For Peer Review Only

BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from

Suboptimal prescribing of proton pump inhibitors in low- dose aspirin users in primary care.

ForJournal: peerBMJ Open review only Manuscript ID: bmjopen-2013-003044

Article Type: Research

Date Submitted by the Author: 12-Apr-2013

Complete List of Authors: de Jong, Hilda; NIVEL, Korevaar, J; Netherlands Institute for Health Services Research (NIVEL), van Dijk, Liset; NIVEL, Voogd, Eef; NIVEL, Dijk, Christel; Netherlands Institute of Health Services Research NIVEL van Oijen, Martijn; UCLA, Center for Outcomes Research and Education (CORE)

Primary Subject General practice / Family practice Heading:

Secondary Subject Heading: Gastroenterology and hepatology

PRIMARY CARE, GASTROENTEROLOGY, PREVENTIVE MEDICINE, Cardiology Keywords: http://bmjopen.bmj.com/ < INTERNAL MEDICINE

on September 30, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Suboptimal prescribing of proton pump inhibitors in low-dose aspirin users in primary 4 5 care. 6 7 Hilda JI De Jong, Joke C Korevaar, Liset Van Dijk, Eef Voogd, Christel E Van Dijk, Martijn 8 9 10 GH Van Oijen 11 12 13 14 Affiliates 15 For peer review only 16 NIVEL, Netherlands Institute for Health Services Research, Utrecht, The Netherlands, Hilda 17 18 de Jong PhD-student, Joke Korevaar Research Coordinator General Practice Care, Liset van 19 20 21 Dijk Research Coordinator Pharmaceutical Care, Eef Voogd PhD-student, Christel van Dijk 22 23 Senior researcher. 24 25 Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, 26 27 California, USA and UCLA/VA Center for Outcomes Research and Education (CORE), Los 28 29 30 Angeles, California, USA, Martijn van Oijen assistant professor. 31 32

33 http://bmjopen.bmj.com/ 34 Corresponding author 35 JC Korevaar 36 P.O. Box 1568 37 3500 BN Utrecht 38 The Netherlands 39 40 +31 30 27 29 711 [email protected]

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 Keywords: low-dose aspirin, proton pump inhibitors, GI complications, primary care 45 46 Wordcount: 3089 47 48 Funding: AstraZeneca; NIVEL 49 50 51 Short title: suboptimal prescribing of PPIs in LDASA users in primary care 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 2 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Abstract 4 5 Objective 6 7 Adherence to recommendations of concomitant PPI treatment in regular LDASA users, taking 8 9 10 factors associated with the probability of receiving a PPI into account. 11 12 Design 13 14 Cohort study 15 For peer review only 16 Setting 17 18 Data were obtained from 120 Dutch primary care centres participating in the Netherlands 19 20 21 Information Network of Primary Care (LINH). 22 23 Participants 24 25 Patients 18 years and older who were regularly prescribed LDASA (30-325 mg) in 2008-2010 26 27 were included. 28 29 30 Main outcome measures 31 32 Regular medication use was defined as receiving each consecutive prescription within 6

33 http://bmjopen.bmj.com/ 34 months after the previous one. Based upon national guidelines, we categorised LDASA users 35 36 into low and high GI risk. A multilevel multivariable logistic regression analysis was applied 37 38 to identify patient characteristics that influenced on the probability of regular PPI 39 40 prescriptions.

33 http://bmjopen.bmj.com/ 34 primary care physicians. 35 36 37 38 39 40

33 http://bmjopen.bmj.com/ 34 Strengths and limitations of this study 35 36 37 • Large representative sample of patients monitored in daily practice in primary care 38 39 • No information available why patients with an increased GI risk did not obtain PPI 40

41 prescriptions, or why they became an irregular PPI user on September 30, 2021 by guest. Protected copyright. 42 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.xhtml4 Page 5 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Introduction 4 5 Worldwide, the number of deaths from cardiovascular disease was estimated at 17.3 million 6 7 in 2008, and it is expected to increase to approximately 23.6 million by 2030 1. Treatment 8 9 10 with low-dose of aspirin (LDASA) is recommended for the prevention of cardiovascular 11 12 events in patients with a history of myocardial infarction, stroke, transient ischaemic attack or 13 14 (in)stable angina 2-4. While LDASA use is associated with a decreased risk of cardiovascular 15 For peer review only 16 events 5, its use is also associated with a wide variety of gastrointestinal (GI) side effects, such 17 18 as dyspepsia, peptic ulcers, and upper and lower GI bleedings 6;7. 19 20 21 22 23 GI complications associated with LDASA use are more frequently present in patients who are 24 25 older than 70 years, have a history of peptic ulcer, have had an infection with Helicobacter 26 27 pylori, and/or used concomitant drug therapies with non-steroidal anti-inflammatory drugs 28 29 30 (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, other antiplatelet agents or 31 6;7 32 anticoagulants, glucocorticosteroids, and/or selective serotonin reuptake inhibitors (SSRIs) .

33 http://bmjopen.bmj.com/ 34 Concomitant proton pump inhibitor (PPI) therapy is associated with a reduction of the risk of 35 36 GI complications 8-11. 37 38 39 40 Therefore, concomitant use of PPIs for patients who use regular LDASA and are at increased

41 on September 30, 2021 by guest. Protected copyright. 42 43 risk for GI complications has been described in guidelines from medical societies and 44 45 scientific associations from both the USA and Europe 12;13. In the Netherlands - the setting of 46 47 our study - an expert group with a focus on optimising extramural medication safety 48 49 50 published specific recommendations for adequate gastrointestinal protection, i.e. prescribing 51 52 PPIs in regular LDASA users with an increased risk of GI complications in 2008, which was 53 54 finalised in 2009 14. These recommendations are in line with the US, NICE and ESC 55 56 guidelines 12;13;15, and describe that PPIs are the preferred agents for the therapy and 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml5 BMJ Open Page 6 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 12 3 prophylaxis of aspirin-associated GI injury . Risk reduction due to PPI treatment observed in 4 5 case-control and cohort studies ranged in most cases from 40 to 80%.16 6 7 8 9 10 Several observational studies described the use of concomitant PPI in a patients receiving 11 12 NSAID including aspirin, and showed that 67-90% of the users with at least one risk factor 13 14 did not receive gastroprotective therapy as recommended 17 18;19. Two studies focussed on 15 For peer review only 16 LDASA patients; in one study the definition of increased GI risk was limited, namely a 17 18 positive Helicobacter pylori status, the other study had a small sample size of LDASA 19

20 20;21 21 patients. . Although evidence regarding the adherence to concomitant PPI use in patients 22 23 with an increased risk for GI complications is increasing, the adherence and persistence of PPI 24 25 use is still indefinite. 26 27 28 29 30 The objective of this study is to determine the adherence to recommendations of concomitant 31 32 PPI treatment in regular LDASA users, taking factors associated with the probability of

33 http://bmjopen.bmj.com/ 34 receiving a PPI into account. 35 36 37 38 39 40

33 http://bmjopen.bmj.com/ 34 35 36 In this longitudinal, observational study, all patients aged 18 years and older who started with 37 38 regular use of LDASA (30-325 mg) treatment between January 1, 2008, and December 31, 39 40 2010 were included under the condition that their history was available at least one year

41 on September 30, 2021 by guest. Protected copyright. 42 43 before the date of the first prescription of LDASA. This time period was chosen to confirm 44 45 that no LDASA prescriptions were given in the year prior to inclusion. Regular use of 46 47 LDASA was defined as receiving each consecutive prescription within six months after the 48 49 50 previous one. A gap of maximal six months was chosen because in daily practice patients 51 52 rarely collect a subsequent prescription exactly on the day their supply of their previous 53 54 prescription has ended, normally 90 days, but rather earlier (overlap of two prescriptions) or 55 56 later (gap between two prescriptions). In order not to bias our results towards irregular user 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml7 BMJ Open Page 8 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 categorisation, we used a maximum period of six months. Aspirin therapy was identified by a 4 5 prescription of acetylsalicylic acid (ATC-codes B01AC06, N02BA01 and N02BA51), 6 7 carbasalate calcium (B01AC08, N02BA15 and N02BA65), or acetylsalicylic acid in 8 9 10 combination with other drugs (B01AC30). 11 12 13 14 Based upon the HARM-WRESTLING recommendations 14, we categorised new LDASA 15 For peer review only 16 users into low or increased risk of GI complications. Patients with an increased risk of GI 17 18 complications were identified by the following selection rules applied in consecutive order: 1) 19 20 21 80 years or older; 2) 70 years or older with simultaneous use of NSAIDs, oral anticoagulants, 22 23 platelet aggregation inhibitors, glucocorticosteroids, SSRIs and/or spironolacton; or 3) 60 24 25 years or older with a history of a peptic ulcer. 26 27 28 29 30 PPI treatment was identified by ATC-code A02BC. All patients were divided into three 31 32 categories: no user, irregular, or regular user of PPIs. Patients who never received a

33 http://bmjopen.bmj.com/ 34 prescription of PPI during the follow-up period were defined as no PPI users. In line with our 35 36 definition of a regular LDASA user, patients were defined as regular PPI users if they 37 38 received each consecutive prescription within 6 months after their previous one. All others 39 40 were considered as irregular users.

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 45 We considered patients to be previous starters of PPIs when they received a prescription of 46 47 PPI in the year prior to the first prescription of LDASA. Patients who started the use of PPIs 48 49 50 within a week after the first prescription of LDASA were considered as simultaneous starters 51 52 of PPIs. Patients who received a prescription of PPI more than a week after the first 53 54 prescription of LDASA were subsequent starters of PPIs. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml8 Page 9 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Relevant co-morbidity was determined in the year before and after the date of the first 4 5 prescription of LDASA. Cardiovascular and cerebrovascular diseases were identified by 6 7 ICPC-codes K71, K73-K84, K89-K96 and K99. Hypertension was considered present when 8 9 10 the patient had a medical record of ICPC-codes K86 or K87. Patients were classified as 11 12 diabetic if a diagnosis code for diabetes (T90) was identified, or when they received anti- 13 14 diabetic therapy (ATC-codes A10A and A10B). Patients who had a diagnosis of lipid disorder 15 For peer review only 16 (T93) or when they received lipid modifying agents (C10) were considered as 17 18 hypercholesterolaemic. GI complications, including peptic ulcers, were identified by D02, 19 20 21 D03, D09, D10, D14, D16, D85-87, and D90 (Appendix I). 22 23 24 25 To classify patients as having an increased GI risk based on HARM-WRESTLING 26 27 recommendation, we determined prescriptions for NSAIDs (M01), including Cox-2 28 29 30 inhibitors, oral anticoagulants and platelet aggregation inhibitors (B01AA and B01AC), 31 32 glucocorticosteroids (H02AB and H02), and SSRIs (N06AB) [16]. In addition, we identified

33 http://bmjopen.bmj.com/ 34 all prescriptions for cardiovascular system (C01-C10), acid related disorders (A02 (PPIs 35 36 excluded)), and functional gastro-intestinal disorders (A03) in the year before and after the 37 38 date of the first LDASA prescription. 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 Statistical analysis 44 45 To identify the relative influence of patient characteristics on the probability to obtain regular 46 47 PPI prescriptions, multilevel multivariable logistic regression analyses (backward elimination 48 49 50 method) was conducted. The models were estimated taking the clustering of patients (level 1) 51 52 within primary care centres (level 2) into account. The probability of receiving a PPI was 53 54 determined by comparing no PPI users with regular PPI users. This analyses was performed 55 56 without the irregular users to rule out the effect of these users. In addition, separate analyses 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml9 BMJ Open Page 10 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 were performed for increased GI risk patients. All data were analysed using the statistical 4 5 programs SAS version 9·2 (SAS Institute, Cary, North Carolina) and ‘Multilevel models for 6 7 windows’ (MLwin 2·02). Adjustment for multiple testing was performed by using a False 8 9 10 Discovery Rate correction. 11 12 13 14 Choices of our definition of subsequent and simultaneous start of PPIs, and our period of 15 For peer review only 16 describing patients’ characteristics were based on assumptions, and therefore we tested the 17 18 robustness of our findings by performing sensitivity analyses. We made the definition of 19 20 21 simultaneous starters of PPIs more strictly, i.e. receiving a prescription of PPIs at exactly the 22 23 same date as the first prescription of LDASA. Secondly, we changed the medical and 24 25 prescription history into only one year before the date of the first LDASA prescription. 26 27 Thirdly, as LDASA therapy was frequently prescribed for patients with cardiovascular 28 29 30 diseases, a separate analysis with solely cardiovascular patients was conducted. Finally, we 31 32 investigated the influence of irregular users of PPIs into our analysis by performing two

33 http://bmjopen.bmj.com/ 34 analyses in which we (1) merged irregular users with regular users of PPIs and in which we 35 36 (2) added irregular users to the no PPI users group. 37 38 39 40 Role of the funding source

41 on September 30, 2021 by guest. Protected copyright. 42 43 The sponsor of the study had no decisive role in design and conduct of the study, collection, 44 45 analysis, or interpretation of the data, or decision to submit the manuscript for publication. 46 47 JK and LvD had full access to all data in the study and take responsibility for the integrity of 48 49 50 the data and accuracy of the data analysis. All authors had final responsibility for the decision 51 52 to submit for publication 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml10 Page 11 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Results 4 5 In the study population, 18,137 new LDASA users of 18 years and older were identified of 6 7 whom 12,343 were regular users during the years 2008-2010 (Figure 1). Of these incident 8 9 10 regular LDASA users, 3,213 (26.0%) were at increased risk for GI complications. The vast 11 12 majority was at an increased GI risk due to their age. In total, 64.5% of the patients who were 13 14 at increased GI risk obtained a PPI prescription; 46.1% was a regular and 18.4% an irregular 15 For peer review only 16 user. In the group of patients with an increased GI risk without PPI prescription, the main 17 18 reason for having an increased GI risk was age, above 80 years (n=994, 87%). Cardiovascular 19 20 21 diseases are reported in almost half of the patients, and are significantly more prevalent 22 23 among patients with increased GI risk (49.3% vs. 46.0%, p=0·002). The use of co-medication 24 25 is generally higher in the increased GI risk group, with the exception of lipid modifying 26 27 agents (Table 1). 28 29 30 31 32 In total, 4,204 (34.1%) patients were regular PPI users, 2,456 (19.9%) were irregular users,

33 http://bmjopen.bmj.com/ 34 and 5,683 (46·0%) used no PPI (Table 2). Of the regular PPI users nearly half of the patients 35 36 (48%) started PPI therapy previously, 25% started PPI therapy simultaneously, and 27% 37 38 started subsequently. Patients that started PPI previously, more often were prescribed with 39 40 drugs for functional gastrointestinal disorders or acid related disorders, cardiac therapy,

41 on September 30, 2021 by guest. Protected copyright. 42 43 diuretics, beta blocking agents, and vasoprotective agents. 44 45 46 47 Table 3 shows the probability of receiving regular PPI prescriptions versus no PPI usage. This 48 49 50 probability is significantly increased by different risk factors for GI side effects, by morbidity, 51 52 medication, and increased age. LDASA users with a history of gastrointestinal complications 53 54 were more likely to receive regular PPI prescriptions (adjusted OR 13.9; 95% CI: 11.8-16.4), 55 56 as was found for the different medications used to define patients with an increased GI risk. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml11 BMJ Open Page 12 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Simultaneous use of SSRIs (adjusted OR 9.1 (6.7-12.2)), NSAIDs (5.2 (4.3-6.3)), 4 5 glucocorticosteroids (6.1 (4.6-8.0)), and being 80 years and older (1.9 (1.5-2.3)) were strongly 6 7 related to receiving a PPI regularly. Sensitivity analyses for the group with an increased GI 8 9 10 risk did not alter our findings; similar predicting factors influenced the probability with equal 11 12 magnitude, except for age. Age was no longer a predicting factor (data not shown). 13 14 15 For peer review only 16 Applying the different sensitivity analyses did not alter our findings. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

33 http://bmjopen.bmj.com/ 34 gastroprotective agent. These numbers are almost in the same range as our results; however, 35 36 this study made no distinction between specific types of NSAIDs 17. A Spanish cross 37 38 sectional, multi-centre study in which 3,357 patients from 713 primary care physicians 39 40 participated, found that 82% of the NSAID and/or LDASA users with an increased GI risk

41 on September 30, 2021 by guest. Protected copyright. 42 43 received PPIs and 62% of the low GI risk patients 20. So, the vast majority of all 44 45 NSAID/LDASA users, even the patients with a low risk, received a PPI prescription, which is 46 47 much higher than observed in our study. Yet, our study has a longitudinal design, and 48 49 50 consequently has the information to label a patient as regular or irregular user of PPI. If we 51 52 drop the strict condition of being a regular PPI user, to mimic a cross-sectional design, 64.5% 53 54 of the patients with an increased risk obtained PPIs and 50.2% of the low risk patients. These 55 56 numbers are more in line with the Spanish results, although still lower. Next to the number of 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml13 BMJ Open Page 14 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 increased risk patients receiving PPIs, the timing of the initiation of PPI treatment is 4 5 important. Our study showed that the vast majority of patients started with PPI treatment 6 7 before or simultaneously with the first prescription of LDASA, thereby acting as preventive 8 9 10 agent. 11 12 13 14 In line with the HARM-WRESTLING recommendations, the US, NICE and ESC guidelines 15 For peer review only 16 also recommend to prescribe PPIs to LDASA users who are 60-70 years of age or older 17 18 and/or concomitantly use of SSRIs, NSAIDs, or glucocorticosteroids.12;13;15 Therefore, we 19 20 21 believe our findings are not only relevant for the Netherlands, but have international 22 23 implications as well. 24 25 26 27 The study of Lanas et al. found that gastroprotective treatment in LDASA users was 28 29 30 significantly associated with a prior history of peptic ulcer, high dose NSAID therapy and 31 20 32 concomitant use of oral corticosteroids and antithrombotics . Our data support these

33 http://bmjopen.bmj.com/ 34 findings. In several other population-based studies, having a history of GI complications, 35 36 including ulcers, is the strongest predictor for receiving a PPI, as is found in our study 6;7;26. 37 38 39 40 Albeit the number of LDASA users with low GI risk that obtain PPIs is significantly lower

41 on September 30, 2021 by guest. Protected copyright. 42 43 compared to the high risk population, over treatment with PPIs may occur in this group. In 44 45 total, 30% of patients with low GI risk received regularly PPI treatment. Although PPI 46 47 treatment is considered to be cheap, relatively safe, long-term treatment with this drug has 48 49 50 been shown to increase the susceptibility to GI infections and pneumonia, and it has been 51 27-29 52 associated with an increased risk of fractures . Unfortunately, the reasons why these low 53 54 GI risk patients obtained (regular) PPI’s by their primary care physician is very incompletely 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml14 Page 15 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 recorded in our database, refraining us to comment on the necessity of these prescriptions in 4 5 patients with a low GI risk. 6 7 8 9 10 The only difference between patients who were at increased GI risk with or without regular 11 12 PPI therapy was the reason of being a patient with an increased GI risk; nearly 90% of the 13 14 patients who were at increased GI risk without regular PPI therapy were above 80 years, 15 For peer review only 16 whereas of the patients with regular PPI use, just 74% was above 80 years. Another possible 17 18 explanation why not all patients with an increased GI risk use PPIs regularly might be limited 19 20 21 awareness of primary care physicians of the current recommendation, since the draft version 22 23 was first published in 2008 and the final version in 2009, during the first months of our study 24 25 period. 26 27 28 29 30 A strong point of our study is that we had a large representative sample of patients monitored 31 32 in daily practice. The vast majority of the primary care centres in the Netherlands have a

33 http://bmjopen.bmj.com/ 34 computerised EMR, allowing us to use routinely recorded medical and prescription data from 35 36 primary care centres minimising the risk of recall bias. The participating primary care centres 37 38 are equally distributed throughout the Netherlands and we took possible differences between 39 40 practices into account by performing multilevel analyses. Another strength is that in our large

41 on September 30, 2021 by guest. Protected copyright. 42 43 sample, we had complete data for each individual patient, including all physicians’ diagnoses 44 45 and prescription data. This enabled us to study several different subpopulations of patients 46 47 combining LDASA and PPI treatment. Finally, we performed a range of sensitivity analyses 48 49 50 regarding exposure definition, and in- and exclusion criteria. 51 52 53 54 A limitation of this study includes the lack of information about prescriptions by medical 55 56 specialists. If PPIs were prescribed by medical specialists, the prescription of the patient 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml15 BMJ Open Page 16 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 might not always appear in our dataset. Yet, the Dutch guidelines for optimising primary care- 4 5 medical specialist communication support medical specialists to inform primary care 6 7 physicians with the first results of diagnostics and treatments of the referred patient 30;31. Due 8 9 10 to this, we may have underestimated regular PPI use. However, it is plausible that LDASA 11 12 prescription was initiated by the same medical specialist, so if PPI prescriptions are missing, 13 14 probably LDASA prescriptions are missing as well. In such a case the patient was not 15 For peer review only 16 included in our study, limiting the impact of missing PPI prescriptions. Our results are based 17 18 on an observational study which may be subjected to residual confounding due to potential 19 20 21 unmeasured differences in GI risk profile and patient characteristics between LDASA users 22 23 who received or did not received PPI prescriptions. Finally, we do not have any information 24 25 why patients with an increased GI risk did not obtain PPI prescriptions, nor do we know the 26 27 reason why patients become an irregular PPI user, and whether this was patient or physician 28 29 30 related. 31 32

33 http://bmjopen.bmj.com/ 34 In conclusion, primary care physicians do not fully adhere to the current recommendations to 35 36 prescribe PPIs regularly to LDASA users with an increased GI risk. Despite widespread 37 38 recommendations, more than half of the patients with an increased GI risk are not treated 39 40 sufficiently with a concomitant PPI, increasing the risk of gastrointestinal side effects. This

41 on September 30, 2021 by guest. Protected copyright. 42 43 finding underlines the necessity to consider merging recommendations into one common, 44 45 standard and frequently used recommendation by primary care physicians. Further studies are 46 47 needed to determine which motivations and attitudes may play a role for primary care 48 49 50 physicians to be aware of the guidelines and be able to accept, and adhere to them. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml16 Page 17 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Contributors: 4 5 HJIdJ contributed to the design of the study, performed data analyses and drafted the report. 6 7 JCK provided data, contributed to the design of the study and the interpretation of the results, 8 9 10 and drafted and reviewed the report. LvD initiated and obtained the funding for the project, 11 12 contributed to the design of the study and interpretation of the results, and drafted and 13 14 reviewed the paper. EV and ECvD performed data analyses, contributed to the interpretation 15 For peer review only 16 of the data, and reviewed the paper. MGHvO contributed to the design of the study and 17 18 analysis plan, and interpretation of the results, and reviewed the paper. 19 20 21 Conflicts of interest 22 23 This study was funded by Astra Zeneca. The institute of JK and LvD received research 24 25 funding from Astra Zeneca and Bristol-Myers Squibb for a study not related to this study. 26 27 MGHvO has served as a consultant for AstraZeneca and Pfizer, and has received unrestricted 28 29 30 research grants from AstraZeneca, Shire and Janssen. 31 32 Funding:

33 http://bmjopen.bmj.com/ 34 The sponsor of the study, AstraZeneca, had no decisive role in design and conduct of the 35 36 study, collection, analysis, or interpretation of the data, or decision to submit the manuscript 37 38 for publication. 39 40 JK and LvD had full access to all data in the study and take responsibility for the integrity of

41 on September 30, 2021 by guest. Protected copyright. 42 43 the data and accuracy of the data analysis. All authors had final responsibility for the decision 44 45 to submit for publication 46 47 Data sharing statement: No additional data are available 48 49 50 Ethics approval: The privacy regulation of LINH was approved by the Dutch Data Protection 51 52 Authority. According to Dutch legislation, neither obtaining informed consent nor approval 53 54 by a medical ethics committee is obligatory for database studies 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml17 BMJ Open Page 18 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Copyright 4 5 The Corresponding Author has the right to grant on behalf of all authors and does grant on 6 7 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in 8 9 10 all forms, formats and media (whether known now or created in the future), to i) publish, 11 12 reproduce, distribute, display and store the Contribution, ii) translate the Contribution into 13 14 other languages, create adaptations, reprints, include within collections and create summaries, 15 For peer review only 16 extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on 17 18 the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of 19 20 21 electronic links from the Contribution to third party material where-ever it may be located; 22 23 and, vi) licence any third party to do any or all of the above.” 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

17 || 18 LDASA plus PPI use (%) 19 No user of PPI 1 142 (35·5) 4 541 (49·8) <0·0001 20 Regular user of PPI 1 480 (46·1) 2 724 (29·8) 21 Irregular user of PPI 591 (18·4) 1 865 (20·4) 22 Co-morbidity (%)¶ 23 24 Tractus digestives 25 Gastrointestinal complications 664 (20·7) 1 475 (16·2) <0·0001 26 Duodenal ulcer 24 (0·8) 21 (0·2) <0·0001 27 Peptic ulcer 34 (1·1) 11 (0·1) <0·0001 28 Hiatus Hernia 29 (0·9) 58 (0·6) 0·13 29 30 Heart burn 75 (2·3) 233 (2·6) 0·52 31 Haematemesis 7 (0·2) 10 (0·1) 0·19 32 Rectal bleeding 50 (1·6) 97 (1·1) 0·04

33 Cardiovascular diseases http://bmjopen.bmj.com/

34 ** 35 Cardiovascular diseases 1 584 (49·3) 4 196 (46·0) 0·002 36 Acute myocardial infarction 223 (6·9) 792 (8·7) 0·003 37 Heart failure 432 (13·5) 257 (2·8) <0·0001 38 Atrial fibrillation 237 (7·4) 509 (5·6) 0·0003 39 Ischaemic heart disease w. angina 476 (14·8) 1 328 (14·6) 0·72 40 Ischaemic heart disease w/o angina 173 (5·4) 638 (7·0) 0·003

41 on September 30, 2021 by guest. Protected copyright. 42 Atherosclerosis 176 (5·5) 644 (7·1) 0·003 43 Cerebrovascular diseases** 756 (23·5) 1 480 (16·2) <0·0001 44 Stroke 362 (11·3) 731 (8·0) <0·0001 45 Transient Ischaemic Attack (TIA) 326 (10·2) 541 (5·9) <0·0001 46 47 Hypertension 1 307 (40·7) 3 546 (38·8) 0·08 48 Diabetes Mellitus 779 (24·3) 1 960 (21·5) 0·002 49 Hypercholesteroleamia 1 567 (48·8) 6 374 (69·8) <0·0001 50 Co-medication (%)¶ 51 52 Other drugs for acid related disorders 196 (6·1) 477 (5·2) 0·07 53 Drugs for functional gastrointestinal disorders 277 (8·6) 544 (6·0) <0·0001 54 Cardiac therapy 964 (30·0) 2 152 (23·6) <0·0001 55 Antihypertensive agents 2 748 (85·5) 7 357 (80·6) <0·0001 56 Antihypertensives 55 (1·7) 171 (1·9) 0·58 57 58 Diuretics 1 594 (49·6) 2 456 (26·9) <0·0001 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml19 BMJ Open Page 20 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Beta blocking agents 1 728 (53·8) 5 250 (57·5) 0·0005 4 Calcium channel blockers 825 (25·7) 2 113 (23·1) 0·005 5 RAAS agents†† 1 672 (52·0) 4 616 (50·6) 0·17 6 7 Peripheral vasodilators 4 (0·1) 11 (0·1) 1·00 8 Vasoprotectives 103 (3·2) 232 (2·5) 0·06 9 Lipid modifying agents 1 557 (48·5) 6 311 (69·1) <0·0001 10 Antidiabetics 624 (19·4) 1 604 (17·6) 0·03 11 *GI: gastrointestinal 12 †LDASA: low-dose acetylsalicyclic acid 13 ‡NSAIDs: non-steroidal anti-inflammatory drugs 14 §SSRIs: selective serotonin reuptake inhibitors 15 ||PPIs: proton pumpFor inhibitors peer review only 16 ¶Determined in the year before and after the first prescription of LDASA 17 **not all indications are included, only the major ones ††RAAS: renin-angiotensin-aldosterone system 18 ‡‡ 19 p-values are corrected for multiple testing by using false discovery rate. 20

21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 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.xhtml20 Page 21 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 2. Characteristics of regular low-dose aspirin users and low-dose aspirin plus irregular and regular 4 proton pump inhibitors users, stratified by time of proton pump inhibitor use Use of Irregular use Regular use of PPI 5 LDASA* of PPI† p-value** N = 4 204 6 N = 5 683 N = 2 456 7 Previous starters Simultaneous Subsequent 8 of PPI starters of PPI starters of PPI N = 2 015 N = 1 064 N = 1 125 9 Age 10 11 18-50 599 (10·5) 208 (8·5) 176 (8·7) 58 (5·4) 81 (7·2) <0·0001 12 51-65 2 026 (35·7) 829 (33·8) 592 (29·4) 292 (27·4) 331 (29·4) 13 66-80 2 163 (38·1) 1 043 (42·5) 801 (39·8) 424 (39·9) 494 (43·9) 14 80+ 895 (15·8) 376 (15·3) 446 (2·1) 290 (27·3) 219 (19·5) 15 For peer review only Sex 16 17 Men 3 308 (58·2) 1 288 (52·4) 912 (45·3) 530 (49·8) 597 (53·1) <0·0001 18 Risk of GI complications (%)‡,|| 19 Increased risk of GI complications 1 142 (20·1) 591 (24·1) 756 (37·5) 414 (38·9) 310 (27·6) <0·0001 20 Low risk of GI complications 4 541 (79·9) 1 865 (75·9) 1 259 (62·5) 650 (61·1) 815 (72·4) 21 § 22 Co-morbidity (%) 23 Gastrointestinal complications 214 (3·8) 594 (24·2) 831 (41·2) 217 (20·4) 283 (25·2) <0·0001 24 Ulcers 6 (0·1) 24 (1·0) 38 (1·9) 9 (0·9) 13 (1·2) <0·0001 25 Cardiovascular diseases 2 447 (43·6) 1 190 (48·5) 1 110 (55·1) 456 (42·9) 547 (48·6) <0·0001 26 27 Cerebrovascular diseases 1 052 (18·5) 400 (16·3) 406 (20·2) 171 (16·1) 207 (18·4) 0·007 28 Hypertension 2 221 (39·1) 989 (40·3) 831 (41·2) 335 (31·5) 477 (42·4) <0·0001 29 Diabetes Mellitus 1 189 (20·9) 544 (22·2) 458 (22·7) 292 (27·4) 256 (22·8) 0·0001 30 31 Hypercholesteroleamia 3 600 (63·4) 1 592 (64·8) 1 302 (64·6) 721 (67·8) 726 (64·5) 0·09 32 Co-medication (%)§ Other drugs for acid related 33 227 (4·0) 144 (5·9) 163 (8·1) 54 (5·1) 85 (7·6) <0·0001 http://bmjopen.bmj.com/ disorders 34 Drugs for functional gastrointestinal 151 (2·7) 211 (8·6) 275 (13·7) 83 (7·8) 101 (9·0) <0·0001 35 disorders 36 Cardiac therapy 1 142 (20·1) 664 (27·0) 672 (33·4) 324 (30·5) 314 (27·9) <0·0001 37 Antihypertensive agents 4 523 (79·6) 1 997 (81·3) 1 721 (85·4) 912 (85·7) 952 (84·6) <0·0001 38 Antihypertensives 102 (1·8) 36 (1·5) 44 (2·2) 22 (2·1) 22 (2·0) 0·48 39 40 Diuretics 1 607 (28·3) 782 (31·8) 826 (41·0) 410 (38·5) 425 (37·8) <0·0001 Beta blocking agents 3 078 (54·2) 1 370 (55·8) 1 255 (62·3) 633 (59·5) 642 (57·1) <0·0001

41 on September 30, 2021 by guest. Protected copyright. 42 Calcium channel blockers 1 078 (21·5) 571 (23·3) 551 (27·3) 286 (26·9) 309 (27·5) <0·0001 43 RAAS agents¶ 3 221 (49·3) 1 205 (49·6) 1 081 (53·7) 576 (54·1) 624 (55·5) <0·0001 44 Vasoprotectives 111 (2·0) 77 (3·1) 84 (4·2) 25 (2·4) 38 (3·4) <0·0001 45 46 Lipid modifying agents 3 568 (62·8) 1 578 (64·3) 1 288 (63·9) 717 (67·4) 717 (63·7) 0·08 47 Antidiabetics 974 (17·1) 420 (17·1) 378 (18·8) 244 (22·9) 212 (18·8) 0·0001 48 *LDASA: low-dose acetylsalicyclic acid 49 †PPIs: proton pump inhibitors 50 ‡Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 51 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 52 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. § 53 Determined in the year before and after the first prescription of LDASA || 54 GI: gastrointestinal ¶RAAS: renin-angiotensin-aldosterone system 55 ** 56 p-values relate to the comparison of the five groups, and are corrected for multiple testing by using false discovery rate. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml21 BMJ Open Page 22 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 3. The probability of receiving a proton pump inhibitor regularly versus no PPI in patients treated 4 regularly with low-dose aspirin LDASA users

5 (N = 9 887)* 6 Univariate Multivariate 7 analysis analysis p-value|| † 8 (OR; 95% CI) (OR; 95% CI) 9 Age (ref = 18-50) 10 51-65 1·28 (1·13 – 1·46) 1·09 (0·91 – 1·31) 0·39 11 66-80 1·77 (1·56 – 2·00) 1·54 (1·28 – 1·84) <0·0001 12 80+ 2·16 (1·88 – 2·48) 1·88 (1·54 – 2·30) <0·0001 13 Gender (ref = male) 1·48 (1·38 – 1·59) 1·26 (1·15 – 1·39) <0·0001 14 ‡,§, 15 Increased risk of GIFor complications (refpeer = low) 2·15review (1·99 – 2·33) only 16 NSAIDs 4·05 (3·72 – 4·41) 5·20 (4·31 – 6·28) <0·0001 17 Oral anticoagulants 1·48 (1·30 – 1·68) 1·46 (1·12 – 1·90) 0·008 18 Glucocorticosteroids 4·39 (3·92 – 4·91) 6·06 (4·59 – 7·99) <0·0001 19 20 SSRIs 5·88 (4·95 – 6·99) 9·07 (6·73 – 12·22) <0·0001 21 Spironolacton 2·46 (2·04 – 2·96) 1·64 (1·22 – 2·22) 0·002 22 Ulcer 13·09 (6·75 – 25·40) 23 Gastrointestinal complications 14·88 (13·08 – 16·93) 13·89 (11·78 – 16·37) <0·0001 24 Cardiovascular diseases 1·37 (1·27 – 1·47) 25 26 Cerebrovascular diseases 0·98 (0·89 – 1·07) 27 Hypertension 1·13 (1·05 – 1·22) 0·83 (0·75 – 0·92) 0·001 28 Diabetes Mellitus 1·21 (1·11 – 1·31) 29 Hypercholesterolemia 1·19 (1·11 – 1·28) 1·19 (1·07 – 1·32) 0·003 30 Other drugs for acid related disorders 1·84 (1·58 – 2·13) 31 32 Drugs for functional gastrointestinal disorders 4·62 (3·96 – 5·40) 2·40 (1·92 – 3·00) <0·0001

33 Cardiac therapy 1·85 (1·71 – 2·00) 1·55 (1·39 – 1·73) <0·0001 http://bmjopen.bmj.com/ 34 Antihypertensive agents 1·62 (1·48 – 1·77) 1·34 (1·17 – 1·55) <0·0001 35 36 Vasoprotectives 1·91 (1·55 – 2·33) 1·42 (1·06 – 1·91) 0·03 37 Lipid modifying agents 1·18 (1·10 – 1·27) 38 Antidiabetics 1·22 (1·11 – 1·33) 1·11 (0·98 – 1·26) 0·1 39 *LDASA: low-dose acetylsalicyclic acid 40 †OR: odds ratio, CI: confidence interval ‡

41 GI: gastrointestinal on September 30, 2021 by guest. Protected copyright. 42 §Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 43 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 44 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. 45 ||p-values presented are for the multivariate analyses and are corrected for multiple testing by using false 46 discovery rate. 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.xhtml22 Page 23 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Figure 1. Study flow diagram 4 5 6 LDASA, low-dose acetylsalicyclic acid; GI, gastrointestinal; PPI, proton pump inhibitors; reg., regular; irreg., 7 irregular 8 9

10 11 12 13 14 15 For peer review only 16 Reference List 17 18 19 (1) World Health Organisation. Global atlas on cardiovascular disease prevention and 20 control. 10-1-2012. 21 22 23 (2) Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised 24 trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke 25 in high risk patients. BMJ 2002; 324(7329):71-86. 26 27 (3) Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R et al. Aspirin in the 28 primary and secondary prevention of vascular disease: collaborative meta-analysis of 29 30 individual participant data from randomised trials. Lancet 2009; 373(9678):1849- 31 1860. 32

33 (4) Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS et al. Indications for http://bmjopen.bmj.com/ 34 early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized 35 patients from the chinese acute stroke trial and the international stroke trial. On behalf 36 of the CAST and IST collaborative groups. Stroke 2000; 31(6):1240-1249. 37 38 (5) Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: 39 an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern 40 Med 2009; 150(6):405-410.

41 on September 30, 2021 by guest. Protected copyright. 42 (6) McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low- 43 44 dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 45 119(8):624-638. 46 47 (7) Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson B et al. 48 Prevalence and incidence of gastroduodenal ulcers during treatment with vascular 49 protective doses of aspirin. Aliment Pharmacol Ther 2005; 22(9):795-801. 50 51 (8) Hsiao FY, Tsai YW, Huang WF, Wen YW, Chen PF, Chang PY et al. A comparison 52 of aspirin and clopidogrel with or without proton pump inhibitors for the secondary 53 prevention of cardiovascular events in patients at high risk for gastrointestinal 54 bleeding. Clin Ther 2009; 31(9):2038-2047. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml23 BMJ Open Page 24 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (9) Ng FH, Wong SY, Lam KF, Chu WM, Chan P, Ling YH et al. Famotidine is inferior 4 to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. 5 Gastroenterology 2010; 138(1):82-88. 6 7 (10) Scheiman JM, Devereaux PJ, Herlitz J, Katelaris PH, Lanas A, Veldhuyzen vZ et al. 8 Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development 9 treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON). 10 11 Heart 2011; 97(10):797-802. 12 13 (11) Yeomans ND. Reducing the risk of gastroduodenal ulcers with a fixed combination of 14 esomeprazole and low-dose acetyl salicylic acid. Expert Rev Gastroenterol Hepatol 15 2011;For 5(4):447-455. peer review only 16 17 (12) Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD et al. 18 ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal 19 risks of antiplatelet therapy and NSAID use: a report of the American College of 20 Cardiology Foundation Task Force on Clinical Expert Consensus Documents. 21 Circulation 2008; 118(18):1894-1909. 22 23 (13) Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H et al. ESC 24 25 Guidelines for the management of acute coronary syndromes in patients presenting 26 without persistent ST-segment elevation: The Task Force for the management of acute 27 coronary syndromes (ACS) in patients presenting without persistent ST-segment 28 elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 29 32(23):2999-3054. 30 31 (14) Ministerie van Volksgezondheid WeS. Een voorstel van de Expertgroep 32 Medicatieveiligheid met betrekking tot concrete interventies die de extramurale 33 medicatieveiligheid op korte termijn kunnen verbeteren. HARM-WRESTLING. http://bmjopen.bmj.com/ 34 2009. Den Haag, The Netherlands. 35 36 37 (15) NICE. Acute upper gastrointestinal bleedings: management. NICE clinical guideline 38 141. 2012. 39 40

41 (16) Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB et al. on September 30, 2021 by guest. Protected copyright. 42 ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton 43 pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 44 expert consensus document on reducing the gastrointestinal risks of antiplatelet 45 therapy and NSAID use. A Report of the American College of Cardiology Foundation 46 Task Force on Expert Consensus Documents. J Am Coll Cardiol 2010; 56(24):2051- 47 48 2066. 49 50 (17) Valkhoff VE, van Soest EM, Sturkenboom MC, Kuipers EJ. Time-trends in 51 gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs). Aliment 52 Pharmacol Ther 2010; 31(11):1218-1228. 53 54 (18) Hartnell NR, Flanagan PS, Mackinnon NJ, Bakowsky VS. Use of gastrointestinal 55 preventive therapy among elderly persons receiving antiarthritic agents in Nova 56 Scotia, Canada. Am J Geriatr Pharmacother 2004; 2(3):171-180. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml24 Page 25 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (19) Sturkenboom MC, Burke TA, Dieleman JP, Tangelder MJ, Lee F, Goldstein JL. 4 Underutilization of preventive strategies in patients receiving NSAIDs. Rheumatology 5 (Oxford) 2003; 42 Suppl 3:iii23-iii31. 6 7 (20) Lanas A, Plazas MA, Gimeno E, Munoz-Tuduri M. Gastroprotection in NSAID and 8 low-dose aspirin users: a cross-sectional study in primary care. Gastroenterol Hepatol 9 2012; 35(1):1-7. 10 11 (21) Bianco MA, Rotondano G, Buri L, Tessari F, Cipolletta L. Gastro-protective strategies 12 13 in primary care in Italy: the "Gas.Pro." survey. Dig Liver Dis 2010; 42(5):359-364. 14 15 (22) Stirbu-WagnerFor I, Dorsmanpeer SA, Visscherreview S, Davids R, Gravensteinonly JV, Abrahamse H 16 et al. Netherlands Information Network of General Practice (LINH). 2012. Utrecht / 17 Nijmegen, NIVEL/IQ. 18 19 20 (23) Schellevis FG, Westert GP, De Bakker DH. [The actual role of general practice in the 21 dutch health-care system. Results of the second dutch national survey of general 22 practice]. Med Klin (Munich) 2005; 100(10):656-661. 23 24 (24) World Health Organisation. Guidelines for ATC classification and DDD assignment. 25 26 Oslo: WHO Collaborating Centre for Drug Statistics Methodology - Nordic Council 27 on Medicines; 1999. 28 29 (25) Lamberts H, Wood M. ICPC. International Classification of Primary Care. Oxford: 30 Oxford University Press; 1987. 31 32 (26) Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin:

33 meta-analysis. BMJ 2000; 321(7270):1183-1187. http://bmjopen.bmj.com/ 34 35 (27) Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection 36 in patients taking acid suppression. Am J Gastroenterol 2007; 102(9):2047-2056. 37 38 (28) Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk 39 of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 40 2004; 292(16):1955-1960.

41 on September 30, 2021 by guest. Protected copyright. 42 43 (29) Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy 44 and risk of hip fracture. JAMA 2006; 296(24):2947-2953. 45 46 (30) Richtlijn overdracht van medicatie gegevens in de keten. 2008. VWS and IGZ. 47 48 (31) Kvamme OJ, Olesen F, Samuelson M. Improving the interface between primary and 49 secondary care: a statement from the European Working Party on Quality in Family 50 Practice (EQuiP). Qual Health Care 2001; 10(1):33-39. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml25 BMJ Open Page 26 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Figure 1. Study flow diagram 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 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 LDASA, low-dose acetylsalicyclic acid; GI, gastrointestinal; PPI, proton pump inhibitors; reg., regular; irreg., 37 irregular 38 39 40

33 http://bmjopen.bmj.com/ 34 Cerebrovascular Transient cerebral ischaemia (K89), 35 Disease Stroke/cerebrovascular accident (K90), 36 Cerebrovascular disease (K91) 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 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.xhtml1 BMJ Open Page 28 of 29 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 STROBE Statement—Checklist of items that should be included in reports of cohort studies 2 Item 3 Page No Recommendation 4 a 5 1 Title and abstract 1 ( ) Indicate the study’s design with a commonly used term in the 6 title or the abstract 7 2+3 (b) Provide in the abstract an informative and balanced summary of 8 what was done and what was found 9 10 Introduction 11 5+6 Background/rationale 2 Explain the scientific background and rationale for the investigation 12 being reported 13 6 Objectives 3 State specific objectives, including any prespecified hypotheses 14 15 MethodsFor peer review only 16 7 Study design 4 Present key elements of study design early in the paper 17 7 Setting 5 Describe the setting, locations, and relevant dates, including periods 18 19 of recruitment, exposure, follow-up, and data collection 20 7 Participants 6 (a) Give the eligibility criteria, and the sources and methods of 21 selection of participants. Describe methods of follow-up 22 n.a. (b) For matched studies, give matching criteria and number of 23 24 exposed and unexposed 25 7-9 Variables 7 Clearly define all outcomes, exposures, predictors, potential 26 confounders, and effect modifiers. Give diagnostic criteria, if 27 applicable 28 7-10 Data sources/ 8* For each variable of interest, give sources of data and details of 29 30 measurement methods of assessment (measurement). Describe comparability of 31 assessment methods if there is more than one group 32 10 Bias 9 Describe any efforts to address potential sources of bias 33 7 Study size 10 Explain how the study size was arrived at http://bmjopen.bmj.com/ 34 35 7-10 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If 36 applicable, describe which groupings were chosen and why 37 9+10 Statistical methods 12 (a) Describe all statistical methods, including those used to control 38 for confounding 39 b 40 10 ( ) Describe any methods used to examine subgroups and interactions

41 on September 30, 2021 by guest. Protected copyright. 42 10 (c) Explain how missing data were addressed 43 n.a. (d) If applicable, explain how loss to follow-up was addressed 44 10 (e) Describe any sensitivity analyses 45 46 Results 47 Participants 13* (a) Report numbers of individuals at each stage of study—eg 48 numbers potentially eligible, examined for eligibility, confirmed 49 50 11 eligible, included in the study, completing follow-up, and analysed 51 Fig 1 (b) Give reasons for non-participation at each stage 52 Fig 1 (c) Consider use of a flow diagram 53 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, 54 55 clinical, social) and information on exposures and potential 56 Table1 confounders 57 n.a. (b) Indicate number of participants with missing data for each 58 variable of interest 59 60 7 (c) Summarise follow-up time (eg, average and total amount) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 Page 29 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 Fig 1 Outcome data 15* Report numbers of outcome events or summary measures over time 2 11-12 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder- 3 adjusted estimates and their precision (eg, 95% confidence interval). 4 5 Make clear which confounders were adjusted for and why they were 6 included 7 Tables (b) Report category boundaries when continuous variables were 8 categorized 9 c 10 ( ) If relevant, consider translating estimates of relative risk into 11 absolute risk for a meaningful time period 12 12 Other analyses 17 Report other analyses done—eg analyses of subgroups and 13 interactions, and sensitivity analyses 14 15 DiscussionFor peer review only 16 13 Key results 18 Summarise key results with reference to study objectives 17 15-16 Limitations 19 Discuss limitations of the study, taking into account sources of 18 potential bias or imprecision. Discuss both direction and magnitude 19 20 of any potential bias 21 16 Interpretation 20 Give a cautious overall interpretation of results considering 22 objectives, limitations, multiplicity of analyses, results from similar 23 studies, and other relevant evidence 24 16 Generalisability 21 Discuss the generalisability (external validity) of the study results 25 26 Other information 27 17 Funding 22 Give the source of funding and the role of the funders for the present 28 study and, if applicable, for the original study on which the present 29 30 article is based 31 32 *Give information separately for exposed and unexposed groups.

33 http://bmjopen.bmj.com/ 34 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 35 36 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 37 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 38 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 39 available at http://www.strobe-statement.org. 40

Suboptimal prescribing of proton pump inhibitors in low- dose aspirin users; a cohort study in primary care.

ForJournal: peerBMJ Open review only Manuscript ID: bmjopen-2013-003044.R1

Article Type: Research

Date Submitted by the Author: 11-Jun-2013

Primary Subject General practice / Family practice Heading:

Secondary Subject Heading: Gastroenterology and hepatology

PRIMARY CARE, GASTROENTEROLOGY, PREVENTIVE MEDICINE, Cardiology Keywords: http://bmjopen.bmj.com/ < INTERNAL MEDICINE

on September 30, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Suboptimal prescribing of proton pump inhibitors in low-dose aspirin users; a cohort 4 5 study in primary care. 6 7 Hilda JI De Jong, Joke C Korevaar, Liset Van Dijk, Eef Voogd, Christel E Van Dijk, Martijn 8 9 10 GH Van Oijen 11 12 13 14 Affiliates 15 For peer review only 16 NIVEL, Netherlands Institute for Health Services Research, Utrecht, The Netherlands, Hilda 17 18 de Jong PhD-student, Joke Korevaar Research Coordinator General Practice Care, Liset van 19 20 21 Dijk Research Coordinator Pharmaceutical Care, Eef Voogd PhD-student, Christel van Dijk 22 23 Senior researcher. 24 25 Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, 26 27 California, USA and UCLA/VA Center for Outcomes Research and Education (CORE), Los 28 29 30 Angeles, California, USA, Martijn van Oijen assistant professor. 31 32

33 http://bmjopen.bmj.com/ 34 Corresponding author 35 JC Korevaar 36 P.O. Box 1568 37 3500 BN Utrecht 38 The Netherlands 39 40 +31 30 27 29 711 [email protected]

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 Keywords: low-dose aspirin, proton pump inhibitors, GI complications, primary care 45 46 Wordcount: 3089 47 48 Funding: AstraZeneca; NIVEL 49 50 51 Short title: suboptimal prescribing of PPIs in LDASA users in primary care 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 2 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Abstract 4 5 Objective 6 7 Determine the adherence to recommendations of concomitant PPI treatment in regular 8 9 10 LDASA users, taking factors associated with the probability of receiving a PPI into account. 11 12 Design 13 14 Cohort study 15 For peer review only 16 Setting 17 18 Data were obtained from 120 Dutch primary care centres participating in the Netherlands 19 20 21 Information Network of Primary Care (LINH). 22 23 Participants 24 25 Patients 18 years and older who were regularly prescribed LDASA (30-325 mg) in 2008-2010 26 27 were included. 28 29 30 Main outcome measures 31 32 Regular medication use was defined as receiving each consecutive prescription within 6

33 http://bmjopen.bmj.com/ 34 primary care physicians. 35 36 37 38 39 40

41 prescriptions, or why they became an irregular PPI user on September 30, 2021 by guest. Protected copyright. 42 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.xhtml4 Page 5 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Introduction 4 5 Worldwide, the number of deaths from cardiovascular disease was estimated at 17.3 million 6 7 in 2008, and it is expected to increase to approximately 23.6 million by 2030 1. Treatment 8 9 10 with low-dose of aspirin (LDASA) is recommended for the prevention of cardiovascular 11 12 events in patients with a history of myocardial infarction, stroke, transient ischaemic attack or 13 14 (in)stable angina 2-4. While LDASA use is associated with a decreased risk of cardiovascular 15 For peer review only 16 events 5, its use is also associated with a wide variety of gastrointestinal (GI) side effects, such 17 18 as dyspepsia, peptic ulcers, and upper and lower GI bleedings 6;7. 19 20 21 22 23 GI complications associated with LDASA use are more frequently present in patients who are 24 25 older than 70 years, have a history of peptic ulcer, have had an infection with Helicobacter 26 27 pylori, and/or used concomitant drug therapies with non-steroidal anti-inflammatory drugs 28 29 30 (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, other antiplatelet agents or 31 6;7 32 anticoagulants, glucocorticosteroids, and/or selective serotonin reuptake inhibitors (SSRIs) .

41 on September 30, 2021 by guest. Protected copyright. 42 43 risk for GI complications has been described in guidelines from medical societies and 44 45 scientific associations from both the USA and Europe 12;13. In the Netherlands - the setting of 46 47 our study - an expert group with a focus on optimising extramural medication safety 48 49 50 published specific recommendations for adequate gastrointestinal protection, i.e. prescribing 51 52 PPIs in regular LDASA users with an increased risk of GI complications in 2008, which was 53 54 finalised in 2009 14. These recommendations are in line with the US, NICE and ESC 55 56 guidelines 12;13;15, and describe that PPIs are the preferred agents for the therapy and 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml5 BMJ Open Page 6 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 12 3 prophylaxis of aspirin-associated GI injury . Risk reduction due to PPI treatment observed in 4 5 case-control and cohort studies ranged in most cases from 40 to 80%.16 6 7 8 9 10 Several observational studies described the use of concomitant PPI in a patients receiving 11 12 NSAID including aspirin, and showed that 67-90% of the users with at least one risk factor 13 14 did not receive gastroprotective therapy as recommended 17 18;19. Two studies focussed on 15 For peer review only 16 LDASA patients; in one study the definition of increased GI risk was limited, namely a 17 18 positive Helicobacter pylori status, the other study had a small sample size of LDASA 19

33 http://bmjopen.bmj.com/ 34 receiving a PPI into account. 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 before the date of the first prescription of LDASA. This time period was chosen to confirm 44 45 that no LDASA prescriptions were given in the year prior to inclusion. Regular use of 46 47 LDASA was defined as receiving each consecutive prescription within six months after the 48 49 50 previous one. A gap of maximal six months was chosen because in daily practice patients 51 52 rarely collect a subsequent prescription exactly on the day their supply of their previous 53 54 prescription has ended, normally 90 days, but rather earlier (overlap of two prescriptions) or 55 56 later (gap between two prescriptions). In order not to bias our results towards irregular user 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml7 BMJ Open Page 8 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 categorisation, we used a maximum period of six months. Irregular LDASA users, according 4 5 to our definition, were excluded from the analyses as well as users with just one LDASA 6 7 prescription. Aspirin therapy was identified by a prescription of acetylsalicylic acid (ATC- 8 9 10 codes B01AC06, N02BA01 and N02BA51), carbasalate calcium (B01AC08, N02BA15 and 11 12 N02BA65), or acetylsalicylic acid in combination with other drugs (B01AC30). 13 14 15 For peer review only 16 Based upon the HARM-WRESTLING recommendations 14, we categorised new LDASA 17 18 users into low or increased risk of GI complications. Patients with an increased risk of GI 19 20 21 complications were identified by the following selection rules applied in consecutive order: 1) 22 23 80 years or older; 2) 70 years or older with simultaneous use of NSAIDs, oral anticoagulants, 24 25 platelet aggregation inhibitors, glucocorticosteroids, SSRIs and/or spironolacton; or 3) 60 26 27 years or older with a history of a peptic ulcer. 28 29 30 31 32 PPI treatment was identified by ATC-code A02BC. All patients were divided into three

33 http://bmjopen.bmj.com/ 34 categories: no user, irregular, or regular user of PPIs. Patients who never received a 35 36 prescription of PPI during the follow-up period were defined as no PPI users. In line with our 37 38 definition of a regular LDASA user, patients were defined as regular PPI users if they 39 40 received each consecutive prescription within 6 months after their previous one. All others

41 on September 30, 2021 by guest. Protected copyright. 42 43 were considered as irregular users. 44 45 46 47 We considered patients to be previous starters of PPIs when they received a prescription of 48 49 50 PPI in the year prior to the first prescription of LDASA. Patients who started the use of PPIs 51 52 within a week after the first prescription of LDASA were considered as simultaneous starters 53 54 of PPIs. Patients who received a prescription of PPI more than a week after the first 55 56 prescription of LDASA were subsequent starters of PPIs. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml8 Page 9 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 4 5 Relevant co-morbidity was determined in the year before and after the date of the first 6 7 prescription of LDASA. Cardiovascular and cerebrovascular diseases were identified by 8 9 10 ICPC-codes K71, K73-K84, K89-K96 and K99. Hypertension was considered present when 11 12 the patient had a medical record of ICPC-codes K86 or K87. Patients were classified as 13 14 diabetic if a diagnosis code for diabetes (T90) was identified, or when they received anti- 15 For peer review only 16 diabetic therapy (ATC-codes A10A and A10B). Patients who had a diagnosis of lipid disorder 17 18 (T93) or when they received lipid modifying agents (C10) were considered as 19 20 21 hypercholesterolaemic. GI complications, including peptic ulcers, were identified by D02, 22 23 D03, D09, D10, D14, D16, D85-87, and D90 (Appendix I). To classify patients as having an 24 25 increased GI risk based on HARM-WRESTLING recommendation, we determined 26 27 prescriptions for NSAIDs (M01), including Cox-2 inhibitors, oral anticoagulants and platelet 28 29 30 aggregation inhibitors (B01AA and B01AC), glucocorticosteroids (H02AB and H02), and 31 32 SSRIs (N06AB) [16]. In addition, we identified all prescriptions for cardiovascular system

33 http://bmjopen.bmj.com/ 34 (C01-C10), acid related disorders (A02 (PPIs excluded)), and functional gastro-intestinal 35 36 disorders (A03) in the year before and after the date of the first LDASA prescription. Finally, 37 38 cardiac therapy was defined as a prescription of an ATC-code C01 in the year before or after 39 40 the first LDASA prescription.

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 45 Statistical analysis 46 47 Differences between groups were tested with a Chi-square test. To identify the relative 48 49 50 influence of patient characteristics on the probability to obtain regular PPI prescriptions, 51 52 multilevel multivariable logistic regression analyses (backward elimination method) was 53 54 conducted. The models were estimated taking the clustering of patients (level 1) within 55 56 primary care centres (level 2) into account. The probability of receiving a PPI was determined 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml9 BMJ Open Page 10 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 by comparing no PPI users with regular PPI users. This analyses was performed without the 4 5 irregular users to rule out the effect of these users. In addition, separate analyses were 6 7 performed for increased GI risk patients. All data were analysed using the statistical programs 8 9 10 SAS version 9·2 (SAS Institute, Cary, North Carolina) and ‘Multilevel models for windows’ 11 12 (MLwin 2·02). Adjustment for multiple testing was performed by using a False Discovery 13 14 Rate correction. 15 For peer review only 16 17 18 Choices of our definition of subsequent and simultaneous start of PPIs, and our period of 19 20 21 describing patients’ characteristics were based on assumptions, and therefore we tested the 22 23 robustness of our findings by performing sensitivity analyses. We made the definition of 24 25 simultaneous starters of PPIs more strictly, i.e. receiving a prescription of PPIs at exactly the 26 27 same date as the first prescription of LDASA. Secondly, we changed the medical and 28 29 30 prescription history into only one year before the date of the first LDASA prescription. 31 32 Thirdly, as LDASA therapy was frequently prescribed for patients with cardiovascular

33 http://bmjopen.bmj.com/ 34 diseases, a separate analysis with solely cardiovascular patients was conducted. Finally, we 35 36 investigated the influence of irregular users of PPIs into our analysis by performing two 37 38 analyses in which we (1) merged irregular users with regular users of PPIs and in which we 39 40 (2) added irregular users to the no PPI users group.

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 45 Role of the funding source 46 47 The sponsor had no decisive role in the study, i.e. the sponsor thought along with the study 48 49 50 and supplied suggestions regarding the content of the study, but the sponsor was not involved 51 52 in the decisions regarding the analysis, the conduct of the study, nor the publication. JK and 53 54 LvD had full access to all data in the study and take responsibility for the integrity of the data 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml10 Page 11 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 and accuracy of the data analysis. All authors had final responsibility for the decision to 4 5 submit for publication. 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 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 diuretics, beta blocking agents, and vasoprotective agents. 44 45 46 47 Table 3 shows the probability of receiving regular PPI prescriptions versus no PPI usage. This 48 49 50 probability is significantly increased by different risk factors for GI side effects, by morbidity, 51 52 medication, and increased age. LDASA users with a history of gastrointestinal complications 53 54 were more likely to receive regular PPI prescriptions (adjusted OR 13.9; 95% CI: 11.8-16.4), 55 56 as was found for the different medications used to define patients with an increased GI risk. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml12 Page 13 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Simultaneous use of SSRIs (adjusted OR 9.1 (6.7-12.2)), NSAIDs (5.2 (4.3-6.3)), 4 5 glucocorticosteroids (6.1 (4.6-8.0)), and being 80 years and older (1.9 (1.5-2.3)) were strongly 6 7 related to receiving a PPI regularly. Sensitivity analyses for the group with an increased GI 8 9 10 risk did not alter our findings; similar predicting factors influenced the probability with equal 11 12 magnitude, except for age. Age was no longer a predicting factor (data not shown). 13 14 15 For peer review only 16 Applying the different sensitivity analyses did not alter our findings. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 received PPIs and 62% of the low GI risk patients 20. So, the vast majority of all 44 45 NSAID/LDASA users, even the patients with a low risk, received a PPI prescription, which is 46 47 much higher than observed in our study. Yet, our study has a longitudinal design, and 48 49 50 consequently has the information to label a patient as regular or irregular user of PPI. If we 51 52 drop the strict condition of being a regular PPI user, to mimic a cross-sectional design, 64.5% 53 54 of the patients with an increased risk obtained PPIs and 50.2% of the low risk patients. These 55 56 numbers are more in line with the Spanish results, although still lower. Next to the number of 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml14 Page 15 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 increased risk patients receiving PPIs, the timing of the initiation of PPI treatment is 4 5 important. Our study showed that the vast majority of patients started with PPI treatment 6 7 before or simultaneously with the first prescription of LDASA, thereby acting as preventive 8 9 10 agent. 11 12 13 14 In line with the HARM-WRESTLING recommendations, the US, NICE and ESC guidelines 15 For peer review only 16 also recommend to prescribe PPIs to LDASA users who are 60-70 years of age or older 17 18 and/or concomitantly use of SSRIs, NSAIDs, or glucocorticosteroids.12;13;15 Therefore, we 19 20 21 believe our findings are not only relevant for the Netherlands, but have international 22 23 implications as well. 24 25 26 27 The study of Lanas et al. found that gastroprotective treatment in LDASA users was 28 29 30 significantly associated with a prior history of peptic ulcer, high dose NSAID therapy and 31 20 32 concomitant use of oral corticosteroids and antithrombotics . Our data support these

41 on September 30, 2021 by guest. Protected copyright. 42 43 compared to the high risk population, over treatment with PPIs may occur in this group. In 44 45 total, 30% of patients with low GI risk received regularly PPI treatment. Although PPI 46 47 treatment is considered to be cheap, relatively safe, long-term treatment with this drug has 48 49 50 been shown to increase the susceptibility to GI infections and pneumonia, and it has been 51 27-29 52 associated with an increased risk of fractures . Unfortunately, the reasons why these low 53 54 GI risk patients obtained (regular) PPI’s by their primary care physician is very incompletely 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml15 BMJ Open Page 16 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 recorded in our database, refraining us to comment on the necessity of these prescriptions in 4 5 patients with a low GI risk. 6 7 8 9 10 The only difference between patients who were at increased GI risk with or without regular 11 12 PPI therapy was the reason of being a patient with an increased GI risk; nearly 90% of the 13 14 patients who were at increased GI risk without regular PPI therapy were above 80 years, 15 For peer review only 16 whereas of the patients with regular PPI use, just 74% was above 80 years. Another possible 17 18 explanation why not all patients with an increased GI risk use PPIs regularly might be limited 19 20 21 awareness of primary care physicians of the current recommendation, since the draft version 22 23 was first published in 2008 and the final version in 2009, during the first months of our study 24 25 period. 26 27 28 29 30 A strong point of our study is that we had a large representative sample of patients monitored 31 32 in daily practice. The vast majority of the primary care centres in the Netherlands have a

41 on September 30, 2021 by guest. Protected copyright. 42 43 sample, we had complete data for each individual patient, including all physicians’ diagnoses 44 45 and prescription data. This enabled us to study several different subpopulations of patients 46 47 combining LDASA and PPI treatment. Finally, we performed a range of sensitivity analyses 48 49 50 regarding exposure definition, and in- and exclusion criteria. 51 52 53 54 A limitation of this study includes the lack of information about prescriptions by medical 55 56 specialists. If PPIs were prescribed by medical specialists, the prescription of the patient 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml16 Page 17 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 might not always appear in our dataset. Yet, the Dutch guidelines for optimising primary care- 4 5 medical specialist communication support medical specialists to inform primary care 6 7 physicians with the first results of diagnostics and treatments of the referred patient 30;31. Due 8 9 10 to this, we may have underestimated regular PPI use. However, it is plausible that LDASA 11 12 prescription was initiated by the same medical specialist, so if PPI prescriptions are missing, 13 14 probably LDASA prescriptions are missing as well. In such a case the patient was not 15 For peer review only 16 included in our study, limiting the impact of missing PPI prescriptions. Our results are based 17 18 on an observational study which may be subjected to residual confounding due to potential 19 20 21 unmeasured differences in GI risk profile and patient characteristics between LDASA users 22 23 who received or did not received PPI prescriptions. Finally, we do not have any information 24 25 why patients with an increased GI risk did not obtain PPI prescriptions, nor do we know the 26 27 reason why patients become an irregular PPI user, and whether this was patient or physician 28 29 30 related. 31 32

41 on September 30, 2021 by guest. Protected copyright. 42 43 finding underlines the necessity to consider merging recommendations into one common, 44 45 standard and frequently used recommendation by primary care physicians. Further studies are 46 47 needed to determine which motivations and attitudes may play a role for primary care 48 49 50 physicians to be aware of the guidelines and be able to accept, and adhere to them. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml17 BMJ Open Page 18 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Contributors: 4 5 HJIdJ contributed to the design of the study, performed data analyses and drafted the report. 6 7 JCK provided data, contributed to the design of the study and the interpretation of the results, 8 9 10 and drafted and reviewed the report. LvD initiated and obtained the funding for the project, 11 12 contributed to the design of the study and interpretation of the results, and drafted and 13 14 reviewed the paper. EV and ECvD performed data analyses, contributed to the interpretation 15 For peer review only 16 of the data, and reviewed the paper. MGHvO contributed to the design of the study and 17 18 analysis plan, and interpretation of the results, and reviewed the paper. 19 20 21 Conflicts of interest 22 23 This study was funded by Astra Zeneca. The institute of JK and LvD received research 24 25 funding from Astra Zeneca and Bristol-Myers Squibb for a study not related to this study. 26 27 MGHvO has served as a consultant for AstraZeneca and Pfizer, and has received unrestricted 28 29 30 research grants from AstraZeneca, Shire and Janssen. 31 32 Funding:

41 on September 30, 2021 by guest. Protected copyright. 42 43 the data and accuracy of the data analysis. All authors had final responsibility for the decision 44 45 to submit for publication 46 47 Data sharing statement: No additional data are available 48 49 50 Ethics approval: The privacy regulation of LINH was approved by the Dutch Data Protection 51 52 Authority. According to Dutch legislation, neither obtaining informed consent nor approval 53 54 by a medical ethics committee is obligatory for database studies 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml18 Page 19 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Copyright 4 5 The Corresponding Author has the right to grant on behalf of all authors and does grant on 6 7 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in 8 9 10 all forms, formats and media (whether known now or created in the future), to i) publish, 11 12 reproduce, distribute, display and store the Contribution, ii) translate the Contribution into 13 14 other languages, create adaptations, reprints, include within collections and create summaries, 15 For peer review only 16 extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on 17 18 the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of 19 20 21 electronic links from the Contribution to third party material where-ever it may be located; 22 23 and, vi) licence any third party to do any or all of the above.” 24 25 26 27 28 29 30 31 32

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17 || 18 LDASA plus PPI use (%) 19 No user of PPI 1 142 (35·5) 4 541 (49·8) <0·0001 20 Regular user of PPI 1 480 (46·1) 2 724 (29·8) 21 Irregular user of PPI 591 (18·4) 1 865 (20·4) 22 Co-morbidity (%)¶ 23 24 Gastrointestinal tract 25 Gastrointestinal complications 664 (20·7) 1 475 (16·2) <0·0001 26 Duodenal ulcer 24 (0·8) 21 (0·2) <0·0001 27 Peptic ulcer 34 (1·1) 11 (0·1) <0·0001 28 Hiatus Hernia 29 (0·9) 58 (0·6) 0·13 29 30 Heart burn 75 (2·3) 233 (2·6) 0·52 31 Haematemesis 7 (0·2) 10 (0·1) 0·19 32 Rectal bleeding 50 (1·6) 97 (1·1) 0·04

33 Cardiovascular diseases http://bmjopen.bmj.com/

41 on September 30, 2021 by guest. Protected copyright. 42 Atherosclerosis 176 (5·5) 644 (7·1) 0·003 43 Cerebrovascular diseases** 756 (23·5) 1 480 (16·2) <0·0001 44 Stroke 362 (11·3) 731 (8·0) <0·0001 45 Transient Ischaemic Attack (TIA) 326 (10·2) 541 (5·9) <0·0001 46 47 Hypertension 1 307 (40·7) 3 546 (38·8) 0·08 48 Diabetes Mellitus 779 (24·3) 1 960 (21·5) 0·002 49 Hypercholesteroleamia 1 567 (48·8) 6 374 (69·8) <0·0001 50 Co-medication (%)¶ 51 52 Other drugs for acid related disorders 196 (6·1) 477 (5·2) 0·07 53 Drugs for functional gastrointestinal disorders 277 (8·6) 544 (6·0) <0·0001 54 Cardiac therapy 964 (30·0) 2 152 (23·6) <0·0001 55 Antihypertensive agents 2 748 (85·5) 7 357 (80·6) <0·0001 56 Antihypertensives 55 (1·7) 171 (1·9) 0·58 57 58 Diuretics 1 594 (49·6) 2 456 (26·9) <0·0001 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml20 Page 21 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Beta blocking agents 1 728 (53·8) 5 250 (57·5) 0·0005 4 Calcium channel blockers 825 (25·7) 2 113 (23·1) 0·005 5 RAAS agents†† 1 672 (52·0) 4 616 (50·6) 0·17 6 7 Peripheral vasodilators 4 (0·1) 11 (0·1) 1·00 8 Vasoprotectives 103 (3·2) 232 (2·5) 0·06 9 Lipid modifying agents 1 557 (48·5) 6 311 (69·1) <0·0001 10 Antidiabetics 624 (19·4) 1 604 (17·6) 0·03 11 *GI: gastrointestinal 12 †LDASA: low-dose acetylsalicyclic acid 13 ‡NSAIDs: non-steroidal anti-inflammatory drugs 14 §SSRIs: selective serotonin reuptake inhibitors 15 ||PPIs: proton pumpFor inhibitors peer review only 16 ¶Determined in the year before and after the first prescription of LDASA 17 **not all indications are included, only the major ones ††RAAS: renin-angiotensin-aldosterone system 18 ‡‡ 19 p-values are corrected for multiple testing by using false discovery rate. 20

21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 30, 2021 by guest. Protected copyright. 42 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.xhtml21 BMJ Open Page 22 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 2. Characteristics of regular low-dose aspirin users and low-dose aspirin plus irregular and regular 4 proton pump inhibitors users, stratified by time of proton pump inhibitor use No Use of Irregular use Regular use of PPI 5 LDASA* of PPI† p-value** N = 4 204 6 N = 5 683 N = 2 456 7 Previous starters Simultaneous Subsequent 8 of PPI starters of PPI starters of PPI N = 2 015 N = 1 064 N = 1 125 9 Age 10 11 18-50 599 (10·5) 208 (8·5) 176 (8·7) 58 (5·4) 81 (7·2) <0·0001 12 51-65 2 026 (35·7) 829 (33·8) 592 (29·4) 292 (27·4) 331 (29·4) 13 66-80 2 163 (38·1) 1 043 (42·5) 801 (39·8) 424 (39·9) 494 (43·9) 14 80+ 895 (15·8) 376 (15·3) 446 (2·1) 290 (27·3) 219 (19·5) 15 For peer review only Sex 16 17 Men 3 308 (58·2) 1 288 (52·4) 912 (45·3) 530 (49·8) 597 (53·1) <0·0001 18 Risk of GI complications (%)‡,|| 19 Increased risk of GI complications 1 142 (20·1) 591 (24·1) 756 (37·5) 414 (38·9) 310 (27·6) <0·0001 20 Low risk of GI complications 4 541 (79·9) 1 865 (75·9) 1 259 (62·5) 650 (61·1) 815 (72·4) 21 § 22 Co-morbidity (%) 23 Gastrointestinal complications 214 (3·8) 594 (24·2) 831 (41·2) 217 (20·4) 283 (25·2) <0·0001 24 Ulcers 6 (0·1) 24 (1·0) 38 (1·9) 9 (0·9) 13 (1·2) <0·0001 25 Cardiovascular diseases 2 447 (43·6) 1 190 (48·5) 1 110 (55·1) 456 (42·9) 547 (48·6) <0·0001 26 27 Cerebrovascular diseases 1 052 (18·5) 400 (16·3) 406 (20·2) 171 (16·1) 207 (18·4) 0·007 28 Hypertension 2 221 (39·1) 989 (40·3) 831 (41·2) 335 (31·5) 477 (42·4) <0·0001 29 Diabetes Mellitus 1 189 (20·9) 544 (22·2) 458 (22·7) 292 (27·4) 256 (22·8) 0·0001 30 31 Hypercholesteroleamia 3 600 (63·4) 1 592 (64·8) 1 302 (64·6) 721 (67·8) 726 (64·5) 0·09 32 Co-medication (%)§ Other drugs for acid related 33 227 (4·0) 144 (5·9) 163 (8·1) 54 (5·1) 85 (7·6) <0·0001 http://bmjopen.bmj.com/ disorders 34 Drugs for functional gastrointestinal 151 (2·7) 211 (8·6) 275 (13·7) 83 (7·8) 101 (9·0) <0·0001 35 disorders 36 Cardiac therapy 1 142 (20·1) 664 (27·0) 672 (33·4) 324 (30·5) 314 (27·9) <0·0001 37 Antihypertensive agents 4 523 (79·6) 1 997 (81·3) 1 721 (85·4) 912 (85·7) 952 (84·6) <0·0001 38 Antihypertensives 102 (1·8) 36 (1·5) 44 (2·2) 22 (2·1) 22 (2·0) 0·48 39 40 Diuretics 1 607 (28·3) 782 (31·8) 826 (41·0) 410 (38·5) 425 (37·8) <0·0001 Beta blocking agents 3 078 (54·2) 1 370 (55·8) 1 255 (62·3) 633 (59·5) 642 (57·1) <0·0001

41 on September 30, 2021 by guest. Protected copyright. 42 Calcium channel blockers 1 078 (21·5) 571 (23·3) 551 (27·3) 286 (26·9) 309 (27·5) <0·0001 43 RAAS agents¶ 3 221 (49·3) 1 205 (49·6) 1 081 (53·7) 576 (54·1) 624 (55·5) <0·0001 44 Vasoprotectives 111 (2·0) 77 (3·1) 84 (4·2) 25 (2·4) 38 (3·4) <0·0001 45 46 Lipid modifying agents 3 568 (62·8) 1 578 (64·3) 1 288 (63·9) 717 (67·4) 717 (63·7) 0·08 47 Antidiabetics 974 (17·1) 420 (17·1) 378 (18·8) 244 (22·9) 212 (18·8) 0·0001 48 *LDASA: low-dose acetylsalicyclic acid 49 †PPIs: proton pump inhibitors 50 ‡Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 51 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 52 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. § 53 Determined in the year before and after the first prescription of LDASA || 54 GI: gastrointestinal ¶RAAS: renin-angiotensin-aldosterone system 55 ** 56 p-values relate to the comparison of the five groups, and are corrected for multiple testing by using false discovery rate. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml22 Page 23 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 3. The probability of receiving a proton pump inhibitor regularly versus no PPI in patients treated 4 regularly with low-dose aspirin LDASA users

41 GI: gastrointestinal on September 30, 2021 by guest. Protected copyright. 42 §Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 43 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 44 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. 45 ||p-values presented are for the multivariate analyses and are corrected for multiple testing by using false 46 discovery rate. 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.xhtml23 BMJ Open Page 24 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Figure 1. Study flow diagram 4 5 6 LDASA, low-dose acetylsalicyclic acid; GI, gastrointestinal; PPI, proton pump inhibitors; reg., regular; irreg., 7 irregular 8 9

10 11 12 13 14 15 For peer review only 16 Reference List 17 18 19 (1) World Health Organisation. Global atlas on cardiovascular disease prevention and 20 control. 10-1-2012. 21 22 23 (2) Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised 24 trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke 25 in high risk patients. BMJ 2002; 324(7329):71-86. 26 27 (3) Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary 28 prevention of vascular disease: collaborative meta-analysis of individual participant 29 30 data from randomised trials. Lancet 2009; 373(9678):1849-1860. 31 32 (4) Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute

33 ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese http://bmjopen.bmj.com/ 34 acute stroke trial and the international stroke trial. On behalf of the CAST and IST 35 collaborative groups. Stroke 2000; 31(6):1240-1249. 36 37 (5) Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: 38 an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern 39 Med 2009; 150(6):405-410. 40

41 (6) McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low- on September 30, 2021 by guest. Protected copyright. 42 dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 43 44 119(8):624-638. 45 46 (7) Yeomans ND, Lanas AI, Talley NJ, et al. Prevalence and incidence of gastroduodenal 47 ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol 48 Ther 2005; 22(9):795-801. 49 50 (8) Hsiao FY, Tsai YW, Huang WF, et al. A comparison of aspirin and clopidogrel with 51 or without proton pump inhibitors for the secondary prevention of cardiovascular 52 events in patients at high risk for gastrointestinal bleeding. Clin Ther 2009; 53 31(9):2038-2047. 54 55 (9) Ng FH, Wong SY, Lam KF, Chu WM, et al. Famotidine is inferior to pantoprazole in 56 preventing recurrence of aspirin-related peptic ulcers or erosions. Gastroenterology 57 58 2010; 138(1):82-88. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml24 Page 25 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (10) Scheiman JM, Devereaux PJ, Herlitz J, et al. Prevention of peptic ulcers with 4 esomeprazole in patients at risk of ulcer development treated with low-dose 5 acetylsalicylic acid: a randomised, controlled trial (OBERON). Heart 2011; 6 97(10):797-802. 7 8 (11) Yeomans ND. Reducing the risk of gastroduodenal ulcers with a fixed combination of 9 esomeprazole and low-dose acetyl salicylic acid. Expert Rev Gastroenterol Hepatol 10 11 2011; 5(4):447-455. 12 13 (12) Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus 14 document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: 15 a reportFor of the American peer College reviewof Cardiology Foundation only Task Force on Clinical 16 Expert Consensus Documents. Circulation 2008; 118(18):1894-1909. 17 18 (13) Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of 19 acute coronary syndromes in patients presenting without persistent ST-segment 20 elevation: The Task Force for the management of acute coronary syndromes (ACS) in 21 patients presenting without persistent ST-segment elevation of the European Society 22 of Cardiology (ESC). Eur Heart J 2011; 32(23):2999-3054. 23 24 25 (14) Ministerie van Volksgezondheid WeS. Een voorstel van de Expertgroep 26 Medicatieveiligheid met betrekking tot concrete interventies die de extramurale 27 medicatieveiligheid op korte termijn kunnen verbeteren. HARM-WRESTLING. 28 2009. Den Haag, The Netherlands. 29 30 (15) NICE. Acute upper gastrointestinal bleedings: management. NICE clinical guideline 31 141. 2012. 32

33 http://bmjopen.bmj.com/ 34 (16) Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert 35 36 consensus document on the concomitant use of proton pump inhibitors and 37 thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus 38 document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. 39 A Report of the American College of Cardiology Foundation Task Force on Expert 40 Consensus Documents. J Am Coll Cardiol 2010; 56(24):2051-2066.

41 on September 30, 2021 by guest. Protected copyright. 42 (17) Valkhoff VE, van Soest EM, Sturkenboom MC, et al. Time-trends in gastroprotection 43 with nonsteroidal anti-inflammatory drugs (NSAIDs). Aliment Pharmacol Ther 2010; 44 31(11):1218-1228. 45 46 (18) Hartnell NR, Flanagan PS, Mackinnon NJ, et al. Use of gastrointestinal preventive 47 therapy among elderly persons receiving antiarthritic agents in Nova Scotia, Canada. 48 49 Am J Geriatr Pharmacother 2004; 2(3):171-180. 50 51 (19) Sturkenboom MC, Burke TA, Dieleman JP, et al. Underutilization of preventive 52 strategies in patients receiving NSAIDs. Rheumatology (Oxford) 2003; 42 Suppl 53 3:iii23-iii31. 54 55 (20) Lanas A, Plazas MA, Gimeno E, et al. Gastroprotection in NSAID and low-dose 56 aspirin users: a cross-sectional study in primary care. Gastroenterol Hepatol 2012; 57 35(1):1-7. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml25 BMJ Open Page 26 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (21) Bianco MA, Rotondano G, Buri L, et al. Gastro-protective strategies in primary care in 4 Italy: the "Gas.Pro." survey. Dig Liver Dis 2010; 42(5):359-364. 5 6 (22) Stirbu-Wagner I, Dorsman SA, Visscher S, et al. Netherlands Information Network of 7 General Practice (LINH). 2012. Utrecht / Nijmegen, NIVEL/IQ. 8 9 10 (23) Schellevis FG, Westert GP, De Bakker DH. [The actual role of general practice in the 11 dutch health-care system. Results of the second dutch national survey of general 12 13 practice]. Med Klin (Munich) 2005; 100(10):656-661. 14 15 (24) WorldFor Health Organisation. peer Guidelines review for ATC classification only and DDD assignment. 16 Oslo: WHO Collaborating Centre for Drug Statistics Methodology - Nordic Council 17 on Medicines; 1999. 18 19 (25) Lamberts H, Wood M. ICPC. International Classification of Primary Care. Oxford: 20 Oxford University Press; 1987. 21 22 (26) Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: 23 meta-analysis. BMJ 2000; 321(7270):1183-1187. 24 25 (27) Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection 26 in patients taking acid suppression. Am J Gastroenterol 2007; 102(9):2047-2056. 27 28 29 (28) Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired 30 pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292(16):1955- 31 1960. 32

33 (29) Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and http://bmjopen.bmj.com/ 34 risk of hip fracture. JAMA 2006; 296(24):2947-2953. 35 36 (30) Richtlijn overdracht van medicatie gegevens in de keten. 2008. VWS and IGZ. 37 38 (31) Kvamme OJ, Olesen F, Samuelson M. Improving the interface between primary and 39 secondary care: a statement from the European Working Party on Quality in Family 40 Practice (EQuiP). Qual Health Care 2001; 10(1):33-39.

33 http://bmjopen.bmj.com/ 34 Corresponding author 35 JC Korevaar 36 P.O. Box 1568 37 3500 BN Utrecht 38 The Netherlands 39 40 +31 30 27 29 711 [email protected]

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 Keywords: low-dose aspirin, proton pump inhibitors, GI complications, primary care 45 46 Wordcount: 3089 47 48 Funding: AstraZeneca; NIVEL 49 50 51 Short title: suboptimal prescribing of PPIs in LDASA users in primary care 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 28 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Abstract 4 5 Objective 6 7 Determine the adherence to recommendations of concomitant PPI treatment in regular 8 9 10 LDASA users, taking factors associated with the probability of receiving a PPI into account. 11 12 Design 13 14 Cohort study 15 For peer review only 16 Setting 17 18 Data were obtained from 120 Dutch primary care centres participating in the Netherlands 19 20 21 Information Network of Primary Care (LINH). 22 23 Participants 24 25 Patients 18 years and older who were regularly prescribed LDASA (30-325 mg) in 2008-2010 26 27 were included. 28 29 30 Main outcome measures 31 32 Regular medication use was defined as receiving each consecutive prescription within 6

33 http://bmjopen.bmj.com/ 34 primary care physicians. 35 36 37 38 39 40

41 prescriptions, or why they became an irregular PPI user on September 30, 2021 by guest. Protected copyright. 42 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.xhtml4 Page 31 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Introduction 4 5 Worldwide, the number of deaths from cardiovascular disease was estimated at 17.3 million 6 7 in 2008, and it is expected to increase to approximately 23.6 million by 2030 1. Treatment 8 9 10 with low-dose of aspirin (LDASA) is recommended for the prevention of cardiovascular 11 12 events in patients with a history of myocardial infarction, stroke, transient ischaemic attack or 13 14 (in)stable angina 2-4. While LDASA use is associated with a decreased risk of cardiovascular 15 For peer review only 16 events 5, its use is also associated with a wide variety of gastrointestinal (GI) side effects, such 17 18 as dyspepsia, peptic ulcers, and upper and lower GI bleedings 6;7. 19 20 21 22 23 GI complications associated with LDASA use are more frequently present in patients who are 24 25 older than 70 years, have a history of peptic ulcer, have had an infection with Helicobacter 26 27 pylori, and/or used concomitant drug therapies with non-steroidal anti-inflammatory drugs 28 29 30 (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, other antiplatelet agents or 31 6;7 32 anticoagulants, glucocorticosteroids, and/or selective serotonin reuptake inhibitors (SSRIs) .

41 on September 30, 2021 by guest. Protected copyright. 42 43 risk for GI complications has been described in guidelines from medical societies and 44 45 scientific associations from both the USA and Europe 12;13. In the Netherlands - the setting of 46 47 our study - an expert group with a focus on optimising extramural medication safety 48 49 50 published specific recommendations for adequate gastrointestinal protection, i.e. prescribing 51 52 PPIs in regular LDASA users with an increased risk of GI complications in 2008, which was 53 54 finalised in 2009 14. These recommendations are in line with the US, NICE and ESC 55 56 guidelines 12;13;15, and describe that PPIs are the preferred agents for the therapy and 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml5 BMJ Open Page 32 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 12 3 prophylaxis of aspirin-associated GI injury . Risk reduction due to PPI treatment observed in 4 5 case-control and cohort studies ranged in most cases from 40 to 80%.16 6 7 8 9 10 Several observational studies described the use of concomitant PPI in a patients receiving 11 12 NSAID including aspirin, and showed that 67-90% of the users with at least one risk factor 13 14 did not receive gastroprotective therapy as recommended 17 18;19. Two studies focussed on 15 For peer review only 16 LDASA patients; in one study the definition of increased GI risk was limited, namely a 17 18 positive Helicobacter pylori status, the other study had a small sample size of LDASA 19

33 http://bmjopen.bmj.com/ 34 receiving a PPI into account. 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 before the date of the first prescription of LDASA. This time period was chosen to confirm 44 45 that no LDASA prescriptions were given in the year prior to inclusion. Regular use of 46 47 LDASA was defined as receiving each consecutive prescription within six months after the 48 49 50 previous one. A gap of maximal six months was chosen because in daily practice patients 51 52 rarely collect a subsequent prescription exactly on the day their supply of their previous 53 54 prescription has ended, normally 90 days, but rather earlier (overlap of two prescriptions) or 55 56 later (gap between two prescriptions). In order not to bias our results towards irregular user 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml7 BMJ Open Page 34 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 categorisation, we used a maximum period of six months. Irregular LDASA users, according 4 5 to our definition, were excluded from the analyses as well as users with just one LDASA 6 7 prescription. Aspirin therapy was identified by a prescription of acetylsalicylic acid (ATC- 8 9 10 codes B01AC06, N02BA01 and N02BA51), carbasalate calcium (B01AC08, N02BA15 and 11 12 N02BA65), or acetylsalicylic acid in combination with other drugs (B01AC30). 13 14 15 For peer review only 16 Based upon the HARM-WRESTLING recommendations 14, we categorised new LDASA 17 18 users into low or increased risk of GI complications. Patients with an increased risk of GI 19 20 21 complications were identified by the following selection rules applied in consecutive order: 1) 22 23 80 years or older; 2) 70 years or older with simultaneous use of NSAIDs, oral anticoagulants, 24 25 platelet aggregation inhibitors, glucocorticosteroids, SSRIs and/or spironolacton; or 3) 60 26 27 years or older with a history of a peptic ulcer. 28 29 30 31 32 PPI treatment was identified by ATC-code A02BC. All patients were divided into three

41 on September 30, 2021 by guest. Protected copyright. 42 43 were considered as irregular users. 44 45 46 47 We considered patients to be previous starters of PPIs when they received a prescription of 48 49 50 PPI in the year prior to the first prescription of LDASA. Patients who started the use of PPIs 51 52 within a week after the first prescription of LDASA were considered as simultaneous starters 53 54 of PPIs. Patients who received a prescription of PPI more than a week after the first 55 56 prescription of LDASA were subsequent starters of PPIs. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml8 Page 35 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 4 5 Relevant co-morbidity was determined in the year before and after the date of the first 6 7 prescription of LDASA. Cardiovascular and cerebrovascular diseases were identified by 8 9 10 ICPC-codes K71, K73-K84, K89-K96 and K99. Hypertension was considered present when 11 12 the patient had a medical record of ICPC-codes K86 or K87. Patients were classified as 13 14 diabetic if a diagnosis code for diabetes (T90) was identified, or when they received anti- 15 For peer review only 16 diabetic therapy (ATC-codes A10A and A10B). Patients who had a diagnosis of lipid disorder 17 18 (T93) or when they received lipid modifying agents (C10) were considered as 19 20 21 hypercholesterolaemic. GI complications, including peptic ulcers, were identified by D02, 22 23 D03, D09, D10, D14, D16, D85-87, and D90 (Appendix I). To classify patients as having an 24 25 increased GI risk based on HARM-WRESTLING recommendation, we determined 26 27 prescriptions for NSAIDs (M01), including Cox-2 inhibitors, oral anticoagulants and platelet 28 29 30 aggregation inhibitors (B01AA and B01AC), glucocorticosteroids (H02AB and H02), and 31 32 SSRIs (N06AB) [16]. In addition, we identified all prescriptions for cardiovascular system

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 45 Statistical analysis 46 47 Differences between groups were tested with a Chi-square test. To identify the relative 48 49 50 influence of patient characteristics on the probability to obtain regular PPI prescriptions, 51 52 multilevel multivariable logistic regression analyses (backward elimination method) was 53 54 conducted. The models were estimated taking the clustering of patients (level 1) within 55 56 primary care centres (level 2) into account. The probability of receiving a PPI was determined 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml9 BMJ Open Page 36 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 by comparing no PPI users with regular PPI users. This analyses was performed without the 4 5 irregular users to rule out the effect of these users. In addition, separate analyses were 6 7 performed for increased GI risk patients. All data were analysed using the statistical programs 8 9 10 SAS version 9·2 (SAS Institute, Cary, North Carolina) and ‘Multilevel models for windows’ 11 12 (MLwin 2·02). Adjustment for multiple testing was performed by using a False Discovery 13 14 Rate correction. 15 For peer review only 16 17 18 Choices of our definition of subsequent and simultaneous start of PPIs, and our period of 19 20 21 describing patients’ characteristics were based on assumptions, and therefore we tested the 22 23 robustness of our findings by performing sensitivity analyses. We made the definition of 24 25 simultaneous starters of PPIs more strictly, i.e. receiving a prescription of PPIs at exactly the 26 27 same date as the first prescription of LDASA. Secondly, we changed the medical and 28 29 30 prescription history into only one year before the date of the first LDASA prescription. 31 32 Thirdly, as LDASA therapy was frequently prescribed for patients with cardiovascular

41 on September 30, 2021 by guest. Protected copyright. 42 43 44 45 Role of the funding source 46 47 The sponsor had no decisive role in the study, i.e. the sponsor thought along with the study 48 49 50 and supplied suggestions regarding the content of the study, but the sponsor was not involved 51 52 in the decisions regarding the analysis, the conduct of the study, nor the publication. JK and 53 54 LvD had full access to all data in the study and take responsibility for the integrity of the data 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml10 Page 37 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 and accuracy of the data analysis. All authors had final responsibility for the decision to 4 5 submit for publication. 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 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 diuretics, beta blocking agents, and vasoprotective agents. 44 45 46 47 Table 3 shows the probability of receiving regular PPI prescriptions versus no PPI usage. This 48 49 50 probability is significantly increased by different risk factors for GI side effects, by morbidity, 51 52 medication, and increased age. LDASA users with a history of gastrointestinal complications 53 54 were more likely to receive regular PPI prescriptions (adjusted OR 13.9; 95% CI: 11.8-16.4), 55 56 as was found for the different medications used to define patients with an increased GI risk. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml12 Page 39 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Simultaneous use of SSRIs (adjusted OR 9.1 (6.7-12.2)), NSAIDs (5.2 (4.3-6.3)), 4 5 glucocorticosteroids (6.1 (4.6-8.0)), and being 80 years and older (1.9 (1.5-2.3)) were strongly 6 7 related to receiving a PPI regularly. Sensitivity analyses for the group with an increased GI 8 9 10 risk did not alter our findings; similar predicting factors influenced the probability with equal 11 12 magnitude, except for age. Age was no longer a predicting factor (data not shown). 13 14 15 For peer review only 16 Applying the different sensitivity analyses did not alter our findings. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 43 received PPIs and 62% of the low GI risk patients 20. So, the vast majority of all 44 45 NSAID/LDASA users, even the patients with a low risk, received a PPI prescription, which is 46 47 much higher than observed in our study. Yet, our study has a longitudinal design, and 48 49 50 consequently has the information to label a patient as regular or irregular user of PPI. If we 51 52 drop the strict condition of being a regular PPI user, to mimic a cross-sectional design, 64.5% 53 54 of the patients with an increased risk obtained PPIs and 50.2% of the low risk patients. These 55 56 numbers are more in line with the Spanish results, although still lower. Next to the number of 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml14 Page 41 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 increased risk patients receiving PPIs, the timing of the initiation of PPI treatment is 4 5 important. Our study showed that the vast majority of patients started with PPI treatment 6 7 before or simultaneously with the first prescription of LDASA, thereby acting as preventive 8 9 10 agent. 11 12 13 14 In line with the HARM-WRESTLING recommendations, the US, NICE and ESC guidelines 15 For peer review only 16 also recommend to prescribe PPIs to LDASA users who are 60-70 years of age or older 17 18 and/or concomitantly use of SSRIs, NSAIDs, or glucocorticosteroids.12;13;15 Therefore, we 19 20 21 believe our findings are not only relevant for the Netherlands, but have international 22 23 implications as well. 24 25 26 27 The study of Lanas et al. found that gastroprotective treatment in LDASA users was 28 29 30 significantly associated with a prior history of peptic ulcer, high dose NSAID therapy and 31 20 32 concomitant use of oral corticosteroids and antithrombotics . Our data support these

41 on September 30, 2021 by guest. Protected copyright. 42 43 compared to the high risk population, over treatment with PPIs may occur in this group. In 44 45 total, 30% of patients with low GI risk received regularly PPI treatment. Although PPI 46 47 treatment is considered to be cheap, relatively safe, long-term treatment with this drug has 48 49 50 been shown to increase the susceptibility to GI infections and pneumonia, and it has been 51 27-29 52 associated with an increased risk of fractures . Unfortunately, the reasons why these low 53 54 GI risk patients obtained (regular) PPI’s by their primary care physician is very incompletely 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml15 BMJ Open Page 42 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 recorded in our database, refraining us to comment on the necessity of these prescriptions in 4 5 patients with a low GI risk. 6 7 8 9 10 The only difference between patients who were at increased GI risk with or without regular 11 12 PPI therapy was the reason of being a patient with an increased GI risk; nearly 90% of the 13 14 patients who were at increased GI risk without regular PPI therapy were above 80 years, 15 For peer review only 16 whereas of the patients with regular PPI use, just 74% was above 80 years. Another possible 17 18 explanation why not all patients with an increased GI risk use PPIs regularly might be limited 19 20 21 awareness of primary care physicians of the current recommendation, since the draft version 22 23 was first published in 2008 and the final version in 2009, during the first months of our study 24 25 period. 26 27 28 29 30 A strong point of our study is that we had a large representative sample of patients monitored 31 32 in daily practice. The vast majority of the primary care centres in the Netherlands have a

41 on September 30, 2021 by guest. Protected copyright. 42 43 sample, we had complete data for each individual patient, including all physicians’ diagnoses 44 45 and prescription data. This enabled us to study several different subpopulations of patients 46 47 combining LDASA and PPI treatment. Finally, we performed a range of sensitivity analyses 48 49 50 regarding exposure definition, and in- and exclusion criteria. 51 52 53 54 A limitation of this study includes the lack of information about prescriptions by medical 55 56 specialists. If PPIs were prescribed by medical specialists, the prescription of the patient 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml16 Page 43 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 might not always appear in our dataset. Yet, the Dutch guidelines for optimising primary care- 4 5 medical specialist communication support medical specialists to inform primary care 6 7 physicians with the first results of diagnostics and treatments of the referred patient 30;31. Due 8 9 10 to this, we may have underestimated regular PPI use. However, it is plausible that LDASA 11 12 prescription was initiated by the same medical specialist, so if PPI prescriptions are missing, 13 14 probably LDASA prescriptions are missing as well. In such a case the patient was not 15 For peer review only 16 included in our study, limiting the impact of missing PPI prescriptions. Our results are based 17 18 on an observational study which may be subjected to residual confounding due to potential 19 20 21 unmeasured differences in GI risk profile and patient characteristics between LDASA users 22 23 who received or did not received PPI prescriptions. Finally, we do not have any information 24 25 why patients with an increased GI risk did not obtain PPI prescriptions, nor do we know the 26 27 reason why patients become an irregular PPI user, and whether this was patient or physician 28 29 30 related. 31 32

41 on September 30, 2021 by guest. Protected copyright. 42 43 finding underlines the necessity to consider merging recommendations into one common, 44 45 standard and frequently used recommendation by primary care physicians. Further studies are 46 47 needed to determine which motivations and attitudes may play a role for primary care 48 49 50 physicians to be aware of the guidelines and be able to accept, and adhere to them. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml17 BMJ Open Page 44 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Contributors: 4 5 HJIdJ contributed to the design of the study, performed data analyses and drafted the report. 6 7 JCK provided data, contributed to the design of the study and the interpretation of the results, 8 9 10 and drafted and reviewed the report. LvD initiated and obtained the funding for the project, 11 12 contributed to the design of the study and interpretation of the results, and drafted and 13 14 reviewed the paper. EV and ECvD performed data analyses, contributed to the interpretation 15 For peer review only 16 of the data, and reviewed the paper. MGHvO contributed to the design of the study and 17 18 analysis plan, and interpretation of the results, and reviewed the paper. 19 20 21 Conflicts of interest 22 23 This study was funded by Astra Zeneca. The institute of JK and LvD received research 24 25 funding from Astra Zeneca and Bristol-Myers Squibb for a study not related to this study. 26 27 MGHvO has served as a consultant for AstraZeneca and Pfizer, and has received unrestricted 28 29 30 research grants from AstraZeneca, Shire and Janssen. 31 32 Funding:

41 on September 30, 2021 by guest. Protected copyright. 42 43 the data and accuracy of the data analysis. All authors had final responsibility for the decision 44 45 to submit for publication 46 47 Data sharing statement: No additional data are available 48 49 50 Ethics approval: The privacy regulation of LINH was approved by the Dutch Data Protection 51 52 Authority. According to Dutch legislation, neither obtaining informed consent nor approval 53 54 by a medical ethics committee is obligatory for database studies 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml18 Page 45 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Copyright 4 5 The Corresponding Author has the right to grant on behalf of all authors and does grant on 6 7 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in 8 9 10 all forms, formats and media (whether known now or created in the future), to i) publish, 11 12 reproduce, distribute, display and store the Contribution, ii) translate the Contribution into 13 14 other languages, create adaptations, reprints, include within collections and create summaries, 15 For peer review only 16 extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on 17 18 the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of 19 20 21 electronic links from the Contribution to third party material where-ever it may be located; 22 23 and, vi) licence any third party to do any or all of the above.” 24 25 26 27 28 29 30 31 32

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17 || 18 LDASA plus PPI use (%) 19 No user of PPI 1 142 (35·5) 4 541 (49·8) <0·0001 20 Regular user of PPI 1 480 (46·1) 2 724 (29·8) 21 Irregular user of PPI 591 (18·4) 1 865 (20·4) 22 Co-morbidity (%)¶ 23 24 Gastrointestinal tract 25 Gastrointestinal complications 664 (20·7) 1 475 (16·2) <0·0001 26 Duodenal ulcer 24 (0·8) 21 (0·2) <0·0001 27 Peptic ulcer 34 (1·1) 11 (0·1) <0·0001 28 Hiatus Hernia 29 (0·9) 58 (0·6) 0·13 29 30 Heart burn 75 (2·3) 233 (2·6) 0·52 31 Haematemesis 7 (0·2) 10 (0·1) 0·19 32 Rectal bleeding 50 (1·6) 97 (1·1) 0·04

33 Cardiovascular diseases http://bmjopen.bmj.com/

41 on September 30, 2021 by guest. Protected copyright. 42 Atherosclerosis 176 (5·5) 644 (7·1) 0·003 43 Cerebrovascular diseases** 756 (23·5) 1 480 (16·2) <0·0001 44 Stroke 362 (11·3) 731 (8·0) <0·0001 45 Transient Ischaemic Attack (TIA) 326 (10·2) 541 (5·9) <0·0001 46 47 Hypertension 1 307 (40·7) 3 546 (38·8) 0·08 48 Diabetes Mellitus 779 (24·3) 1 960 (21·5) 0·002 49 Hypercholesteroleamia 1 567 (48·8) 6 374 (69·8) <0·0001 50 Co-medication (%)¶ 51 52 Other drugs for acid related disorders 196 (6·1) 477 (5·2) 0·07 53 Drugs for functional gastrointestinal disorders 277 (8·6) 544 (6·0) <0·0001 54 Cardiac therapy 964 (30·0) 2 152 (23·6) <0·0001 55 Antihypertensive agents 2 748 (85·5) 7 357 (80·6) <0·0001 56 Antihypertensives 55 (1·7) 171 (1·9) 0·58 57 58 Diuretics 1 594 (49·6) 2 456 (26·9) <0·0001 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml20 Page 47 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Beta blocking agents 1 728 (53·8) 5 250 (57·5) 0·0005 4 Calcium channel blockers 825 (25·7) 2 113 (23·1) 0·005 5 RAAS agents†† 1 672 (52·0) 4 616 (50·6) 0·17 6 7 Peripheral vasodilators 4 (0·1) 11 (0·1) 1·00 8 Vasoprotectives 103 (3·2) 232 (2·5) 0·06 9 Lipid modifying agents 1 557 (48·5) 6 311 (69·1) <0·0001 10 Antidiabetics 624 (19·4) 1 604 (17·6) 0·03 11 *GI: gastrointestinal 12 †LDASA: low-dose acetylsalicyclic acid 13 ‡NSAIDs: non-steroidal anti-inflammatory drugs 14 §SSRIs: selective serotonin reuptake inhibitors 15 ||PPIs: proton pumpFor inhibitors peer review only 16 ¶Determined in the year before and after the first prescription of LDASA 17 **not all indications are included, only the major ones ††RAAS: renin-angiotensin-aldosterone system 18 ‡‡ 19 p-values are corrected for multiple testing by using false discovery rate. 20

21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 30, 2021 by guest. Protected copyright. 42 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.xhtml21 BMJ Open Page 48 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 2. Characteristics of regular low-dose aspirin users and low-dose aspirin plus irregular and regular 4 proton pump inhibitors users, stratified by time of proton pump inhibitor use No Use of Irregular use Regular use of PPI 5 LDASA* of PPI† p-value** N = 4 204 6 N = 5 683 N = 2 456 7 Previous starters Simultaneous Subsequent 8 of PPI starters of PPI starters of PPI N = 2 015 N = 1 064 N = 1 125 9 Age 10 11 18-50 599 (10·5) 208 (8·5) 176 (8·7) 58 (5·4) 81 (7·2) <0·0001 12 51-65 2 026 (35·7) 829 (33·8) 592 (29·4) 292 (27·4) 331 (29·4) 13 66-80 2 163 (38·1) 1 043 (42·5) 801 (39·8) 424 (39·9) 494 (43·9) 14 80+ 895 (15·8) 376 (15·3) 446 (2·1) 290 (27·3) 219 (19·5) 15 For peer review only Sex 16 17 Men 3 308 (58·2) 1 288 (52·4) 912 (45·3) 530 (49·8) 597 (53·1) <0·0001 18 Risk of GI complications (%)‡,|| 19 Increased risk of GI complications 1 142 (20·1) 591 (24·1) 756 (37·5) 414 (38·9) 310 (27·6) <0·0001 20 Low risk of GI complications 4 541 (79·9) 1 865 (75·9) 1 259 (62·5) 650 (61·1) 815 (72·4) 21 § 22 Co-morbidity (%) 23 Gastrointestinal complications 214 (3·8) 594 (24·2) 831 (41·2) 217 (20·4) 283 (25·2) <0·0001 24 Ulcers 6 (0·1) 24 (1·0) 38 (1·9) 9 (0·9) 13 (1·2) <0·0001 25 Cardiovascular diseases 2 447 (43·6) 1 190 (48·5) 1 110 (55·1) 456 (42·9) 547 (48·6) <0·0001 26 27 Cerebrovascular diseases 1 052 (18·5) 400 (16·3) 406 (20·2) 171 (16·1) 207 (18·4) 0·007 28 Hypertension 2 221 (39·1) 989 (40·3) 831 (41·2) 335 (31·5) 477 (42·4) <0·0001 29 Diabetes Mellitus 1 189 (20·9) 544 (22·2) 458 (22·7) 292 (27·4) 256 (22·8) 0·0001 30 31 Hypercholesteroleamia 3 600 (63·4) 1 592 (64·8) 1 302 (64·6) 721 (67·8) 726 (64·5) 0·09 32 Co-medication (%)§ Other drugs for acid related 33 227 (4·0) 144 (5·9) 163 (8·1) 54 (5·1) 85 (7·6) <0·0001 http://bmjopen.bmj.com/ disorders 34 Drugs for functional gastrointestinal 151 (2·7) 211 (8·6) 275 (13·7) 83 (7·8) 101 (9·0) <0·0001 35 disorders 36 Cardiac therapy 1 142 (20·1) 664 (27·0) 672 (33·4) 324 (30·5) 314 (27·9) <0·0001 37 Antihypertensive agents 4 523 (79·6) 1 997 (81·3) 1 721 (85·4) 912 (85·7) 952 (84·6) <0·0001 38 Antihypertensives 102 (1·8) 36 (1·5) 44 (2·2) 22 (2·1) 22 (2·0) 0·48 39 40 Diuretics 1 607 (28·3) 782 (31·8) 826 (41·0) 410 (38·5) 425 (37·8) <0·0001 Beta blocking agents 3 078 (54·2) 1 370 (55·8) 1 255 (62·3) 633 (59·5) 642 (57·1) <0·0001

41 on September 30, 2021 by guest. Protected copyright. 42 Calcium channel blockers 1 078 (21·5) 571 (23·3) 551 (27·3) 286 (26·9) 309 (27·5) <0·0001 43 RAAS agents¶ 3 221 (49·3) 1 205 (49·6) 1 081 (53·7) 576 (54·1) 624 (55·5) <0·0001 44 Vasoprotectives 111 (2·0) 77 (3·1) 84 (4·2) 25 (2·4) 38 (3·4) <0·0001 45 46 Lipid modifying agents 3 568 (62·8) 1 578 (64·3) 1 288 (63·9) 717 (67·4) 717 (63·7) 0·08 47 Antidiabetics 974 (17·1) 420 (17·1) 378 (18·8) 244 (22·9) 212 (18·8) 0·0001 48 *LDASA: low-dose acetylsalicyclic acid 49 †PPIs: proton pump inhibitors 50 ‡Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 51 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 52 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. § 53 Determined in the year before and after the first prescription of LDASA || 54 GI: gastrointestinal ¶RAAS: renin-angiotensin-aldosterone system 55 ** 56 p-values relate to the comparison of the five groups, and are corrected for multiple testing by using false discovery rate. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml22 Page 49 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Table 3. The probability of receiving a proton pump inhibitor regularly versus no PPI in patients treated 4 regularly with low-dose aspirin LDASA users

41 GI: gastrointestinal on September 30, 2021 by guest. Protected copyright. 42 §Based upon HARM-WRESTLING recommendations: patients who are > 80 years old, or > 70 years old and 43 simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, glucocorticosteroids, 44 selective serotonin reuptake inhibitors (SSRIs) and/or spironolacton, or > 60 years old and history of an ulcer. 45 ||p-values presented are for the multivariate analyses and are corrected for multiple testing by using false 46 discovery rate. 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.xhtml23 BMJ Open Page 50 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 Figure 1. Study flow diagram 4 5 6 LDASA, low-dose acetylsalicyclic acid; GI, gastrointestinal; PPI, proton pump inhibitors; reg., regular; irreg., 7 irregular 8 9

41 on September 30, 2021 by guest. Protected copyright. 42 (6) McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low- 43 44 dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 45 119(8):624-638. 46 47 (7) Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson B et al. 48 Prevalence and incidence of gastroduodenal ulcers during treatment with vascular 49 protective doses of aspirin. Aliment Pharmacol Ther 2005; 22(9):795-801. 50 51 (8) Hsiao FY, Tsai YW, Huang WF, Wen YW, Chen PF, Chang PY et al. A comparison 52 of aspirin and clopidogrel with or without proton pump inhibitors for the secondary 53 prevention of cardiovascular events in patients at high risk for gastrointestinal 54 bleeding. Clin Ther 2009; 31(9):2038-2047. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml24 Page 51 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (9) Ng FH, Wong SY, Lam KF, Chu WM, Chan P, Ling YH et al. Famotidine is inferior 4 to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions. 5 Gastroenterology 2010; 138(1):82-88. 6 7 (10) Scheiman JM, Devereaux PJ, Herlitz J, Katelaris PH, Lanas A, Veldhuyzen vZ et al. 8 Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development 9 treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON). 10 11 Heart 2011; 97(10):797-802. 12 13 (11) Yeomans ND. Reducing the risk of gastroduodenal ulcers with a fixed combination of 14 esomeprazole and low-dose acetyl salicylic acid. Expert Rev Gastroenterol Hepatol 15 2011;For 5(4):447-455. peer review only 16 17 (12) Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD et al. 18 ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal 19 risks of antiplatelet therapy and NSAID use: a report of the American College of 20 Cardiology Foundation Task Force on Clinical Expert Consensus Documents. 21 Circulation 2008; 118(18):1894-1909. 22 23 (13) Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H et al. ESC 24 25 Guidelines for the management of acute coronary syndromes in patients presenting 26 without persistent ST-segment elevation: The Task Force for the management of acute 27 coronary syndromes (ACS) in patients presenting without persistent ST-segment 28 elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 29 32(23):2999-3054. 30 31 (14) Ministerie van Volksgezondheid WeS. Een voorstel van de Expertgroep 32 Medicatieveiligheid met betrekking tot concrete interventies die de extramurale 33 medicatieveiligheid op korte termijn kunnen verbeteren. HARM-WRESTLING. http://bmjopen.bmj.com/ 34 2009. Den Haag, The Netherlands. 35 36 37 (15) NICE. Acute upper gastrointestinal bleedings: management. NICE clinical guideline 38 141. 2012. 39 40

41 (16) Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB et al. on September 30, 2021 by guest. Protected copyright. 42 ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton 43 pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 44 expert consensus document on reducing the gastrointestinal risks of antiplatelet 45 therapy and NSAID use. A Report of the American College of Cardiology Foundation 46 Task Force on Expert Consensus Documents. J Am Coll Cardiol 2010; 56(24):2051- 47 48 2066. 49 50 (17) Valkhoff VE, van Soest EM, Sturkenboom MC, Kuipers EJ. Time-trends in 51 gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs). Aliment 52 Pharmacol Ther 2010; 31(11):1218-1228. 53 54 (18) Hartnell NR, Flanagan PS, Mackinnon NJ, Bakowsky VS. Use of gastrointestinal 55 preventive therapy among elderly persons receiving antiarthritic agents in Nova 56 Scotia, Canada. Am J Geriatr Pharmacother 2004; 2(3):171-180. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml25 BMJ Open Page 52 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 2 3 (19) Sturkenboom MC, Burke TA, Dieleman JP, Tangelder MJ, Lee F, Goldstein JL. 4 Underutilization of preventive strategies in patients receiving NSAIDs. Rheumatology 5 (Oxford) 2003; 42 Suppl 3:iii23-iii31. 6 7 (20) Lanas A, Plazas MA, Gimeno E, Munoz-Tuduri M. Gastroprotection in NSAID and 8 low-dose aspirin users: a cross-sectional study in primary care. Gastroenterol Hepatol 9 2012; 35(1):1-7. 10 11 (21) Bianco MA, Rotondano G, Buri L, Tessari F, Cipolletta L. Gastro-protective strategies 12 13 in primary care in Italy: the "Gas.Pro." survey. Dig Liver Dis 2010; 42(5):359-364. 14 15 (22) Stirbu-WagnerFor I, Dorsmanpeer SA, Visscherreview S, Davids R, Gravensteinonly JV, Abrahamse H 16 et al. Netherlands Information Network of General Practice (LINH). 2012. Utrecht / 17 Nijmegen, NIVEL/IQ. 18 19 20 (23) Schellevis FG, Westert GP, De Bakker DH. [The actual role of general practice in the 21 dutch health-care system. Results of the second dutch national survey of general 22 practice]. Med Klin (Munich) 2005; 100(10):656-661. 23 24 (24) World Health Organisation. Guidelines for ATC classification and DDD assignment. 25 26 Oslo: WHO Collaborating Centre for Drug Statistics Methodology - Nordic Council 27 on Medicines; 1999. 28 29 (25) Lamberts H, Wood M. ICPC. International Classification of Primary Care. Oxford: 30 Oxford University Press; 1987. 31 32 (26) Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin:

41 on September 30, 2021 by guest. Protected copyright. 42 43 (29) Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy 44 and risk of hip fracture. JAMA 2006; 296(24):2947-2953. 45 46 (30) Richtlijn overdracht van medicatie gegevens in de keten. 2008. VWS and IGZ. 47 48 (31) Kvamme OJ, Olesen F, Samuelson M. Improving the interface between primary and 49 secondary care: a statement from the European Working Party on Quality in Family 50 Practice (EQuiP). Qual Health Care 2001; 10(1):33-39. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml26 Page 53 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. 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 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 96x90mm (300 x 300 DPI) 40

1 2 3 Appendix I. The definitions and ICPC- and ATC-codes for co-morbidity

4 Co-morbidity At least one medical record of diseases before and At least one prescription of drugs BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 5 after the first prescription of LDASA (ICPC- before and after the first prescription 6 codes) of LDASA (ATC-codes) 7 8 9 Diabetes Diabetes (T90) Insulin (A10A), Oral blood glucose 10 lowering drugs (A10B) 11 12 Hypertension Hypertension uncomplicated (K86), Hypertension 13 complicated (K87) 14 Hyperlipidaemia Lipid disorder (T93) Lipid modifying agents (C10) 15 16 GI complications Abdominal pain epigastric (D02), Heartburn 17 For(D03), Nausea peer (D09), Vomiting review (D10), only 18 Haematemesis/ vomiting blood (D14), Rectal 19 bleeding (D16), Duodenal ulcer (D85), Peptic 20 ulcer other (D86), Stomach function disorder 21 (D87), Hiatus hernia (D90) 22 Cardio- Heart disease (K71), Congenital anomaly 23 cardiovascular (K73), Ischaemic heart disease w. 24 vascular Disease angina (K74), Acute myocardial infarction (K75), 25 Ischaemic heart disease w/o angina (K76), Heart 26 failure (K77), Atrial fibrillation/ flutter (K78), 27 Paroxysmal tachycardia (K79), Cardiac arrhythmia 28 (K80), Heart/ arterial murmur (K81), Pulmonary 29 30 heart disease (K82), Heart valve disease (K83), 31 Heart disease other (K84), Atherosclerosis (K92), 32 Pulmonary embolism (K93), Phlebitis/ 33 thrombophlebitis (K94), Varicose veins of leg 34 (K95), Haemorrhoids (K96), Cardiovascular 35 disease other (K99) 36 Cerebrovascular Transient cerebral ischaemia (K89), 37 Disease Stroke/cerebrovascular accident (K90), http://bmjopen.bmj.com/ 38 Cerebrovascular disease (K91) 39 40 41 42 43 44 45 46 on September 30, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 56 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 STROBE Statement—Checklist of items that should be included in reports of cohort studies 2 Item 3 Page No Recommendation 4 a 5 1 Title and abstract 1 ( ) Indicate the study’s design with a commonly used term in the 6 title or the abstract 7 2+3 (b) Provide in the abstract an informative and balanced summary of 8 what was done and what was found 9 10 Introduction 11 5+6 Background/rationale 2 Explain the scientific background and rationale for the investigation 12 being reported 13 6 Objectives 3 State specific objectives, including any prespecified hypotheses 14 15 MethodsFor peer review only 16 7 Study design 4 Present key elements of study design early in the paper 17 7 Setting 5 Describe the setting, locations, and relevant dates, including periods 18 19 of recruitment, exposure, follow-up, and data collection 20 7 Participants 6 (a) Give the eligibility criteria, and the sources and methods of 21 selection of participants. Describe methods of follow-up 22 n.a. (b) For matched studies, give matching criteria and number of 23 24 exposed and unexposed 25 7-9 Variables 7 Clearly define all outcomes, exposures, predictors, potential 26 confounders, and effect modifiers. Give diagnostic criteria, if 27 applicable 28 7-10 Data sources/ 8* For each variable of interest, give sources of data and details of 29 30 measurement methods of assessment (measurement). Describe comparability of 31 assessment methods if there is more than one group 32 10 Bias 9 Describe any efforts to address potential sources of bias 33 7 Study size 10 Explain how the study size was arrived at http://bmjopen.bmj.com/ 34 35 7-10 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If 36 applicable, describe which groupings were chosen and why 37 9+10 Statistical methods 12 (a) Describe all statistical methods, including those used to control 38 for confounding 39 b 40 10 ( ) Describe any methods used to examine subgroups and interactions

41 on September 30, 2021 by guest. Protected copyright. 42 10 (c) Explain how missing data were addressed 43 n.a. (d) If applicable, explain how loss to follow-up was addressed 44 10 (e) Describe any sensitivity analyses 45 46 Results 47 Participants 13* (a) Report numbers of individuals at each stage of study—eg 48 numbers potentially eligible, examined for eligibility, confirmed 49 50 11 eligible, included in the study, completing follow-up, and analysed 51 Fig 1 (b) Give reasons for non-participation at each stage 52 Fig 1 (c) Consider use of a flow diagram 53 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, 54 55 clinical, social) and information on exposures and potential 56 Table1 confounders 57 n.a. (b) Indicate number of participants with missing data for each 58 variable of interest 59 60 7 (c) Summarise follow-up time (eg, average and total amount) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 56 of 56 BMJ Open: first published as 10.1136/bmjopen-2013-003044 on 24 July 2013. Downloaded from 1 Fig 1 Outcome data 15* Report numbers of outcome events or summary measures over time 2 11-12 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder- 3 adjusted estimates and their precision (eg, 95% confidence interval). 4 5 Make clear which confounders were adjusted for and why they were 6 included 7 Tables (b) Report category boundaries when continuous variables were 8 categorized 9 c 10 ( ) If relevant, consider translating estimates of relative risk into 11 absolute risk for a meaningful time period 12 12 Other analyses 17 Report other analyses done—eg analyses of subgroups and 13 interactions, and sensitivity analyses 14 15 DiscussionFor peer review only 16 13 Key results 18 Summarise key results with reference to study objectives 17 15-16 Limitations 19 Discuss limitations of the study, taking into account sources of 18 potential bias or imprecision. Discuss both direction and magnitude 19 20 of any potential bias 21 16 Interpretation 20 Give a cautious overall interpretation of results considering 22 objectives, limitations, multiplicity of analyses, results from similar 23 studies, and other relevant evidence 24 16 Generalisability 21 Discuss the generalisability (external validity) of the study results 25 26 Other information 27 17 Funding 22 Give the source of funding and the role of the funders for the present 28 study and, if applicable, for the original study on which the present 29 30 article is based 31 32 *Give information separately for exposed and unexposed groups.

41 on September 30, 2021 by guest. Protected copyright. 42 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.xhtml2