 Ramipril 10mg Capsule (Actavis UK Ltd) 57 45342 Doxazosin 4mg tablets (Sandoz Ltd) 58 45343 Propranolol SR 80mg Modified-release capsule (C P Pharmaceuticals Ltd) 59 60 45494 Propranolol 10mg tablets (Almus Pharmaceuticals Ltd) 45554 Ramipril 5mg/5ml oral solution 45578 Clonidine 25microgram tablets (A A H Pharmaceuticals Ltd)

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1 2 45583 Doxazosin 2mg tablets (Dexcel-Pharma Ltd) 3 45584 Phenoxybenzamine 100mg/2ml solution for infusion ampoules BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 45600 Diovan 160mg Tablet (Novartis Pharmaceuticals UK Ltd) 6 45641 Sildenafil 40mg/50ml solution for injection vials 7 8 45685 Adanif XL 30mg tablets (Focus Pharmaceuticals Ltd) 9 45759 Diltiazem HCl 240mg Capsule (PLIVA Pharma Ltd) 10 45765 Syprol 40mg/5ml oral solution (Rosemont Pharmaceuticals Ltd) 11 12 45816 Lisinopril 5mg tablets (Almus Pharmaceuticals Ltd) 13 45877 Beta-Prograne 160mg modified-release capsules (Teva UK Ltd) 14 45916 Hydroflumethiazide with spironolactone 50mg+50mg Tablet 15 16 45938 Perindopril erbumine 8mg tablets (Teva UK Ltd) 17 46009 Verapamil 120mg tablets (Kent Pharmaceuticals Ltd)For peer review only 18 46066 Cardozin XL 4mg tablets (Almus Pharmaceuticals Ltd) 19 20 46116 Furosemide 10mg/ml Injection (Antigen Pharmaceuticals) 21 46206 Pamsvax XL 400microgram capsules (Almus Pharmaceuticals Ltd) 22 23 46233 Amlodipine Oral solution 24 46249 Revatio 10mg/12.5ml solution for injection vials (Pfizer Ltd) 25 46302 Neo-Naclex 2.5mg tablets (AMCo) 26 27 46355 Sevikar HCT 20mg/5mg/12.5mg tablets (Daiichi Sankyo UK Ltd) 28 46363 Half Beta-Prograne 80mg modified-release capsules (Teva UK Ltd) 29 46365 Quinil 20mg tablets (Tillomed Laboratories Ltd) 30 31 46445 Nifedipine 10mg capsules (IVAX Pharmaceuticals UK Ltd) 32 46525 Torasemide 5mg tablets (Teva UK Ltd) 33 34 46526 Raporsin XL 4mg tablets (Actavis UK Ltd) 35 46614 Lopresor 50mg tablets (Recordati Pharmaceuticals Ltd) 36 46674 Spironolactone 50mg/5ml Oral suspension sugar free (Rosemont Pharmaceuticals Ltd) 37 38 46675 Indapamide 1.5mg modified-release tablets (A A H Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 46687 Olmesartan medoxomil with amlodipine and hydrochlorothiazide 20mg + 5mg + 12.5mg 40 Tablet 41 42 46699 Furosemide 40mg tablets (Almus Pharmaceuticals Ltd) 43 46715 Olmesartan medoxomil with amlodipine and hydrochlorothiazide 40mg + 10mg + 12.5mg 44 Tablet 45 46 46724 Amlodipine 5mg/5ml oral solution 47 46740 Lopresor 100mg tablets (Recordati Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 48 46792 Olmesartan medoxomil with amlodipine and hydrochlorothiazide 40mg + 5mg + 12.5mg 49 50 Tablet 51 46795 Sildenafil 10mg/12.5ml solution for injection vials 52 46851 Captopril 5mg/5ml oral solution 53 54 46884 Verapamil hc 240mg Modified-release tablet (Sandoz Ltd) 55 46887 Adanif XL 60mg tablets (Focus Pharmaceuticals Ltd) 56 46890 Ramipril 5mg/5ml oral suspension 57 58 46908 Atenolol 100mg tablets (Kent Pharmaceuticals Ltd) 59 46916 Co-amilozide 5mg/50mg tablets (A A H Pharmaceuticals Ltd) 60 46922 Prazosin 1mg tablets (IVAX Pharmaceuticals UK Ltd) 46930 Amiloride 5mg tablets (Wockhardt UK Ltd) 46931 Atenolol 100mg tablets (Actavis UK Ltd)

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1 2 46935 Carvedilol 3.125mg tablets (Actavis UK Ltd) 3 46936 Carvedilol 3.125mg tablets (A A H Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 46937 Diltiazem 60mg modified-release tablets (Actavis UK Ltd) 6 46948 Furosemide 40mg tablets (Arrow Generics Ltd) 7 8 46951 Captopril 12.5mg tablets (A A H Pharmaceuticals Ltd) 9 46952 Co-tenidone 100mg/25mg tablets (Actavis UK Ltd) 10 46955 Verapamil 80mg tablets (Generics (UK) Ltd) 11 12 46957 Captopril 12.5mg tablets (Tillomed Laboratories Ltd) 13 46974 Enalapril 5mg tablets (Generics (UK) Ltd) 14 46975 Lisinopril 5mg tablets (Sandoz Ltd) 15 16 46979 Lisinopril 20mg tablets (Sandoz Ltd) 17 46990 Spironolactone 50mg/5ml oral suspensionFor peer review only 18 47002 Amlodipine 10mg/5ml sugar free Oral suspension 19 20 47006 Losartan 100mg tablets (Teva UK Ltd) 21 47018 Spironolactone 25mg/5ml oral suspension 22 23 47021 Ramipril 2.5mg/5ml oral solution sugar free 24 47027 Nifedipine 10mg Modified-release tablet (Kent Pharmaceuticals Ltd) 25 47041 Bisoprolol 2.5mg tablets (Generics (UK) Ltd) 26 27 47107 Carvedilol 5mg/5ml oral suspension 28 47159 Lisinopril 10mg tablets (Almus Pharmaceuticals Ltd) 29 47217 Adipine la 60mg Modified-release tablet (Chiesi Ltd) 30 31 47222 Verapamil 120mg modified-release tablets (A A H Pharmaceuticals Ltd) 32 47230 Verapamil 240mg modified-release tablets (Teva UK Ltd) 33 34 47264 Adcirca 20mg tablets (Eli Lilly and Company Ltd) 35 47285 Nifedipine xl 60mg Tablet (Hillcross Pharmaceuticals Ltd) 36 47300 Nebivolol 2.5mg tablets (Glenmark Generics (Europe) Ltd) 37 38 47331 Lercanidipine 10mg tablets (Generics (UK) Ltd) http://bmjopen.bmj.com/ 39 47415 Diltiazem sr 60mg Capsule (Hillcross Pharmaceuticals Ltd) 40 47467 Olmesartan medoxomil with amlodipine and hydrochlorothiazide 40mg + 5mg + 25mg 41 42 Tablet 43 47529 Nifedipine 20mg/ml oral drops 44 47530 Horizem SR 60mg capsules (Horizon lifecare) 45 46 47536 Metoprolol tartrate 12.5mg/5ml Oral suspension 47 47543 Half Beta-Prograne 80mg modified-release capsules (Actavis UK Ltd) on September 25, 2021 by guest. Protected copyright. 48 47573 Sevikar HCT 40mg/5mg/12.5mg tablets (Daiichi Sankyo UK Ltd) 49 50 47608 Zemret 300 XL capsules (Tillomed Laboratories Ltd) 51 47614 Nifedipine 30mg modified-release tablets (A A H Pharmaceuticals Ltd) 52 53 47616 Sevikar HCT 40mg/10mg/12.5mg tablets (Daiichi Sankyo UK Ltd) 54 47647 Co-amilofruse oral liquid 55 47654 Tracleer 62.5mg tablets (Actelion Pharmaceuticals UK Ltd) 56 57 47673 Labetalol 400mg Tablet (Approved Prescription Services Ltd) 58 47674 Labetalol 200mg Tablet (C P Pharmaceuticals Ltd) 59 47687 Spiretic 25mg Tablet (DDSA Pharmaceuticals Ltd) 60 47707 Nifedipine Oral solution 47724 Bi-Carzem XL 240mg capsules (Tillomed Laboratories Ltd)

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1 2 47727 Sevikar HCT 40mg/5mg/25mg tablets (Daiichi Sankyo UK Ltd) 3 47732 Zemret 180 XL capsules (Tillomed Laboratories Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 47804 Co-triamterzide 50mg/25mg tablets (A A H Pharmaceuticals Ltd) 6 47807 Doxazosin xl 4mg Tablet (Hillcross Pharmaceuticals Ltd) 7 8 47815 Furosemide 20mg Tablet (Celltech Pharma Europe Ltd) 9 47833 Bedranol SR 80mg capsules (Almus Pharmaceuticals Ltd) 10 47844 Bendroflumethiazide 2.5mg tablets (Kent Pharmaceuticals Ltd) 11 12 47870 Atenolol 25mg tablets (Almus Pharmaceuticals Ltd) 13 47887 Nimodrel XL 60mg tablets (Zurich Pharmaceuticals) 14 47907 Bedranol SR 160mg capsules (Almus Pharmaceuticals Ltd) 15 16 47998 Ramipril 2.5mg capsules (Actavis UK Ltd) 17 48008 Ramipril 5mg capsules (Actavis UK Ltd)For peer review only 18 48009 Felodipine 5mg Modified-release tablet (Sandoz Ltd) 19 20 48039 Losartan 100mg / Hydrochlorothiazide 12.5mg tablets (Teva UK Ltd) 21 48049 Perindopril erbumine 2mg tablets (Generics (UK) Ltd) 22 23 48053 Ramipril 2.5mg capsules (Almus Pharmaceuticals Ltd) 24 48079 Indapamide 2.5mg tablets (Zentiva) 25 48098 Perindopril arginine 4mg with Indapamide 1.25mg tablet 26 27 48099 Indapamide 2.5mg tablets (A A H Pharmaceuticals Ltd) 28 48132 Hydrochlorothiazide Capsule 29 48150 Doxazosin 1mg tablets (Actavis UK Ltd) 30 31 48180 Perindopril erbumine 4mg tablets (Sandoz Ltd) 32 48189 Ismelin 10mg/1ml solution for injection ampoules (Amdipharm Plc) 33 34 48214 Perindopril erbumine 4mg tablets (Actavis UK Ltd) 35 48272 Diltiazem 60mg modified-release capsules (Alliance Healthcare (Distribution) Ltd) 36 48282 Diltiazem 90mg modified-release capsules (A A H Pharmaceuticals Ltd) 37 38 48288 Diltiazem 120mg modified-release capsules (A A H Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 48398 Losartan 25mg tablets (Dexcel-Pharma Ltd) 40 48457 Diltiazem 90mg modified-release capsules (Alliance Healthcare (Distribution) Ltd) 41 42 48682 Propranolol 50mg/5ml oral solution sugar free 43 48745 Timolol 10mg / Amiloride 2.5mg / Hydrochlorothiazide 25mg tablets 44 45 48870 Adizem-SR 90mg capsules (DE Pharmaceuticals) 46 49001 Diltiazem 120mg modified-release tablets (Alliance Healthcare (Distribution) Ltd) on September 25, 2021 by guest. Protected copyright. 47 49142 Carvedilol 3.125mg/5ml oral suspension 48 49 49164 Ramipril 10mg capsules (Actavis UK Ltd) 50 49268 Furosemide 50mg/5ml oral suspension 51 49289 Diltiazem 120mg modified-release capsules (Alliance Healthcare (Distribution) Ltd) 52 53 49338 Nifedipine 20mg modified-release tablets (Alliance Healthcare (Distribution) Ltd) 54 49388 Spironolactone 100mg/5ml oral suspension 55 56 49390 Diltiazem 90mg modified-release tablets (Alliance Healthcare (Distribution) Ltd) 57 49411 Sildenafil 10mg/5ml oral suspension 58 49491 Perindopril erbumine 2mg tablets (Consilient Health Ltd) 59 60 49492 Losartan 25mg tablets (Generics (UK) Ltd) 49529 Indapamide 2.5mg tablets (Phoenix Healthcare Distribution Ltd) 49588 Losartan 100mg tablets (A A H Pharmaceuticals Ltd)

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1 2 49636 Amlodipine 10mg tablets (DE Pharmaceuticals) 3 49752 Metolazone 2.5mg/5ml oral solution BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 49762 Nifedipine 10mg modified-release tablets (Alliance Healthcare (Distribution) Ltd) 6 49863 Propranolol 5mg/5ml oral solution sugar free 7 8 49953 Atenolol 25mg tablets (Bristol Laboratories Ltd) 9 50079 Spironolactone 10mg/5ml oral suspension 10 50185 Candesartan 8mg tablets (Teva UK Ltd) 11 12 50224 Congescor 2.5mg tablets (Teva UK Ltd) 13 50300 Congescor 1.25mg tablets (Teva UK Ltd) 14 50334 Enalapril 4mg/5ml oral suspension 15 16 50347 Coversyl Arginine 5mg tablets (Waymade Healthcare Plc) 17 50362 Sildenafil 12.5mg/5ml oral solutionFor peer review only 18 50370 Spironolactone 5mg/5ml oral suspension 19 20 50402 Perindopril 2mg Tablet (Servier Laboratories Ltd) 21 50403 Bisoprolol 1.25mg Tablet (Teva UK Ltd) 22 23 50467 Doxazosin 2mg tablets (Alliance Healthcare (Distribution) Ltd) 24 50509 Ramipril 10mg/5ml oral solution 25 50514 Bisoprolol 2.5mg tablets (Chanelle Medical UK Ltd) 26 27 50607 Perindopril arginine 2mg with Indapamide 625 micrograms tablet 28 50702 Atenolol 25mg tablets (Alliance Healthcare (Distribution) Ltd) 29 50780 Enalapril 2mg/5ml oral solution 30 31 50863 Enalapril 5mg/5ml oral solution (Drug Tariff Special Order) 32 50971 Losartan 25mg tablets (A A H Pharmaceuticals Ltd) 33 34 51117 Candesartan 8mg tablets (DE Pharmaceuticals) 35 51186 Losartan 25mg tablets (Arrow Generics Ltd) 36 51258 Coversyl Arginine Plus 5mg/1.25mg tablets (DE Pharmaceuticals) 37 38 51261 Tildiem Retard 120mg tablets (Mawdsley-Brooks & Company Ltd) http://bmjopen.bmj.com/ 39 51328 Iloprost 50micrograms/0.5ml solution for infusion ampoules 40 51368 Azilsartan medoxomil 80mg tablets 41 42 51433 Lisinopril 20mg tablets (Tillomed Laboratories Ltd) 43 51447 Metoprolol 12.5mg/5ml oral suspension 44 45 51461 Securon SR 240mg tablets (Waymade Healthcare Plc) 46 51492 Sotalol 25mg/5ml oral solution on September 25, 2021 by guest. Protected copyright. 47 51519 Candesartan 8mg tablets (A A H Pharmaceuticals Ltd) 48 49 51528 Bisoprolol 1.25mg tablets (Actavis UK Ltd) 50 51601 Losartan 50mg tablets (Actavis UK Ltd) 51 51643 Atenolol 25mg/5ml oral solution sugar free (Alliance Healthcare (Distribution) Ltd) 52 53 51647 Candesartan 4mg tablets (Mawdsley-Brooks & Company Ltd) 54 51652 Spironolactone 25mg tablets (DE Pharmaceuticals) 55 56 51665 Tamurex 400microgram modified-release capsules (Somex Pharma) 57 51685 Doxazosin 4mg tablets (Actavis UK Ltd) 58 51701 Ramipril 5mg capsules (Bristol Laboratories Ltd) 59 60 51714 Ramipril 2.5mg capsules (Alliance Healthcare (Distribution) Ltd) 51720 Spironolactone 25mg/5ml oral solution 51807 Coversyl Arginine 5mg tablets (DE Pharmaceuticals)

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1 2 51897 Edarbi 20mg tablets (Takeda UK Ltd) 3 51917 Adalat LA 60 tablets (Sigma Pharmaceuticals Plc) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 51933 Spironolactone 50mg/5ml oral solution 6 51983 Furosemide 5mg/5ml oral suspension 7 8 51998 Atenolol 25mg tablets (Co-Pharma Ltd) 9 52010 Enalapril 10mg tablets (Alliance Healthcare (Distribution) Ltd) 10 52017 Adalat LA 30 tablets (Mawdsley-Brooks & Company Ltd) 11 12 52045 Furosemide 250mg/5ml solution for injection vials 13 52055 Tamsulosin 400microgram oral powder sachets 14 52088 Lisinopril 5mg tablets (Phoenix Healthcare Distribution Ltd) 15 16 52136 Bedranol sr 160mg Capsule (Lagap) 17 52145 Cyclopenthiazide 0.25mg with oxprenolol 160mg modified-release tabletsFor peer review only 18 52159 Tamsulosin 400microgram modified-release capsules (Focus Pharmaceuticals Ltd) 19 20 52189 Losartan 100mg / Hydrochlorothiazide 25mg tablets (A A H Pharmaceuticals Ltd) 21 52197 Ramipril 5mg capsules (Sigma Pharmaceuticals Plc) 22 23 52208 Candesartan 16mg tablets (A A H Pharmaceuticals Ltd) 24 52276 Adizem-XL 180mg capsules (DE Pharmaceuticals) 25 52293 Captopril 2mg capsules 26 27 52310 Atenolol 25mg tablets (Crescent Pharma Ltd) 28 52366 Spironolactone 5mg/5ml oral solution 29 52399 Ramipril 1.25mg capsules (Kent Pharmaceuticals Ltd) 30 31 52407 Ramipril 10mg capsules (Kent Pharmaceuticals Ltd) 32 52427 Cozaar 100mg tablets (Necessity Supplies Ltd) 33 34 52440 Amlodipine 10mg/5ml oral solution 35 52499 Captopril 25mg/5ml oral solution 36 52500 Atenolol 50mg tablets (Almus Pharmaceuticals Ltd) 37 38 52548 Bisoprolol 1.25mg tablets (Almus Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 52555 Clonidine 50micrograms/5ml oral solution 40 52559 Candesartan 8mg tablets (Zentiva) 41 42 52609 Inderal LA 160mg capsules (Sigma Pharmaceuticals Plc) 43 52611 Bisoprolol 10mg/5ml oral solution 44 45 52635 Bisoprolol 5mg tablets (Alliance Healthcare (Distribution) Ltd) 46 52658 Losartan 100mg/5ml oral suspension on September 25, 2021 by guest. Protected copyright. 47 52659 Losartan 50mg/5ml oral solution 48 49 52686 Bisoprolol 2.5mg/5ml oral solution 50 52701 Tildiem LA 200 capsules (Mawdsley-Brooks & Company Ltd) 51 52728 Beta-Adalat modified-release capsules (Lexon (UK) Ltd) 52 53 52777 Propranolol 40mg tablets (Kent Pharmaceuticals Ltd) 54 52858 Co-Diovan 80mg/12.5mg tablets (Sigma Pharmaceuticals Plc) 55 56 52882 Enalapril 5mg/5ml oral suspension sugar free 57 52886 Losartan 12.5mg tablets (A A H Pharmaceuticals Ltd) 58 52887 Furosemide 20mg/2ml solution for injection ampoules (A A H Pharmaceuticals Ltd) 59 60 52900 Furosemide 80mg/8ml solution for injection Minijet pre-filled syringes (UCB Pharma Ltd) 52970 Spironolactone 10mg/5ml oral solution 52972 Irbesartan 300mg tablets (Sigma Pharmaceuticals Plc)

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1 2 53033 Doxzogen XL 4mg tablets (Generics (UK) Ltd) 3 53058 Perindopril erbumine 8mg tablets (Sandoz Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 53084 Cositam XL 400microgram tablets (Consilient Health Ltd) 6 53142 Clonidine 50micrograms/5ml oral suspension 7 8 53177 Propranolol oral solution 9 53204 Atenolol 50mg tablets (Alliance Healthcare (Distribution) Ltd) 10 53215 Atenolol 50mg tablets (Bristol Laboratories Ltd) 11 12 53220 Sevikar HCT 40mg/10mg/25mg tablets (Daiichi Sankyo UK Ltd) 13 53253 Spironolactone 50mg/5ml oral suspension (Drug Tariff Special Order) 14 53271 Lisinopril 10mg tablets (Alliance Healthcare (Distribution) Ltd) 15 16 53278 Adalat LA 30 tablets (Necessity Supplies Ltd) 17 53322 Doxazosin 4mg tablets (Bristol Laboratories Ltd)For peer review only 18 53334 Bisoprolol 10mg tablets (A A H Pharmaceuticals Ltd) 19 20 53357 Nifedipine 10mg/5ml oral suspension 21 53414 Atenolol 50mg tablets (Accord Healthcare Ltd) 22 23 53500 Adalat LA 30 tablets (DE Pharmaceuticals) 24 53508 Spironolactone 5mg/5ml / Chlorothiazide 50mg/5ml oral suspension 25 53551 Lisinopril 20mg tablets (Phoenix Healthcare Distribution Ltd) 26 27 53612 Ramipril 10mg tablets (Alliance Healthcare (Distribution) Ltd) 28 53621 Ramipril 2.5mg capsules (Bristol Laboratories Ltd) 29 53629 Adalat retard 20mg tablets (Lexon (UK) Ltd) 30 31 53664 Bisoprolol 2.5mg tablets (Sandoz Ltd) 32 53674 Metolazone 2.5mg tablets 33 34 53680 Candesartan 16mg tablets (Teva UK Ltd) 35 53719 Enalapril 20mg tablets (Alliance Healthcare (Distribution) Ltd) 36 53755 Candesartan 4mg tablets (Teva UK Ltd) 37 38 53802 Atenolol 25mg tablets (Sigma Pharmaceuticals Plc) http://bmjopen.bmj.com/ 39 53812 Bendroflumethiazide oral solution 40 53820 Lisinopril 5mg tablets (Arrow Generics Ltd) 41 42 53826 Atenolol 25mg tablets (Boston Healthcare Ltd) 43 53833 Valsartan 160mg capsules (Generics (UK) Ltd) 44 45 53868 Amlodipine 5mg tablets (Actavis UK Ltd) 46 53885 Bisoprolol 1.25mg tablets (A A H Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 53896 Iloprost 100micrograms/1ml solution for infusion ampoules 48 49 53915 Enalapril 5mg tablets (Dexcel-Pharma Ltd) 50 53916 Bisoprolol 2.5mg tablets (Almus Pharmaceuticals Ltd) 51 53964 Tamsulosin 400microgram modified-release capsules (A A H Pharmaceuticals Ltd) 52 53 53967 Furosemide 20mg tablets (Bristol Laboratories Ltd) 54 53990 Nifedipine 5mg/5ml oral suspension 55 56 54037 Lisinopril 10mg tablets (Relonchem Ltd) 57 54049 Losartan 50mg tablets (Accord Healthcare Ltd) 58 54057 Losartan 50mg tablets (Teva UK Ltd) 59 60 54106 Carvedilol 1.5mg/5ml oral suspension 54120 Spironolactone 4mg/5ml oral suspension 54201 Lisinopril 20mg / Hydrochlorothiazide 12.5mg tablets (Almus Pharmaceuticals Ltd)

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1 2 54283 Lisinopril 5mg/5ml oral suspension (Drug Tariff Special Order) 3 54288 Lisinopril 10mg tablets (Arrow Generics Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 54297 Propranolol 50mg/5ml oral solution 6 54298 Ramipril 2.5mg capsules (Arrow Generics Ltd) 7 8 54316 Indapamide 2.5mg tablets (Alliance Healthcare (Distribution) Ltd) 9 54326 Candesartan 32mg tablets (Teva UK Ltd) 10 54329 Metolazone 5mg/5ml oral suspension 11 12 54341 Chlorothiazide 5mg/5ml oral suspension 13 54345 Trandolapril 4mg capsules (Arrow Generics Ltd) 14 54404 Losartan 100mg tablets (Actavis UK Ltd) 15 16 54414 Candesartan 16mg tablets (Consilient Health Ltd) 17 54479 Bisoprolol 1.25mg tablets (Alliance Healthcare (Distribution) Ltd)For peer review only 18 54487 Nebivolol 2.5mg tablets (Sigma Pharmaceuticals Plc) 19 20 54497 Galebon 400microgram modified-release capsules (Consilient Health Ltd) 21 54512 Lisinopril Oral solution 22 23 54515 Amlodipine 10mg tablets (Alliance Healthcare (Distribution) Ltd) 24 54542 Atenolol 25mg tablets (Zanza Laboratories Ltd) 25 54544 Captopril 25mg/5ml oral suspension 26 27 54620 Ramipril 2.5mg capsules (Sigma Pharmaceuticals Plc) 28 54623 Beta-Prograne 160mg modified-release capsules (Actavis UK Ltd) 29 54633 Amlodipine 5mg tablets (Bristol Laboratories Ltd) 30 31 54643 Metolazone Oral solution 32 54654 Amlodipine 10mg tablets (Almus Pharmaceuticals Ltd) 33 34 54679 Chlorothiazide 250mg tablets 35 54696 Amlodipine 10mg tablets (Sandoz Ltd) 36 54726 Valsartan 40mg capsules (Teva UK Ltd) 37 38 54733 Perindopril erbumine 8mg tablets (Consilient Health Ltd) http://bmjopen.bmj.com/ 39 54735 Losartan 50mg tablets (Alliance Healthcare (Distribution) Ltd) 40 54740 Losartan 25mg tablets (Actavis UK Ltd) 41 42 54752 Atenolol 50mg tablets (Co-Pharma Ltd) 43 54785 Doxazosin 4mg tablets (Medreich Plc) 44 45 54799 Tildiem LA 300 capsules (Mawdsley-Brooks & Company Ltd) 46 54825 Furosemide 20mg tablets (Sigma Pharmaceuticals Plc) on September 25, 2021 by guest. Protected copyright. 47 54843 Losartan 50mg tablets (Dexcel-Pharma Ltd) 48 49 54899 Perindopril erbumine 2mg tablets (Teva UK Ltd) 50 54918 Phenoxybenzamine oral liquid 51 54928 Lisinopril 10mg tablets (Bristol Laboratories Ltd) 52 53 54941 Ramipril 5mg capsules (Alliance Healthcare (Distribution) Ltd) 54 54942 Perindopril erbumine 8mg tablets (Generics (UK) Ltd) 55 56 54983 Amlodipine 2.5mg/5ml oral suspension 57 54986 Perindopril erbumine 8mg/5ml oral suspension 58 55002 Lisinopril 20mg tablets (Accord Healthcare Ltd) 59 60 55017 Irbesartan 300mg tablets (Accord Healthcare Ltd) 55160 Cozaar-Comp 50mg/12.5mg tablets (Sigma Pharmaceuticals Plc) 55187 Valsartan 160mg capsules (Arrow Generics Ltd)

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1 2 55228 Propranolol 40mg tablets (Boston Healthcare Ltd) 3 55257 Diltiazem 60mg/5ml oral solution BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 55259 Indapamide 2.5mg tablets (Kent Pharmaceuticals Ltd) 6 55296 Losartan 50mg tablets (Generics (UK) Ltd) 7 8 55298 Bisoprolol 10mg tablets (Sigma Pharmaceuticals Plc) 9 55299 Ramipril 1.25mg capsules (A A H Pharmaceuticals Ltd) 10 55306 Folpik XL 5mg tablets (Teva UK Ltd) 11 12 55358 Olmesartan medoxomil with amlodipine and hydrochlorothiazide 40mg + 10mg + 25mg 13 Tablet 14 55368 Sildenafil 10mg/ml oral suspension sugar free 15 16 55399 Lisinopril 20mg / Hydrochlorothiazide 12.5mg tablets (A A H Pharmaceuticals Ltd) 17 55416 Propranolol 40mg tablets (Almus Pharmaceuticals Ltd)For peer review only 18 55446 Losartan 100mg tablets (Bristol Laboratories Ltd) 19 20 55455 Nifedipine 10mg capsules (Co-Pharma Ltd) 21 55456 Lisinopril 5mg tablets (Alliance Healthcare (Distribution) Ltd) 22 55548 Bumetanide 1mg tablets (Alliance Healthcare (Distribution) Ltd) 23 24 55588 Lisinopril 20mg tablets (Sigma Pharmaceuticals Plc) 25 55639 Lisinopril 10mg tablets (Accord Healthcare Ltd) 26 27 55718 Losartan 25mg tablets (Phoenix Healthcare Distribution Ltd) 28 55738 Furosemide 50mg/5ml solution for injection ampoules (Hameln Pharmaceuticals Ltd) 29 55740 Neofel XL 2.5mg tablets (Actavis UK Ltd) 30 31 55777 Metolazone 5mg/5ml oral solution 32 55778 Atenolol 50mg tablets (Phoenix Healthcare Distribution Ltd) 33 55791 Bisoprolol 3.75mg tablets (Actavis UK Ltd) 34 35 55797 Clonidine 25micrograms/5ml oral solution 36 55798 Ramipril 5mg capsules (Waymade Healthcare Plc) 37 38 55821 Valsartan 160mg capsules (Teva UK Ltd) http://bmjopen.bmj.com/ 39 55824 Nifedipine 20mg Modified-release tablet (Berk Pharmaceuticals Ltd) 40 55826 Prazosin 5mg tablets (A A H Pharmaceuticals Ltd) 41 42 55849 Propranolol 160mg tablets (Generics (UK) Ltd) 43 55853 Pindolol 15mg Tablet (Hillcross Pharmaceuticals Ltd) 44 55889 Chlorothiazide oral solution 45 46 55896 Lisinopril 2.5mg tablets (Actavis UK Ltd) 47 55903 Enalapril 10mg tablets (Dexcel-Pharma Ltd) on September 25, 2021 by guest. Protected copyright. 48 55906 Doxazosin 1mg tablets (Dexcel-Pharma Ltd) 49 50 55916 Doxazosin 1mg tablets (Alliance Healthcare (Distribution) Ltd) 51 55929 Bisoprolol 5mg tablets (Accord Healthcare Ltd) 52 53 55949 Propranolol 40mg/5ml oral solution 54 55979 Metoprolol 25mg/5ml oral suspension 55 56013 Ramipril 2.5mg capsules (Waymade Healthcare Plc) 56 57 56038 Ramipril 10mg tablets (Pfizer Ltd) 58 56051 Furosemide 20mg tablets (Kent Pharmaceuticals Ltd) 59 56067 Spironolactone 4mg/5ml oral solution 60 56079 Perindopril tosilate 10mg tablets 56104 Losartan 50mg tablets (A A H Pharmaceuticals Ltd)

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1 2 56129 Ramipril 5mg capsules (Kent Pharmaceuticals Ltd) 3 56145 Doxazosin 2mg tablets (Actavis UK Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 56147 Amlodipine 10mg tablets (Accord Healthcare Ltd) 6 56148 Ramipril 1.25mg tablets (Kent Pharmaceuticals Ltd) 7 8 56157 Perindopril tosilate 5mg / Indapamide 1.25mg tablets 9 56162 Perindopril erbumine 4mg tablets (Consilient Health Ltd) 10 56169 Ramipril 10mg capsules (Arrow Generics Ltd) 11 12 56173 Half Beta-Prograne 80mg modified-release capsules (Actavis UK Ltd) 13 56204 Losartan 50mg / Hydrochlorothiazide 12.5mg tablets (Actavis UK Ltd) 14 56240 Bisoprolol 3.75mg tablets (Sandoz Ltd) 15 16 56244 Lisinopril 20mg / Hydrochlorothiazide 12.5mg tablets (Tillomed Laboratories Ltd) 17 56274 Spironolactone 4.5mg/5ml oral suspensionFor peer review only 18 56279 Lisinopril 2.5mg/5ml oral solution 19 20 56296 Indapamide 2.5mg tablets (Boston Healthcare Ltd) 21 56334 Amlodipine 10mg tablets (Bristol Laboratories Ltd) 22 23 56356 Ramipril 10mg capsules (Alliance Healthcare (Distribution) Ltd) 24 56375 Furosemide 40mg tablets (Accord Healthcare Ltd) 25 56445 Atenolol 25mg/5ml oral solution sugar free (A A H Pharmaceuticals Ltd) 26 27 56459 Bisoprolol 2.5mg tablets (Accord Healthcare Ltd) 28 56467 Tildiem 60mg modified-release tablets (DE Pharmaceuticals) 29 56469 Adalat LA 60 tablets (Necessity Supplies Ltd) 30 31 56472 Perindopril erbumine 4mg tablets (Kent Pharmaceuticals Ltd) 32 56473 Perindopril erbumine 2mg tablets (Sigma Pharmaceuticals Plc) 33 34 56485 Celectol 200mg tablets (Waymade Healthcare Plc) 35 56486 Monocor 10mg tablets (Dowelhurst Ltd) 36 56505 Zestril 5mg tablets (Lexon (UK) Ltd) 37 38 56506 Coversyl 2mg tablets (Dowelhurst Ltd) http://bmjopen.bmj.com/ 39 56508 Coversyl 4mg tablets (Dowelhurst Ltd) 40 56509 Capoten 12.5mg tablets (Dowelhurst Ltd) 41 42 56510 Zestril 20mg tablets (Sigma Pharmaceuticals Plc) 43 56516 Perindopril erbumine 2mg tablets (Sandoz Ltd) 44 45 56536 Spironolactone 100mg/5ml oral solution 46 56606 Azilsartan medoxomil 40mg tablets on September 25, 2021 by guest. Protected copyright. 47 56704 Ramipril 1.25mg capsules (Alliance Healthcare (Distribution) Ltd) 48 49 56758 Diltiazem 90mg modified-release capsules (Cubic Pharmaceuticals Ltd) 50 56760 Indapamide 2.5mg tablets (Co-Pharma Ltd) 51 56763 Ramipril 10mg capsules (Phoenix Healthcare Distribution Ltd) 52 53 56764 Propranolol 40mg tablets (Waymade Healthcare Plc) 54 56767 Lercanidipine 20mg tablets (Generics (UK) Ltd) 55 56 56768 Bisoprolol 2.5mg tablets (Niche Generics Ltd) 57 56804 Chlorothiazide 25mg/5ml oral suspension 58 56850 Ecopace 12.5mg tablets (AMCo) 59 60 56855 Ramipril 10mg capsules (Sigma Pharmaceuticals Plc) 56970 Losartan 100mg tablets (Pfizer Ltd) 56975 Losartan 50mg / Hydrochlorothiazide 12.5mg tablets (A A H Pharmaceuticals Ltd)

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1 2 56994 Lacidipine 4mg tablets (Teva UK Ltd) 3 57023 Bisoprolol 2.5mg tablets (Almus Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 57026 Candesartan 8mg tablets (Waymade Healthcare Plc) 6 57028 Losartan 100mg tablets (Generics (UK) Ltd) 7 8 57048 Lisinopril 10mg tablets (Zentiva) 9 57063 Bedranol SR 80mg capsules (Almus Pharmaceuticals Ltd) 10 57073 Ramipril 1.25mg capsules (Waymade Healthcare Plc) 11 12 57074 Doxazosin 2mg tablets (Sigma Pharmaceuticals Plc) 13 57104 Spironolactone 200mg/5ml oral suspension 14 57145 Terazosin 2mg tablets (A A H Pharmaceuticals Ltd) 15 16 57176 Bisoprolol 10mg tablets (Accord Healthcare Ltd) 17 57208 Diltiazem 120mg modified-release capsules (Cubic Pharmaceuticals Ltd)For peer review only 18 57235 Ramipril 1.25mg tablets (Sandoz Ltd) 19 20 57240 Metoprolol 50mg/5ml oral suspension (Drug Tariff Special Order) 21 57266 Candesartan 2mg tablets (Actavis UK Ltd) 22 23 57273 Candesartan 8mg tablets (Actavis UK Ltd) 24 57333 Perindopril tosilate 5mg tablets 25 57342 Propranolol 40mg tablets (Phoenix Healthcare Distribution Ltd) 26 27 57346 Ramipril 10mg capsules (Waymade Healthcare Plc) 28 57378 Enalapril 2mg/5ml oral suspension 29 57444 Lercanidipine 10mg tablets (Aptil Pharma Ltd) 30 31 57448 Doxazosin 4mg tablets (A A H Pharmaceuticals Ltd) 32 57488 Hydrochlorothiazide Oral solution 33 34 57531 Adalat LA 60 tablets (Waymade Healthcare Plc) 35 57539 Zestoretic 10 tablets (Sigma Pharmaceuticals Plc) 36 57556 Spironolactone 12mg/5ml oral solution 37 38 57567 Propranolol 10mg/5ml oral suspension http://bmjopen.bmj.com/ 39 57573 Celectol 200mg tablets (Dowelhurst Ltd) 40 57578 Cardicor 2.5mg tablets (Necessity Supplies Ltd) 41 42 57588 Zestril 2.5mg tablets (Mawdsley-Brooks & Company Ltd) 43 57594 Tildiem 60mg modified-release tablets (Waymade Healthcare Plc) 44 45 57600 Furosemide 20mg/2ml solution for injection ampoules (Alliance Healthcare (Distribution) 46 Ltd) 47 57610 Furosemide 20mg/5ml oral solution sugar free (Focus Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 48 57626 Bisoprolol 1.25mg/5ml oral solution 49 50 57653 Adalat LA 20 tablets (Sigma Pharmaceuticals Plc) 51 57658 Ramipril 1.25mg tablets (A A H Pharmaceuticals Ltd) 52 53 57680 Lacidipine 4mg tablets (A A H Pharmaceuticals Ltd) 54 57701 Perindopril erbumine 8mg tablets (Actavis UK Ltd) 55 57784 Doxazosin 2mg/5ml oral suspension 56 57 57796 Cozaar-Comp 50mg/12.5mg tablets (DE Pharmaceuticals) 58 57801 Perindopril erbumine 4mg tablets (Glenmark Generics (Europe) Ltd) 59 57817 Atenolol 50mg tablets (Zentiva) 60 57859 Diltiazem 90mg modified-release tablets (Cubic Pharmaceuticals Ltd) 57864 Ramipril 5mg tablets (Sigma Pharmaceuticals Plc)

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1 2 57882 Enalapril 2.5mg/5ml oral suspension 3 57908 Co-amilofruse 5mg/40mg tablets (Kent Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 57933 Spironolactone 40mg/5ml oral suspension 6 57934 Bisoprolol 5mg tablets (Sandoz Ltd) 7 8 57944 Perindopril tosilate 2.5mg tablets 9 57977 Candesartan 16mg tablets (Alliance Healthcare (Distribution) Ltd) 10 58077 Spironolactone 8mg/5ml oral suspension 11 12 58078 Furosemide 8mg/5ml oral solution 13 58090 Clonidine 75micrograms/5ml oral solution 14 58108 Irbesartan 150mg tablets (A A H Pharmaceuticals Ltd) 15 16 58109 Bisoprolol 1.25mg/5ml oral suspension 17 58151 Sildenafil 10mg/5ml oral solutionFor peer review only 18 58195 Captopril 12.5mg/5ml oral solution 19 20 58201 Irbesartan 150mg tablets (Actavis UK Ltd) 21 58224 Furosemide 10mg/5ml oral solution 22 23 58225 Spironolactone 2.5mg/5ml oral suspension 24 58258 Lisinopril 2.5mg/5ml oral suspension 25 58274 Losartan 25mg tablets (Accord Healthcare Ltd) 26 27 58276 Doxazosin 2mg tablets (Medreich Plc) 28 58294 Lisinopril 5mg tablets (Accord Healthcare Ltd) 29 58297 Propranolol 10mg tablets (Kent Pharmaceuticals Ltd) 30 31 58325 Doxazosin 4mg tablets (Phoenix Healthcare Distribution Ltd) 32 58339 Neofel XL 2.5mg tablets (Almus Pharmaceuticals Ltd) 33 34 58407 Propranolol 80mg tablets (Teva UK Ltd) 35 58451 Lisinopril 2.5mg tablets (Almus Pharmaceuticals Ltd) 36 58455 Bisoprolol 7.5mg tablets (Sandoz Ltd) 37 38 58461 Lisinopril 2.5mg tablets (Kent Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 58491 Propranolol 40mg tablets (Alliance Healthcare (Distribution) Ltd) 40 58498 Bisoprolol 2.5mg tablets (Medreich Plc) 41 42 58511 Bisoprolol 1.25mg tablets (Sandoz Ltd) 43 58517 Faramsil 400microgram modified-release tablets (Sandoz Ltd) 44 45 58557 Adalat LA 20 tablets (Necessity Supplies Ltd) 46 58580 Amlodipine 10mg tablets (APC Pharmaceuticals & Chemicals (Europe) Ltd) on September 25, 2021 by guest. Protected copyright. 47 58632 Tracleer 125mg tablets (Actelion Pharmaceuticals UK Ltd) 48 49 58646 Candesartan 4mg tablets (Actavis UK Ltd) 50 58649 Losartan 25mg tablets (Bristol Laboratories Ltd) 51 58669 Valsartan 40mg capsules (Teva UK Ltd) 52 53 58682 Lisinopril 2.5mg tablets (Generics (UK) Ltd) 54 58751 Enalapril 1.25mg/5ml oral suspension 55 56 58757 Spironolactone 20mg/5ml oral suspension 57 58763 Bisoprolol 2.5mg tablets (Waymade Healthcare Plc) 58 58843 Perindopril erbumine 2mg tablets (Kent Pharmaceuticals Ltd) 59 60 58863 Lisinopril 10mg tablets (Phoenix Healthcare Distribution Ltd) 58871 Lisinopril 10mg tablets (Waymade Healthcare Plc) 58874 Perindopril erbumine 2mg tablets (Somex Pharma)

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1 2 58910 Valsartan 80mg capsules (Sigma Pharmaceuticals Plc) 3 58967 Losartan 12.5mg tablets (Alliance Healthcare (Distribution) Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 58973 Bisoprolol 10mg tablets (Niche Generics Ltd) 6 58974 Bisoprolol 2.5mg tablets (Alliance Healthcare (Distribution) Ltd) 7 8 58982 Bisoprolol 10mg tablets (Medreich Plc) 9 58990 Nifedipine 10mg modified-release tablets (Cubic Pharmaceuticals Ltd) 10 59001 Amlodipine 10mg tablets (Generics (UK) Ltd) 11 12 59029 Valsartan 3mg/1ml oral solution 13 59030 Furosemide 20mg/5ml oral solution 14 59037 Bisoprolol 5mg tablets (A A H Pharmaceuticals Ltd) 15 16 59086 Losartan 25mg tablets (Wockhardt UK Ltd) 17 59098 Dilzem XL 180 capsules (Lexon (UK) Ltd)For peer review only 18 59109 Lisinopril 5mg tablets (Tillomed Laboratories Ltd) 19 20 59111 Lisinopril 20mg tablets (Alliance Healthcare (Distribution) Ltd) 21 59148 Bisoprolol 2.5mg tablets (Zentiva) 22 23 59163 Nifedipine 20mg modified-release tablets (Cubic Pharmaceuticals Ltd) 24 59209 Doxazosin 1mg tablets (Kent Pharmaceuticals Ltd) 25 59222 Labetalol 100mg/20ml solution for injection ampoules (Focus Pharmaceuticals Ltd) 26 27 59233 Lercanidipine 20mg tablets (Actavis UK Ltd) 28 59264 Securon SR 240mg tablets (DE Pharmaceuticals) 29 59271 Losartan 25mg tablets (Sandoz Ltd) 30 31 59290 Furosemide 20mg tablets (Alliance Healthcare (Distribution) Ltd) 32 59340 Losartan 12.5mg tablets (Dexcel-Pharma Ltd) 33 34 59351 Losartan 50mg tablets (Pfizer Ltd) 35 59393 Irbesartan 300mg tablets (Sandoz Ltd) 36 59412 Co-amilofruse 5mg/40mg tablets (Waymade Healthcare Plc) 37 38 59415 Propranolol 40mg tablets (Accord Healthcare Ltd) http://bmjopen.bmj.com/ 39 59448 Valsartan 80mg capsules (A A H Pharmaceuticals Ltd) 40 59495 Bisoprolol 1.25mg tablets (Teva UK Ltd) 41 42 59512 Hydralazine 50mg/5ml oral solution 43 59549 Carvedilol 5mg/5ml oral suspension 44 45 59557 Ramipril 2.5mg capsules (Kent Pharmaceuticals Ltd) 46 59585 Uard 120XL capsules (Ennogen Healthcare Ltd) on September 25, 2021 by guest. Protected copyright. 47 59597 Propranolol 160mg modified-release capsules (A A H Pharmaceuticals Ltd) 48 49 59603 Ramipril 2.5mg capsules (Phoenix Healthcare Distribution Ltd) 50 59616 Rawel XL 1.5mg tablets (Consilient Health Ltd) 51 59690 Candesartan 8mg tablets (Consilient Health Ltd) 52 53 59695 Atenolol 50mg tablets (Boston Healthcare Ltd) 54 59699 Captopril 5mg/5ml oral solution sugar free 55 56 59750 Losartan 50mg tablets (Aptil Pharma Ltd) 57 59762 Amlodipine 10mg tablets (Teva UK Ltd) 58 59770 Perindopril erbumine 4mg tablets (Aurobindo Pharma Ltd) 59 60 59771 Sildenafil 25mg/5ml oral suspension 59788 Ramipril 10mg capsules (Bristol Laboratories Ltd) 59790 Perindopril erbumine 8mg tablets (Accord Healthcare Ltd)

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1 2 59802 Candesartan 2mg tablets (Teva UK Ltd) 3 59834 Chlorothiazide 250mg/5ml oral solution BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 59862 Doxazosin 4mg tablets (Dexcel-Pharma Ltd) 6 59863 Dilzem XL 240 capsules (Lexon (UK) Ltd) 7 8 59884 Furosemide 20mg tablets (Phoenix Healthcare Distribution Ltd) 9 59903 Losartan 50mg/5ml oral suspension 10 59911 Furosemide 40mg tablets (Alliance Healthcare (Distribution) Ltd) 11 12 59915 Captopril 25mg/5ml oral solution sugar free 13 59939 Furosemide 20mg/5ml oral suspension 14 59961 Nebivolol 10mg tablets 15 16 59969 Bisoprolol 5mg tablets (Almus Pharmaceuticals Ltd) 17 59972 Perindopril erbumine 2mg tablets (Alliance Healthcare (Distribution) Ltd)For peer review only 18 59982 Atenolol 25mg tablets (Accord Healthcare Ltd) 19 20 59996 Enalapril 20mg tablets (Milpharm Ltd) 21 60007 Generic Sevikar HCT 40mg/10mg/12.5mg tablets 22 23 60010 Lisinopril 10mg tablets (Kent Pharmaceuticals Ltd) 24 60020 Indapamide 1.5mg modified-release tablets (Waymade Healthcare Plc) 25 60065 Perindopril erbumine 4mg tablets (Sigma Pharmaceuticals Plc) 26 27 60067 Perindopril erbumine 4mg / Amlodipine 5mg tablets 28 60076 Valsartan 160mg capsules (Waymade Healthcare Plc) 29 60089 Clonidine 25microgram tablets (Waymade Healthcare Plc) 30 31 60097 Lisinopril 2.5mg tablets (Zentiva) 32 60136 Clonidine 100micrograms/5ml oral solution 33 34 60143 Enalapril 5mg tablets (Medreich Plc) 35 60149 Amiloride 5mg/5ml oral suspension 36 60200 Doxazosin 4mg tablets (DE Pharmaceuticals) 37 38 60232 Lisinopril 5mg tablets (Zentiva) http://bmjopen.bmj.com/ 39 60244 Amlodipine 10mg tablets (Phoenix Healthcare Distribution Ltd) 40 60258 Co-amilofruse 2.5mg/20mg tablets (Aurobindo Pharma Ltd) 41 42 60291 Furosemide 40mg tablets (AMCo) 43 60309 Lisinopril 5mg tablets (Relonchem Ltd) 44 45 60316 Prazosin 1mg Tablet (Approved Prescription Services Ltd) 46 60319 Doxazosin 1mg tablets (Bristol Laboratories Ltd) on September 25, 2021 by guest. Protected copyright. 47 60343 Spironolactone 25mg tablets (Kent Pharmaceuticals Ltd) 48 49 60349 Noyada 25mg/5ml oral solution (Martindale Pharmaceuticals Ltd) 50 60354 Co-amilozide 2.5mg/25mg tablets (Kent Pharmaceuticals Ltd) 51 60415 Dilzem XL 180 capsules (Sigma Pharmaceuticals Plc) 52 53 60465 Furosemide 5mg/5ml oral solution 54 60502 Bisoprolol 3.75mg tablets (DE Pharmaceuticals) 55 56 60506 Losartan 100mg tablets (Dexcel-Pharma Ltd) 57 60565 Propranolol 40mg tablets (Ranbaxy (UK) Ltd) 58 60569 Felodipine 2.5mg modified-release tablets (Waymade Healthcare Plc) 59 60 60597 Irbesartan 150mg tablets (Teva UK Ltd) 60603 Chlorothiazide 50mg/5ml oral suspension 60620 Adizem-XL 240mg capsules (Waymade Healthcare Plc)

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1 2 60652 Parmid XL 2.5mg tablets (Sandoz Ltd) 3 60660 Spironolactone 3mg/5ml oral suspension BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 60684 Perindopril erbumine 4mg / Amlodipine 10mg tablets 6 60699 Lacidipine 2mg tablets (Sigma Pharmaceuticals Plc) 7 8 60730 Ramipril 5mg capsules (Phoenix Healthcare Distribution Ltd) 9 60744 Perindopril erbumine 8mg / Amlodipine 5mg tablets 10 60757 Trandolapril 500microgram capsules (Teva UK Ltd) 11 12 60761 Bisoprolol 1.25mg tablets (Medreich Plc) 13 60780 Generic Sevikar HCT 20mg/5mg/12.5mg tablets 14 60823 Noyada 5mg/5ml oral solution (Martindale Pharmaceuticals Ltd) 15 16 60856 Nifedipine 10mg modified-release tablets (Sigma Pharmaceuticals Plc) 17 60884 Felodipine 2.5mg modified-release tablets (Phoenix Healthcare Distribution Ltd)For peer review only 18 60896 Bisoprolol 5mg tablets (Medreich Plc) 19 20 60898 Moxonidine 200microgram tablets (Generics (UK) Ltd) 21 60934 Propranolol 80mg modified-release capsules (Kent Pharmaceuticals Ltd) 22 23 61010 Diltiazem 120mg modified-release tablets (Cubic Pharmaceuticals Ltd) 24 61025 Spironolactone 20mg/5ml oral solution 25 61036 Physiotens 300microgram tablets (Actavis UK Ltd) 26 27 61053 Losartan 100mg tablets (Alliance Healthcare (Distribution) Ltd) 28 61066 Doxazosin 2mg tablets (Bristol Laboratories Ltd) 29 61067 Ramipril 5mg capsules (Almus Pharmaceuticals Ltd) 30 31 61115 Bisoprolol 5mg/5ml oral solution 32 61116 Hydralazine 50mg/5ml oral suspension 33 34 61117 Perindopril erbumine 4mg/5ml oral solution 35 61123 Terazosin 2mg tablets and Terazosin 1mg tablets 36 61133 Enalapril 10mg tablets (Phoenix Healthcare Distribution Ltd) 37 38 61177 Telmisartan 20mg tablets (Sigma Pharmaceuticals Plc) http://bmjopen.bmj.com/ 39 61230 Perhexiline maleate 100mg tablets 40 61245 Diltiazem 60mg modified-release capsules (Sigma Pharmaceuticals Plc) 41 42 61256 Clonidine 5micrograms/5ml oral suspension 43 61262 Lisinopril 20mg tablets (Bristol Laboratories Ltd) 44 45 61270 Perindopril erbumine 4mg tablets (Accord Healthcare Ltd) 46 61283 Doxazosin 4mg tablets (Alliance Healthcare (Distribution) Ltd) on September 25, 2021 by guest. Protected copyright. 47 61288 Losartan 100mg tablets (Accord Healthcare Ltd) 48 49 61292 Quinapril 40mg tablets (Generics (UK) Ltd) 50 61339 Ramipril 10mg capsules (Almus Pharmaceuticals Ltd) 51 61340 Bisoprolol 5mg tablets (DE Pharmaceuticals) 52 53 61365 Furosemide 40mg/5ml oral suspension 54 61374 Amlodipine 4mg/5ml oral suspension 55 56 61422 Amlodipine 5mg tablets (Accord Healthcare Ltd) 57 61442 Valsartan 160mg capsules (Teva UK Ltd) 58 61475 Furosemide 20mg tablets (DE Pharmaceuticals) 59 60 61495 Losartan 25mg tablets (Aptil Pharma Ltd) 61499 Ramipril 2.5mg tablets (Actavis UK Ltd) 61532 Diltiazem 120mg modified-release capsules (Sigma Pharmaceuticals Plc)

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1 2 61564 Bisoprolol 3.75mg tablets (Waymade Healthcare Plc) 3 61573 Atenolol 25mg/5ml oral solution BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 61611 Lercanidipine 10mg tablets (DE Pharmaceuticals) 6 61651 Bisoprolol 7.5mg tablets (Almus Pharmaceuticals Ltd) 7 8 61663 Carvedilol 3.125mg tablets (Teva UK Ltd) 9 61693 Perindopril erbumine 8mg tablets (Aurobindo Pharma Ltd) 10 61694 Ramipril 5mg tablets (Zentiva) 11 12 61710 Clonidine 25microgram tablets (Teva UK Ltd) 13 61719 Beta-Adalat modified-release capsules (Waymade Healthcare Plc) 14 61727 Propranolol 10mg tablets (Accord Healthcare Ltd) 15 16 61754 Losartan 25mg/5ml oral suspension 17 61781 Irbesartan 300mg tablets (Teva UK Ltd)For peer review only 18 61846 Zaroxolyn 2.5mg tablets (IDIS) 19 20 61985 Ramipril 1.25mg tablets (Teva UK Ltd) 21 62019 Doxazosin 1mg tablets (Almus Pharmaceuticals Ltd) 22 23 62024 Bumetanide 5mg tablets (A A H Pharmaceuticals Ltd) 24 62035 Candesartan 16mg tablets (Waymade Healthcare Plc) 25 62036 Ramipril 5mg tablets (Waymade Healthcare Plc) 26 27 62039 Ramipril 1.25mg tablets (Zentiva) 28 62064 Diltiazem 120mg modified-release tablets (Mawdsley-Brooks & Company Ltd) 29 62065 Diltiazem 90mg modified-release tablets (Colorama Pharmaceuticals Ltd) 30 31 62066 Cardide SR 1.5mg tablets (Teva UK Ltd) 32 62140 Candesartan 4mg tablets (Sandoz Ltd) 33 34 62158 Doxazosin 4mg tablets (Almus Pharmaceuticals Ltd) 35 62207 Adizem-SR 120mg capsules (Waymade Healthcare Plc) 36 62249 Co-amilozide 5mg/50mg tablets (Alliance Healthcare (Distribution) Ltd) 37 38 62300 Phenoxybenzamine 10mg capsules (AMCo) http://bmjopen.bmj.com/ 39 62325 Atenolol 25mg tablets (Waymade Healthcare Plc) 40 62337 Irbesartan 300mg / Hydrochlorothiazide 12.5mg tablets (Actavis UK Ltd) 41 42 62351 Doxazosin 2mg tablets (Phoenix Healthcare Distribution Ltd) 43 62361 Bisoprolol 1.25mg tablets (Chanelle Medical UK Ltd) 44 45 62376 Actelsar HCT 80mg/12.5mg tablets (Actavis UK Ltd) 46 62388 Losartan 12.5mg tablets (DE Pharmaceuticals) on September 25, 2021 by guest. Protected copyright. 47 62407 Bisoprolol oral solution 48 49 62415 Irbesartan 300mg tablets (A A H Pharmaceuticals Ltd) 50 62513 Methyldopa 250mg tablets (Sovereign Medical Ltd) 51 62516 Hydrochlorothiazide 12.5mg tablets 52 53 62537 Co-tenidone 100mg/25mg tablets (DE Pharmaceuticals) 54 62552 Verapamil 80mg tablets (Alliance Healthcare (Distribution) Ltd) 55 56 62553 Tamsulosin 400microgram modified-release capsules (Alliance Healthcare (Distribution) 57 Ltd) 58 62564 Lisinopril 10mg/5ml oral solution 59 62638 Labetalol 100mg tablets (Actavis UK Ltd) 60 62659 Sildenafil 12.5mg/5ml oral suspension

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1 2 Medical code list: 'at risk' of hypercholesterolaemia 3 Read Code Read Code BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 1W1..00 Possible familial hypercholesterolaemia 6 44P2.00 Serum cholesterol borderline 7 44P3.00 Serum cholesterol raised 8 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: hypercholesterolaemia 3 Read Code Read Code BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 1W2..00 Probable familial hypercholesterolaemia 6 44P4.00 Serum cholesterol very high 7 C320.00 Pure hypercholesterolaemia 8 C320.11 Familial hypercholesterolaemia 9 10 C320000 Familial hypercholesterolaemia 11 C320600 Polygenic hypercholesterolaemia 12 C320y00 Other specified pure hypercholesterolaemia 13 14 C320z00 Pure hypercholesterolaemia NOS 15 C329.00 Hypercholesterolaemia 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for hypercholesterolaemia 3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 25 Simvastatin 20mg tablets 6 28 Atorvastatin 10mg tablets 7 8 42 Simvastatin 10mg tablets 9 51 Simvastatin 40mg tablets 10 75 Atorvastatin 20mg tablets 11 12 184 Bezafibrate 200mg tablets 13 379 Fluvastatin 20mg capsules 14 420 Cerivastatin 100microgram tablets 15 16 490 Pravastatin 10mg tablets 17 602 Bezafibrate 400mg modified-release tabletsFor peer review only 18 644 Colestyramine 4g oral powder sachets 19 20 653 Ezetimibe 10mg tablets 21 713 Rosuvastatin 10mg tablets 22 23 730 Pravastatin 20mg tablets 24 745 Atorvastatin 40mg tablets 25 802 Simvador 40mg tablets (Discovery Pharmaceuticals Ltd) 26 27 818 Simvastatin 20mg/5ml oral solution sugar free 28 1212 Colestipol 5g granules sachets sugar free 29 1214 Bezalip 400mg Tablet (Roche Products Ltd) 30 31 1215 Fenofibrate 100mg Capsule 32 1217 Lipantil micro 200 200mg Capsule (Fournier Pharmaceuticals Ltd) 33 34 1219 Pravastatin 40mg tablets 35 1221 Lipostat 10mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 36 1223 Lipostat 40mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 37 38 1322 Clofibrate 500mg capsules http://bmjopen.bmj.com/ 39 1324 Bezalip 200mg Tablet (Roche Products Ltd) 40 1477 Atromid -s 500mg Capsule (AstraZeneca UK Ltd) 41 42 1716 Questran 4g oral powder sachets (Bristol-Myers Squibb Pharmaceuticals Ltd) 43 1764 Questran Light 4g oral powder sachets (Bristol-Myers Squibb Pharmaceuticals Ltd) 44 45 2137 Fluvastatin 40mg capsules 46 2215 Lopid 300mg capsules (Pfizer Ltd) on September 25, 2021 by guest. Protected copyright. 47 2435 Lipantil 100mg Capsule (Fournier Pharmaceuticals Ltd) 48 49 2662 MaxEPA 1g capsules (Seven Seas Ltd) 50 2718 Zocor 10mg tablets (Merck Sharp & Dohme Ltd) 51 2955 Lipitor 40mg tablets (Pfizer Ltd) 52 53 3089 Ciprofibrate 100mg tablets 54 3159 Fenofibrate 200mg capsules 55 56 3204 MaxEPA liquid (Seven Seas Ltd) 57 3318 Gemfibrozil 300mg capsules 58 3411 Lipitor 10mg tablets (Pfizer Ltd) 59 60 3690 Lipostat 20mg tablets (Bristol-Myers Squibb Pharmaceuticals Ltd) 4062 Lopid 600mg tablets (Pfizer Ltd) 4067 Olbetam 250mg capsules (Pfizer Ltd)

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1 2 4920 Fenofibrate micronised 200mg capsules 3 4928 Lipantil Micro 200 capsules (Abbott Healthcare Products Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 4961 Lipobay 300microgram Tablet (Bayer Plc) 6 5009 Cerivastatin 200microgram tablets 7 8 5148 Simvastatin 80mg tablets 9 5216 Bezalip mono 400mg Modified-release tablet (Roche Products Ltd) 10 5251 Cerivastatin 300microgram tablets 11 12 5278 Cerivastatin 400microgram tablets 13 5390 Fenofibrate micronised 267mg capsules 14 5564 Colestid Orange sachets (Pharmacia Ltd) 15 16 5775 Atorvastatin 80mg tablets 17 5985 Lescol XL 80mg tablets (Novartis Pharmaceuticals UK Ltd)For peer review only 18 6024 Eicosapentaenoic acid 460mg / Docosahexaenoic acid 380mg capsules 19 20 6120 Ezetrol 10mg tablets (Merck Sharp & Dohme Ltd) 21 6155 Colestyramine with aspartame 4g sugar free powder 22 23 6168 Zocor 40mg tablets (Merck Sharp & Dohme Ltd) 24 6213 Rosuvastatin 20mg tablets 25 6365 Colestid 5g granules sachets plain (Pfizer Ltd) 26 27 6572 Omacor capsules (Abbott Healthcare Products Ltd) 28 7196 Zocor 20mg tablets (Merck Sharp & Dohme Ltd) 29 7347 Crestor 10mg tablets (AstraZeneca UK Ltd) 30 31 7374 Lipitor 20mg tablets (Pfizer Ltd) 32 7540 Lipantil Micro 267 capsules (Abbott Healthcare Products Ltd) 33 34 7544 Niaspan 750mg modified-release tablets (Abbott Laboratories Ltd) 35 7551 Niaspan 1g modified-release tablets (Abbott Laboratories Ltd) 36 7552 Simvastatin 20mg / Ezetimibe 10mg tablets 37 38 7554 Rosuvastatin 5mg tablets http://bmjopen.bmj.com/ 39 8082 Gemfibrozil 600mg tablets 40 8104 Acipimox 250mg capsules 41 42 8380 Lescol 20mg capsules (Novartis Pharmaceuticals UK Ltd) 43 8706 Modalim 100mg tablets (Sanofi) 44 45 9153 Lescol 40mg capsules (Novartis Pharmaceuticals UK Ltd) 46 9315 Lipobay 100microgram Tablet (Bayer Plc) on September 25, 2021 by guest. Protected copyright. 47 9316 Lipobay 200microgram Tablet (Bayer Plc) 48 49 9491 Fenofibrate micronised 67mg capsules 50 9639 Fenofibrate micronised 160mg tablets 51 9716 Supralip 160mg tablets (Abbott Healthcare Products Ltd) 52 53 9897 Rosuvastatin 40mg tablets 54 9920 Simvador 20mg tablets (Discovery Pharmaceuticals Ltd) 55 56 9930 Crestor 40mg tablets (AstraZeneca UK Ltd) 57 10094 Niaspan titration pack (Abbott Laboratories Ltd) 58 10172 Simvastatin 40mg / Ezetimibe 10mg tablets 59 60 10183 Simvastatin 40mg with ezetimibe 10mg tablet 10206 Simvastatin 80mg with ezetimibe 10mg tablet 11627 Fluvastatin 80mg modified-release tablets

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1 2 11785 Colestyramine 4g oral powder sachets sugar free 3 11815 Simvastatin 20mg with ezetimibe 10mg tablet BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 11976 Niaspan 500mg modified-release tablets (Abbott Laboratories Ltd) 6 12211 Nicotinic acid 50mg tablets 7 8 13041 Simvador 10mg tablets (Discovery Pharmaceuticals Ltd) 9 14037 Eicosapentaenoic acid 170mg / Docosahexaenoic acid 115mg capsules 10 14209 Eicosapentaenoic acid 170mg/g / Docosahexaenoic acid 115mg/g oral liquid 11 12 14219 Simvastatin 80mg / Ezetimibe 10mg tablets 13 14379 Lipantil Micro 67 capsules (Abbott Healthcare Products Ltd) 14 14963 Nicotinic acid 500mg modified-release tablets 15 16 15209 Crampex tablets (Thornton & Ross Ltd) 17 15252 Crestor 20mg tablets (AstraZeneca UK Ltd)For peer review only 18 16186 Inegy 10mg/80mg tablets (Merck Sharp & Dohme Ltd) 19 20 17059 Inegy 10mg/40mg tablets (Merck Sharp & Dohme Ltd) 21 17614 Zimbacol XL 400mg tablets (Archimedes Pharma UK Ltd) 22 23 17683 Lipitor 80mg tablets (Pfizer Ltd) 24 17688 Crestor 5mg tablets (AstraZeneca UK Ltd) 25 17813 Nicotinic acid 100mg Tablet 26 27 17824 Nicotinic acid 25mg Tablet 28 18081 Colestid Orange 5g granules sachets (Pfizer Ltd) 29 18098 Nicotinic acid 375mg + 500mg + 750mg Modified-release tablet 30 31 18126 Nicotinic acid 1g modified-release tablets 32 18442 Lipobay 400microgram Tablet (Bayer Plc) 33 34 19938 Colestipol with aspartame granules 35 21020 Inegy 10mg/20mg tablets (Merck Sharp & Dohme Ltd) 36 21924 Acetomenapthone 7mg / Nicotinic acid 25mg tablets 37 38 22579 Zocor 80mg tablets (Merck Sharp & Dohme Ltd) http://bmjopen.bmj.com/ 39 23153 Liparol 400 XL tablets (Ashbourne Pharmaceuticals Ltd) 40 23956 Maxepa Liquid (Seven Seas Ltd) 41 42 24084 Colestyramine 4g oral powder sachets sugar free (PLIVA Pharma Ltd) 43 24583 Nicotinic acid 750mg modified-release tablets 44 45 29213 Bezagen XL 400mg tablets (Generics (UK) Ltd) 46 29328 Bezafibrate 200mg tablets (A A H Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 31221 Bezafibrate 200mg tablets (Generics (UK) Ltd) 48 49 31658 Cerivastatin 800microgram tablets 50 31783 Fenogal 200mg capsules (Genus Pharmaceuticals Ltd) 51 31930 Zocor heart-pro 10mg Tablet (McNeil Products Ltd) 52 53 32110 Colestyramine 4g Sachets (Dominion Pharma) 54 32909 Simvastatin 80mg tablets (A A H Pharmaceuticals Ltd) 55 56 32921 Pravastatin 10mg Tablet (Dr Reddy's Laboratories (UK) Ltd) 57 33082 Simvastatin 20mg tablets (A A H Pharmaceuticals Ltd) 58 33603 Fibrazate XL 400mg tablets (Sandoz Ltd) 59 60 33944 Bezafibrate 200mg tablets (Teva UK Ltd) 34181 Bezafibrate 400mg Modified-release tablet (Hillcross Pharmaceuticals Ltd) 34201 Colestyramine 4g oral powder sachets sugar free (Actavis UK Ltd)

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1 2 34277 Gemfibrozil 600mg tablets (Teva UK Ltd) 3 34312 Simvastatin 20mg tablets (Generics (UK) Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 34316 Simvastatin 20mg tablets (Teva UK Ltd) 6 34353 Simvastatin 40mg tablets (Generics (UK) Ltd) 7 8 34366 Simvastatin 20mg tablets (IVAX Pharmaceuticals UK Ltd) 9 34376 Simvastatin 40mg tablets (Teva UK Ltd) 10 34381 Simvastatin 40mg tablets (IVAX Pharmaceuticals UK Ltd) 11 12 34476 Simvastatin 20mg Tablet (Ratiopharm UK Ltd) 13 34481 Simvastatin 10mg tablets (IVAX Pharmaceuticals UK Ltd) 14 34502 Simvastatin 40mg tablets (A A H Pharmaceuticals Ltd) 15 16 34535 Simvastatin 10mg tablets (Generics (UK) Ltd) 17 34545 Simvastatin 40mg Tablet (Ratiopharm UK Ltd)For peer review only 18 34560 Simvastatin 10mg Tablet (Ratiopharm UK Ltd) 19 20 34746 Simvastatin 20mg Tablet (Niche Generics Ltd) 21 34814 Simvastatin 20mg tablets (Wockhardt UK Ltd) 22 23 34820 Pravastatin 40mg tablets (A A H Pharmaceuticals Ltd) 24 34879 Simvastatin 40mg Tablet (Niche Generics Ltd) 25 34891 Simvastatin 20mg tablets (Kent Pharmaceuticals Ltd) 26 27 34907 Simvastatin 40mg tablets (Wockhardt UK Ltd) 28 34955 Simvastatin 10mg tablets (A A H Pharmaceuticals Ltd) 29 34969 Simvastatin 40mg tablets (Actavis UK Ltd) 30 31 36377 Pravastatin 20mg tablets (Teva UK Ltd) 32 37266 Colesevelam 625mg tablets 33 34 37434 Simvastatin 40mg tablets (Sandoz Ltd) 35 37953 Cholestagel 625mg tablets (Sanofi) 36 39060 Simvastatin 20mg tablets (Dexcel-Pharma Ltd) 37 38 39420 Bezalip Mono 400mg modified-release tablets (Actavis UK Ltd) http://bmjopen.bmj.com/ 39 39576 Bezalip 200mg tablets (Actavis UK Ltd) 40 39652 Simvastatin 40mg/5ml oral solution sugar free 41 42 39675 Simvastatin 20mg/5ml Oral suspension (Martindale Pharmaceuticals Ltd) 43 39870 Simvador 80mg tablets (Discovery Pharmaceuticals Ltd) 44 45 40340 Simvastatin 10mg tablets (Teva UK Ltd) 46 40382 Pravastatin 20mg tablets (A A H Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 47 40601 Simvastatin 20mg tablets (Ranbaxy (UK) Ltd) 48 49 40729 Tredaptive 1000mg/20mg modified-release tablets (Merck Sharp & Dohme Ltd) 50 40885 Nicotinic acid 1g / Laropiprant 20mg modified-release tablets 51 41396 Fenofibrate micronised 200mg capsules (A A H Pharmaceuticals Ltd) 52 53 41657 Simvastatin 80mg tablets (Teva UK Ltd) 54 42801 Bezafibrate xl 400mg Modified-release tablet (Generics (UK) Ltd) 55 56 43218 Pravastatin 10mg tablets (Teva UK Ltd) 57 44528 Simvastatin 20mg/5ml oral suspension sugar free (Rosemont Pharmaceuticals Ltd) 58 44650 Simvastatin 40mg tablets (Dexcel-Pharma Ltd) 59 60 44878 Ranzolont 10mg tablets (Ranbaxy (UK) Ltd) 45219 Simvastatin 40mg tablets (Kent Pharmaceuticals Ltd) 45235 Simvastatin 20mg tablets (Sandoz Ltd)

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1 2 45245 Simvastatin 20mg tablets (Actavis UK Ltd) 3 45346 Simvastatin 40mg tablets (Arrow Generics Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 46878 Simvastatin 40mg tablets (Almus Pharmaceuticals Ltd) 6 46956 Simvastatin 80mg tablets (Arrow Generics Ltd) 7 8 47065 Atorvastatin 20mg chewable tablets sugar free 9 47090 Atorvastatin 10mg chewable tablets sugar free 10 47630 Lipitor 20mg chewable tablets (Pfizer Ltd) 11 12 47721 Lipitor 10mg chewable tablets (Pfizer Ltd) 13 47774 Simvastatin 10mg tablets (Arrow Generics Ltd) 14 47935 Fenofibrate 200mg Capsule (Teva UK Ltd) 15 16 47948 Simvastatin 10mg tablets (Tillomed Laboratories Ltd) 17 47988 Pravastatin 40mg tablets (Generics (UK) Ltd)For peer review only 18 48018 Simvastatin 20mg tablets (Arrow Generics Ltd) 19 20 48051 Simvastatin 10mg tablets (Kent Pharmaceuticals Ltd) 21 48058 Simvastatin 10mg tablets (Ranbaxy (UK) Ltd) 22 23 48078 Simvastatin 10mg tablets (Actavis UK Ltd) 24 48097 Pravastatin 40mg tablets (Teva UK Ltd) 25 48221 Simvastatin 20mg/5ml oral suspension sugar free 26 27 48346 Atorvastatin 60mg tablets 28 48431 Simvastatin 40mg/5ml oral suspension sugar free 29 48518 Atorvastatin 10mg/5ml oral solution 30 31 48867 Simvastatin 40mg tablets (Alliance Healthcare (Distribution) Ltd) 32 48973 Atorvastatin 30mg tablets 33 34 49061 Simvastatin 40mg tablets (Bristol Laboratories Ltd) 35 49062 Simvastatin 20mg tablets (Alliance Healthcare (Distribution) Ltd) 36 49558 Atorvastatin 20mg tablets (A A H Pharmaceuticals Ltd) 37 38 49587 Simvastatin 80mg tablets (Almus Pharmaceuticals Ltd) http://bmjopen.bmj.com/ 39 49609 Bezafibrate 400mg Modified-release tablet (Sandoz Ltd) 40 49751 Atorvastatin 40mg tablets (Alliance Healthcare (Distribution) Ltd) 41 42 50071 Fenofibrate 160mg Tablet (Teva UK Ltd) 43 50236 Atorvastatin 10mg tablets (Zentiva) 44 45 50272 Atorvastatin 40mg tablets (Pfizer Ltd) 46 50483 Simvastatin 40mg tablets (Relonchem Ltd) on September 25, 2021 by guest. Protected copyright. 47 50564 Simvastatin 20mg tablets (Relonchem Ltd) 48 49 50670 Simvastatin 40mg tablets (Aurobindo Pharma Ltd) 50 50703 Simvastatin 40mg tablets (Accord Healthcare Ltd) 51 50754 Simvastatin 20mg tablets (Medreich Plc) 52 53 50788 Atorvastatin 20mg tablets (Pfizer Ltd) 54 50790 Atorvastatin 20mg tablets (Dexcel-Pharma Ltd) 55 56 50882 Simvastatin 40mg tablets (Somex Pharma) 57 50925 Pravastatin 10mg tablets (Sigma Pharmaceuticals Plc) 58 50963 Atorvastatin 40mg tablets (Teva UK Ltd) 59 60 51085 Simvastatin 10mg tablets (Medreich Plc) 51134 Atorvastatin 10mg tablets (A A H Pharmaceuticals Ltd) 51166 Simvastatin 40mg tablets (Medreich Plc)

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1 2 51200 Atorvastatin 40mg tablets (Arrow Generics Ltd) 3 51233 Simvastatin 10mg tablets (Alliance Healthcare (Distribution) Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 51359 Atorvastatin 20mg tablets (Arrow Generics Ltd) 6 51483 Simvastatin 20mg tablets (Aurobindo Pharma Ltd) 7 8 51622 Atorvastatin 20mg tablets (Consilient Health Ltd) 9 51676 Pravastatin 40mg tablets (Medreich Plc) 10 51715 Simvastatin 10mg tablets (Sigma Pharmaceuticals Plc) 11 12 51876 Atorvastatin 40mg tablets (Consilient Health Ltd) 13 51890 Pravastatin 20mg tablets (Medreich Plc) 14 52097 Atorvastatin 40mg tablets (Wockhardt UK Ltd) 15 16 52098 Simvastatin 40mg tablets (Ranbaxy (UK) Ltd) 17 52168 Atorvastatin 20mg tablets (Aspire Pharma Ltd)For peer review only 18 52211 Atorvastatin 20mg tablets (Actavis UK Ltd) 19 20 52257 Simvastatin 20mg tablets (Accord Healthcare Ltd) 21 52397 Atorvastatin 40mg tablets (Dr Reddy's Laboratories (UK) Ltd) 22 23 52398 Atorvastatin 40mg tablets (A A H Pharmaceuticals Ltd) 24 52459 Atorvastatin 80mg tablets (Actavis UK Ltd) 25 52460 Atorvastatin 40mg tablets (Aspire Pharma Ltd) 26 27 52625 Simvastatin 10mg tablets (Wockhardt UK Ltd) 28 52676 Simvastatin 10mg/5ml oral suspension 29 52755 Pravastatin 20mg tablets (Alliance Healthcare (Distribution) Ltd) 30 31 52812 Simvastatin 20mg tablets (Sigma Pharmaceuticals Plc) 32 52814 Bezafibrate 400mg modified-release tablets (Alliance Healthcare (Distribution) Ltd) 33 34 52821 Atorvastatin 80mg tablets (Dr Reddy's Laboratories (UK) Ltd) 35 52953 Simvastatin 20mg tablets (Bristol Laboratories Ltd) 36 52962 Simvastatin 80mg tablets (Medreich Plc) 37 38 53087 Simvastatin 20mg tablets (Somex Pharma) http://bmjopen.bmj.com/ 39 53250 Modalim 100mg tablets (Lexon (UK) Ltd) 40 53340 Zocor 40mg tablets (Lexon (UK) Ltd) 41 42 53415 Simvastatin 10mg tablets (Aurobindo Pharma Ltd) 43 53460 Crestor 10mg tablets (DE Pharmaceuticals) 44 45 53594 Lipitor 80mg tablets (Mawdsley-Brooks & Company Ltd) 46 53676 Simvastatin 20mg tablets (Tillomed Laboratories Ltd) on September 25, 2021 by guest. Protected copyright. 47 53770 Fluvastatin 40mg capsules (A A H Pharmaceuticals Ltd) 48 49 53772 Atorvastatin 80mg tablets (Alliance Healthcare (Distribution) Ltd) 50 53822 Simvastatin 10mg tablets (Bristol Laboratories Ltd) 51 53887 Atorvastatin 40mg tablets (Actavis UK Ltd) 52 53 53890 Atorvastatin 80mg tablets (Pfizer Ltd) 54 53908 Simvastatin 10mg tablets (Dexcel-Pharma Ltd) 55 56 53966 Simvastatin 40mg tablets (Phoenix Healthcare Distribution Ltd) 57 54240 Simvastatin 40mg tablets (Sigma Pharmaceuticals Plc) 58 54266 Simvastatin 20mg/5ml oral suspension 59 60 54435 Pravastatin 40mg tablets (Almus Pharmaceuticals Ltd) 54493 Simvastatin 10mg tablets (Relonchem Ltd) 54535 Atorvastatin 10mg tablets (Pfizer Ltd)

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1 2 54606 Simvastatin 20mg/5ml oral suspension sugar free (A A H Pharmaceuticals Ltd) 3 54607 Pravastatin 20mg tablets (Almus Pharmaceuticals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 54655 Simvastatin 10mg tablets (Accord Healthcare Ltd) 6 54819 Simvastatin 40mg/5ml oral suspension sugar free (Rosemont Pharmaceuticals Ltd) 7 8 54947 Simvastatin 20mg tablets (Almus Pharmaceuticals Ltd) 9 54976 Simvastatin 10mg tablets (Somex Pharma) 10 54985 Simvastatin 40mg/5ml oral suspension 11 12 54992 Atorvastatin 10mg/5ml oral suspension 13 55032 Atorvastatin 10mg tablets (Dexcel-Pharma Ltd) 14 55034 Atorvastatin 40mg/5ml oral suspension 15 16 55444 Atorvastatin 40mg tablets (Zentiva) 17 55452 Simvastatin 20mg tablets (Phoenix Healthcare Distribution Ltd)For peer review only 18 55727 Atorvastatin 10mg tablets (Actavis UK Ltd) 19 20 55912 Pravastatin 40mg tablets (Alliance Healthcare (Distribution) Ltd) 21 55971 Prestylon 1g capsules (Teva UK Ltd) 22 23 56016 Lipitor 20mg chewable tablets (Pfizer Ltd) 24 56065 Simvastatin 20mg/5ml oral suspension sugar free (Waymade Healthcare Plc) 25 56097 Atorvastatin 10mg chewable tablets sugar free 26 27 56146 Pravastatin 10mg tablets (Waymade Healthcare Plc) 28 56165 Atorvastatin 20mg chewable tablets sugar free 29 56182 Atorvastatin 80mg tablets (Zentiva) 30 31 56248 Atorvastatin 20mg tablets (Sigma Pharmaceuticals Plc) 32 56426 Teromeg 1000mg capsules (AMCo) 33 34 56481 Zocor 10mg tablets (Sigma Pharmaceuticals Plc) 35 56494 Zocor 20mg tablets (Sigma Pharmaceuticals Plc) 36 56564 Atorvastatin 20mg tablets (Almus Pharmaceuticals Ltd) 37 38 56607 Pravastatin 20mg tablets (Waymade Healthcare Plc) http://bmjopen.bmj.com/ 39 56735 Pravastatin 20mg tablets (Generics (UK) Ltd) 40 56841 Atorvastatin 40mg tablets (Dexcel-Pharma Ltd) 41 42 56893 Pravastatin 40mg tablets (Accord Healthcare Ltd) 43 56916 Pravastatin 40mg tablets (PLIVA Pharma Ltd) 44 45 57108 Pravastatin 40mg tablets (Waymade Healthcare Plc) 46 57117 Atorvastatin 80mg tablets (Waymade Healthcare Plc) on September 25, 2021 by guest. Protected copyright. 47 57137 Pravastatin 10mg tablets (Almus Pharmaceuticals Ltd) 48 49 57219 Fenofibrate micronised 200mg capsules (Sandoz Ltd) 50 57234 Omacor capsules (DE Pharmaceuticals) 51 57296 Pravastatin 20mg tablets (Phoenix Healthcare Distribution Ltd) 52 53 57329 Simvastatin 25mg/5ml oral suspension 54 57348 Atorvastatin 10mg tablets (Consilient Health Ltd) 55 56 57397 Pravastatin 10mg tablets (Accord Healthcare Ltd) 57 57489 Ciprofibrate 100mg tablets (Zentiva) 58 57568 Zocor 10mg tablets (Lexon (UK) Ltd) 59 60 57583 Eicosapentaenoic acid 460mg / Docosahexaenoic acid 380mg capsules (Huxley Europe Ltd) 57763 Rosuvastatin 10mg tablets (Waymade Healthcare Plc) 57834 Atorvastatin 40mg tablets (DE Pharmaceuticals)

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1 2 57836 Atorvastatin 80mg tablets (Teva UK Ltd) 3 57999 Crestor 40mg tablets (Lexon (UK) Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 58041 Atorvastatin 20mg tablets (Teva UK Ltd) 6 58110 Atorvastatin 20mg tablets (Zentiva) 7 8 58315 Simvastatin 20mg tablets (Waymade Healthcare Plc) 9 58394 Atorvastatin 20mg tablets (Alliance Healthcare (Distribution) Ltd) 10 58418 Atorvastatin 80mg tablets (A A H Pharmaceuticals Ltd) 11 12 58617 Rosuvastatin 20mg/5ml oral suspension 13 58635 Bezalip Mono 400mg modified-release tablets (DE Pharmaceuticals) 14 58655 Omega 3-acid-ethyl esters 1000mg capsules (Glenmark Generics (Europe) Ltd) 15 16 58742 Atorvastatin 80mg tablets (Arrow Generics Ltd) 17 58755 Simvastatin 10mg tablets (Phoenix Healthcare Distribution Ltd)For peer review only 18 58834 Atorvastatin 10mg tablets (DE Pharmaceuticals) 19 20 58868 Atorvastatin 10mg tablets (Sigma Pharmaceuticals Plc) 21 59002 Bezafibrate 400mg modified-release tablets (DE Pharmaceuticals) 22 23 59272 Atorvastatin 20mg tablets (Waymade Healthcare Plc) 24 59278 Fluvastatin 20mg capsules (Zentiva) 25 59331 Lipitor 10mg tablets (DE Pharmaceuticals) 26 27 59357 Atorvastatin 10mg tablets (Ranbaxy (UK) Ltd) 28 59446 Atorvastatin 40mg tablets (Almus Pharmaceuticals Ltd) 29 59447 Crestor 20mg tablets (Waymade Healthcare Plc) 30 31 59452 Rosuvastatin 5mg tablets (Waymade Healthcare Plc) 32 59508 Pravastatin 20mg tablets (Accord Healthcare Ltd) 33 34 59776 Atorvastatin 80mg tablets (Aspire Pharma Ltd) 35 59859 Atorvastatin 10mg tablets (Teva UK Ltd) 36 60101 Colestyramine 4g oral powder sachets sugar free (Teva UK Ltd) 37 38 60160 Rosuvastatin 5mg tablets (Mawdsley-Brooks & Company Ltd) http://bmjopen.bmj.com/ 39 60251 Pravastatin 10mg tablets (Sandoz Ltd) 40 60385 Bezalip Mono 400mg modified-release tablets (Lexon (UK) Ltd) 41 42 60464 Atorvastatin 20mg/5ml oral suspension 43 60511 Atorvastatin 40mg tablets (Ranbaxy (UK) Ltd) 44 45 60607 Atorvastatin 80mg tablets (DE Pharmaceuticals) 46 60788 Fenofibrate micronised 267mg capsules (Zentiva) on September 25, 2021 by guest. Protected copyright. 47 60989 Atorvastatin 80mg tablets (Phoenix Healthcare Distribution Ltd) 48 49 61087 Questran Light 4g oral powder sachets (Mawdsley-Brooks & Company Ltd) 50 61134 Pravastatin 20mg tablets (Sigma Pharmaceuticals Plc) 51 61149 Atorvastatin 10mg tablets (Waymade Healthcare Plc) 52 53 61155 Simvastatin 40mg/5ml oral suspension sugar free (A A H Pharmaceuticals Ltd) 54 61269 Nebbaro 1000mg capsules (Zentiva) 55 56 61321 Simvastatin 10mg tablets (Sandoz Ltd) 57 61360 Simvastatin 10mg tablets (Almus Pharmaceuticals Ltd) 58 61523 Omega 3 1000mg capsules (Alissa Healthcare Research Ltd) 59 60 61665 Simvastatin 10mg tablets (Waymade Healthcare Plc) 62137 Simvastatin 40mg tablets (Waymade Healthcare Plc) 62148 Fluvastatin 20mg capsules (Actavis UK Ltd)

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1 2 62219 Atorvastatin 20mg tablets (DE Pharmaceuticals) 3 62429 Atorvastatin 20mg tablets (DE Pharmaceuticals) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 62476 Atorvastatin 80mg tablets (Almus Pharmaceuticals Ltd) 6 7 8 9 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: 'at risk' of diabetes 3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 R10D.00 [D]Elevated blood glucose level 6 R102.00 [D]Glucose tolerance test abnormal 7 R105700 [D]Glucose, blood level abnormal 8 R10D011 [D]Impaired fasting glucose 9 10 R10D000 [D]Impaired fasting glycaemia 11 R10E.00 [D]Impaired glucose tolerance 12 R102.12 [D]Impaired glucose tolerance test 13 14 R102.11 [D]Prediabetes 15 14O8.00 At risk of diabetes mellitus 16 44U9.00 Blood glucose abnormal 17 For peer review only 44Uz.00 Blood glucose raised NOS 18 19 C313500 Glucose intolerance 20 44V2.00 Glucose tol. test impaired 21 14O8000 High risk of diabetes mellitus 22 23 C11y300 Impaired fasting glycaemia 24 C11y400 Impaired glucose regulation 25 C11y200 Impaired glucose tolerance 26 C11y500 Pre-diabetes 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: type 2 diabetes 3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C106100 Diabetes mellitus, adult onset, + neurological manifestation 6 C105100 Diabetes mellitus, adult onset, + ophthalmic manifestation 7 C10z100 Diabetes mellitus, adult onset, + unspecified complication 8 C100100 Diabetes mellitus, adult onset, no mention of complication 9 10 C102100 Diabetes mellitus, adult onset, with hyperosmolar coma 11 C101100 Diabetes mellitus, adult onset, with ketoacidosis 12 C103100 Diabetes mellitus, adult onset, with ketoacidotic coma 13 14 C104100 Diabetes mellitus, adult onset, with renal manifestation 15 C107200 Diabetes mellitus, adult with gangrene 16 C10y100 Diabetes mellitus, adult, + other specified manifestation 17 For peer review only C107100 Diabetes mellitus, adult, + peripheral circulatory disorder 18 19 44V3.00 Glucose tol. test diabetic 20 C10FK00 Hyperosmolar non-ketotic state in type 2 diabetes mellitus 21 C109K00 Hyperosmolar non-ketotic state in type 2 diabetes mellitus 22 23 C10FK11 Hyperosmolar non-ketotic state in type II diabetes mellitus 24 C109J11 Insulin treated non-insulin dependent diabetes mellitus 25 C10FJ00 Insulin treated Type 2 diabetes mellitus 26 C109J00 Insulin treated Type 2 diabetes mellitus 27 28 C109J12 Insulin treated Type II diabetes mellitus 29 C10FJ11 Insulin treated Type II diabetes mellitus 30 C109.11 NIDDM - Non-insulin dependent diabetes mellitus 31 32 C109E00 Non-insulin depend diabetes mellitus with diabetic cataract 33 C100112 Non-insulin dependent diabetes mellitus 34 C109.00 Non-insulin dependent diabetes mellitus 35 C109700 Non-insulin dependent diabetes mellitus - poor control 36 37 C109G00 Non-insulin dependent diabetes mellitus with arthropathy 38 C109500 Non-insulin dependent diabetes mellitus with gangrene http://bmjopen.bmj.com/ 39 C109D00 Non-insulin dependent diabetes mellitus with hypoglyca coma 40 41 C109A00 Non-insulin dependent diabetes mellitus with mononeuropathy 42 C109C00 Non-insulin dependent diabetes mellitus with nephropathy 43 C109B00 Non-insulin dependent diabetes mellitus with polyneuropathy 44 C109400 Non-insulin dependent diabetes mellitus with ulcer 45 46 C109300 Non-insulin-dependent diabetes mellitus with multiple comps 47 C109200 Non-insulin-dependent diabetes mellitus with neuro comps on September 25, 2021 by guest. Protected copyright. 48 C109100 Non-insulin-dependent diabetes mellitus with ophthalm comps 49 50 C109000 Non-insulin-dependent diabetes mellitus with renal comps 51 C109600 Non-insulin-dependent diabetes mellitus with retinopathy 52 C109900 Non-insulin-dependent diabetes mellitus without complication 53 L180600 Pre-existing diabetes mellitus, non-insulin-dependent 54 55 C10F.00 Type 2 diabetes mellitus 56 C109.12 Type 2 diabetes mellitus 57 C10F700 Type 2 diabetes mellitus - poor control 58 59 C109712 Type 2 diabetes mellitus - poor control 60 C109G12 Type 2 diabetes mellitus with arthropathy C10FG00 Type 2 diabetes mellitus with arthropathy C109E12 Type 2 diabetes mellitus with diabetic cataract

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1 2 C10FE00 Type 2 diabetes mellitus with diabetic cataract 3 C10FQ00 Type 2 diabetes mellitus with exudative maculopathy BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C10F500 Type 2 diabetes mellitus with gangrene 6 C109512 Type 2 diabetes mellitus with gangrene 7 C10FR00 Type 2 diabetes mellitus with gastroparesis 8 C10FD00 Type 2 diabetes mellitus with hypoglycaemic coma 9 10 C109D12 Type 2 diabetes mellitus with hypoglycaemic coma 11 C10FN00 Type 2 diabetes mellitus with ketoacidosis 12 C10FP00 Type 2 diabetes mellitus with ketoacidotic coma 13 14 C10FA00 Type 2 diabetes mellitus with mononeuropathy 15 C10F300 Type 2 diabetes mellitus with multiple complications 16 C109312 Type 2 diabetes mellitus with multiple complications 17 For peer review only C10FC00 Type 2 diabetes mellitus with nephropathy 18 19 C109C12 Type 2 diabetes mellitus with nephropathy 20 C10F200 Type 2 diabetes mellitus with neurological complications 21 C109212 Type 2 diabetes mellitus with neurological complications 22 23 C10FH00 Type 2 diabetes mellitus with neuropathic arthropathy 24 C109H12 Type 2 diabetes mellitus with neuropathic arthropathy 25 C10F100 Type 2 diabetes mellitus with ophthalmic complications 26 C109112 Type 2 diabetes mellitus with ophthalmic complications 27 28 C10FF00 Type 2 diabetes mellitus with peripheral angiopathy 29 C109F12 Type 2 diabetes mellitus with peripheral angiopathy 30 C10FM00 Type 2 diabetes mellitus with persistent microalbuminuria 31 32 C10FL00 Type 2 diabetes mellitus with persistent proteinuria 33 C10FB00 Type 2 diabetes mellitus with polyneuropathy 34 C109012 Type 2 diabetes mellitus with renal complications 35 C10F000 Type 2 diabetes mellitus with renal complications 36 37 C10F600 Type 2 diabetes mellitus with retinopathy 38 C109612 Type 2 diabetes mellitus with retinopathy http://bmjopen.bmj.com/ 39 C10F400 Type 2 diabetes mellitus with ulcer 40 41 C109412 Type 2 diabetes mellitus with ulcer 42 C10F900 Type 2 diabetes mellitus without complication 43 C109912 Type 2 diabetes mellitus without complication 44 C109.13 Type II diabetes mellitus 45 46 C10F.11 Type II diabetes mellitus 47 C109711 Type II diabetes mellitus - poor control on September 25, 2021 by guest. Protected copyright. 48 C10F711 Type II diabetes mellitus - poor control 49 50 C109G11 Type II diabetes mellitus with arthropathy 51 C10FG11 Type II diabetes mellitus with arthropathy 52 C109E11 Type II diabetes mellitus with diabetic cataract 53 C10FE11 Type II diabetes mellitus with diabetic cataract 54 55 C109511 Type II diabetes mellitus with gangrene 56 C10F511 Type II diabetes mellitus with gangrene 57 C109D11 Type II diabetes mellitus with hypoglycaemic coma 58 59 C10FD11 Type II diabetes mellitus with hypoglycaemic coma 60 C10FN11 Type II diabetes mellitus with ketoacidosis C10FP11 Type II diabetes mellitus with ketoacidotic coma C109A11 Type II diabetes mellitus with mononeuropathy

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1 2 C10FA11 Type II diabetes mellitus with mononeuropathy 3 C10F311 Type II diabetes mellitus with multiple complications BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C109C11 Type II diabetes mellitus with nephropathy 6 C10FC11 Type II diabetes mellitus with nephropathy 7 C109211 Type II diabetes mellitus with neurological complications 8 C10F211 Type II diabetes mellitus with neurological complications 9 10 C109H11 Type II diabetes mellitus with neuropathic arthropathy 11 C10FH11 Type II diabetes mellitus with neuropathic arthropathy 12 C109111 Type II diabetes mellitus with ophthalmic complications 13 14 C10F111 Type II diabetes mellitus with ophthalmic complications 15 C109F11 Type II diabetes mellitus with peripheral angiopathy 16 C10FF11 Type II diabetes mellitus with peripheral angiopathy 17 For peer review only C10FM11 Type II diabetes mellitus with persistent microalbuminuria 18 19 C10FL11 Type II diabetes mellitus with persistent proteinuria 20 C109B11 Type II diabetes mellitus with polyneuropathy 21 C10FB11 Type II diabetes mellitus with polyneuropathy 22 23 C109011 Type II diabetes mellitus with renal complications 24 C10F011 Type II diabetes mellitus with renal complications 25 C10F611 Type II diabetes mellitus with retinopathy 26 C109611 Type II diabetes mellitus with retinopathy 27 28 C109411 Type II diabetes mellitus with ulcer 29 C10F411 Type II diabetes mellitus with ulcer 30 C10F911 Type II diabetes mellitus without complication 31 32 C109911 Type II diabetes mellitus without complication 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: unspecified diabetes 3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 R054200 [D]Gangrene of toe in diabetic 6 R054300 [D]Widespread diabetic foot gangrene 7 Cyu2.00 [X]Diabetes mellitus 8 Kyu0300 [X]Glomerular disorders in diabetes mellitus 9 10 Cyu2000 [X]Other specified diabetes mellitus 11 Cyu2300 [X]Unspecified diabetes mellitus with renal complications 12 F372000 Acute painful diabetic neuropathy 13 14 F420300 Advanced diabetic maculopathy 15 F420500 Advanced diabetic retinal disease 16 F372200 Asymptomatic diabetic neuropathy 17 For peer review only F171100 Autonomic neuropathy due to diabetes 18 19 F420000 Background diabetic retinopathy 20 M037200 Cellulitis in diabetic foot 21 F372100 Chronic painful diabetic neuropathy 22 23 K08yA11 Clinical diabetic nephropathy 24 C10..00 Diabetes mellitus 25 C10P.00 Diabetes mellitus in remission 26 C102z00 Diabetes mellitus NOS with hyperosmolar coma 27 28 C101z00 Diabetes mellitus NOS with ketoacidosis 29 C103z00 Diabetes mellitus NOS with ketoacidotic coma 30 C106z00 Diabetes mellitus NOS with neurological manifestation 31 32 C100z00 Diabetes mellitus NOS with no mention of complication 33 C105z00 Diabetes mellitus NOS with ophthalmic manifestation 34 C10yz00 Diabetes mellitus NOS with other specified manifestation 35 C107z00 Diabetes mellitus NOS with peripheral circulatory disorder 36 37 C10zz00 Diabetes mellitus NOS with unspecified complication 38 C107.11 Diabetes mellitus with gangrene http://bmjopen.bmj.com/ 39 C102.00 Diabetes mellitus with hyperosmolar coma 40 41 C101.00 Diabetes mellitus with ketoacidosis 42 C103.00 Diabetes mellitus with ketoacidotic coma 43 C104z00 Diabetes mellitus with nephropathy NOS 44 C106.00 Diabetes mellitus with neurological manifestation 45 46 C106.12 Diabetes mellitus with neuropathy 47 C100.00 Diabetes mellitus with no mention of complication on September 25, 2021 by guest. Protected copyright. 48 C105.00 Diabetes mellitus with ophthalmic manifestation 49 50 C10y.00 Diabetes mellitus with other specified manifestation 51 C107.00 Diabetes mellitus with peripheral circulatory disorder 52 C106.13 Diabetes mellitus with polyneuropathy 53 C104.00 Diabetes mellitus with renal manifestation 54 55 C10z.00 Diabetes mellitus with unspecified complication 56 C107.12 Diabetes with gangrene 57 66AI.00 Diabetic - good control 58 59 66AJ.00 Diabetic - poor control 60 66AJz00 Diabetic - poor control NOS F381311 Diabetic amyotrophy C106.11 Diabetic amyotrophy

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1 2 F464000 Diabetic cataract 3 N030100 Diabetic Charcot arthropathy BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 N030000 Diabetic cheiroarthropathy 6 N030011 Diabetic cheiropathy 7 F440700 Diabetic iritis 8 F420400 Diabetic maculopathy 9 10 F345000 Diabetic mononeuritis multiplex 11 F35z000 Diabetic mononeuritis NOS 12 F3y0.00 Diabetic mononeuropathy 13 14 C104.11 Diabetic nephropathy 15 F372.12 Diabetic neuropathy 16 G73y000 Diabetic peripheral angiopathy 17 For peer review only F372.11 Diabetic polyneuropathy 18 19 F420.00 Diabetic retinopathy 20 F420z00 Diabetic retinopathy NOS 21 8A13.00 Diabetic stabilisation 22 23 K27y700 Erectile dysfunction due to diabetes mellitus 24 2G5C.00 Foot abnormality - diabetes related 25 2G51000 Foot abnormality - diabetes related 26 F420800 High risk non proliferative diabetic retinopathy 27 28 F420700 High risk proliferative diabetic retinopathy 29 2BBr.00 Impaired vision due to diabetic retinopathy 30 M271000 Ischaemic ulcer diabetic foot 31 32 C10ER00 Latent autoimmune diabetes mellitus in adult 33 C10M.00 Lipoatrophic diabetes mellitus 34 M271200 Mixed diabetic ulcer - foot 35 F381300 Myasthenic syndrome due to diabetic amyotrophy 36 37 K01x100 Nephrotic syndrome in diabetes mellitus 38 M271100 Neuropathic diabetic ulcer - foot http://bmjopen.bmj.com/ 39 F420600 Non proliferative diabetic retinopathy 40 41 C103y00 Other specified diabetes mellitus with coma 42 C101y00 Other specified diabetes mellitus with ketoacidosis 43 C108y00 Other specified diabetes mellitus with multiple comps 44 C106y00 Other specified diabetes mellitus with neurological comps 45 46 C105y00 Other specified diabetes mellitus with ophthalmic complicatn 47 C10yy00 Other specified diabetes mellitus with other spec comps on September 25, 2021 by guest. Protected copyright. 48 C104y00 Other specified diabetes mellitus with renal complications 49 50 C10zy00 Other specified diabetes mellitus with unspecified comps 51 8BL2.00 Patient on maximal tolerated therapy for diabetes 52 F372.00 Polyneuropathy in diabetes 53 L180X00 Pre-existing diabetes mellitus, unspecified 54 55 F420200 Preproliferative diabetic retinopathy 56 F420100 Proliferative diabetic retinopathy 57 K08yA00 Proteinuric diabetic nephropathy 58 59 C314.11 Renal diabetes 60 2BBF.00 Retinal abnormality - diabetes related C108z00 Unspecified diabetes mellitus with multiple complications 66AJ.11 Unstable diabetes

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1 2 C108.11 IDDM-Insulin dependent diabetes mellitus 3 C108900 Insulin dependent diabetes maturity onset BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C10E912 Insulin dependent diabetes maturity onset 6 C100011 Insulin dependent diabetes mellitus 7 C108.00 Insulin dependent diabetes mellitus 8 C10E.12 Insulin dependent diabetes mellitus 9 10 C108800 Insulin dependent diabetes mellitus - poor control 11 C10E812 Insulin dependent diabetes mellitus - poor control 12 C108H00 Insulin dependent diabetes mellitus with arthropathy 13 14 C108F00 Insulin dependent diabetes mellitus with diabetic cataract 15 C10EF12 Insulin dependent diabetes mellitus with diabetic cataract 16 C108600 Insulin dependent diabetes mellitus with gangrene 17 For peer review only C10E612 Insulin dependent diabetes mellitus with gangrene 18 19 C108E00 Insulin dependent diabetes mellitus with hypoglycaemic coma 20 C10EE12 Insulin dependent diabetes mellitus with hypoglycaemic coma 21 C108B00 Insulin dependent diabetes mellitus with mononeuropathy 22 23 C10E312 Insulin dependent diabetes mellitus with multiple complicat 24 C108300 Insulin dependent diabetes mellitus with multiple complicatn 25 C108D00 Insulin dependent diabetes mellitus with nephropathy 26 C10ED12 Insulin dependent diabetes mellitus with nephropathy 27 28 C108C00 Insulin dependent diabetes mellitus with polyneuropathy 29 C10EC12 Insulin dependent diabetes mellitus with polyneuropathy 30 C108700 Insulin dependent diabetes mellitus with retinopathy 31 32 C10E712 Insulin dependent diabetes mellitus with retinopathy 33 C108500 Insulin dependent diabetes mellitus with ulcer 34 C10E512 Insulin dependent diabetes mellitus with ulcer 35 C108200 Insulin-dependent diabetes mellitus with neurological comps 36 37 C10E212 Insulin-dependent diabetes mellitus with neurological comps 38 C108100 Insulin-dependent diabetes mellitus with ophthalmic comps http://bmjopen.bmj.com/ 39 C10E112 Insulin-dependent diabetes mellitus with ophthalmic comps 40 41 C108000 Insulin-dependent diabetes mellitus with renal complications 42 C10E012 Insulin-dependent diabetes mellitus with renal complications 43 C108A00 Insulin-dependent diabetes without complication 44 C10EA12 Insulin-dependent diabetes without complication 45 46 ZRbH.00 Perceived control of insulin-dependent diabetes 47 L180500 Pre-existing diabetes mellitus, insulin-dependent on September 25, 2021 by guest. Protected copyright. 48 C108400 Unstable insulin dependent diabetes mellitus 49 50 C10E412 Unstable insulin dependent diabetes mellitus 51 52 53 54 55 56 57 58 59 60

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1 2 Medical code list: type 1 diabetes 3 Read Code Read Term BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C107000 Diabetes mellitus, juvenile +peripheral circulatory disorder 6 C105000 Diabetes mellitus, juvenile type, + ophthalmic manifestation 7 C10z000 Diabetes mellitus, juvenile type, + unspecified complication 8 C100000 Diabetes mellitus, juvenile type, no mention of complication 9 10 C102000 Diabetes mellitus, juvenile type, with hyperosmolar coma 11 C101000 Diabetes mellitus, juvenile type, with ketoacidosis 12 C103000 Diabetes mellitus, juvenile type, with ketoacidotic coma 13 14 C104000 Diabetes mellitus, juvenile type, with renal manifestation 15 C106000 Diabetes mellitus, juvenile, + neurological manifestation 16 C10E.00 Type 1 diabetes mellitus 17 For peer review only C108.12 Type 1 diabetes mellitus 18 19 C10E800 Type 1 diabetes mellitus - poor control 20 C108812 Type 1 diabetes mellitus - poor control 21 C10E900 Type 1 diabetes mellitus maturity onset 22 23 C108912 Type 1 diabetes mellitus maturity onset 24 C10EH00 Type 1 diabetes mellitus with arthropathy 25 C10EF00 Type 1 diabetes mellitus with diabetic cataract 26 C10EP00 Type 1 diabetes mellitus with exudative maculopathy 27 28 C10E600 Type 1 diabetes mellitus with gangrene 29 C10EQ00 Type 1 diabetes mellitus with gastroparesis 30 C10EE00 Type 1 diabetes mellitus with hypoglycaemic coma 31 32 C108E12 Type 1 diabetes mellitus with hypoglycaemic coma 33 C10EM00 Type 1 diabetes mellitus with ketoacidosis 34 C10EN00 Type 1 diabetes mellitus with ketoacidotic coma 35 C10EB00 Type 1 diabetes mellitus with mononeuropathy 36 37 C10E300 Type 1 diabetes mellitus with multiple complications 38 C10ED00 Type 1 diabetes mellitus with nephropathy http://bmjopen.bmj.com/ 39 C10E200 Type 1 diabetes mellitus with neurological complications 40 41 C108212 Type 1 diabetes mellitus with neurological complications 42 C108J12 Type 1 diabetes mellitus with neuropathic arthropathy 43 C10EJ00 Type 1 diabetes mellitus with neuropathic arthropathy 44 C10E100 Type 1 diabetes mellitus with ophthalmic complications 45 46 C108112 Type 1 diabetes mellitus with ophthalmic complications 47 C10EG00 Type 1 diabetes mellitus with peripheral angiopathy on September 25, 2021 by guest. Protected copyright. 48 C10EL00 Type 1 diabetes mellitus with persistent microalbuminuria 49 50 C10EK00 Type 1 diabetes mellitus with persistent proteinuria 51 C10EC00 Type 1 diabetes mellitus with polyneuropathy 52 C108012 Type 1 diabetes mellitus with renal complications 53 C10E000 Type 1 diabetes mellitus with renal complications 54 55 C10E700 Type 1 diabetes mellitus with retinopathy 56 C108712 Type 1 diabetes mellitus with retinopathy 57 C10E500 Type 1 diabetes mellitus with ulcer 58 59 C108512 Type 1 diabetes mellitus with ulcer 60 C10EA00 Type 1 diabetes mellitus without complication C10E.11 Type I diabetes mellitus C108.13 Type I diabetes mellitus

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1 2 C108811 Type I diabetes mellitus - poor control 3 C10E811 Type I diabetes mellitus - poor control BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 C10P000 Type I diabetes mellitus in remission 6 C108911 Type I diabetes mellitus maturity onset 7 C10E911 Type I diabetes mellitus maturity onset 8 C108H11 Type I diabetes mellitus with arthropathy 9 10 C108F11 Type I diabetes mellitus with diabetic cataract 11 C10EP11 Type I diabetes mellitus with exudative maculopathy 12 C10E611 Type I diabetes mellitus with gangrene 13 14 C10EQ11 Type I diabetes mellitus with gastroparesis 15 C108E11 Type I diabetes mellitus with hypoglycaemic coma 16 C10EM11 Type I diabetes mellitus with ketoacidosis 17 For peer review only C10EN11 Type I diabetes mellitus with ketoacidotic coma 18 19 C108B11 Type I diabetes mellitus with mononeuropathy 20 C10E311 Type I diabetes mellitus with multiple complications 21 C108311 Type I diabetes mellitus with multiple complications 22 23 C108D11 Type I diabetes mellitus with nephropathy 24 C108211 Type I diabetes mellitus with neurological complications 25 C108J11 Type I diabetes mellitus with neuropathic arthropathy 26 C10E111 Type I diabetes mellitus with ophthalmic complications 27 28 C10EL11 Type I diabetes mellitus with persistent microalbuminuria 29 C10EC11 Type I diabetes mellitus with polyneuropathy 30 C108011 Type I diabetes mellitus with renal complications 31 32 C108711 Type I diabetes mellitus with retinopathy 33 C10E711 Type I diabetes mellitus with retinopathy 34 C108511 Type I diabetes mellitus with ulcer 35 C10E511 Type I diabetes mellitus with ulcer 36 37 C10EA11 Type I diabetes mellitus without complication 38 C108A11 Type I diabetes mellitus without complication http://bmjopen.bmj.com/ 39 C10E400 Unstable type 1 diabetes mellitus 40 41 C108412 Unstable type 1 diabetes mellitus 42 C10E411 Unstable type I diabetes mellitus 43 C108411 Unstable type I diabetes mellitus 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: treatments for type 2 diabetes 3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 4163 Rapitard MC 100unit/ml Injection (Novo Nordisk Ltd) 6 13416 Insulin biphasic 100 units/ml Injection 7 16142 Insulin aspart 100units/ml solution for injection 3ml cartridges 8 53251 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (DE Pharmaceuticals) 9 10 11 10067 Insulin biphasic aspart human pyr 30:70; 100 units/ml Injection 12 5892 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 13 14 Ltd) 15 11337 NovoRapid Novolet 100units/ml solution for injection (Novo Nordisk Ltd) 16 6061 Novomix 30 30/70 100units/ml Injection (Novo Nordisk Ltd) 17 For peer review only 53118 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Mawdsley- 18 19 Brooks & Company Ltd) 20 29567 Insulin aspart 100units/ml solution for injection 10ml vials 21 6209 NovoRapid 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 22 23 6447 Insulin aspart human pyr 100 iu/ml Injection 24 59533 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Sigma 25 Pharmaceuticals Plc) 26 51743 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Sigma 27 28 Pharmaceuticals Plc) 29 49108 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Necessity Supplies 30 Ltd) 31 32 46666 NovoRapid FlexTouch 100units/ml solution for injection 3ml pre-filled pen (Novo 33 Nordisk Ltd) 34 19877 Insulin aspart 100units/ml solution for injection 3ml pre-filled disposable devices 35 5021 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 36 37 56489 NovoMix 30 Penfill 100units/ml suspension for injection 3ml cartridges (Waymade 38 Healthcare Plc) http://bmjopen.bmj.com/ 39 7267 NovoMix 30 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 40 41 Ltd) 42 23099 Insulin aspart biphasic 30/70 100units/ml suspension for injection 3ml pre-filled 43 disposable devices 44 7228 NovoMix 30 FlexPen 100units/ml suspension for injection 3ml pre-filled pen (Novo 45 46 Nordisk Ltd) 47 24795 Insulin aspart biphasic 30/70 100units/ml suspension for injection 3ml cartridges on September 25, 2021 by guest. Protected copyright. 48 55462 Tresiba FlexTouch 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 49 50 Ltd) 51 55910 Tresiba Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 52 55234 Tresiba FlexTouch 200units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 53 Ltd) 54 55 55907 Insulin degludec 100units/ml solution for injection 3ml cartridges 56 6958 Levemir FlexPen 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk Ltd) 57 55618 Levemir FlexPen 100units/ml solution for injection 3ml pre-filled pen (Waymade 58 59 Healthcare Plc) 60 35260 Levemir InnoLet 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk Ltd) 6965 Levemir Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 14301 Insulin detemir 100units/ml solution for injection 3ml cartridges

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1 2 14330 Insulin detemir 100units/ml solution for injection 3ml pre-filled disposable devices 3 10184 Insulin detemir 100 iu/ml Solution for injection BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 7400 Insulin glargine 100units/ml solution for injection 3ml pre-filled disposable devices 6 5953 Insulin glargine 100iu/ml Injection 7 10225 Lantus 100units/ml solution for injection 3ml OptiClik cartridges (Sanofi) 8 36853 Lantus 100units/ml solution for injection 3ml pre-filled SoloStar pen (Sanofi) 9 10 7266 Lantus 100units/ml solution for injection 3ml cartridges (Sanofi) 11 10259 Insulin glargine 100units/ml solution for injection 10ml vials 12 7393 Insulin glargine 100units/ml solution for injection 3ml cartridges 13 14 50633 Lantus 100units/ml solution for injection 3ml cartridges (Necessity Supplies Ltd) 15 6057 Lantus 100iu/ml Injection (Aventis Pharma) 16 56495 Lantus 100units/ml solution for injection 3ml pre-filled OptiSet pen (Waymade 17 For peer review only Healthcare Plc) 18 19 7237 Lantus 100units/ml solution for injection 3ml pre-filled OptiSet pen (Sanofi) 20 7402 Lantus 100units/ml solution for injection 10ml vials (Sanofi) 21 49831 Lantus 100units/ml solution for injection 3ml pre-filled SoloStar pen (Necessity Supplies 22 23 Ltd) 24 29953 Apidra 100units/ml solution for injection 3ml OptiClik cartridges (Sanofi) 25 21583 Apidra 100units/ml solution for injection 3ml pre-filled OptiSet pen (Sanofi) 26 28101 Insulin glulisine 100units/ml solution for injection 10ml vials 27 28 28442 Insulin glulisine 100unit/ml Solution for injection 29 14345 Apidra 100units/ml solution for injection 3ml cartridges (Sanofi) 30 21590 Insulin glulisine 100units/ml solution for injection 3ml pre-filled disposable devices 31 32 36920 Apidra 100units/ml solution for injection 3ml pre-filled SoloStar pen (Sanofi) 33 19491 Apidra 100units/ml solution for injection 10ml vials (Sanofi) 34 14299 Insulin glulisine 100units/ml solution for injection 3ml cartridges 35 53710 Insulin human 500units/ml solution for injection 20ml vials 36 37 36356 Insulin human 3mg inhalation powder blisters 38 31465 Exubera 1mg inhalation powder blisters (Pfizer Ltd) http://bmjopen.bmj.com/ 39 62276 Humulin R 500units/ml solution for injection 20ml vials (Imported (United States)) 40 41 36355 Insulin human 1mg inhalation powder blisters 42 31467 Exubera 3mg inhalation powder blisters (Pfizer Ltd) 43 28588 Hypurin Bovine Isophane 100units/ml suspension for injection 3ml cartridges 44 (Wockhardt UK Ltd) 45 46 30236 Isophane insulin 100iu/ml Injection 47 36066 Insulin isophane bovine 100units/ml suspension for injection 3ml cartridges on September 25, 2021 by guest. Protected copyright. 48 15484 Insulin isophane bovine 100units/ml suspension for injection 1.5ml cartridges 49 50 18590 Insulin isophane bovine 100units/ml suspension for injection 10ml vials 51 47856 Neuphane 100unit/ml Injection (Wellcome Medical Division) 52 14340 Hypurin Bovine Isophane 100units/ml suspension for injection 10ml vials (Wockhardt UK 53 Ltd) 54 55 13516 Hypurin bovine isophane 100unit/ml Injection (C P Pharmaceuticals Ltd) 56 38422 Isophane 100iu/ml Injection (Celltech Pharma Europe Ltd) 57 43950 Humulin I KwikPen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly and 58 59 Company Ltd) 60 10207 Insulin isophane human 100units/ml suspension for injection 3ml cartridges 14928 Insulatard 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 8118 Humaject i 100iu/ml Pen (Eli Lilly and Company Ltd)

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1 2 35468 Insuman Basal 100units/ml suspension for injection 5ml vials (Sanofi) 3 9737 Insulatard innolet 100iu/ml Injection (Novo Nordisk Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 27461 Insuman Basal 100units/ml suspension for injection 3ml cartridges (Sanofi) 6 33966 Insulatard 100unit/ml Injection (Novo Nordisk Ltd) 7 4760 Humulin i 100unit/ml Injection (Eli Lilly and Company Ltd) 8 14918 Humulin I 100units/ml suspension for injection 10ml vials (Eli Lilly and Company Ltd) 9 10 13729 Insulin isophane human emp 100unit/ml Injection 11 1593 Insulatard penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 12 23992 Insuman Basal 100units/ml suspension for injection 3ml pre-filled OptiSet pen (Sanofi) 13 14 14925 Insulin isophane human vial 100unit/ml Sterile suspension injection 15 55517 Insulin isophane human 100units/ml suspension for injection 10ml vials 16 7771 Human protaphane penfill 100 100unit/ml Penfill (Novo Nordisk Ltd) 17 For peer review only 52748 Insulatard Penfill 100units/ml suspension for injection 3ml cartridges (Waymade 18 19 Healthcare Plc) 20 11080 Insulin isophane human prb 100iu/ml Injection 21 5501 Insuman basal 100iu/ml Injection (Aventis Pharma) 22 23 10175 Insulin isophane human 100units/ml suspension for injection 1.5ml cartridges 24 59500 Insulin isophane human 100units/ml suspension for injection 5ml vials 25 7772 Human protaphane 100unit/ml Injection (Novo Nordisk Ltd) 26 1595 Insulatard NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) 27 28 1886 Insulatard 100iu/ml GE injection (Novo Nordisk Ltd) 29 46001 Insuman Basal 100units/ml suspension for injection 3ml pre-filled SoloStar pen (Sanofi) 30 5891 Insulatard FlexPen 100units/ml suspension for injection (Novo Nordisk Ltd) 31 32 14357 Humulin I 100units/ml suspension for injection 3ml cartridges (Eli Lilly and Company Ltd) 33 34 10208 Insulatard InnoLet 100units/ml suspension for injection 3ml pre-filled pen (Novo Nordisk 35 Ltd) 36 37 15961 Insulin isophane human crb 100iu/ml Injection 38 14290 Insulatard Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk Ltd) http://bmjopen.bmj.com/ 39 25812 Insulin isophane human 100units/ml suspension for injection 3ml pre-filled disposable 40 41 devices 42 10229 Humulin I Pen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly and 43 Company Ltd) 44 20422 Insuman comb 15 100iu/ml Injection (Aventis Pharma) 45 46 1843 Pork Insulatard 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 47 7350 Insulin isophane porcine 100units/ml suspension for injection 10ml vials on September 25, 2021 by guest. Protected copyright. 48 13819 Hypurin Porcine Isophane 100units/ml suspension for injection 1.5ml cartridges (C P 49 50 Pharmaceuticals Ltd) 51 28183 Hypurin Porcine Isophane 100units/ml suspension for injection 10ml vials (Wockhardt 52 UK Ltd) 53 30686 Insulin isophane porcine 100units/ml suspension for injection 3ml cartridges 54 55 8895 Initard 50/50 100unit/ml Injection (Novo Nordisk Ltd) 56 4247 Insulin isophane porcine 100units/ml suspension for injection 1.5ml cartridges 57 14933 Hypurin Porcine Isophane 100units/ml suspension for injection 3ml cartridges 58 59 (Wockhardt UK Ltd) 60 18224 Humalog 100units/ml solution for injection 10ml vials (Eli Lilly and Company Ltd) 57564 Humalog KwikPen 100units/ml solution for injection 3ml pre-filled pen (Waymade Healthcare Plc)

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1 2 7318 Humalog 100units/ml solution for injection 3ml cartridges (Eli Lilly and Company Ltd) 3 57529 Humalog 100units/ml solution for injection 10ml vials (Dowelhurst Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 26060 Insulin lispro 100units/ml solution for injection 10ml vials 6 5214 Insulin lispro 100units/ml solution for injection 1.5ml cartridges 7 5250 Insulin biphasic lispro human prb 25:75; 100 units/ml Injection 8 14313 Insulin lispro 100units/ml solution for injection 3ml cartridges 9 10 322 Humalog 100units/ml solution for injection 1.5ml cartridges (Eli Lilly and Company Ltd) 11 14362 Insulin lispro 100units/ml solution for injection 3ml pre-filled disposable devices 12 38986 Humalog KwikPen 100units/ml solution for injection 3ml pre-filled pen (Eli Lilly and 13 14 Company Ltd) 15 4715 Humalog mix 25 25/75 100units/ml Injection (Eli Lilly and Company Ltd) 16 27177 Insulin biphasic lispro human prb 50:50; 100 units/ml Injection 17 For peer review only 10264 Humalog Pen 100units/ml solution for injection 3ml pre-filled pen (Eli Lilly and Company 18 19 Ltd) 20 55603 Humalog KwikPen 100units/ml solution for injection 3ml pre-filled pen (DE 21 Pharmaceuticals) 22 23 18593 Humalog Mix50 100units/ml suspension for injection 3ml cartridges (Eli Lilly and 24 Company Ltd) 25 43953 Insulin lispro biphasic 25/75 100units/ml suspension for injection 10ml vials 26 42395 Humalog Mix25 100units/ml suspension for injection 10ml vials (Eli Lilly and Company 27 28 Ltd) 29 36146 Insulin lispro biphasic 50/50 100units/ml suspension for injection 3ml cartridges 30 57622 Humalog Mix50 KwikPen 100units/ml suspension for injection 3ml pre-filled pen 31 32 (Waymade Healthcare Plc) 33 52522 Humalog Mix50 KwikPen 100units/ml suspension for injection 3ml pre-filled pen (DE 34 Pharmaceuticals) 35 35701 Insulin lispro biphasic 50/50 100units/ml suspension for injection 3ml pre-filled 36 37 disposable devices 38 10001 Humalog Mix50 Pen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly and http://bmjopen.bmj.com/ 39 Company Ltd) 40 41 39086 Humalog Mix50 KwikPen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly 42 and Company Ltd) 43 31258 Insulin lispro biphasic 25/75 100units/ml suspension for injection 3ml pre-filled 44 disposable devices 45 46 10243 Humalog Mix25 100units/ml suspension for injection 3ml cartridges (Eli Lilly and 47 Company Ltd) on September 25, 2021 by guest. Protected copyright. 48 28185 Insulin lispro biphasic 25/75 100units/ml suspension for injection 3ml cartridges 49 50 14270 Humalog Mix25 Pen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly and 51 Company Ltd) 52 39006 Humalog Mix25 KwikPen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly 53 and Company Ltd) 54 55 14505 Insulin protamine zinc bovine 100units/ml suspension for injection 10ml vials 56 9503 Hypurin Bovine Protamine Zinc 100units/ml suspension for injection 10ml vials 57 (Wockhardt UK Ltd) 58 59 18592 Insulin soluble bovine 100units/ml solution for injection 10ml vials 60 14938 Insulin soluble bovine cartridge 100unit/ml Solution for injection 14339 Hypurin Bovine Neutral 100units/ml solution for injection 10ml vials (Wockhardt UK Ltd)

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1 2 23231 Hypurin Bovine Neutral 100units/ml solution for injection 3ml cartridges (Wockhardt UK 3 Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 10572 Insulin soluble bovine 100unit/ml Injection 6 24593 Neutral insulin bovine 100unit/ml Injection 7 12297 Hypurin bovine neutral 100unit/ml Injection (C P Pharmaceuticals Ltd) 8 47360 Neutral insulin 100unit/ml Injection (Celltech Pharma Europe Ltd) 9 10 1592 Actrapid penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 11 56115 Human Actrapid Penfill 100units/ml solution for injection 1.5ml cartridges (Novo Nordisk 12 Ltd) 13 14 22945 Insuman rapid 100iu/ml Injection (Aventis Pharma) 15 10910 Humaject m2 100iu/ml M2 pen (Eli Lilly and Company Ltd) 16 1588 Actrapid 100iu/ml Injection (Novo Nordisk Ltd) 17 For peer review only 4199 Humulin m1 100unit/ml M1 injection (Eli Lilly and Company Ltd) 18 19 10915 Humaject m1 100iu/ml M1 pen (Eli Lilly and Company Ltd) 20 11107 Humulin m4 100unit/ml M4 injection (Eli Lilly and Company Ltd) 21 10887 Penmix 40/60 100iu/ml Penfill (Novo Nordisk Ltd) 22 23 3551 Mixtard 20 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 24 22155 Humaject m5 100iu/ml M5 pen (Eli Lilly and Company Ltd) 25 11056 Insulin biphasic isophane human pyr 30:70; 100 units/ml Injection 26 7349 Actrapid 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 27 28 1649 Human actraphane 100iu/ml Injection (Novo Nordisk Ltd) 29 22058 Pur-in mix 15/85 Injection (C P Pharmaceuticals Ltd) 30 14649 Insulin biphasic isophane human pyr 10:90; 100 units/ml Injection 31 32 2929 Mixtard 30 100iu/ml GE injection (Novo Nordisk Ltd) 33 2454 Mixtard 30 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 34 1806 Penmix 30/70 100iu/ml Penfill (Novo Nordisk Ltd) 35 26403 Pur-in mix 25/75 Injection (C P Pharmaceuticals Ltd) 36 37 10484 Penmix 20/80 Penfill (Novo Nordisk Ltd) 38 3550 Mixtard 40 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) http://bmjopen.bmj.com/ 39 54462 Insulin biphasic isophane human emp 25:75; 100 units/ml Injection 40 41 4198 Humulin m3 100unit/ml M3 injection (Eli Lilly and Company Ltd) 42 17809 Humaject m4 100iu/ml M4 pen (Eli Lilly and Company Ltd) 43 41959 Penject 100unit/ml Injection device (Hypoguard Ltd) 44 14644 Insulin biphasic isophane human prb 20:80; 100 units/ml Injection 45 46 21110 Insulin biphasic isophane human prb 50:50; 100 units/ml Injection 47 24846 Pur-in neutral 100unit/ml Injection (C P Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 48 34097 Human initard 50/50 100unit/ml Injection (Novo Nordisk Ltd) 49 50 12654 Insulin soluble human prb 100unit/ml Injection 51 17336 Novopen 100unit/ml Injection device (Novo Nordisk Ltd) 52 9341 Insulin biphasic isophane human prb 30:70; 100 units/ml Injection 53 16129 Insulin soluble human 100units/ml solution for injection 3ml cartridges 54 55 33167 Insulin biphasic isophane human crb 25:75; 100 units/ml Injection 56 3439 Penmix 10/90 Pen (Novo Nordisk Ltd) 57 11055 Insulin biphasic isophane human pyr 20:80; 100 units/ml Injection 58 59 1840 Humulin s 100unit/ml Injection (Eli Lilly and Company Ltd) 60 21347 Penmix 40/60 100iu/ml Injection (Novo Nordisk Ltd) 13837 Insulin biphasic isophane human prb 10:90; 100 units/ml Injection 5255 Mixtard 10 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd)

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1 2 15199 Insuman comb 25 100iu/ml Injection (Aventis Pharma) 3 15710 Insulin soluble human emp 100unit/ml Injection BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 21395 Insulin biphasic isophane human pyr 40:60; 100 units/ml Injection 6 21374 Insulin biphasic isophane human prb 40:60; 100 units/ml Injection 7 1594 Actrapid NovoLet 100units/ml solution for injection (Novo Nordisk Ltd) 8 22983 Insuman Rapid 100units/ml solution for injection 3ml cartridges (Sanofi) 9 10 26621 Insulin soluble human crb 100iu/ml Injection 11 12638 Insulin soluble human pyr 100unit/ml Injection 12 23993 Insuman Rapid 100units/ml solution for injection 3ml pre-filled OptiSet pen (Sanofi) 13 14 4706 Velosulin 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 15 14944 Humulin S 100units/ml solution for injection 3ml cartridges (Eli Lilly and Company Ltd) 16 27614 Penmix 30/70 100iu/ml Injection (Novo Nordisk Ltd) 17 For peer review only 27402 Insulin soluble human 100units/ml solution for injection 10ml vials 18 19 36430 Insulin soluble human 100units/ml solution for injection 3ml pre-filled disposable 20 devices 21 56502 Actrapid Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 22 23 9565 HumaJect S Pen 100units/ml solution for injection (Eli Lilly and Company Ltd) 24 3396 Penmix 10/90 Penfill (Novo Nordisk Ltd) 25 21235 Humulin S 100units/ml solution for injection 10ml vials (Eli Lilly and Company Ltd) 26 2220 Penmix 20/80 Pen (Novo Nordisk Ltd) 27 28 29837 Insulin biphasic isophane human prb 25:75; 100 units/ml Injection 29 1805 Mixtard 30/70 100unit/ml Injection (Novo Nordisk Ltd) 30 41120 Insulin isophane biphasic human 50/50 100units/ml suspension for injection 3ml pre- 31 32 filled disposable devices 33 10277 Humulin M3 100units/ml suspension for injection 3ml cartridges (Eli Lilly and Company 34 Ltd) 35 2221 Mixtard 30 NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) 36 37 8203 Penmix 50/50 100iu/ml Penfill (Novo Nordisk Ltd) 38 31205 Insuman Comb 50 100units/ml suspension for injection 3ml pre-filled OptiSet pen http://bmjopen.bmj.com/ 39 (Sanofi) 40 41 22697 Insulin isophane biphasic human 50/50 100units/ml suspension for injection 1.5ml 42 cartridges 43 24002 Insuman Comb 25 100units/ml suspension for injection 5ml vials (Sanofi) 44 21554 Insuman comb 50 100iu/ml Injection (Aventis Pharma) 45 46 60938 Mixtard 30 100units/ml suspension for injection 10ml vials (Waymade Healthcare Plc) 47 5933 Mixtard 50 NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) on September 25, 2021 by guest. Protected copyright. 48 60933 Humulin M3 100units/ml suspension for injection 10ml vials (Sigma Pharmaceuticals Plc) 49 50 51 50691 Human Mixtard 20 Penfill 100units/ml suspension for injection 1.5ml cartridges (Novo 52 Nordisk Ltd) 53 16160 Humulin M3 Pen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly and 54 55 Company Ltd) 56 56857 Insulin isophane biphasic human 15/85 100units/ml suspension for injection 3ml 57 cartridges 58 59 17731 Penmix 50/50 100iu/ml Injection (Novo Nordisk Ltd) 60 2812 Mixtard 40 NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) 25736 Insulin isophane biphasic human 10/90 100units/ml suspension for injection 3ml cartridges

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1 2 16152 Insulin isophane biphasic human 30/70 100units/ml suspension for injection 3ml 3 cartridges BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 52722 Human Mixtard 30 Penfill 100units/ml suspension for injection 1.5ml cartridges (Novo 6 Nordisk Ltd) 7 12818 Human Mixtard 50 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 8 21422 Insulin isophane biphasic human 40/60 100units/ml suspension for injection 3ml 9 10 cartridges 11 35253 Insuman Comb 50 100units/ml suspension for injection 3ml cartridges (Sanofi) 12 10245 Mixtard 10 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 13 14 Ltd) 15 43991 Humulin M3 KwikPen 100units/ml suspension for injection 3ml pre-filled pen (Eli Lilly 16 and Company Ltd) 17 For peer review only 36194 Insulin isophane biphasic human 25/75 100units/ml suspension for injection 3ml 18 19 cartridges 20 21232 Insulin isophane biphasic human 30/70 100units/ml suspension for injection 10ml vials 21 13277 Mixtard 50 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 22 23 Ltd) 24 7319 Mixtard 20 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 25 Ltd) 26 25735 Insulin isophane biphasic human 20/80 100units/ml suspension for injection 3ml 27 28 cartridges 29 24993 Insuman Comb 25 100units/ml suspension for injection 3ml cartridges (Sanofi) 30 28096 Insulin isophane biphasic human 50/50 100units/ml suspension for injection 3ml 31 32 cartridges 33 44480 Insuman Comb 25 100units/ml suspension for injection 3ml pre-filled SoloStar pen 34 (Sanofi) 35 7231 Mixtard 30 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 36 37 Ltd) 38 33232 Insulin isophane biphasic human 50/50 100units/ml suspension for injection 5ml vials http://bmjopen.bmj.com/ 39 30819 Insuman Comb 15 100units/ml suspension for injection 3ml pre-filled OptiSet pen 40 41 (Sanofi) 42 10244 Mixtard 40 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 43 Ltd) 44 45158 Insuman Comb 15 100units/ml suspension for injection 3ml cartridges (Sanofi) 45 46 7300 Mixtard 30 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 47 7793 HumaJect M3 Pen 100units/ml suspension for injection (Eli Lilly and Company Ltd) on September 25, 2021 by guest. Protected copyright. 48 8841 Humulin M5 100units/ml suspension for injection 10ml vials (Eli Lilly and Company Ltd) 49 50 4093 Humulin M2 100units/ml suspension for injection 3ml cartridges (Eli Lilly and Company 51 Ltd) 52 25133 Insuman Comb 25 100units/ml suspension for injection 3ml pre-filled OptiSet pen 53 (Sanofi) 54 55 5845 Mixtard 30 InnoLet 100units/ml suspension for injection 3ml pre-filled pen (Novo 56 Nordisk Ltd) 57 2456 Mixtard 10 NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) 58 59 44378 Insulin isophane biphasic human 25/75 100units/ml suspension for injection 3ml pre- 60 filled disposable devices 42954 Insulin isophane biphasic human 25/75 100units/ml suspension for injection 5ml vials

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1 2 57620 Humulin M3 100units/ml suspension for injection 10ml vials (Mawdsley-Brooks & 3 Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 19513 Humulin M3 100units/ml suspension for injection 10ml vials (Eli Lilly and Company Ltd) 6 2455 Mixtard 20 NovoLet 100units/ml suspension for injection (Novo Nordisk Ltd) 7 4790 Mixtard 50 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 8 19878 Insulin isophane biphasic human 30/70 100units/ml suspension for injection 3ml pre- 9 10 filled disposable devices 11 13622 Hypurin porcine neutral 100unit/ml Injection (C P Pharmaceuticals Ltd) 12 27396 Insulin soluble porcine 100units/ml solution for injection 10ml vials 13 14 26098 Hypurin Porcine Neutral 100units/ml solution for injection 10ml vials (Wockhardt UK 15 Ltd) 16 14930 Hypurin Porcine Neutral 100units/ml solution for injection 3ml cartridges (Wockhardt 17 For peer review only UK Ltd) 18 19 25479 Insulin soluble porcine 100units/ml solution for injection 3ml cartridges 20 1842 Pork velosulin 100unit/ml Injection (Novo Nordisk Ltd) 21 36513 Velosulin cartridge 100unit/ml Injection (Novo Nordisk Ltd) 22 23 4129 Insulin soluble porcine 100units/ml solution for injection 1.5ml cartridges 24 30209 Actrapid mc 100unit/ml Injection (Arun Products Ltd) 25 9521 Pork Actrapid 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 26 36031 Insulin isophane biphasic porcine 30/70 100units/ml suspension for injection 3ml 27 28 cartridges 29 14619 Insulin isophane biphasic porcine 30/70 100units/ml suspension for injection 1.5ml 30 cartridges 31 32 20995 Hypurin Porcine 30/70 Mix 100units/ml suspension for injection 3ml cartridges 33 (Wockhardt UK Ltd) 34 2459 Pork Mixtard 30 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 35 24800 Hypurin Porcine 30/70 Mix 100units/ml suspension for injection 10ml vials (Wockhardt 36 37 UK Ltd) 38 27280 Insulin isophane biphasic porcine 30/70 100units/ml suspension for injection 10ml vials http://bmjopen.bmj.com/ 39 9618 Hypurin Porcine 30/70 Mix 100units/ml suspension for injection 1.5ml cartridges (C P 40 41 Pharmaceuticals Ltd) 42 9376 Insulin zinc suspension crystalline human pyr 100unit/ml long acting Injection 43 18931 Insulin zinc crystalline human 100units/ml suspension for injection 10ml vials 44 8322 Insulin zinc suspension mixed human pyr 100unit/ml Injection 45 46 7537 Humulin Zn 100units/ml suspension for injection 10ml vials (Eli Lilly and Company Ltd) 47 1844 Ultratard 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) on September 25, 2021 by guest. Protected copyright. 48 16682 Tempulin 100unit/ml Injection (Knoll Ltd) 49 50 16700 Insulin zinc mixed bovine vial 100unit/ml Sterile suspension injection 51 12035 Insulin zinc mixed bovine 100units/ml suspension for injection 10ml vials 52 41834 Insulin zinc suspension lente 100iu/ml Injection (Celltech Pharma Europe Ltd) 53 17712 Hypurin Bovine Lente 100units/ml suspension for injection 10ml vials (Wockhardt UK 54 55 Ltd) 56 10547 Humulin Lente 100units/ml suspension for injection 10ml vials (Eli Lilly and Company 57 Ltd) 58 59 1587 Monotard 100units/ml suspension for injection 10ml vials (Novo Nordisk Ltd) 60 18461 Insulin zinc mixed human 100units/ml suspension for injection 10ml vials 44251 Insulin zinc suspension mixed porcine 100unit/ml Injection 34031 Monotard mc 100unit/ml Injection (Novo Nordisk Ltd)

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1 2 26498 Insulin zinc suspension mixed bovine and porcine 100unit/ml Injection 3 4784 Lentard mc 100unit/ml Injection (Novo Nordisk Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 12299 Semitard mc 100unit/ml Injection (Novo Nordisk Ltd) 6 34713 Insulin 1 ml syringe 7 2321 Insulin 0.5ml disposable syringe 8 23636 Insulin 1ml disposable syringe 9 10 40085 Insulin 2ml syringe 11 22060 Insulin 0.5 0.5ml Syringe 12 47588 Insulin 1ml click count 13 14 38093 Insulin 1ml pre-set syringe 15 16959 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 16 needle 0.3mm/30gauge 17 For peer review only 2808 INSULIN LENTARD INJ 18 19 9363 U100 Insulin syringe 0.5ml 20 30861 INSULIN ZINC HUMAN SUSPENSION 21 24485 INSULIN ZINC ANIMAL SUSPENSION 22 23 45045 NovoTwist hypodermic insulin needles for pre-filled / reusable pen injectors screw on 24 5mm/32gauge (Novo Nordisk Ltd) 25 56656 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 26 0.3ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 27 28 54629 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 29 8mm/31gauge (Spirit Healthcare Ltd) 30 6554 Autopen 24 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 31 32 range 1-21 units (Owen Mumford Ltd) 33 43568 ClikSTAR hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 34 range 1-80 units Silver (Sanofi) 35 15040 INSULIN MONOPHANE (ISOPHANE) 100 I/U INJ 36 37 35454 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw 38 on 8mm/31gauge (Disposable Medical Equipment Ltd) http://bmjopen.bmj.com/ 39 48633 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw 40 41 on 4mm/31gauge (Disposable Medical Equipment Ltd) 42 54573 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-21 43 units 44 55687 Insulin degludec 100units/ml solution for injection 3ml pre-filled disposable devices 45 46 43833 ClikSTAR hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 47 range 1-80 units Blue (Sanofi) on September 25, 2021 by guest. Protected copyright. 48 8483 MONOJECT INSULIN NEEDLES 49 50 52232 Hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial up / range 1-30 51 units 52 33356 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 53 12mm/29gauge 54 55 49479 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 56 4mm/31gauge 57 12840 B-d u-100 0.5ml Insulin syringe (Becton, Dickinson UK Ltd) 58 59 56691 Insulin degludec 200units/ml solution for injection 3ml pre-filled disposable devices 60 55627 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 5mm/31gauge (Spirit Healthcare Ltd)

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 118 of 152

1 2 12892 Clinipak u100 single use ins syr+12mm need28g 0.5ml [rand] 0.5ml Insulin syringe with 3 28gauge needle 12mm (Rand Rocket Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 31267 INSULIN PUR-IN MIX 50/50 100 I/U INJ 6 24845 INSULIN PUR-IN ISOPHANE 100 I/U INJ 7 26795 SYRINGE INSULIN DISPOSABLE 8 11521 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 9 10 needle 0.4mm/27gauge 11 5967 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with not 12 less than 12mm needle 0.33mm/29gauge 13 14 14504 INSULIN HYPURIN PROTAMINE ZINC 100 I/U INJ 15 14642 Bd m 0.3ml Insulin syringe with 29gauge needle 12mm (Becton, Dickinson UK Ltd) 16 40555 HumaPen Memoir hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 17 For peer review only up / range 1-60 units (Eli Lilly and Company Ltd) 18 19 58745 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 4mm/31gauge (GlucoRx Ltd) 21 11271 B-d u-100 1ml Insulin syringe (Becton, Dickinson UK Ltd) 22 23 6233 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 24 on 10mm/29gauge (Ypsomed Ltd) 25 58579 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 26 4mm/32.5gauge 27 28 8354 INSULIN ISOPHANE 70%/NEUTRAL 30% 100 I/U INJ 29 56879 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 30 up / range 1-60 units Graphite (Eli Lilly and Company Ltd) 31 32 10566 INSULIN HUMULIN M CARTRIDGE 100 I/U 33 13550 INSULIN BP 100 I/U 34 5345 Monoject hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml 35 with 12mm needle 0.36mm/28gauge (Covidien (UK) Commercial Ltd) 36 37 5121 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 38 on 12.7mm/29gauge (Becton, Dickinson UK Ltd) http://bmjopen.bmj.com/ 39 7763 INSULIN NEUPHANE (ISOPHANE)(PURIFIED) 100 I/U INJ 40 41 8646 INSULIN ZINC CRYSTALLINE susp 100 I/U INJ 42 1591 U100 Insulin syringe 1ml 43 13036 Unifine hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 44 12mm needle 0.33mm/29gauge (Owen Mumford Ltd) 45 46 24722 INSULIN ISOPHANE 50%/NEUTRAL 50% 100 I/U INJ 47 21459 SYRINGE INSULIN U100 S/U+8MM NEEDLE on September 25, 2021 by guest. Protected copyright. 48 27151 SYRINGE INSULIN U100 S/U+8MM NEEDLE 49 50 50798 Hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial up / range 1-35 51 units 52 48342 HumaPen Luxura hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 53 up / range 1-60 units Burgundy (Eli Lilly and Company Ltd) 54 55 61562 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 56 8mm/29gauge 57 16866 Unifine hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 58 59 12mm needle 0.33mm/29gauge (Owen Mumford Ltd) 60 9834 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap on 12mm/29gauge (Ypsomed Ltd)

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 119 of 152 BMJ Open

1 2 51650 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge (B.Braun Medical Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 12300 SYRINGE INSULIN (BS1619/1) 2ML 6 37427 HumaPen Luxura HD hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit 7 dial up / range 1-30 units (Eli Lilly and Company Ltd) 8 39150 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 9 10 safety needle 0.33mm/29gauge 11 5634 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 12 needle 0.36mm/28gauge 13 14 19707 INSULIN HUMULIN S (NEUTRAL SOLUBLE) 15 7412 U100 Insulin syringe 0.5ml 16 18446 Unifine hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 17 For peer review only 12mm needle 0.33mm/29gauge (Owen Mumford Ltd) 18 19 7959 INSULIN MIXTARD 30/70 40 I/U INJ 20 18149 Monoject u100 insulin syringe 12mm(29g)0.5ml 12mm29G 0.5ml Insulin syringe 21 (Covidien (UK) Commercial Ltd) 22 23 10133 U100 Insulin syringe 1ml 24 22823 INSULIN ISOPHANE (PURIFIED) 100 I/U INJ 25 60028 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 4mm/32gauge 26 27 28 11346 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 29 14506 INSULIN BOVINE PROTAMINE ZINC 100 I/U INJ 30 13009 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 31 32 needle 0.36mm/28gauge 33 56352 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 34 up / range 1-60 units Green (Eli Lilly and Company Ltd) 35 44810 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 5mm/32gauge 38 19029 SYRINGE PRE-SET INSULIN FOR BLIND 2ML http://bmjopen.bmj.com/ 39 38774 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 40 41 range 1-60 units Blue (Novo Nordisk Ltd) 42 10258 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 43 8mm/31gauge 44 21945 INSULIN PORK INSULATARD 45 46 56808 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 47 12mm/29gauge (B.Braun Medical Ltd) on September 25, 2021 by guest. Protected copyright. 48 43670 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 4mm/32gauge 51 6991 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 52 0.5ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 53 5649 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 1 unit dial up / 54 55 range 1-16 units (Owen Mumford Ltd) 56 33101 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 12.7mm/29gauge 58 59 14887 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 60 5mm/31gauge 1751 Hypodermic U100 insulin syringe glass reusable 1ml 8839 INSULIN SEMITARD 100 I/U INJ

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1 2 28978 INSULIN PUR-IN MIX 15/85 100 I/U INJ 3 19977 Omnican 50 hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 with 12mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 6 51612 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 7 5mm/29gauge 8 35218 Optipen pro 1 yellow insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 9 10 Pharma) 11 60609 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12 6mm/32gauge (Spirit Healthcare Ltd) 13 14 58801 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 15 screw on 10mm/29gauge (GlucoRx Ltd) 16 20195 INSULIN BOVINE PROTAMINE ZINC 40 I/U INJ 17 For peer review only 6009 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml 18 19 with 12mm needle 0.4mm/27gauge (Terumo UK Ltd) 20 6091 NovoPen 3 Fun hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 21 / range 2-70 units Red (Novo Nordisk Ltd) 22 23 35057 OptiClik hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 24 range 1-80 units Blue (Sanofi) 25 5059 NovoPen 3 Classic hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 26 up / range 2-70 units (Novo Nordisk Ltd) 27 28 51881 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 29 8mm/31gauge (B.Braun Medical Ltd) 30 10145 Humapen luxura insulin pen 3ml/1-60 units Insulin pen 3ml/1-60 units (Eli Lilly and 31 32 Company Ltd) 33 28723 INSULIN ZINC BOVINE SUSPENSION 34 6470 Autopen 24 hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial up / 35 range 2-42 units (Owen Mumford Ltd) 36 37 13474 U100 Insulin syringe Sp.36 [2A] 1ml 38 60967 Nanopass hypodermic insulin needles for pre-filled / reusable pen injectors screw on http://bmjopen.bmj.com/ 39 8mm/32.5gauge (Terumo UK Ltd) 40 41 48576 BD AutoShield Duo hypodermic insulin needles for pre-filled / reusable pen injectors 42 screw on 5mm/30gauge (Becton, Dickinson UK Ltd) 43 23003 INSULIN ISOPHANE (NPH) 40 I/U 44 14646 Hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 12mm 45 46 needle 0.33mm/29gauge 47 19829 INSULIN NOVO MONOTARD MC on September 25, 2021 by guest. Protected copyright. 48 48501 HumaPen Luxura hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 49 50 up / range 1-60 units Champagne (Eli Lilly and Company Ltd) 51 12060 INSULIN QUICKSOL (SOLUBLE NEUTRAL) 100 I/U INJ 52 7861 INSULIN HUMULIN S (NEUTRAL) CARTRIDGE 100 I/U 53 5267 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 54 55 0.5ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 56 5022 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 12mm/28gauge (Novo Nordisk Ltd) 58 59 62180 Insulin aspart 100units/ml solution for injection 1.6ml cartridges 60 57387 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd)

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1 2 10242 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 27911 INSULIN HUMAN ACTRAPID PENFILL 6 25006 INSULIN HUMAN ACTRAPID (NEUTRAL) 7 58817 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 8 screw on 12mm/29gauge (GlucoRx Ltd) 9 10 6753 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 11 up / range 1-35 units Green (Novo Nordisk Ltd) 12 21223 U100 Insulin syringe 0.3ml 13 14 35017 Optipen pro 1 white insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 15 Pharma) 16 22946 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 17 For peer review only with 12mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 18 19 49451 Mylife Clickfine AutoProtect hypodermic insulin needles for pre-filled / reusable pen 20 injectors screw on 8mm/29gauge (Ypsomed Ltd) 21 57451 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 22 23 screw on 8mm/31gauge (Cambridge Sensors Ltd) 24 59846 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 25 on 4mm/32gauge (Ypsomed Ltd) 26 48811 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 27 28 screw on 6mm/31gauge (Owen Mumford Ltd) 29 7757 INSULIN NEULENTE (ZINC SUSP)(PURIFIED) 100 I/U INJ 30 7062 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 31 32 12mm needle 0.4mm/27gauge (Terumo UK Ltd) 33 5850 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 34 on 6mm/31gauge (Ypsomed Ltd) 35 55521 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 4mm/32gauge (Spirit Healthcare Ltd) 38 16209 INSULIN HYPURIN SOLUBLE 100 I/U INJ http://bmjopen.bmj.com/ 39 8838 INSULIN SEMITARD 40 I/U INJ 40 41 5789 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 8mm 42 needle 0.3mm/30gauge 43 11245 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 44 7783 INSULIN ISOPHANE (HUMAN) 100 I/U INJ 45 46 60951 Insulin human 100units/ml solution for injection 10ml vials 47 5164 NovoPen 3 Demi hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial on September 25, 2021 by guest. Protected copyright. 48 up / range 1-35 units (Novo Nordisk Ltd) 49 50 321 INSULIN HUMAN ACTRAPID (NEUTRAL) 40 I/U INJ 51 57243 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 52 10mm/30gauge (B.Braun Medical Ltd) 53 6060 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 54 55 on 6mm/30gauge (Owen Mumford Ltd) 56 4896 Monoject hypodermic U100 insulin syringe sterile single use / single patient use 1ml 57 with 12mm needle 0.36mm/28gauge (Covidien (UK) Commercial Ltd) 58 59 22161 INSULIN HUMULIN M1 VIAL 60 5769 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm needle 0.4mm/27gauge

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1 2 54028 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 3 screw on 12mm/29gauge (Owen Mumford Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 59005 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 6 screw on 8mm/31gauge (Ypsomed Ltd) 7 8376 INSULIN ISOPHANE 100 I/U 8 58961 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 9 10 screw on 4mm/32gauge (Ypsomed Ltd) 11 23437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12 12mm/28gauge 13 14 18208 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 15 10mm/29gauge 16 22987 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 17 For peer review only 12mm/29gauge 18 19 59004 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 6mm/32gauge (Ypsomed Ltd) 21 60750 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/33gauge 24 11878 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 8mm 25 needle 0.3mm/30gauge 26 35081 OptiClik hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 27 28 range 1-80 units Grey (Sanofi) 29 49052 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 30 screw on 8mm/31gauge (Owen Mumford Ltd) 31 32 48765 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 5mm/31gauge (Owen Mumford Ltd) 34 54885 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 35 8mm/32gauge 36 37 18195 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 6mm/31gauge 38 http://bmjopen.bmj.com/ 39 20672 INSULIN HUM/ACTRAPID 40 41 51107 Hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial up / range 2-42 42 units 43 47751 TS-A Safety hypodermic U100 insulin syringe sterile single use / single patient use 1ml 44 with 12mm safety needle 0.33mm/29gauge (Minsmed) 45 46 48435 BD AutoShield hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 5mm/29gauge (Becton, Dickinson UK Ltd) on September 25, 2021 by guest. Protected copyright. 48 5421 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Novo Nordisk Ltd) 51 11408 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 52 up / range 1-21 units (Owen Mumford Ltd) 53 59133 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 54 55 0.5ml with 8mm safety needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 56 58798 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 57 screw on 6mm/31gauge (GlucoRx Ltd) 58 59 6724 U100 Insulin syringe 0.3ml 60 9578 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12mm/29gauge (Owen Mumford Ltd) 26784 INSULIN ZINC SEMILENTE SUSP BP 100 I/U INJ

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1 2 5557 NovoPen 3 Fun hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 3 / range 2-70 units Blue (Novo Nordisk Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 11086 B-d u-100 0.5ml Insulin syringe (Becton, Dickinson UK Ltd) 6 25422 Hypoguard u100 click/count 1ml Insulin syringe (Hypoguard Ltd) 7 14191 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial up 8 / range 2-42 units (Owen Mumford Ltd) 9 10 30918 ABCare hypodermic U100 insulin syringe glass reusable 0.5ml (Rand Rocket Ltd) 11 35143 NovoFine Autocover hypodermic insulin needles for pre-filled / reusable pen injectors 12 screw on 8mm/30gauge (Novo Nordisk Ltd) 13 14 24866 INSULIN INSULATARD (LEO RETARD) 40 I/U INJ 15 6138 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 16 / range 1-60 units Burgundy (Eli Lilly and Company Ltd) 17 For peer review only 7764 INSULIN NEUSULIN (NEUTRAL)(PURIFIED) 100 I/U INJ 18 19 15624 INSULIN ISOPHANE (HIGHLY PURIFIED) 100 I/U INJ 20 49172 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 21 up / range 0.5-30 units Red (Novo Nordisk Ltd) 22 23 1645 INSULIN NOVO ACTRAPID MC 100 I/U INJ 24 11345 Bd Ultra Pen 3ml Insulin pen (Becton, Dickinson UK Ltd) 25 58754 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 27 28 31699 ABCare hypodermic U100 insulin syringe glass reusable 1ml (Rand Rocket Ltd) 29 56639 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 30 up / range 1-60 units Blue (Eli Lilly and Company Ltd) 31 32 5142 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 8mm/31gauge (Becton, Dickinson UK Ltd) 34 48771 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 35 screw on 5mm/31gauge (Owen Mumford Ltd) 36 37 4248 INSULIN NOVO ULTRATARD MC 100 I/U INJ 38 6981 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 1-35 units Yellow (Novo Nordisk Ltd) 40 41 58878 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 42 10mm/29gauge 43 6781 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial 44 up / range 2-42 units (Owen Mumford Ltd) 45 46 7164 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 6mm/31gauge (Owen Mumford Ltd) on September 25, 2021 by guest. Protected copyright. 48 58449 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 49 50 on 4mm/32gauge (Owen Mumford Ltd) 51 56642 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 52 screw on 6mm/31gauge (Cambridge Sensors Ltd) 53 38808 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 54 55 range 1-60 units Silver (Novo Nordisk Ltd) 56 22328 Unifine single use Insulin syringe with 30gauge needle 8mm 0.5ml (Owen Mumford Ltd) 57 15294 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 58 59 1-70 units Green (Novo Nordisk Ltd) 60 25786 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/31gauge (Disposable Medical Equipment Ltd) 1839 INSULIN HUMULIN I (ISOPHANE) 100 I/U INJ

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1 2 18301 INSULIN SOLUBLE INJ I/U^2 3 13108 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 1 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 unit dial up / range 1-21 units (Owen Mumford Ltd) 6 58578 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 7 0.5ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 8 32053 INSULIN HUMALOG MIX 25 9 10 13969 U100 Insulin syringe 0.3ml 11 1643 INSULIN NOVO MONOTARD MC 100 I/U INJ 12 57388 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 15 56983 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 16 6mm/31gauge (Spirit Healthcare Ltd) 17 For peer review only 31466 Exubera insulin release unit (Pfizer Ltd) 18 19 55746 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 20 8mm/32gauge (Spirit Healthcare Ltd) 21 7203 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 22 23 on 8mm/31gauge (Owen Mumford Ltd) 24 9702 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 25 1ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 26 22496 INSULIN ZINC LENTE PURIFIED SUSPENSION 27 28 16389 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 29 12mm needle 0.33mm/29gauge (Terumo UK Ltd) 30 22974 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 8mm/31gauge 31 32 33 3076 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 34 6mm/30gauge (Novo Nordisk Ltd) 35 20671 INSULIN HUM/ACTRAPHANE 36 37 58995 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 38 0.5ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) http://bmjopen.bmj.com/ 39 59243 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 40 41 0.3ml with 8mm safety needle 0.25mm/31gauge (Becton, Dickinson UK Ltd) 42 30305 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 43 needle 0.3mm/30gauge 44 53437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 45 46 5mm/30gauge 47 60621 Hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial up / range 0.5- on September 25, 2021 by guest. Protected copyright. 48 30 units 49 50 58884 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 51 screw on 8mm/31gauge (GlucoRx Ltd) 52 52319 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-80 53 units 54 55 57153 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 56 0.5ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 57 18645 INSULIN NEUTRAL (PURIFIED) 100 I/U INJ 58 59 54027 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 60 4.5mm/31gauge 22806 INSULIN PORK ACTRAPID 22094 INSULIN HUMULIN M2 VIAL

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1 2 56785 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Red (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 62098 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6 8mm/32.5gauge 7 5015 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 8 8mm/30gauge (Novo Nordisk Ltd) 9 10 6730 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with not less 11 than 12mm needle 0.33mm/29gauge 12 59311 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 15 57493 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 16 up / range 1-60 units Silver (Eli Lilly and Company Ltd) 17 For peer review only 15951 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 18 19 / range 1-21 units (Owen Mumford Ltd) 20 37055 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 21 0.5ml with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 22 23 57744 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 24 4mm/31gauge (B.Braun Medical Ltd) 25 7127 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 27 28 61780 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 29 12mm/29gauge (Spirit Healthcare Ltd) 30 35078 Optipen pro 1 blue insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 31 32 Pharma) 33 17643 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 2 34 unit dial up / range 2-42 units (Owen Mumford Ltd) 35 15895 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 36 37 1-70 units Orange (Novo Nordisk Ltd) 38 48829 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 0.5-30 units Blue (Novo Nordisk Ltd) 40 41 36959 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 12mm/29gauge (Disposable Medical Equipment Ltd) 43 53148 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-60 44 units 45 46 1589 U100 Insulin syringe 0.5ml 47 10545 INSULIN HUMULIN M4 CARTRIDGE 100 I/U on September 25, 2021 by guest. Protected copyright. 48 45639 IME-FINE hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Arctic Medical Ltd) 51 5742 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 52 on 8mm/30gauge (Owen Mumford Ltd) 53 49307 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 54 55 on 4.5mm/31gauge (Ypsomed Ltd) 56 62562 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 4mm/33gauge (Spirit Healthcare Ltd) 58 59 10546 INSULIN HUMULIN M4 100 I/U INJ 60 54886 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/32gauge

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1 2 56939 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Pink (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6228 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 6 0.3ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 7 12244 INSULIN ZINC BOVINE susp 100 I/U INJ 8 13274 Clinipak u100 single use ins syr+12mm need28g 1ml [rand] 1ml Insulin syringe with 9 10 28gauge needle 12mm (Rand Rocket Ltd) 11 56624 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 12 0.5ml with 12mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 13 14 9619 Bd Ultra Pen 1.5ml Insulin pen (Becton, Dickinson UK Ltd) 15 5966 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 16 on 8mm/31gauge (Ypsomed Ltd) 17 For peer review only 2373 INSULIN HUMAN VELOSULIN 100 I/U INJ 18 19 43489 BD Micro-Fine Ultra hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 4mm/32gauge (Becton, Dickinson UK Ltd) 21 59475 Nanopass hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/32.5gauge (Terumo UK Ltd) 24 59793 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 25 screw on 4mm/32gauge (Cambridge Sensors Ltd) 26 17076 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 27 28 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 29 9079 INSULIN SOLUBLE 100 I/U INJ 30 5620 U100 Insulin syringe 0.3ml 31 32 38236 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 1ml 33 with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 34 20196 INSULIN SOLUBLE 40 I/U INJ 35 7765 INSULIN NEUTRAL (HUMAN) 100 I/U INJ 36 37 58581 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 38 screw on 5mm/31gauge (GlucoRx Ltd) http://bmjopen.bmj.com/ 39 10691 INSULIN ISOPHANE (NPH) 100 I/U INJ 40 41 5873 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 5mm/31gauge (Becton, Dickinson UK Ltd) 43 24554 Unifine single use Insulin syringe with 30gauge needle 8mm 0.3ml (Owen Mumford Ltd) 44 28666 Omnican 50 hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml 45 46 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 47 19271 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on on September 25, 2021 by guest. Protected copyright. 48 8mm/30gauge 49 50 6831 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 51 / range 1-60 units Teal (Eli Lilly and Company Ltd) 52 6378 Hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 8mm 53 needle 0.3mm/30gauge 54 55 13096 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 2 unit dial up / 56 range 2-32 units (Owen Mumford Ltd) 57 7075 Optipen Pro 1 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 58 59 range 1-60 units (Sanofi) 60 42797 Injex ampoule pack 60501 (Ocon Chemicals Ltd) 60626 InsuJet starter set 012007GBSP Grey (Spirit Healthcare Ltd) 42305 Injex 10ml vial adaptor pack 60502 (Ocon Chemicals Ltd)

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1 2 51836 InsuJet 3ml cartridge adaptor pack 012071GB1503 (Spirit Healthcare Ltd) 3 26338 Injex starter set 60500 (Ocon Chemicals Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 61845 NovoRapid PumpCart 100units/ml solution for injection 1.6ml cartridges (Novo Nordisk 6 Ltd) 7 51182 InsuJet starter set 012003GBSP Lime (Spirit Healthcare Ltd) 8 44601 Injex 4 monthly refill pack 60504 (Ocon Chemicals Ltd) 9 10 49509 InsuJet starter set 012005GBSP Blue (Spirit Healthcare Ltd) 11 49508 InsuJet 10ml vial adaptor pack 01207GB1510 (Spirit Healthcare Ltd) 12 49507 InsuJet nozzle pack 012070GB15 (Spirit Healthcare Ltd) 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 25, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 Product code list: insulin treatments 3 Product Code Product Name BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 4163 Rapitard MC 100unit/ml Injection (Novo Nordisk Ltd) 6 13416 Insulin biphasic 100 units/ml Injection 7 16142 Insulin aspart 100units/ml solution for injection 3ml cartridges 8 53251 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (DE Pharmaceuticals) 9 10 11 10067 Insulin biphasic aspart human pyr 30:70; 100 units/ml Injection 12 5892 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 13 14 Ltd) 15 11337 NovoRapid Novolet 100units/ml solution for injection (Novo Nordisk Ltd) 16 6061 Novomix 30 30/70 100units/ml Injection (Novo Nordisk Ltd) 17 For peer review only 53118 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Mawdsley- 18 19 Brooks & Company Ltd) 20 29567 Insulin aspart 100units/ml solution for injection 10ml vials 21 6209 NovoRapid 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 22 23 6447 Insulin aspart human pyr 100 iu/ml Injection 24 59533 NovoRapid FlexPen 100units/ml solution for injection 3ml pre-filled pen (Sigma 25 Pharmaceuticals Plc) 26 51743 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Sigma 27 28 Pharmaceuticals Plc) 29 49108 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Necessity Supplies 30 Ltd) 31 32 46666 NovoRapid FlexTouch 100units/ml solution for injection 3ml pre-filled pen (Novo 33 Nordisk Ltd) 34 19877 Insulin aspart 100units/ml solution for injection 3ml pre-filled disposable devices 35 5021 NovoRapid Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 36 37 56489 NovoMix 30 Penfill 100units/ml suspension for injection 3ml cartridges (Waymade 38 Healthcare Plc) http://bmjopen.bmj.com/ 39 7267 NovoMix 30 Penfill 100units/ml suspension for injection 3ml cartridges (Novo Nordisk 40 41 Ltd) 42 23099 Insulin aspart biphasic 30/70 100units/ml suspension for injection 3ml pre-filled 43 disposable devices 44 7228 NovoMix 30 FlexPen 100units/ml suspension for injection 3ml pre-filled pen (Novo 45 46 Nordisk Ltd) 47 24795 Insulin aspart biphasic 30/70 100units/ml suspension for injection 3ml cartridges on September 25, 2021 by guest. Protected copyright. 48 55462 Tresiba FlexTouch 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 49 50 Ltd) 51 55910 Tresiba Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 52 55234 Tresiba FlexTouch 200units/ml solution for injection 3ml pre-filled pen (Novo Nordisk 53 Ltd) 54 55 55907 Insulin degludec 100units/ml solution for injection 3ml cartridges 56 6958 Levemir FlexPen 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk Ltd) 57 55618 Levemir FlexPen 100units/ml solution for injection 3ml pre-filled pen (Waymade 58 59 Healthcare Plc) 60 35260 Levemir InnoLet 100units/ml solution for injection 3ml pre-filled pen (Novo Nordisk Ltd) 6965 Levemir Penfill 100units/ml solution for injection 3ml cartridges (Novo Nordisk Ltd) 14301 Insulin detemir 100units/ml solution for injection 3ml cartridges

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1 2 23231 Hypurin Bovine Neutral 100units/ml solution for injection 3ml cartridges (Wockhardt UK 3 Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 10572 Insulin soluble bovine 100unit/ml Injection 6 24593 Neutral insulin bovine 100unit/ml Injection 7 12297 Hypurin bovine neutral 100unit/ml Injection (C P Pharmaceuticals Ltd) 8 47360 Neutral insulin 100unit/ml Injection (Celltech Pharma Europe Ltd) 9 10 1592 Actrapid penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 11 56115 Human Actrapid Penfill 100units/ml solution for injection 1.5ml cartridges (Novo 12 Nordisk Ltd) 13 14 22945 Insuman rapid 100iu/ml Injection (Aventis Pharma) 15 10910 Humaject m2 100iu/ml M2 pen (Eli Lilly and Company Ltd) 16 1588 Actrapid 100iu/ml Injection (Novo Nordisk Ltd) 17 For peer review only 4199 Humulin m1 100unit/ml M1 injection (Eli Lilly and Company Ltd) 18 19 10915 Humaject m1 100iu/ml M1 pen (Eli Lilly and Company Ltd) 20 11107 Humulin m4 100unit/ml M4 injection (Eli Lilly and Company Ltd) 21 10887 Penmix 40/60 100iu/ml Penfill (Novo Nordisk Ltd) 22 23 3551 Mixtard 20 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 24 22155 Humaject m5 100iu/ml M5 pen (Eli Lilly and Company Ltd) 25 11056 Insulin biphasic isophane human pyr 30:70; 100 units/ml Injection 26 7349 Actrapid 100units/ml solution for injection 10ml vials (Novo Nordisk Ltd) 27 28 1649 Human actraphane 100iu/ml Injection (Novo Nordisk Ltd) 29 22058 Pur-in mix 15/85 Injection (C P Pharmaceuticals Ltd) 30 14649 Insulin biphasic isophane human pyr 10:90; 100 units/ml Injection 31 32 2929 Mixtard 30 100iu/ml GE injection (Novo Nordisk Ltd) 33 2454 Mixtard 30 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) 34 1806 Penmix 30/70 100iu/ml Penfill (Novo Nordisk Ltd) 35 26403 Pur-in mix 25/75 Injection (C P Pharmaceuticals Ltd) 36 37 10484 Penmix 20/80 Penfill (Novo Nordisk Ltd) 38 3550 Mixtard 40 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd) http://bmjopen.bmj.com/ 39 54462 Insulin biphasic isophane human emp 25:75; 100 units/ml Injection 40 41 4198 Humulin m3 100unit/ml M3 injection (Eli Lilly and Company Ltd) 42 17809 Humaject m4 100iu/ml M4 pen (Eli Lilly and Company Ltd) 43 41959 Penject 100unit/ml Injection device (Hypoguard Ltd) 44 14644 Insulin biphasic isophane human prb 20:80; 100 units/ml Injection 45 46 21110 Insulin biphasic isophane human prb 50:50; 100 units/ml Injection 47 24846 Pur-in neutral 100unit/ml Injection (C P Pharmaceuticals Ltd) on September 25, 2021 by guest. Protected copyright. 48 34097 Human initard 50/50 100unit/ml Injection (Novo Nordisk Ltd) 49 50 12654 Insulin soluble human prb 100unit/ml Injection 51 17336 Novopen 100unit/ml Injection device (Novo Nordisk Ltd) 52 9341 Insulin biphasic isophane human prb 30:70; 100 units/ml Injection 53 16129 Insulin soluble human 100units/ml solution for injection 3ml cartridges 54 55 33167 Insulin biphasic isophane human crb 25:75; 100 units/ml Injection 56 3439 Penmix 10/90 Pen (Novo Nordisk Ltd) 57 11055 Insulin biphasic isophane human pyr 20:80; 100 units/ml Injection 58 59 1840 Humulin s 100unit/ml Injection (Eli Lilly and Company Ltd) 60 21347 Penmix 40/60 100iu/ml Injection (Novo Nordisk Ltd) 13837 Insulin biphasic isophane human prb 10:90; 100 units/ml Injection 5255 Mixtard 10 penfill 100 100iu/ml Penfill (Novo Nordisk Ltd)

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1 2 51650 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge (B.Braun Medical Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 12300 SYRINGE INSULIN (BS1619/1) 2ML 6 37427 HumaPen Luxura HD hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit 7 dial up / range 1-30 units (Eli Lilly and Company Ltd) 8 39150 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 9 10 safety needle 0.33mm/29gauge 11 5634 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 12 needle 0.36mm/28gauge 13 14 19707 INSULIN HUMULIN S (NEUTRAL SOLUBLE) 15 7412 U100 Insulin syringe 0.5ml 16 18446 Unifine hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 17 For peer review only 12mm needle 0.33mm/29gauge (Owen Mumford Ltd) 18 19 7959 INSULIN MIXTARD 30/70 40 I/U INJ 20 18149 Monoject u100 insulin syringe 12mm(29g)0.5ml 12mm29G 0.5ml Insulin syringe 21 (Covidien (UK) Commercial Ltd) 22 23 10133 U100 Insulin syringe 1ml 24 22823 INSULIN ISOPHANE (PURIFIED) 100 I/U INJ 25 60028 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 26 4mm/32gauge 27 28 11346 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 29 14506 INSULIN BOVINE PROTAMINE ZINC 100 I/U INJ 30 13009 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 31 32 needle 0.36mm/28gauge 33 56352 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 34 up / range 1-60 units Green (Eli Lilly and Company Ltd) 35 44810 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 5mm/32gauge 38 19029 SYRINGE PRE-SET INSULIN FOR BLIND 2ML http://bmjopen.bmj.com/ 39 38774 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 40 41 range 1-60 units Blue (Novo Nordisk Ltd) 42 10258 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 43 8mm/31gauge 44 21945 INSULIN PORK INSULATARD 45 46 56808 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 47 12mm/29gauge (B.Braun Medical Ltd) on September 25, 2021 by guest. Protected copyright. 48 43670 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 4mm/32gauge 51 6991 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 52 0.5ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 53 5649 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 1 unit dial up / 54 55 range 1-16 units (Owen Mumford Ltd) 56 33101 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 12.7mm/29gauge 58 59 14887 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 60 5mm/31gauge 1751 Hypodermic U100 insulin syringe glass reusable 1ml 8839 INSULIN SEMITARD 100 I/U INJ

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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 140 of 152

1 2 10242 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 27911 INSULIN HUMAN ACTRAPID PENFILL 6 25006 INSULIN HUMAN ACTRAPID (NEUTRAL) 7 58817 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 8 screw on 12mm/29gauge (GlucoRx Ltd) 9 10 6753 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 11 up / range 1-35 units Green (Novo Nordisk Ltd) 12 21223 U100 Insulin syringe 0.3ml 13 14 35017 Optipen pro 1 white insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 15 Pharma) 16 22946 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 17 For peer review only with 12mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 18 19 49451 Mylife Clickfine AutoProtect hypodermic insulin needles for pre-filled / reusable pen 20 injectors screw on 8mm/29gauge (Ypsomed Ltd) 21 57451 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 22 23 screw on 8mm/31gauge (Cambridge Sensors Ltd) 24 59846 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 25 on 4mm/32gauge (Ypsomed Ltd) 26 48811 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 27 28 screw on 6mm/31gauge (Owen Mumford Ltd) 29 7757 INSULIN NEULENTE (ZINC SUSP)(PURIFIED) 100 I/U INJ 30 7062 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 31 32 12mm needle 0.4mm/27gauge (Terumo UK Ltd) 33 5850 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 34 on 6mm/31gauge (Ypsomed Ltd) 35 55521 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 4mm/32gauge (Spirit Healthcare Ltd) 38 16209 INSULIN HYPURIN SOLUBLE 100 I/U INJ http://bmjopen.bmj.com/ 39 8838 INSULIN SEMITARD 40 I/U INJ 40 41 5789 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 8mm 42 needle 0.3mm/30gauge 43 11245 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 44 7783 INSULIN ISOPHANE (HUMAN) 100 I/U INJ 45 46 60951 Insulin human 100units/ml solution for injection 10ml vials 47 5164 NovoPen 3 Demi hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit on September 25, 2021 by guest. Protected copyright. 48 dial up / range 1-35 units (Novo Nordisk Ltd) 49 50 321 INSULIN HUMAN ACTRAPID (NEUTRAL) 40 I/U INJ 51 57243 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 52 10mm/30gauge (B.Braun Medical Ltd) 53 6060 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 54 55 on 6mm/30gauge (Owen Mumford Ltd) 56 4896 Monoject hypodermic U100 insulin syringe sterile single use / single patient use 1ml 57 with 12mm needle 0.36mm/28gauge (Covidien (UK) Commercial Ltd) 58 59 22161 INSULIN HUMULIN M1 VIAL 60 5769 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm needle 0.4mm/27gauge

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1 2 54028 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 3 screw on 12mm/29gauge (Owen Mumford Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 59005 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 6 screw on 8mm/31gauge (Ypsomed Ltd) 7 8376 INSULIN ISOPHANE 100 I/U 8 58961 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 9 10 screw on 4mm/32gauge (Ypsomed Ltd) 11 23437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12 12mm/28gauge 13 14 18208 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 15 10mm/29gauge 16 22987 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 17 For peer review only 12mm/29gauge 18 19 59004 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 6mm/32gauge (Ypsomed Ltd) 21 60750 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/33gauge 24 11878 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 8mm 25 needle 0.3mm/30gauge 26 35081 OptiClik hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 27 28 range 1-80 units Grey (Sanofi) 29 49052 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 30 screw on 8mm/31gauge (Owen Mumford Ltd) 31 32 48765 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 5mm/31gauge (Owen Mumford Ltd) 34 54885 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 35 8mm/32gauge 36 37 18195 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 38 6mm/31gauge http://bmjopen.bmj.com/ 39 20672 INSULIN HUM/ACTRAPID 40 41 51107 Hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial up / range 2-42 42 units 43 47751 TS-A Safety hypodermic U100 insulin syringe sterile single use / single patient use 1ml 44 with 12mm safety needle 0.33mm/29gauge (Minsmed) 45 46 48435 BD AutoShield hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 5mm/29gauge (Becton, Dickinson UK Ltd) on September 25, 2021 by guest. Protected copyright. 48 5421 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Novo Nordisk Ltd) 51 11408 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 52 up / range 1-21 units (Owen Mumford Ltd) 53 59133 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 54 55 0.5ml with 8mm safety needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 56 58798 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 57 screw on 6mm/31gauge (GlucoRx Ltd) 58 59 6724 U100 Insulin syringe 0.3ml 60 9578 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12mm/29gauge (Owen Mumford Ltd) 26784 INSULIN ZINC SEMILENTE SUSP BP 100 I/U INJ

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1 2 5557 NovoPen 3 Fun hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 3 / range 2-70 units Blue (Novo Nordisk Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 11086 B-d u-100 0.5ml Insulin syringe (Becton, Dickinson UK Ltd) 6 25422 Hypoguard u100 click/count 1ml Insulin syringe (Hypoguard Ltd) 7 14191 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial 8 up / range 2-42 units (Owen Mumford Ltd) 9 10 30918 ABCare hypodermic U100 insulin syringe glass reusable 0.5ml (Rand Rocket Ltd) 11 35143 NovoFine Autocover hypodermic insulin needles for pre-filled / reusable pen injectors 12 screw on 8mm/30gauge (Novo Nordisk Ltd) 13 14 24866 INSULIN INSULATARD (LEO RETARD) 40 I/U INJ 15 6138 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 16 / range 1-60 units Burgundy (Eli Lilly and Company Ltd) 17 For peer review only 7764 INSULIN NEUSULIN (NEUTRAL)(PURIFIED) 100 I/U INJ 18 19 15624 INSULIN ISOPHANE (HIGHLY PURIFIED) 100 I/U INJ 20 49172 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 21 up / range 0.5-30 units Red (Novo Nordisk Ltd) 22 23 1645 INSULIN NOVO ACTRAPID MC 100 I/U INJ 24 11345 Bd Ultra Pen 3ml Insulin pen (Becton, Dickinson UK Ltd) 25 58754 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 27 28 31699 ABCare hypodermic U100 insulin syringe glass reusable 1ml (Rand Rocket Ltd) 29 56639 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 30 up / range 1-60 units Blue (Eli Lilly and Company Ltd) 31 32 5142 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 8mm/31gauge (Becton, Dickinson UK Ltd) 34 48771 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 35 screw on 5mm/31gauge (Owen Mumford Ltd) 36 37 4248 INSULIN NOVO ULTRATARD MC 100 I/U INJ 38 6981 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 1-35 units Yellow (Novo Nordisk Ltd) 40 41 58878 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 42 10mm/29gauge 43 6781 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial 44 up / range 2-42 units (Owen Mumford Ltd) 45 46 7164 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 6mm/31gauge (Owen Mumford Ltd) on September 25, 2021 by guest. Protected copyright. 48 58449 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 49 50 on 4mm/32gauge (Owen Mumford Ltd) 51 56642 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 52 screw on 6mm/31gauge (Cambridge Sensors Ltd) 53 38808 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 54 55 range 1-60 units Silver (Novo Nordisk Ltd) 56 22328 Unifine single use Insulin syringe with 30gauge needle 8mm 0.5ml (Owen Mumford Ltd) 57 15294 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 58 59 1-70 units Green (Novo Nordisk Ltd) 60 25786 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/31gauge (Disposable Medical Equipment Ltd) 1839 INSULIN HUMULIN I (ISOPHANE) 100 I/U INJ

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1 2 18301 INSULIN SOLUBLE INJ I/U^2 3 13108 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 1 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 unit dial up / range 1-21 units (Owen Mumford Ltd) 6 58578 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 7 0.5ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 8 32053 INSULIN HUMALOG MIX 25 9 10 13969 U100 Insulin syringe 0.3ml 11 1643 INSULIN NOVO MONOTARD MC 100 I/U INJ 12 57388 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 15 56983 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 16 6mm/31gauge (Spirit Healthcare Ltd) 17 For peer review only 31466 Exubera insulin release unit (Pfizer Ltd) 18 19 55746 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 20 8mm/32gauge (Spirit Healthcare Ltd) 21 7203 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 22 23 on 8mm/31gauge (Owen Mumford Ltd) 24 9702 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 25 1ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 26 22496 INSULIN ZINC LENTE PURIFIED SUSPENSION 27 28 16389 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 29 12mm needle 0.33mm/29gauge (Terumo UK Ltd) 30 22974 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 31 32 8mm/31gauge 33 3076 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 34 6mm/30gauge (Novo Nordisk Ltd) 35 20671 INSULIN HUM/ACTRAPHANE 36 37 58995 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 38 0.5ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) http://bmjopen.bmj.com/ 39 59243 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 40 41 0.3ml with 8mm safety needle 0.25mm/31gauge (Becton, Dickinson UK Ltd) 42 30305 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 43 needle 0.3mm/30gauge 44 53437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 45 46 5mm/30gauge 47 60621 Hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial up / range 0.5- on September 25, 2021 by guest. Protected copyright. 48 30 units 49 50 58884 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 51 screw on 8mm/31gauge (GlucoRx Ltd) 52 52319 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-80 53 units 54 55 57153 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 56 0.5ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 57 18645 INSULIN NEUTRAL (PURIFIED) 100 I/U INJ 58 59 54027 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 60 4.5mm/31gauge 22806 INSULIN PORK ACTRAPID 22094 INSULIN HUMULIN M2 VIAL

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1 2 56785 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Red (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 62098 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6 8mm/32.5gauge 7 5015 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 8 8mm/30gauge (Novo Nordisk Ltd) 9 10 6730 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with not less 11 than 12mm needle 0.33mm/29gauge 12 59311 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 15 57493 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 16 up / range 1-60 units Silver (Eli Lilly and Company Ltd) 17 For peer review only 15951 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 18 19 up / range 1-21 units (Owen Mumford Ltd) 20 37055 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 21 0.5ml with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 22 23 57744 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 24 4mm/31gauge (B.Braun Medical Ltd) 25 7127 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 27 28 61780 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 29 12mm/29gauge (Spirit Healthcare Ltd) 30 35078 Optipen pro 1 blue insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 31 32 Pharma) 33 17643 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 2 34 unit dial up / range 2-42 units (Owen Mumford Ltd) 35 15895 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 36 37 1-70 units Orange (Novo Nordisk Ltd) 38 48829 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 0.5-30 units Blue (Novo Nordisk Ltd) 40 41 36959 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 12mm/29gauge (Disposable Medical Equipment Ltd) 43 53148 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-60 44 units 45 46 1589 U100 Insulin syringe 0.5ml 47 10545 INSULIN HUMULIN M4 CARTRIDGE 100 I/U on September 25, 2021 by guest. Protected copyright. 48 45639 IME-FINE hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Arctic Medical Ltd) 51 5742 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 52 on 8mm/30gauge (Owen Mumford Ltd) 53 49307 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 54 55 on 4.5mm/31gauge (Ypsomed Ltd) 56 62562 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 4mm/33gauge (Spirit Healthcare Ltd) 58 59 10546 INSULIN HUMULIN M4 100 I/U INJ 60 54886 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/32gauge

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1 2 56939 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Pink (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6228 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 6 0.3ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 7 12244 INSULIN ZINC BOVINE susp 100 I/U INJ 8 13274 Clinipak u100 single use ins syr+12mm need28g 1ml [rand] 1ml Insulin syringe with 9 10 28gauge needle 12mm (Rand Rocket Ltd) 11 56624 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 12 0.5ml with 12mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 13 14 9619 Bd Ultra Pen 1.5ml Insulin pen (Becton, Dickinson UK Ltd) 15 5966 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 16 on 8mm/31gauge (Ypsomed Ltd) 17 For peer review only 2373 INSULIN HUMAN VELOSULIN 100 I/U INJ 18 19 43489 BD Micro-Fine Ultra hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 4mm/32gauge (Becton, Dickinson UK Ltd) 21 59475 Nanopass hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/32.5gauge (Terumo UK Ltd) 24 59793 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 25 screw on 4mm/32gauge (Cambridge Sensors Ltd) 26 17076 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 27 28 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 29 9079 INSULIN SOLUBLE 100 I/U INJ 30 5620 U100 Insulin syringe 0.3ml 31 32 38236 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 1ml 33 with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 34 20196 INSULIN SOLUBLE 40 I/U INJ 35 7765 INSULIN NEUTRAL (HUMAN) 100 I/U INJ 36 37 58581 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 38 screw on 5mm/31gauge (GlucoRx Ltd) http://bmjopen.bmj.com/ 39 10691 INSULIN ISOPHANE (NPH) 100 I/U INJ 40 41 5873 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 5mm/31gauge (Becton, Dickinson UK Ltd) 43 24554 Unifine single use Insulin syringe with 30gauge needle 8mm 0.3ml (Owen Mumford Ltd) 44 28666 Omnican 50 hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml 45 46 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 47 19271 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on on September 25, 2021 by guest. Protected copyright. 48 8mm/30gauge 49 50 6831 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 51 / range 1-60 units Teal (Eli Lilly and Company Ltd) 52 6378 Hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 8mm 53 needle 0.3mm/30gauge 54 55 13096 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 2 unit dial up / 56 range 2-32 units (Owen Mumford Ltd) 57 7075 Optipen Pro 1 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 58 59 / range 1-60 units (Sanofi) 60 42797 Injex ampoule pack 60501 (Ocon Chemicals Ltd) 60626 InsuJet starter set 012007GBSP Grey (Spirit Healthcare Ltd) 42305 Injex 10ml vial adaptor pack 60502 (Ocon Chemicals Ltd)

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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

Page 147 of 152 BMJ Open

1 2 Power calculations for cohort B where start of follow up is treatment for hypertension 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Beta-adrenoceptor blocking drugs 262081 Control Control Control 6 Angiotensin-converting enzyme inhibitors 187256 262081 449337 0.992 7 Thiazides and related diuretics 176791 262081 438872 0.991 8 Calcium channel blockers 140621 262081 402702 0.991 9 10 Loop diuretics 97675 262081 359756 0.990 11 Alpha-adrenoceptor blocking drugsFor peer review67517 only262081 329598 0.988 12 Centrally acting antihypertensive drugs 25746 262081 287827 0.982 13 14 Angiotensin-ii receptor antagonists 13366 262081 275447 0.975 15 Vasodilator antihypertensive drugs 9679 262081 271760 0.971 16 Potassium-sparing diuretics 7727 262081 269808 0.968

17 http://bmjopen.bmj.com/ 18 19 Power calculations for cohort B where start of follow up is a combination of treatments for hypertension 20 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 21 Beta-adrenoceptor blocking drugs 262081 Control Control Control 22 23 Loop diuretics & potassium-sparing diuretics 20446 262081 282527 0.980 24 Potassium-sparing diuretics & thiazides and related diuretics 6513 262081 268594 0.965 25

Beta-adrenoceptor blocking drugs & thiazides and related diuretics 1789 262081 on September 25, 2021 by guest. Protected copyright. 263870 0.934 26 Angiotensin-converting enzyme inhibitors & thiazides and related diuretics 624 262081 262705 0.888 27 28 Angiotensin-ii receptor antagonists & thiazides and related diuretics 564 262081 262645 0.882 29 Beta-adrenoceptor blocking drugs & potassium-sparing diuretics & thiazides and 46 262081 262127 0.587 30 related diuretics 31 32 Angiotensin-converting enzyme inhibitors & calcium channel blockers 35 262081 262116 0.526 33 Beta-adrenoceptor blocking drugs & loop diuretics & thiazides 22 262081 262103 0.403 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

BMJ Open Page 148 of 152

1 2 Power calculations for cohort B where start of follow up is treatment for hypercholesterolaemia 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Statins 788158 Control Control Control 6 Fibrates 8988 788158 797146 0.970 7 Bile acid sequestrants 7360 788158 795518 0.967 8 Omega-3 fatty acid compounds 2344 788158 790502 0.942 9 10 Ezetimibe 1345 788158 789503 0.924 11 Nicotinic acid group For321 peer788158 review788479 0.844only 12 13 14 15 16 Power calculations for cohort B where start of follow up is a combination of treatments for hypercholesterolaemia

17 http://bmjopen.bmj.com/ Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 18 19 Statins 788158 Control Control Control 20 Ezetimibe & statins 171 788158 788329 0.786 21 22 23 24 25 26 on September 25, 2021 by guest. Protected copyright. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

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1 2 Power calculations for cohort B where start of follow up is treatment for type 2 diabetes 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Biguanides 156304 Control Control Control 6 Sulphonylureas 41812 156304 198116 0.985 7 Other antidiabetic drugs 2471 156304 158775 0.943 8 9 10 11 For peer review only 12 Power calculations for cohort B where start of follow up is a combination of treatments for type 2 diabetes 13 14 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 15 Biguanides 156304 Control Control Control 16 Biguanides & other antidiabetic drugs 213 156304 156517 0.808

17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 26 on September 25, 2021 by guest. Protected copyright. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

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1 2 Power calculations for cohort C where start of follow up is diagnosis of dementia 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Treatment for hypertension prior to diagnosis 28586 76885 105471 0.981 6 Treatment for hypercholesterolaemia prior to diagnosis 26686 78785 105471 0.980 7 Treatment for type 2 diabetes prior to diagnosis 5867 99604 105471 0.964 8 Treatment for hypertension post diagnosis 5548 99923 105471 0.963 9 10 Treatment for hypercholesterolaemia post diagnosis 5062 100409 105471 0.961 11 Treatment for type 2 diabetes post diagnosisFor peer1470 review104001 105471 only 0.931 12 13 14 15 16

Page 151 of 152 BMJ Open

1 2 Power calculations for cohort C where start of follow up is diagnosis of Parkinson's disease 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Treatment for hypertension prior to diagnosis 6225 14461 20686 0.959 6 Treatment for hypercholesterolaemia prior to diagnosis 4563 16123 20686 0.955 7 Treatment for hypertension post diagnosis 2051 18635 20686 0.938 8 Treatment for hypercholesterolaemia post diagnosis 1842 18844 20686 0.936 9 10 Treatment for type 2 diabetes prior to diagnosis 907 19779 20686 0.913 11 Treatment for type 2 diabetes post diagnosisFor peer357 review20329 20686 only 0.870 12 13 14 15 16

BMJ Open Page 152 of 152

1 2 Power calculations for cohort C where start of follow up is diagnosis of amyotrophic lateral sclerosis 3 Exposure Exposed Group Unexposed Group Sample Size Detectable Hazard Ratio 4 5 Treatment for hypertension prior to diagnosis 670 1557 2227 0.881 6 Treatment for hypercholesterolaemia prior to diagnosis 530 1697 2227 0.874 7 Treatment for hypertension post diagnosis 152 2075 2227 0.807 8 Treatment for type 2 diabetes prior to diagnosis 86 2141 2227 0.762 9 10 Treatment for hypercholesterolaemia post diagnosis 66 2161 2227 0.739 11 Treatment for type 2 diabetes post diagnosisFor peer18 review2209 2227only 0.600 12 13 14 15 16

17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 26 on September 25, 2021 by guest. Protected copyright. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

For peer review only Journal: BMJ Open

Manuscript ID bmjopen-2016-012044.R1

Article Type: Protocol

Date Submitted by the Author: 21-Jul-2016

Primary Subject Pharmacology and therapeutics Heading:

Secondary Subject Heading: Neurology, Epidemiology

Dementia < NEUROLOGY, Parkinson-s disease < NEUROLOGY, Motor Keywords:

neurone disease < NEUROLOGY, EPIDEMIOLOGY, THERAPEUTICS http://bmjopen.bmj.com/

on September 25, 2021 by guest. Protected copyright.

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34 http://bmjopen.bmj.com/ 35 Alzheimer’s disease, Neurodegenerative Disease, Drug Repurposing, Clinical Practice 36 Research Datalink, Pharmacoepidemiology 37 38 39 WORD COUNT 40 41 42 3,807 words excluding title page, abstract, references, figures and tables. on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

34 patients and has a minimum detectable hazard ratio of 0.931. http://bmjopen.bmj.com/ 35 • We plan to use four different statistical methods in our analysis, which have different 36 approaches for modelling confounding. By doing this, we will be able to assess the 37 38 merits of each method in the given situation in order to minimize confounding. 39 • Dementia is a heterogeneous outcome, and electronic codes used to define cases in 40 primary care may not be as accurate as cases in clinical cohorts. We will undertake 41 sensitivity analyses to explore how this may affect our results. 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

48 49 We will focus on the following medications: 50 a. Treatments for hypertension 51 b. Treatments for hypercholesterolemia 52 c. Treatments for type 2 diabetes 53 54 Along with the following neurodegenerative diseases: 55 a. Alzheimer’s disease (AD) 56 b. Non-Alzheimer’s disease dementias (NADD) 57 c. Parkinson’s disease (PD) 58 d. Amyotrophic lateral sclerosis (ALS) 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 METHODS AND ANALYSIS 4 5 Study Design 6

34 http://bmjopen.bmj.com/ 35 time of diagnosis of their neurodegenerative disease; and ii) using those issued new 36 prescriptions post-diagnosis. The structure of these three cohorts is summarized in Table 1 37 and further explained in the text that follows. All of the cohorts rely on defined diagnoses and 38 exposures, which are recorded in the CPRD through the use of Read and product codes 39 respectively. Read codes uniquely identify clinical terms recorded by the GP during a 40 consultation, while product codes uniquely identify prescriptions issued. Both types of code 41 are recorded with a date and this will be used to determine the dates of diagnosis and 42 exposure required to define the cohorts. on September 25, 2021 by guest. Protected copyright. 43

44 45 Table 1: Comparison of the three cohort types. 46 Cohort A Cohort B Cohort C 47 To investigate To investigate To investigate 48 incidence by comparing incidence by comparing progression by 49 Purpose the different drug treated and untreated comparing treated and 50 subclasses of each individuals. untreated individuals. 51 treatment. 52 There will be three 53 There will be three There will be three Number of cohorts of this type, one 54 cohorts of this type, one cohorts of this type, one cohorts for each of dementia 55 for each treatment of for each treatment of 56 required (AD or NADD), PD interest. interest. 57 and ALS. 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Treatments for Treatments for Treatments for 4 hypertension, hypertension, hypertension, Exposures 5 hypercholesterolaemia hypercholesterolaemia hypercholesterolaemia, 6 and type 2 diabetes. and type 2 diabetes. and type 2 diabetes. 7 8 Date at first risk of the 9 condition the treatment 10 Start of is used for or date of Date of first Date of first diagnosis 11 follow-up first diagnosis of the prescription of a of neurodegenerative 12 (index date) condition itself if there treatment of interest. disease of interest. 13 was no preceding 14 period ‘at risk’. 15 ForDiagnosis peer of reviewDiagnosis of only 16 Outcome neurodegenerative neurodegenerative Death. 17 18 disease of interest. disease of interest. 19 Individuals prescribed both treatment and 20 Individuals with less Individuals with less 21 control medications at Exclusion than 12 consecutive than 12 consecutive 22 the same time or with Criteria months of records prior months of records prior 23 less than 12 consecutive to cohort entry. to cohort entry. 24 months of records prior 25 to cohort entry. 26 Conventional Conventional 27 Conventional regression, propensity regression, propensity 28 regression, propensity Statistical score regression, score regression, 29 score regression and Analysis instrumental variable instrumental variable 30 marginal structural 31 analysis and marginal analysis and marginal models. 32 structural models. structural models. 33 34 Cohort A http://bmjopen.bmj.com/ 35 36 37 For each treatment, we will create a cohort of patients who are diagnosed with the condition 38 the treatment is used for or ‘at risk’ of that condition. This will be determined by the 39 indications and test results described in Table 2. We will split each cohort into ‘exposed’ and 40 ‘unexposed’ groups. The ‘exposed’ group will consist of patients who received a treatment of 41 interest within 6 months of initial diagnosis of the condition for which the treatment is being 42 given (the ‘indication’ for treatment). The ‘unexposed’ group will consist of all others in the on September 25, 2021 by guest. Protected copyright. 43 cohort. Patients will be identified as having received a treatment of interest by product codes 44 (see Supplementary Files 1-3). Therefore, in this analysis, we will compare an ‘exposed’ 45 group of individuals who were prescribed the treatment to an ‘unexposed’ group of 46 47 individuals who received similar test results (i.e. were ‘at risk’ of or diagnosed with the 48 indication for treatment), but did not receive the treatment, as illustrated in Figure 1. The aim 49 of this approach is to address confounding by indication that could cause bias if the 50 ‘unexposed’ group is drawn from the full population, whom are likely to be healthier. It will 51 also allow us to minimise excluded immortal time bias as patients will be followed from a 52 consistent index date (date first at risk or date of first diagnosis of the condition itself if there 53 was no preceding period at risk). 54 55 Follow up for cohort A will start on the first date a patient is diagnosed with the condition the 56 57 treatment is used for or ‘at risk’ of that condition (See Table 2 and Supplementary Files 1-3.) 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Follow-up will end with the earliest of a relevant neurodegenerative disease diagnosis, death, 4 or censoring due to the end of registration at a CPRD general practice. 5 6 Table 2: The cohorts of type A, one for each treatment of interest. 7 Cohort Entry Criteria 8 9 Patients who are ‘at risk’ of hypertension as indicated by one of the 10 following: 11 • Medical code indicating a diagnosis of ‘at risk’ of hypertension 12 • Recorded systolic blood pressure test result between 120-139 mmHg 13 • Recorded diastolic blood pressure test result between 80-89 mmHg 14 15 ForIn the peer case of no period review ‘at risk’, patients only who have hypertension as 16 Treatments for 17 hypertension indicated by one of the following: 18 • Medical code indicating a diagnosis of hypertension 19 • Product code indicating treatment for hypertension 20 • Recorded systolic blood pressure test result of 140 mmHg or more 21 • Recorded diastolic blood pressure test result of 90 mmHg or more 22 23 24 See Supplementary File 1 for code lists relating to hypertension. 25 Patients who are ‘at risk’ of hypercholesterolaemia as indicated by one of 26 the following: 27 • Medical code indicating a diagnosis of ‘at risk’ of hypercholesterolaemia 28 • Recorded test result where total cholesterol level is between 4-5 mmol/L 29 • Recorded test result where LDL level is between 2-3 mmol/L 30

31 Treatments for In the case of no period ‘at risk’, patients who have hypercholesterolaemia 32 Hypercholest- as indicated by one of the following: 33 erolaemia

34 • Medical code indicating a diagnosis of hypercholesterolaemia http://bmjopen.bmj.com/ 35 • Product code indicating treatment for hypercholesterolaemia 36 • Recorded test result where total cholesterol level exceeds 5 mmol/L 37 • Recorded test result where LDL level exceeds 3 mmol/L 38 39 40 See Supplementary File 2 for code lists relating to hypercholesterolaemia. 41 Patients who are ‘at risk’ of type 2 diabetes as indicated by a medical code. 42 on September 25, 2021 by guest. Protected copyright. 43 In the case of no period ‘at risk’, patients who have type 2 diabetes as 44 indicated by one of the following: 45 • Medical code indicating a diagnosis of type 2 diabetes 46 47 • Product code indicating treatment for type 2 diabetes Medical code indicating a diagnosis of unspecified diabetes, first received 48 Treatments for • over the age of 40 49 type 2 diabetes 50 • Product code indicating treatment with insulin, first received over the age 51 of 40 52 53 This assumes that patients treated with insulin or receiving a diagnosis of 54 unspecified diabetes after the age of 40 have type 2 diabetes. Patients with a 55 56 recorded diagnosis of type 1 diabetes at any age will be excluded. See 57 Supplementary File 3 for code lists relating to type 2 diabetes. 58 59 60 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Cohort B 4 5 In this analysis we will compare different drug sub-classes that exist for a given treatment 6 (listed in Table 3). To do this, we will create a cohort of all patients who were prescribed a 7 treatment and categorise them by the drug sub-class they initially received. This will allow us 8 9 to compare the outcomes for each of the resulting sub-groups. For each treatment, we have 10 defined the most frequently prescribed sub-class as the control (indicated in Table 3). In the 11 primary analysis of this cohort we will exclude patients initially prescribed the control sub- 12 class if they receive another sub-class of the same treatment at the same time, however we do 13 not expect this to be a common. We will explore the outcomes of individuals prescribed 14 multiple sub-classes, other than that specified above, in a sensitivity analysis. 15 For peer review only 16 Follow-up for cohort B will start on the date of first eligible prescription as determined by a 17 product code (see the treatment code lists in Supplementary Files 1-3). Follow-up will end 18 19 with the earliest of a relevant neurodegenerative disease diagnosis, death, or censoring due to 20 the end of registration at a CPRD general practice. 21 22 Table 3: The drug sub-classes of interest for each treatment group with the control 23 treatments indicated. 24 Treatments for hypertension 25 • Beta-adrenoceptor blocking drugs (control) 26 27 • Angiotensin-converting enzyme inhibitors 28 • Thiazides and related diuretics 29 • Calcium channel blockers 30 • Loop diuretics 31 • Alpha-adrenoceptor blocking drugs 32 • Centrally acting antihypertensive drugs 33 • Angiotensin-II receptor antagonists 34 http://bmjopen.bmj.com/ 35 • Vasodilator antihypertensive drugs 36 • Potassium-sparing diuretics and aldosterone antagonists 37 Treatments for hypercholesterolaemia 38 • Statins (control) 39 • Fibrates 40 41 • Bile acid sequestrants 42 • Omega-3 fatty acid compounds on September 25, 2021 by guest. Protected copyright. 43 • Ezetimibe 44 • Nicotinic acid group 45 Treatments for type 2 diabetes 46 47 • Biguanides (control) 48 • Sulphonylureas 49 • Other antidiabetic drugs 50 51 Cohort C 52 53 For each neurodegenerative disease group of interest, we will create a cohort of individuals 54 with a read code indicating this outcome (see Supplementary File 4) or a product code 55 56 indicating they received treatment for the outcome (see Supplementary File 5). These cohorts 57 will be used to investigate the associations of neurodegenerative disease progression with 58 exposure to one of the three treatment groups of interest: treatments for hypertension, 59 60 5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 treatments for hypercholesterolaemia and treatments for type 2 diabetes. We will investigate 4 both exposure before and after the diagnosis of a neurodegenerative disease. For all of the 5 treatments we consider, each cohort will be split into ‘exposed’ and ‘unexposed’ groups. In 6 the analysis, individuals in the ‘exposed’ group, i.e. those who were prescribed the treatment 7 under investigation, will be compared with individuals in the ‘unexposed’ groups, i.e. those 8 9 who did not receive the treatment. 10 11 Follow-up for cohort C will start with the first recorded read code indicating Alzheimer’s or 12 other neurodegenerative disease (see Supplementary File 4) or, in the absence of a diagnosis, 13 the first recorded product code indicating they received treatment for a neurodegenerative 14 disease (See Supplementary File 5). Follow-up will end with the earliest of death or 15 censoring dueFor to the end peerof registration atreview a CPRD general practice. only 16 17 18 Variables 19 20 Exposures 21 22 For our primary analysis we will define all exposures based on the first prescription observed 23 in the database.[10] This is so that the target parameter estimated in the observational study 24 will be comparable to that estimated by a randomised controlled trial (RCT). Analogous to an 25 intention-to-treat analysis in a RCT, patients initially prescribed an active treatment 26 medication (exposed), but later stop that medication or switch to a control drug (unexposed), 27 28 will be allocated to treatment (i.e. classified as exposed, irrespective of what happens in the 29 future) and vice-versa. First time prescriptions of the medications of interest (treatment and 30 control) will be defined as people who received at least one prescription of the product but 31 who had no use of a related product during the 12 months before the start of follow-up. The 32 prescriptions will be identified using product codes recorded in the therapy file in the CPRD, 33 which details the date each prescription was issued, the quantity of drug prescribed and the

34 dosage. Patients initially receiving more than one prescription of a drug of interest will be http://bmjopen.bmj.com/ 35 included in our analysis in a group representing the specific combination of drugs they 36 receive. The effects of treatment switching and disease control will be explored using 37 38 marginal structural models. We will also consider disease severity for the treatment 39 indications through the use of instrumental variable analysis. 40 41 Outcomes 42

on September 25, 2021 by guest. Protected copyright. 43 For incidence, we will identify the neurodegenerative disease outcomes (Alzheimer’s disease, 44 non-Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) by the first 45 record of a relevant read code (see Supplementary File 4) or the first record of a product code 46 indicating treatment for the neurodegenerative disease (see Supplementary File 5). For both 47 48 incidence and progression, we will identify deaths using linked Office of National Statistics 49 (ONS) data. 50 51 Covariates 52 53 We will match all covariates on date of birth, sex, year of index date and years of recorded 54 history in the database before the index date. The covariates we will include in our analyses 55 are: body mass index, smoking status, alcohol consumption, a postcode-based measure of 56 57 socioeconomic position, previous history of coronary-artery disease, previous coronary- 58 bypass surgery and cerebrovascular disease including stroke. We will also control for other 59 60 6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 major chronic illness (including cancer, arthritis) using the Charlson index [11,12] and for 4 consultation rate, calculated by dividing the total number of clinic visits prior to the index 5 date by the length of each patient's follow-up. If there are missing data in the covariates we 6 will consider using multiple imputation. Unfortunately not all covariates of interest, such as 7 exercise, are recorded within the CPRD and this may lead to unmeasured confounding. We 8 9 hope to minimize this confounding by using methods, such as instrumental variable analysis, 10 which can account for it to some degree. 11 12 Data Sources 13 14 The main data source for this project is the CPRD. Cause-specific mortality from linked ONS 15 data are moreFor accurate thanpeer CPRD data review on mortality from general only practices.[13] Therefore, 16 we will use the ONS data to identify date and cause of death and test our hypotheses relating 17 18 to mortality using data from linked practices only. We will also be using the Index of 19 Multiple Deprivation (IMD) in order to define socioeconomic position, which is listed as a 20 covariate in our analysis. 21 22 Study Size 23 24 The table below (Table 4) details the expected number of events for the event used to define 25 26 the start of follow up with the minimum sample size and detectable hazard ratio (alpha=0.05, 27 beta=0.80) for the Cox regression analysis of cohorts B and C. The minimum detectable 28 hazard ratio is taken to be the detectable hazard ratio for the smallest exposed group tested 29 against the control group. The minimum sample size is the sum of patients in the smallest 30 exposed group and the control group. It is difficult to provide such details for cohort A due to 31 its novel design that includes patients who are ‘at risk’ of the condition the treatment is used 32 for. We can however consider the expected number of events listed for cohort B to be 33 conservative estimates for the sample size of cohort A as all patients receiving treatment are 34 included in cohort A by definition. This study will involve a large sample of data and has http://bmjopen.bmj.com/ 35 36 considerable power to detect even relatively small effects. Therefore, our statistical power 37 will be more than adequate to test all of our proposed hypotheses, even under highly 38 conservative Bonferroni corrections. Further details concerning the sample size and 39 detectable hazard ratios (alpha=0.05, beta=0.80) for specific comparisons within cohorts B 40 and C can be found in Supplementary Files 6 and 7. Further details concerning the expected 41 number of events, including at the drug subclass level, can be found in Supplementary File 8. 42 on September 25, 2021 by guest. Protected copyright. 43 Table 4: The expected number of events for the event used to define the start of follow 44 up presented with the minimum sample size and detectable hazard ratio (alpha=0.05, 45 46 beta=0.80) for the Cox regression analysis of cohorts B and C. Expected Minimum 47 Minimum Cohort Start of Follow Up Number of Detectable 48 Sample Size 49 Events Hazard Ratio 50 Treatment for 1,018,519 269,808 0.968 51 hypertension 52 Treatment for B 808,687 788,479 0.844 53 hypercholesterolaemia 54 Treatment for 55 200,800 158,775 0.943 56 type 2 diabetes Diagnosis of dementia 57 C 105,471 105,471 0.931 58 (AD and NADD) 59 60 7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Diagnosis of Parkinson’s 20,686 20,686 0.870 4 disease 5 Diagnosis of 2,227 2,227 0.600 6 ALS 7 8 9 Bias 10 11 There are three main sources of bias in our results: ascertainment bias, collider bias and 12 immortal time bias. To overcome ascertainment bias, we will control for consultation rate in 13 our analyses because people who have more chronic conditions such as hypertension, 14 diabetes or renal insufficiency may have higher rates of consultation, which may also increase 15 the opportunityFor for recording peer other diagnoses review such as dementia. only Collider bias could occur if 16 17 we conditioned on events that happened as a result of the prescription the patient was issued. 18 To prevent this form of bias from affecting our results, we will define each covariate using 19 data inputted prior to the index date.[14] Finally, we will minimise the risk of immortal time 20 bias in two ways. Firstly, to prevent misclassified immortal time, we will define exposures 21 based on the first prescription observed in the database[10] and use an intention-to-treat 22 analysis. Secondly, to minimise immortal time, we will follow-up patients (exposed and 23 unexposed) from a consistent index date. This will be a test result or a read code indicating 24 diagnosis where possible[15] however, to capture all relevant patients, we will allow those 25 receiving treatment without a recorded diagnosis to be included. 26 27 28 Confounding 29 30 We have identified two key sources of confounding in our study: confounding by indication 31 and time dependent confounding. To address the former, we will use four different statistical 32 methods, which have different approaches for modelling confounding. Through examination 33 of these approaches, we hope to highlight any uncontrolled confounding that may be leading

34 http://bmjopen.bmj.com/ 35 to false conclusions about drug effect. We will also account for confounding by indication in 36 the construction of our cohorts. Consider cohort A, where we compare ‘exposed’ and 37 ‘unexposed’ groups of individuals. Drawing the ‘unexposed’ group from the full population 38 can introduce bias as they are likely to be in better health. We will avoid this by defining 39 cohort entry on the basis of first test or recording of a relevant read code so the ‘exposed’ and 40 ‘unexposed’ groups will have more in common. In addition to this, we will address time 41 dependent confounding in our study. This will be done by using marginal structural models, 42 which can allow for time dependent confounding and treatment switching between products. on September 25, 2021 by guest. Protected copyright. 43 44 45 Missing Data 46 47 We will automatically use multiple imputation if there are missing data, as we are aware that 48 a small amount of missing data across multiple variables could result in a large number of 49 incomplete cases and consequently limit the sample for a complete case analysis. We will 50 conduct sensitivity analyses to investigate the effect of imputing these missing data on our 51 results.[16–18] 52

53 54 55 56 57 58 59 60 8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Multiple Testing 4 5 We will account for multiple testing using permutation analysis where appropriate. A portion 6 of the data included in this project was previously used in a study investigating the 7 association of alpha-adrenoceptor blocking drugs and angiotensin-II receptor antagonists with 8 9 Alzheimer’s disease and non-Alzheimer’s disease dementias.[19] We anticipate the overlap 10 between our study and this previous study to be around 4% for each of cohorts A and B and 11 9% for cohort C. We acknowledge that this might be a concern for multiple testing however 12 wish to highlight that the analyses conducted in this study will differ from those used before. 13 14 Statistical Methods 15 For peer review only 16 17 We will use four statistical approaches in our study – they are: multivariable adjusted Cox 18 regression, propensity matched regression, instrumental variable analysis and marginal 19 structural models. We are committed to presenting the findings from all our analyses, 20 irrespective of the direction of findings, and will handle discrepancies between them by 21 assessing the merits of each method in the given situation. If we discover large main effects 22 of specific medications we may investigate interactions between covariates, and will seek to 23 replicate any interactions in other large samples. 24 25 We will be using an intention to treat analysis in our primary analysis. The reasons for this 26 27 are two-fold. First, whilst there are theoretical statistical models for estimating the effects of 28 treatment switching such as marginal structural models, these methods require the strong 29 assumption that there are no unmeasured confounders. Second, to our knowledge there are no 30 instrumental variable methods for estimating the effects of treatment switching. We will 31 investigate treatment switching using marginal structural models in a secondary analysis. All 32 of the methods we will use for this study are summarised below. 33 34 Multivariable adjusted Cox regression http://bmjopen.bmj.com/ 35 36 37 In our first analyses, a conventional observational analysis, we will estimate the hazard ratios 38 of incidence and survival using Cox-proportional hazards models. Both analyses will use the 39 actual prescriptions issued to the patients.[20] We will report these associations adjusted for 40 basic confounders (age and gender), and results adjusted for all measured covariates 41 described previously. We will also perform tests of the proportional hazards assumption. 42 on September 25, 2021 by guest. Protected copyright. 43 Propensity matched regression 44 45 In our second analysis we will construct a sample of patients balanced on covariates and risk 46 47 factors using a propensity score.[21–24] We will construct propensity scores using a logistic 48 regression of the actual treatment received on the covariates described above. Therefore, each 49 participant’s propensity score will be their conditional probability (odds) of receiving 50 treatment or not (Cohort types A and C), or receiving treatment versus control therapy 51 (Cohort type B). We will match each patient receiving one treatment to another patient 52 receiving the control treatment with the closest propensity score on a ratio of 1:1 using a 53 nearest neighbour algorithm with no replacement, and matching will be restricted to the 54 common support region. Patients outside the common support region are those prescribed the 55 treatment therapy with propensity scores higher than any patient prescribed the control 56 57 treatment and vice versa. We will estimate odds-ratios and hazard ratios of the outcomes 58 using the propensity score matched sample using logistic and Cox-regressions. 59 60 9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Instrumental variable analysis 4 5 In our third analysis, we will estimate the effects i) treatment or no treatment, and ii) the 6 specific sub-class of medication prescribed using physicians’ prescribing preferences as 7 instruments for the prescriptions the GPs issue to their patients. We cannot directly measure 8 9 the physicians’ preferences; therefore, we will use the prescriptions they issued to their 10 previous patients as a proxy for their preferences. For example, if the instrument were based 11 on just one previous prescription, physicians who previously prescribed the treatment therapy 12 would be categorised as a “treatment” prescriber otherwise they would be categorised as 13 “control”. As with our previous studies we will use seven prior prescriptions to improve the 14 strength of the instruments.[25–27] Using multiple prior prescriptions will maximise power. 15 We will reportFor risk differences peer in the review outcomes using additive only structural mean models 16 estimated via the generalised method of moments.[28–30] We will categorise each of the 17 adverse event outcomes as occurring within 3, 6, 9, 12, 24 and 48 months of index date. 18 19 Methods for estimating survival models using instrumental variables are not well developed. 20 Therefore we will explore potential instrumental variable survival models in a secondary 21 analysis.[31] 22 23 Marginal structural models 24 25 In our fourth analysis, we will estimate the effects of each treatment using marginal structural 26 models.[32] We will use these models to account for time dependent confounding and 27 treatment switching. We will construct inverse probability weights for each treatment based 28 29 on the patients’ observed characteristics such as: gender, age, comorbidities and concurrent 30 treatments. We will use these models to estimate the odds and hazard ratios of disease 31 incidence and progression. 32 33 ETHICS

34 http://bmjopen.bmj.com/ 35 This protocol has been approved by the CPRD’s Independent Scientific Advisory Committee 36 (ISAC). Although this study does not directly involve patients, the topic of identifying new 37 repurposable drug candidates for neurodegenerative diseases is becoming widely supported 38 39 by patient and user groups from various communities. In the event that we progress any drug 40 candidates identified from this study into a formal clinical trial, then we will consult with 41 relevant representatives in the design of that study. We have direct experience of this from 42 the currently underway NIHR funded RADAR trial, the case for which was supported by on September 25, 2021 by guest. Protected copyright. 43 work undertaken as part of a previous study using CPRD data [ISAC protocol 08_101]. 44 45 DISSEMINATION 46 47 We will publish the results of the study as open-access peer-reviewed publications. We will 48 49 disseminate findings through national and international conferences as are appropriate. 50 Depending on the findings we would also explore additional options for focussed 51 dissemination within appropriate communities, e.g. via an Alzheimer’s Society dissemination 52 grant. 53 54 CONTRIBUTORSHIP STATEMENT 55 56 VMW, NMD, PGK, and RMM contributed to planning the analysis. TJ provided the 57 feasibility numbers and refined the cohort definitions. VMW drafted this protocol and all 58 59 60 10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 others edited and revised the manuscript. PGK and RMM were responsible for securing the 4 funding. 5 6 FUNDING STATEMENT 7 8 9 This project is supported by a generous donation from the Perros Trust, obtained through the 10 University of Bristol Campaigns and Alumni Office. This project is also supported by the 11 MRC Integrative Epidemiology Unit at the University of Bristol. The MRC Integrative 12 Epidemiology Unit is supported by the Medical Research Council and the University of 13 Bristol [MC_UU_12013/9]. NMD is supported by the Economics and Social Research 14 Council (ESRC) via a Future Research Leaders Fellowship [ES/N000757/1]. PGK has a 15 ProfessorshipFor supported peer by the Sigmund review Gestetner Foundation. only TJ is supported by the 16 National Institute for Health Research (NIHR) Collaboration for Leadership in Applied 17 Health Research and Care (CLAHRC) West at University Hospitals Bristol NHS Foundation 18 19 Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, 20 the NIHR or the Department of Health. 21 22 COMPETING INTERESTS STATEMENT 23 24 PGK is the principal investigator on a non-commercial NIHR-funded clinical trial of losartan 25 in Alzheimer’s disease [ISRCTN 93682878, EudraCT 2012-003641-15]. 26 27 REFERENCES 28 29 30 1 Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for 31 existing drugs. Nat Rev Drug Discov 2004;3:673–83. doi:10.1038/nrd1468 32 33 2 Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev

34 Drug Discov 2012;11:833–46. doi:10.1038/nrd3869 http://bmjopen.bmj.com/ 35 36 3 Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus 37 study. The Lancet 2005;366:2112–7. doi:10.1016/S0140-6736(05)67889-0 38 39 4 Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of 40 dementia in individuals aged 65 years and older from three geographical areas of 41 England: results of the Cognitive Function and Ageing Study I and II. The Lancet 42 on September 25, 2021 by guest. Protected copyright. 43 2013;382:1405–12. doi:10.1016/S0140-6736(13)61570-6 44 45 5 Herrett E, Gallagher AM, Bhaskaran K, et al. Data Resource Profile: Clinical Practice 46 Research Datalink (CPRD). Int J Epidemiol 2015;44:827–36. doi:10.1093/ije/dyv098 47 48 6 Unger T. Comparing the cerebroprotective properties of antihypertensive drugs in terms 49 of their effects on angiotensin. Nat Clin Pract Nephrol 2008;4:12–3. 50 doi:10.1038/ncpneph0672 51 52 7 Asahi M, Thomas S, Yoshimura S, et al. Protective Effects of Statins after Embolic Focal 53 Cerebral Ischemia in Endothelial Nitric Oxide Synthase Knockout Mice. J Cereb Blood 54 Flow Metab Off J Int Soc Cereb Blood Flow Metab 2005;25:722–9. 55 doi:10.1038/sj.jcbfm.9600070 56 57 58 59 60 11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 8 Huxley RR, Hawkins MH, Humphries SE, et al. Risk of Fatal Stroke in Patients With 4 Treated Familial Hypercholesterolemia A Prospective Registry Study. Stroke 5 2003;34:22–5. doi:10.1161/01.STR.0000047123.14312.3E 6 7 9 Liu Y, Tang G, Li Y, et al. Metformin attenuates blood-brain barrier disruption in mice 8 following middle cerebral artery occlusion. J Neuroinflammation 2014;11. 9 10 doi:10.1186/s12974-014-0177-4 11 12 10 Hernán MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized 13 experiments: an application to postmenopausal hormone therapy and coronary heart 14 disease. Epidemiol Camb Mass 2008;19:766–79. doi:10.1097/EDE.0b013e3181875e61 15 For peer review only 16 11 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic 17 comorbidity in longitudinal studies: development and validation. J Chronic Dis 18 1987;40:373–83. 19 20 12 Khan NF, Perera R, Harper S, et al. Adaptation and validation of the Charlson Index for 21 Read/OXMIS coded databases. BMC Fam Pract 2010;11:1. doi:10.1186/1471-2296-11-1 22 23 13 Thomas KH, Davies N, Metcalfe C, et al. Validation of Suicide and Self-harm records in 24 the Clinical Practice Research Datalink. Br J Clin Pharmacol Published Online First: 6 25 26 December 2012. doi:10.1111/bcp.12059 27 28 14 Cole SR, Platt RW, Schisterman EF, et al. Illustrating bias due to conditioning on a 29 collider. Int J Epidemiol 2009;39:417–20. doi:10.1093/ije/dyp334 30 31 15 Suissa S, Azoulay L. Metformin and the Risk of Cancer: Time-related biases in 32 observational studies. Diabetes Care 2012;35:2665–73. doi:10.2337/dc12-0788 33

34 16 Royston P. Multiple imputation of missing values: Further update of ice, with an http://bmjopen.bmj.com/ 35 emphasis on categorical variables. Stata J 2009;9:466–77. 36 37 17 Sterne JAC, White IR, Carlin JB, et al. Multiple imputation for missing data in 38 epidemiological and clinical research: potential and pitfalls. BMJ 2009;338:b2393– 39 b2393. doi:10.1136/bmj.b2393 40 41 42 18 White IR, Kalaitzaki E, Thompson SG. Allowing for missing outcome data and on September 25, 2021 by guest. Protected copyright. 43 incomplete uptake of randomised interventions, with application to an Internet-based 44 alcohol trial. Stat Med 2011;30:3192–207. doi:10.1002/sim.4360 45 46 19 Davies NM, Kehoe PG, Ben-Shlomo Y, et al. Associations of anti-hypertensive 47 treatments with Alzheimer’s disease, vascular dementia, and other dementias. J 48 Alzheimers Dis 2011;26:699. 49 50 20 Kirkwood BR. Essential medical statistics. 2nd ed. Malden, Mass: : Blackwell Science 51 2003. 52 53 21 Glynn R, Schneeweiss S, Stürmer T. Indications for propensity scores and review of their 54 use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 2006;98:253–9. 55 56 57 22 Leuven E, Sianesi B. PSMATCH2: Stata module to perform full Mahalanobis and 58 propensity score matching, common support graphing, and covariate imbalance testing. 59 60 12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Stat Softw Compon Published Online First: 4 2012.http://ideas.repec.org/c/boc/bocode/s432001.html (accessed 13 May2013). 5 6 23 Rosenbaum PR, Rubin DB. Constructing a Control Group Using Multivariate Matched 7 Sampling Methods That Incorporate the Propensity Score. Am Stat 1985;39:33. 8 doi:10.2307/2683903 9 10 24 Rosenbaum PR, Rubin DB. The Central Role of the Propensity Score in Observational 11 12 Studies for Causal Effects. Biometrika 1983;70:41. doi:10.2307/2335942 13 14 25 Davies NM, Davey Smith G, Windmeijer F, et al. COX-2 Selective Nonsteroidal Anti- 15 inflammatoryFor Drugs peer and Risk of Gastrointestinalreview Tract Complicationsonly and Myocardial 16 Infarction: An Instrumental Variable Analysis. Epidemiology 2013;24:352–62. 17 doi:10.1097/EDE.0b013e318289e024 18 19 26 Thomas KH, Martin RM, Davies NM, et al. Smoking cessation treatment and risk of 20 depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective 21 cohort study. BMJ 2013;347:f5704–f5704. doi:10.1136/bmj.f5704 22 23 27 Davies NM, Gunnell D, Thomas KH, et al. Physicians’ prescribing preferences were a 24 potential instrument for patients’ actual prescriptions of antidepressants. J Clin Epidemiol 25 26 Published Online First: September 2013. doi:10.1016/j.jclinepi.2013.06.008 27 28 28 Clarke PS, Windmeijer F. Instrumental Variable Estimators for Binary Outcomes. J Am 29 Stat Assoc 2012;107:1638–52. doi:10.1080/01621459.2012.734171 30 31 29 Hansen L, Singleton K. Generalized instrumental variables estimation of nonlinear 32 rational expectations models. Econometrica 1982;50:1269–86. 33

34 30 Clarke PS, Windmeijer F. Identification of causal effects on binary outcomes using http://bmjopen.bmj.com/ 35 structural mean models. Biostatistics 2010;11:756–70. doi:10.1093/biostatistics/kxq024 36 37 31 Tchetgen Tchetgen EJ, Walter S, Vansteelandt S, et al. Instrumental Variable Estimation 38 in a Survival Context. Epidemiol Camb Mass Published Online First: 16 February 2015. 39 doi:10.1097/EDE.0000000000000262 40 41 42 32 Hernán MA, Brumback B, Robins JM. Marginal Structural Models to Estimate the Joint on September 25, 2021 by guest. Protected copyright. 43 Causal Effect of Nonrandomized Treatments. J Am Stat Assoc 2001;96:440–8. 44 doi:10.1198/016214501753168154 45 46 33 Levesque LE, Hanley JA, Kezouh A, et al. Problem of immortal time bias in cohort 47 studies: example using statins for preventing progression of diabetes. Br Med J 48 2010;340:b5087–b5087. doi:10.1136/bmj.b5087 49 50 34 Suissa S. Immortal time bias in pharmacoepidemiology. Am J Epidemiol 2008;167:492– 51 9. 52 53 54

55 56 57 58 59 60 13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 158 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 Figure 1: The cohort construction for cohort type A, designed to eliminate immortal 4 time bias. For those without a period ‘at risk’, cohort entry will occur when they are 5 diagnosed with the condition. 6 7 Figure 1 – Mono Image.tif 8 9 10 A patient will enter the cohort for a given treatment when they first become ‘at risk’ of the 11 condition the treatment is used for or, in the case of no period ‘at risk’, when they are first 12 diagnosed with the condition (see Table 2). For example, when they are diagnosed as at ‘at 13 risk of’ hypertension or, in the case of no period ‘at risk’, when they receive a diagnosis of 14 hypertension. We define cohort entry in this way to avoid excluded immortal time bias that 15 can occur whenFor cohort entrypeer is determined review by treatment variation only over time.[33,34] Immortal 16 time is the period during follow-up when the outcome cannot occur. Consider the 17 18 hypertension example above, suppose we started following the treated patients in our cohort 19 from the date of their first prescription of a treatment for hypertension and the untreated 20 patients from a matched date. This would make it impossible for the treated patients to have 21 an outcome, such as dementia, prior to their first prescription. Consequently, patients in this 22 group would all have a period before treatment, when they could not be diagnosed with 23 dementia i.e. they could not experience the outcome. This period is their immortal time, and 24 it must be correctly attributed to the ‘unexposed’ group so that their outcome is not falsely 25 attributed to their exposure. To do this, patients in the ‘exposed’ and ‘unexposed’ groups 26 must be followed-up and compared from the same start date. In this cohort we are minimizing 27 28 excluded immortal time by following patients from either a test result or diagnosis where 29 possible. In order to capture all relevant patients, we will allow those receiving treatment 30 without a recorded diagnosis to be included as it is assumed treatment suggests a diagnosis. 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 25, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 158 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 The cohort construction for cohort type A, designed to eliminate immortal time bias. For those without a 28 period ‘at risk’, cohort entry will occur when they are diagnosed with the condition. 29 Figure 1 173x101mm (300 x 300 DPI) 30 31 32 33

1 2 Medical code list: 'at risk' of hypertension

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1 2 Medical code list: hypertension

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1 2 51650 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge (B.Braun Medical Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 12300 SYRINGE INSULIN (BS1619/1) 2ML 6 37427 HumaPen Luxura HD hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit 7 dial up / range 1-30 units (Eli Lilly and Company Ltd) 8 39150 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 9 10 safety needle 0.33mm/29gauge 11 5634 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 12mm 12 needle 0.36mm/28gauge 13 14 19707 INSULIN HUMULIN S (NEUTRAL SOLUBLE) 15 7412 U100 Insulin syringe 0.5ml 16 18446 Unifine hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 17 For peer review only 12mm needle 0.33mm/29gauge (Owen Mumford Ltd) 18 19 7959 INSULIN MIXTARD 30/70 40 I/U INJ 20 18149 Monoject u100 insulin syringe 12mm(29g)0.5ml 12mm29G 0.5ml Insulin syringe 21 (Covidien (UK) Commercial Ltd) 22 23 10133 U100 Insulin syringe 1ml 24 22823 INSULIN ISOPHANE (PURIFIED) 100 I/U INJ 25 60028 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 26 4mm/32gauge 27 28 11346 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 29 14506 INSULIN BOVINE PROTAMINE ZINC 100 I/U INJ 30 13009 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 31 32 needle 0.36mm/28gauge 33 56352 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 34 up / range 1-60 units Green (Eli Lilly and Company Ltd) 35 44810 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 5mm/32gauge 38 19029 SYRINGE PRE-SET INSULIN FOR BLIND 2ML http://bmjopen.bmj.com/ 39 38774 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 40 41 range 1-60 units Blue (Novo Nordisk Ltd) 42 10258 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 43 8mm/31gauge 44 21945 INSULIN PORK INSULATARD 45 46 56808 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 47 12mm/29gauge (B.Braun Medical Ltd) on September 25, 2021 by guest. Protected copyright. 48 43670 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 4mm/32gauge 51 6991 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 52 0.5ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 53 5649 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 1 unit dial up / 54 55 range 1-16 units (Owen Mumford Ltd) 56 33101 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 12.7mm/29gauge 58 59 14887 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 60 5mm/31gauge 1751 Hypodermic U100 insulin syringe glass reusable 1ml 8839 INSULIN SEMITARD 100 I/U INJ

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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 124 of 158

1 2 10242 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 3 6mm/31gauge BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 27911 INSULIN HUMAN ACTRAPID PENFILL 6 25006 INSULIN HUMAN ACTRAPID (NEUTRAL) 7 58817 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 8 screw on 12mm/29gauge (GlucoRx Ltd) 9 10 6753 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 11 up / range 1-35 units Green (Novo Nordisk Ltd) 12 21223 U100 Insulin syringe 0.3ml 13 14 35017 Optipen pro 1 white insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 15 Pharma) 16 22946 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 17 For peer review only with 12mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 18 19 49451 Mylife Clickfine AutoProtect hypodermic insulin needles for pre-filled / reusable pen 20 injectors screw on 8mm/29gauge (Ypsomed Ltd) 21 57451 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 22 23 screw on 8mm/31gauge (Cambridge Sensors Ltd) 24 59846 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 25 on 4mm/32gauge (Ypsomed Ltd) 26 48811 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 27 28 screw on 6mm/31gauge (Owen Mumford Ltd) 29 7757 INSULIN NEULENTE (ZINC SUSP)(PURIFIED) 100 I/U INJ 30 7062 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 31 32 12mm needle 0.4mm/27gauge (Terumo UK Ltd) 33 5850 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 34 on 6mm/31gauge (Ypsomed Ltd) 35 55521 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 36 37 4mm/32gauge (Spirit Healthcare Ltd) 38 16209 INSULIN HYPURIN SOLUBLE 100 I/U INJ http://bmjopen.bmj.com/ 39 8838 INSULIN SEMITARD 40 I/U INJ 40 41 5789 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 8mm 42 needle 0.3mm/30gauge 43 11245 B-d u-100 0.3ml Insulin syringe (Becton, Dickinson UK Ltd) 44 7783 INSULIN ISOPHANE (HUMAN) 100 I/U INJ 45 46 60951 Insulin human 100units/ml solution for injection 10ml vials 47 5164 NovoPen 3 Demi hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit on September 25, 2021 by guest. Protected copyright. 48 dial up / range 1-35 units (Novo Nordisk Ltd) 49 50 321 INSULIN HUMAN ACTRAPID (NEUTRAL) 40 I/U INJ 51 57243 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 52 10mm/30gauge (B.Braun Medical Ltd) 53 6060 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 54 55 on 6mm/30gauge (Owen Mumford Ltd) 56 4896 Monoject hypodermic U100 insulin syringe sterile single use / single patient use 1ml 57 with 12mm needle 0.36mm/28gauge (Covidien (UK) Commercial Ltd) 58 59 22161 INSULIN HUMULIN M1 VIAL 60 5769 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm needle 0.4mm/27gauge

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1 2 54028 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 3 screw on 12mm/29gauge (Owen Mumford Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 59005 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 6 screw on 8mm/31gauge (Ypsomed Ltd) 7 8376 INSULIN ISOPHANE 100 I/U 8 58961 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 9 10 screw on 4mm/32gauge (Ypsomed Ltd) 11 23437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12 12mm/28gauge 13 14 18208 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 15 10mm/29gauge 16 22987 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 17 For peer review only 12mm/29gauge 18 19 59004 Mylife Penfine Classic hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 6mm/32gauge (Ypsomed Ltd) 21 60750 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/33gauge 24 11878 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 8mm 25 needle 0.3mm/30gauge 26 35081 OptiClik hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 27 28 range 1-80 units Grey (Sanofi) 29 49052 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 30 screw on 8mm/31gauge (Owen Mumford Ltd) 31 32 48765 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 5mm/31gauge (Owen Mumford Ltd) 34 54885 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 35 8mm/32gauge 36 37 18195 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 38 6mm/31gauge http://bmjopen.bmj.com/ 39 20672 INSULIN HUM/ACTRAPID 40 41 51107 Hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial up / range 2-42 42 units 43 47751 TS-A Safety hypodermic U100 insulin syringe sterile single use / single patient use 1ml 44 with 12mm safety needle 0.33mm/29gauge (Minsmed) 45 46 48435 BD AutoShield hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 5mm/29gauge (Becton, Dickinson UK Ltd) on September 25, 2021 by guest. Protected copyright. 48 5421 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Novo Nordisk Ltd) 51 11408 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 52 up / range 1-21 units (Owen Mumford Ltd) 53 59133 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 54 55 0.5ml with 8mm safety needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 56 58798 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 57 screw on 6mm/31gauge (GlucoRx Ltd) 58 59 6724 U100 Insulin syringe 0.3ml 60 9578 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw on 12mm/29gauge (Owen Mumford Ltd) 26784 INSULIN ZINC SEMILENTE SUSP BP 100 I/U INJ

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1 2 5557 NovoPen 3 Fun hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 3 / range 2-70 units Blue (Novo Nordisk Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 11086 B-d u-100 0.5ml Insulin syringe (Becton, Dickinson UK Ltd) 6 25422 Hypoguard u100 click/count 1ml Insulin syringe (Hypoguard Ltd) 7 14191 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial 8 up / range 2-42 units (Owen Mumford Ltd) 9 10 30918 ABCare hypodermic U100 insulin syringe glass reusable 0.5ml (Rand Rocket Ltd) 11 35143 NovoFine Autocover hypodermic insulin needles for pre-filled / reusable pen injectors 12 screw on 8mm/30gauge (Novo Nordisk Ltd) 13 14 24866 INSULIN INSULATARD (LEO RETARD) 40 I/U INJ 15 6138 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 16 / range 1-60 units Burgundy (Eli Lilly and Company Ltd) 17 For peer review only 7764 INSULIN NEUSULIN (NEUTRAL)(PURIFIED) 100 I/U INJ 18 19 15624 INSULIN ISOPHANE (HIGHLY PURIFIED) 100 I/U INJ 20 49172 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial 21 up / range 0.5-30 units Red (Novo Nordisk Ltd) 22 23 1645 INSULIN NOVO ACTRAPID MC 100 I/U INJ 24 11345 Bd Ultra Pen 3ml Insulin pen (Becton, Dickinson UK Ltd) 25 58754 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 27 28 31699 ABCare hypodermic U100 insulin syringe glass reusable 1ml (Rand Rocket Ltd) 29 56639 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 30 up / range 1-60 units Blue (Eli Lilly and Company Ltd) 31 32 5142 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 33 on 8mm/31gauge (Becton, Dickinson UK Ltd) 34 48771 Unifine Pentips Plus hypodermic insulin needles for pre-filled / reusable pen injectors 35 screw on 5mm/31gauge (Owen Mumford Ltd) 36 37 4248 INSULIN NOVO ULTRATARD MC 100 I/U INJ 38 6981 Novopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 1-35 units Yellow (Novo Nordisk Ltd) 40 41 58878 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 42 10mm/29gauge 43 6781 Autopen Classic hypodermic insulin injection pen reusable for 3ml cartridge 2 unit dial 44 up / range 2-42 units (Owen Mumford Ltd) 45 46 7164 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 47 on 6mm/31gauge (Owen Mumford Ltd) on September 25, 2021 by guest. Protected copyright. 48 58449 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 49 50 on 4mm/32gauge (Owen Mumford Ltd) 51 56642 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 52 screw on 6mm/31gauge (Cambridge Sensors Ltd) 53 38808 NovoPen 4 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / 54 55 range 1-60 units Silver (Novo Nordisk Ltd) 56 22328 Unifine single use Insulin syringe with 30gauge needle 8mm 0.5ml (Owen Mumford Ltd) 57 15294 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 58 59 1-70 units Green (Novo Nordisk Ltd) 60 25786 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/31gauge (Disposable Medical Equipment Ltd) 1839 INSULIN HUMULIN I (ISOPHANE) 100 I/U INJ

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1 2 18301 INSULIN SOLUBLE INJ I/U^2 3 13108 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 1 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 unit dial up / range 1-21 units (Owen Mumford Ltd) 6 58578 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 7 0.5ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 8 32053 INSULIN HUMALOG MIX 25 9 10 13969 U100 Insulin syringe 0.3ml 11 1643 INSULIN NOVO MONOTARD MC 100 I/U INJ 12 57388 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 15 56983 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 16 6mm/31gauge (Spirit Healthcare Ltd) 17 For peer review only 31466 Exubera insulin release unit (Pfizer Ltd) 18 19 55746 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 20 8mm/32gauge (Spirit Healthcare Ltd) 21 7203 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 22 23 on 8mm/31gauge (Owen Mumford Ltd) 24 9702 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 25 1ml with 12.7mm needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) 26 22496 INSULIN ZINC LENTE PURIFIED SUSPENSION 27 28 16389 Myjector hypodermic U100 insulin syringe sterile single use / single patient use 1ml with 29 12mm needle 0.33mm/29gauge (Terumo UK Ltd) 30 22974 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 31 32 8mm/31gauge 33 3076 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 34 6mm/30gauge (Novo Nordisk Ltd) 35 20671 INSULIN HUM/ACTRAPHANE 36 37 58995 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 38 0.5ml with 12mm safety needle 0.33mm/29gauge (Becton, Dickinson UK Ltd) http://bmjopen.bmj.com/ 39 59243 BD SafetyGlide hypodermic U100 insulin syringe sterile single use / single patient use 40 41 0.3ml with 8mm safety needle 0.25mm/31gauge (Becton, Dickinson UK Ltd) 42 30305 Hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml with 12mm 43 needle 0.3mm/30gauge 44 53437 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 45 46 5mm/30gauge 47 60621 Hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial up / range 0.5- on September 25, 2021 by guest. Protected copyright. 48 30 units 49 50 58884 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 51 screw on 8mm/31gauge (GlucoRx Ltd) 52 52319 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-80 53 units 54 55 57153 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 56 0.5ml with 8mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 57 18645 INSULIN NEUTRAL (PURIFIED) 100 I/U INJ 58 59 54027 Hypodermic insulin needles for pre-filled / reusable pen injectors snap on 60 4.5mm/31gauge 22806 INSULIN PORK ACTRAPID 22094 INSULIN HUMULIN M2 VIAL

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1 2 56785 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Red (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 62098 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6 8mm/32.5gauge 7 5015 NovoFine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 8 8mm/30gauge (Novo Nordisk Ltd) 9 10 6730 Hypodermic U100 insulin syringe sterile single use / single patient use 1ml with not less 11 than 12mm needle 0.33mm/29gauge 12 59311 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 13 14 1ml with 12mm safety needle 0.33mm/29gauge (Covidien (UK) Commercial Ltd) 15 57493 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 16 up / range 1-60 units Silver (Eli Lilly and Company Ltd) 17 For peer review only 15951 Autopen Junior hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 18 19 up / range 1-21 units (Owen Mumford Ltd) 20 37055 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 21 0.5ml with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 22 23 57744 Omnican Fine hypodermic insulin needles for pre-filled / reusable pen injectors screw on 24 4mm/31gauge (B.Braun Medical Ltd) 25 7127 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 26 1ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 27 28 61780 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 29 12mm/29gauge (Spirit Healthcare Ltd) 30 35078 Optipen pro 1 blue insulin pen 3ml/1-60 units 3ml/1-60 units Insulin pen (Aventis 31 32 Pharma) 33 17643 Autopen Special Edition hypodermic insulin injection pen reusable for 3ml cartridge 2 34 unit dial up / range 2-42 units (Owen Mumford Ltd) 35 15895 Innovo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 36 37 1-70 units Orange (Novo Nordisk Ltd) 38 48829 NovoPen Echo hypodermic insulin injection pen reusable for 3ml cartridge 0.5 unit dial http://bmjopen.bmj.com/ 39 up / range 0.5-30 units Blue (Novo Nordisk Ltd) 40 41 36959 Comfort Point hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 12mm/29gauge (Disposable Medical Equipment Ltd) 43 53148 Hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up / range 1-60 44 units 45 46 1589 U100 Insulin syringe 0.5ml 47 10545 INSULIN HUMULIN M4 CARTRIDGE 100 I/U on September 25, 2021 by guest. Protected copyright. 48 45639 IME-FINE hypodermic insulin needles for pre-filled / reusable pen injectors screw on 49 50 6mm/31gauge (Arctic Medical Ltd) 51 5742 Unifine Pentips hypodermic insulin needles for pre-filled / reusable pen injectors screw 52 on 8mm/30gauge (Owen Mumford Ltd) 53 49307 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 54 55 on 4.5mm/31gauge (Ypsomed Ltd) 56 62562 Insupen hypodermic insulin needles for pre-filled / reusable pen injectors screw on 57 4mm/33gauge (Spirit Healthcare Ltd) 58 59 10546 INSULIN HUMULIN M4 100 I/U INJ 60 54886 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on 6mm/32gauge

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1 2 56939 HumaPen Savvio hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial 3 up / range 1-60 units Pink (Eli Lilly and Company Ltd) BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from 4 5 6228 BD Micro-Fine + hypodermic U100 insulin syringe sterile single use / single patient use 6 0.3ml with 8mm needle 0.3mm/30gauge (Becton, Dickinson UK Ltd) 7 12244 INSULIN ZINC BOVINE susp 100 I/U INJ 8 13274 Clinipak u100 single use ins syr+12mm need28g 1ml [rand] 1ml Insulin syringe with 9 10 28gauge needle 12mm (Rand Rocket Ltd) 11 56624 Kendall Magellan hypodermic U100 insulin syringe sterile single use / single patient use 12 0.5ml with 12mm safety needle 0.3mm/30gauge (Covidien (UK) Commercial Ltd) 13 14 9619 Bd Ultra Pen 1.5ml Insulin pen (Becton, Dickinson UK Ltd) 15 5966 Mylife Clickfine hypodermic insulin needles for pre-filled / reusable pen injectors snap 16 on 8mm/31gauge (Ypsomed Ltd) 17 For peer review only 2373 INSULIN HUMAN VELOSULIN 100 I/U INJ 18 19 43489 BD Micro-Fine Ultra hypodermic insulin needles for pre-filled / reusable pen injectors 20 screw on 4mm/32gauge (Becton, Dickinson UK Ltd) 21 59475 Nanopass hypodermic insulin needles for pre-filled / reusable pen injectors screw on 22 23 4mm/32.5gauge (Terumo UK Ltd) 24 59793 Microdot Droplet hypodermic insulin needles for pre-filled / reusable pen injectors 25 screw on 4mm/32gauge (Cambridge Sensors Ltd) 26 17076 Omnican 100 hypodermic U100 insulin syringe sterile single use / single patient use 1ml 27 28 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 29 9079 INSULIN SOLUBLE 100 I/U INJ 30 5620 U100 Insulin syringe 0.3ml 31 32 38236 Comfort Point hypodermic U100 insulin syringe sterile single use / single patient use 1ml 33 with 12mm needle 0.33mm/29gauge (Disposable Medical Equipment Ltd) 34 20196 INSULIN SOLUBLE 40 I/U INJ 35 7765 INSULIN NEUTRAL (HUMAN) 100 I/U INJ 36 37 58581 GlucoRx FinePoint hypodermic insulin needles for pre-filled / reusable pen injectors 38 screw on 5mm/31gauge (GlucoRx Ltd) http://bmjopen.bmj.com/ 39 10691 INSULIN ISOPHANE (NPH) 100 I/U INJ 40 41 5873 BD Micro-Fine + hypodermic insulin needles for pre-filled / reusable pen injectors screw 42 on 5mm/31gauge (Becton, Dickinson UK Ltd) 43 24554 Unifine single use Insulin syringe with 30gauge needle 8mm 0.3ml (Owen Mumford Ltd) 44 28666 Omnican 50 hypodermic U100 insulin syringe sterile single use / single patient use 0.5ml 45 46 with 8mm needle 0.3mm/30gauge (B.Braun Medical Ltd) 47 19271 Hypodermic insulin needles for pre-filled / reusable pen injectors screw on on September 25, 2021 by guest. Protected copyright. 48 8mm/30gauge 49 50 6831 HumaPen Ergo hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 51 / range 1-60 units Teal (Eli Lilly and Company Ltd) 52 6378 Hypodermic U100 insulin syringe sterile single use / single patient use 0.3ml with 8mm 53 needle 0.3mm/30gauge 54 55 13096 Autopen hypodermic insulin injection pen reusable for 1.5ml cartridge 2 unit dial up / 56 range 2-32 units (Owen Mumford Ltd) 57 7075 Optipen Pro 1 hypodermic insulin injection pen reusable for 3ml cartridge 1 unit dial up 58 59 / range 1-60 units (Sanofi) 60 42797 Injex ampoule pack 60501 (Ocon Chemicals Ltd) 60626 InsuJet starter set 012007GBSP Grey (Spirit Healthcare Ltd) 42305 Injex 10ml vial adaptor pack 60502 (Ocon Chemicals Ltd)

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1 2 Medical code list: possible Alzheimer's disease

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1 2 Medical code list: probable Alzheimer's disease

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1 2 Medical code list: non-specific dementia (non Alzheimer's disease dementias)

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1 2 Medical code list: other dementia (non Alzheimer's disease dementias)

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1 2 Medical code list: vascular dementia (non Alzheimer's disease dementias)

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1 2 Medical code list: amyotrophic lateral sclerosis

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1 2 Medical code list: Parkinson's disease

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1 2 Product code list: treatments for Alzheimer's disease

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1 2 Product code list: treatments for amyotrophic lateral sclerosis

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1 2 Product code list: treatments for Parkinson's disease

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1 2 Feasibility numbers for the treatments for hypertension 3 Subclass # Patients 4 Alpha-adrenoceptor Blocking Drugs 67517 5 6 Angiotensin-converting Enzyme Inhibitors 187256 7 Angiotensin-converting Enzyme Inhibitors AND Calcium Channel Blockers 35 8 Angiotensin-converting Enzyme Inhibitors AND Thiazides and Related Diuretics 624 9 Adrenergic Neurone Blocking Drugs 3 10 11 Angiotensin-ii Receptor AntagonistsFor peer review only 13366 12 Angiotensin-ii Receptor Antagonists AND Calcium Channel Blockers 9 13 Angiotensin-ii Receptor Antagonists AND Calcium Channel Blockers AND Thiazides And Related Diuretics 0 14 Angiotensin-ii Receptor Antagonists AND Thiazides and Related Diuretics 564 15 16 Beta-adrenoceptor Blocking Drugs 262081 Beta-adrenoceptor Blocking Drugs AND Calcium Channel Blockers 3 17 http://bmjopen.bmj.com/ 18 Beta-adrenoceptor Blocking Drugs AND Loop Diuretics 0 19 Beta-adrenoceptor Blocking Drugs AND Loop Diuretics AND Thiazides and Related Diuretics 22 20 21 Beta-adrenoceptor Blocking Drugs AND Potassium-sparing Diuretics And Aldosterone Antagonists AND Thiazides and Related Diuretics 46 22 Beta-adrenoceptor Blocking Drugs AND Thiazides and Related Diuretics 1789 23 Centrally Acting Antihypertensive Drugs 25746 24 Calcium-channel Blockers 140621 25 26 Calcium Channel Blockers AND Thiazides And Related Diuretics on September 25, 2021 by guest. Protected copyright. 0 27 Loop Diuretics 97675 28 Loop Diuretics AND Potassium-sparing Diuretics and Aldosterone Antagonists 20446 29 Potassium-sparing Diuretics and Aldosterone Antagonists 7727 30 31 Potassium-sparing Diuretics and Aldosterone Antagonists AND Thiazides and Related Diuretics 6513 32 Renin Inhibitors 6 33 Thiazides and Related Diuretics 176791 34 Vasodilator Antihypertensive Drugs 9679 35 36 Total 1018519 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-012044 on 13 December 2016. Downloaded from

BMJ Open Page 154 of 158

1 2 Feasibility numbers for the treatments for hypercholesterolaemia 3 Subclass # Patients 4 Bile Acid Sequestrants 7360 5 6 Ezetimibe 1345 7 Ezetimibe AND Statins 171 8 Fibrates 8988 9 Nicotinic Acid Group 321 10 11 Omega-3 Fatty Acid Compounds For2344 peer review only 12 Statins 788158 13 Total 808687 14 15 16

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1 2 Feasibility numbers for the treatments for type 2 diabetes 3 Subclass # Patients 4 Biguanides 156304 5 6 Biguanides AND Other Antidiabetic Drugs 213 7 Other Antidiabetic Drugs 2471 8 Sulphonylureas 41812 9 Total 200800 10 11 For peer review only 12 13 14 15 16

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1 2 Feasibility numbers for the neurodegenerative disease diagnoses 3 Diagnosis # Patients 4 Dementia 105471 5 6 Amyotrophic lateral sclerosis 2227 7 Parkinson's disease 20686 8 9 Feasibility numbers for the treatment for dementia 10 11 Treatment For# Patients peer review only 12 Treatment for Dementia 33071 13 14 15 16

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1 2 Feasibility numbers for the treatments of interest, restricted to patients with a neurodegenerative disease of interest 3 Diagnosis Treatment Treatment First Diagnosis & Treatment Received Together Diagnosis First Total 4 Dementia Hypertension 28586 132 5548 34266 5 6 Hypercholesterolaemia 26686 208 5062 31956 7 Type 2 Diabetes 5687 16 1470 7173 8 Amyotrophic lateral sclerosis Hypertension 670 1 152 823 9 Hypercholesterolaemia 530 0 66 596 10 11 TypeFor 2 Diabetes peer review86 only 0 18 104 12 Parkinson's disease Hypertension 6225 41 2051 8317 13 Hypercholesterolaemia 4563 21 1842 6426 14 Type 2 Diabetes 907 4 357 1268 15 16

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1 2 Average age of patients receiving treatments and diagnoses of interest 3 Event Average Age (years) Standard Deviation (years) 4 Hypertension treatment 61.91 12.91 5 6 Hypercholesterolaemia treatment 64.61 11.42 7 Type 2 diabetes treatment 63.66 12.11 8 Dementia treatment 79.98 7.98 9 Dementa diagnosis 81.43 8.5 10 11 Amyotrophic lateral sclerosis diagnosisFor peer68.45 review10.89 only 12 Parkinson's disease diagnosis 74.62 9.76 13 14 15 16