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For Peer Review Only Journal: BMJ Open BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from Therapy discontinuation or substitution in patients with cardiovascular disease, switching among different products of the same off-patent active substance: a “real-world” retrospective cohort study For peer review only Journal: BMJ Open Manuscript ID bmjopen-2016-012003 Article Type: Research Date Submitted by the Author: 21-Mar-2016 Complete List of Authors: Degli Esposti, Luca; CliCon S.r.l, Health, Economics and Outcomes Research, Sangiorgi, Diego; CliCon S.r.l. Health, Economics and Outcomes Research Buda, Stefano; CliCon S.r.l. Health, Economics and Outcomes Research Degli Esposti, Ezio; CliCon S.r.l. Health, Economics and Outcomes Research Scaglione, Francesco ; University of Milan, Medical Biotechnology and Translational Medicine <b>Primary Subject Cardiovascular medicine Heading</b>: Secondary Subject Heading: Public health http://bmjopen.bmj.com/ Keywords: Simvastatin, Amlodipine, Ramipril, Switching, Adherence to treatment on September 24, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 23 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from 1 2 3 4 5 Therapy discontinuation or substitution in patients with cardiovascular disease, 6 7 switching among different products of the same off-patent active substance: a “real- 8 9 world” retrospective cohort study 10 11 12 13 14 Luca Degli Esposti,1 Diego Sangiorgi,1 Stefano Buda,1 Ezio Degli Esposti,1 Francesco 15 For peer review only 16 2 17 Scaglione 18 19 20 21 22 1CliCon S.r.l. Health, Economics and Outcomes Research, Ravenna, Italy 23 24 2 25 Department of Medical Biotechnology and Translational Medicine, University of Milan, 26 27 Milan, Italy 28 29 30 31 32 Correspondence to 33 34 http://bmjopen.bmj.com/ 35 Luca Degli Esposti, EconD., CliCon S.r.l, Health, Economics and Outcomes Research, Via 36 37 Salara, 36 - 48100 Ravenna, Italy 38 39 40 Tel +39 544 38393 - Fax +39 544 212699. [email protected] 41 42 on September 24, 2021 by guest. Protected copyright. 43 44 45 Keywords 46 47 48 Simvastatin, Amlodipine, Ramipril, Switching, Adherence to treatment 49 50 51 52 53 Word count: 2,452 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 23 BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from 1 2 3 4 ABSTRACT 5 6 Objective: The present study investigated the effects of switching to different products of the 7 8 same off-patent active substance (brand-name or generic) on therapy discontinuation or 9 10 11 substitution with another molecule of the same class, in patients with cardiovascular disease 12 13 treated with statins and antihypertensives in clinical practice. 14 15 For peer review only 16 Design: A retrospective cohort study in a “real-world” setting. 17 18 Setting: Analysis of data performed by integrating administrative databases from three 19 20 21 Italian Local Health Units located in three different regions with a total population of about 22 23 21 million. 24 25 Participants: All patients aged ≥18 years with at least one prescription of simvastatin, 26 27 st st 28 ramipril or amlodipine in the period January 1 to December 31 2010 were included and 29 30 followed-up for two years. 31 32 33 Main outcome measures: Prescription refills occurring during follow-up were evaluated. 34 http://bmjopen.bmj.com/ 35 Frequency of discontinuation of therapy or substitution with another molecule of the same 36 37 class (for example, from simvastatin to a different statin) during follow-up was identified. 38 39 40 Results: During follow-up, therapy discontinuation or substitution was found to be more 41 42 frequent in patients switching to a different product of the same active substance compared on September 24, 2021 by guest. Protected copyright. 43 44 with non-switching patients (11.5% vs 10.8% and 22.2% vs 20.8% [p=0.002], respectively, 45 46 in the simvastatin group; 7.6% vs 7.8% and 19.2% vs 17.0% [p<0.001], respectively, in the 47 48 49 ramipril group; 4.0% vs 3.5% and 24.6% vs 22.7% [p<0.001], respectively, in the amlodipine 50 51 group). These findings were confirmed by multivariate analysis. 52 53 54 Conclusions: Switches among products of the same active substance are quite common in 55 56 patients with cardiovascular disease. Our study suggests that switching may expose patients 57 58 to a higher risk of therapy discontinuation or substitution. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 23 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from 1 2 3 4 5 6 7 STRENGTHS AND LIMITATIONS OF THIS STUDY 8 9 • This study, in a “real-world” setting, is one of only a few studies to investigate 10 11 12 clinical differences related to switching among different products of the same active 13 14 substance in the cardiovascular setting. Until now, most research has focused only on 15 For peer review only 16 comparing brand-name and generic drugs. 17 18 19 • Sample size was relatively limited, and although we used three healthcare databases 20 21 from regions with a total population of about 21 million, large studies are needed to 22 23 confirm and to enhance the generalizability of the findings, and in different 24 25 populations. 26 27 28 • In common with other retrospective, observational studies, reasons for switch, non- 29 30 adherence or discontinuation of treatment were not retrievable from the data set. 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 24, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 23 BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from 1 2 3 4 INTRODUCTION 5 6 7 Cardiovascular diseases (CVD) are the leading cause of death worldwide, accounting for 8 9 approximately one third of all deaths.[1] Combination therapy with antihypertensive drugs 10 11 12 and serum cholesterol-lowering drugs is effective in prevention, and it is estimated that a high 13 14 level of adherence to treatment will reduce the risk of CVD by approximately 80%.[2] A 15 For peer review only 16 number of studies have demonstrated that patients often discontinue long-term treatment or 17 18 take less than prescribed, and that such non-adherence reduces the potential preventive 19 20 benefits.[3] 21 22 23 Many reasons contribute to patient non-adherence to medical therapy, such as ageing, 24 25 comorbidities, polypharmacy, poor relationship between patient and physician, poor memory, 26 27 28 and patients’ low perception of disease severity.[4] On the other hand, it is unlikely that side 29 30 effects are the main cause of poor adherence to preventive treatment, as there seems to be 31 32 little direct relationship between adherence and drug class.[3] Furthermore, some studies 33 34 have demonstrated that switching between different products of the same active substance http://bmjopen.bmj.com/ 35 36 can have an impact on adherence to medication, because variation in packaging and pill 37 38 39 appearance may reduce adherence, especially for chronic diseases.[5, 6] 40 41 There is a perception among patients and physicians alike that frequent changes between 42 on September 24, 2021 by guest. Protected copyright. 43 44 branded and unbranded products (as well as between generics), all containing the same active 45 46 substance, and especially if patients are older and on multi-drug regimens, may cause patients 47 48 to become anxious when the appearance of their drugs changes.[7-9] This can lead to an 49 50 increased risk of patients making mistakes or double medicating, which flows on to increased 51 52 53 drug non-adherence.[10, 11] 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 23 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-012003 on 2 November 2016. Downloaded from 1 2 3 4 Few studies have investigated clinical differences related to switching among different 5 6 products of the same active substance in the cardiovascular setting. Until now, most research 7 8 has focused only on comparing brand-name and generic drugs.[12-16] 9 10 11 The aim of the present study was to investigate the effects of switching to different 12 13 products of the same off-patent active substance (brand-name or generic) on therapy 14 15 For peer review only 16 discontinuation or substitution with another molecule of the same class, in patients with CVD 17 18 treated with statins and antihypertensives in clinical practice. 19 20 21 A version of this article has been previously published as a journal supplement in the 22 23 Italian language.[17] 24 25 26 METHODS 27 28 29 Data collection 30 31 The data used for the analysis were obtained from the administrative databases of three Local 32 33 Health Units (LHUs), including a total population of about two million health-assisted 34 http://bmjopen.bmj.com/ 35 36 individuals, in the Italian regions of Lombardy, Lazio and Campania.
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