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Current Cardiology Reviews

Editor-in-Chief

ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Meta-Analysis

The Impact of Polypill on Adherence and Cardiovascular Outcomes: A Comprehensive Systematic Review with Meta-Analysis

Author(s): Hamza Salim, Basel Musmar, Motaz Saifi, Mohammed Ayyad, Mohammed Ruzieh*, Jehad Azar and Zaher Nazzal*

Volume 20, Issue 2, 2024

Published on: 23 January, 2024

Article ID: e230124225968 Pages: 11

DOI: 10.2174/011573403X283174240110025442

Price: $65

Abstract

Background: Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide. Polypills, containing various combinations of medications for primary and secondary CVD prevention, have been developed to enhance medication adherence and reduce the healthcare burden of CVD. However, their effectiveness compared to usual care remains uncertain.

Objective: This meta-analysis aimed to evaluate the effects of polypills on cardiovascular risk factors, major adverse cardiovascular events (MACE), and medication adherence.

Methods: We conducted a comprehensive search for large-scale randomized controlled trials and observational studies comparing the effects of polypills versus usual care on CVD risk factors and events. Outcomes included changes in systolic and diastolic blood pressure (SBP, DBP), lipid profiles, occurrence of MACE, and medication adherence.

Results: The use of polypills led to a statistically significant yet clinically modest reduction in SBP (mean difference -1.47 mmHg, 95% CI: -2.50 to -0.44, p<0.01) and DBP (mean difference- 1.10 mmHg, 95% CI: -1.68 to -0.51, p< 0.01) compared to usual care. Polypills also showed a significant reduction in the risk of MACE (RR: 0.86, 95% CI: 0.77 -0.95, p<0.01). There was a non-significant reduction in LDL and HDL levels. Adherence to medication improved by up to 17% in polypill users compared to those on usual care (p < 0.01). A multivariable metaregression analysis suggested that adherence may be the underlying factor responsible for the observed effect of the polypills on blood pressure.

Conclusion: Polypills were found to significantly reduce SBP, DBP and MACE. An improvement in medication adherence was also observed among polypill users, which might be responsible for the significant reduction in SBP observed users. Future research might benefit from exploring a more personalized approach to the composition of polypills, which could reveal a more clinically significant impact of increased adherence on CVD outcomes.

Keywords: Polypill, cardiovascular, cardiovascular disease, hypertension, diastolic blood pressure, CVD risk factor.

Graphical Abstract
[1]
Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019. J Am Coll Cardiol 2020; 76(25): 2982-3021.
[http://dx.doi.org/10.1016/j.jacc.2020.11.010] [PMID: 33309175]
[2]
Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: Key concepts, current status, challenges, and future directions. Circulation 2010; 122(20): 2078-88.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.873232] [PMID: 21098469]
[3]
Rao S, Jamal Siddiqi T, Khan MS, et al. Association of polypill therapy with cardiovascular outcomes, mortality, and adherence: A systematic review and meta-analysis of randomized controlled trials. Prog Cardiovasc Dis 2022; 73: 48-55.
[http://dx.doi.org/10.1016/j.pcad.2022.01.005] [PMID: 35114251]
[4]
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326(7404): 1419.
[http://dx.doi.org/10.1136/bmj.326.7404.1419] [PMID: 12829553]
[5]
Kandil OA, Motawea KR, Aboelenein MM, Shah J. Polypills for primary prevention of cardiovascular disease: A systematic review and meta-analysis. Front Cardiovasc Med 2022; 9: 880054.
[http://dx.doi.org/10.3389/fcvm.2022.880054] [PMID: 35498049]
[6]
Sadeghi M, Askari A, Bostan F, et al. Medication adherence with polypill in cardiovascular disease and high-risk patients: A systematic review and meta-analysis of randomized controlled trials involving 7364 participants. Curr Probl Cardiol 2024; 49(1) (1, Part A): 102061.
[http://dx.doi.org/10.1016/j.cpcardiol.2023.102061] [PMID: 37640178]
[7]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372(71): n71.
[http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]
[8]
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629-34.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
[9]
Donner A, Klar N. Issues in the meta‐analysis of cluster randomized trials. Stat Med 2002; 21(19): 2971-80.
[http://dx.doi.org/10.1002/sim.1301] [PMID: 12325113]
[10]
Cochrane handbook for systematic reviews of interventions. Available from: https://training.cochrane.org/handbook Accessed August 11, 2023.
[11]
Patel A, Cass A, Peiris D, et al. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk. Eur J Prev Cardiol 2015; 22(7): 920-30.
[http://dx.doi.org/10.1177/2047487314530382] [PMID: 24676715]
[12]
Oh GC, Han JK, Han KH, et al. Efficacy and safety of fixed-dose combination therapy with telmisartan and rosuvastatin in korean patients with hypertension and dyslipidemia: TELSTA-YU (TELmisartan-rosuvaSTAtin from YUhan), a multicenter, randomized, 4-arm, double-blind, placebo-controlled, phase III study. Clin Ther 2018; 40(5): 676-691.e1.
[http://dx.doi.org/10.1016/j.clinthera.2018.03.010] [PMID: 29673890]
[13]
Selak V, Elley CR, Bullen C, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: Randomised controlled trial in primary care. BMJ 2014; 348(may27 11): g3318.
[http://dx.doi.org/10.1136/bmj.g3318] [PMID: 24868083]
[14]
Cho KI, Kim BH, Park YH, et al. Efficacy and safety of a fixed-dose combination of candesartan and rosuvastatin on blood pressure and cholesterol in patients with hypertension and hypercholesterolemia: A multicenter, randomized, double-blind, parallel phase III clinical study. Clin Ther 2019; 41(8): 1508-21.
[http://dx.doi.org/10.1016/j.clinthera.2019.05.007] [PMID: 31307833]
[15]
Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med 2021; 384(3): 216-28.
[http://dx.doi.org/10.1056/NEJMoa2028220] [PMID: 33186492]
[16]
González-Juanatey JR, Cordero A, Castellano JM, et al. The CNIC-Polypill reduces recurrent major cardiovascular events in real-life secondary prevention patients in Spain: The NEPTUNO study. Int J Cardiol 2022; 361: 116-23.
[http://dx.doi.org/10.1016/j.ijcard.2022.05.015] [PMID: 35569611]
[17]
González-Juanatey JR, Tamargo J, Torres F, Weisser B, Oudovenko N. Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents? Rev Esp Cardiol 2021; 74(1): 51-8.
[http://dx.doi.org/10.1016/j.rec.2019.11.008] [PMID: 31983653]
[18]
Grimm R, Malik M, Yunis C, Sutradhar S, Kursun A. Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial. Vasc Health Risk Manag 2010; 6: 261-71.
[http://dx.doi.org/10.2147/VHRM.S7710] [PMID: 20479948]
[19]
Kim W, Chang K, Cho EJ, et al. A randomized, double‐blind clinical trial to evaluate the efficacy and safety of a fixed‐dose combination of amlodipine/rosuvastatin in patients with dyslipidemia and hypertension. J Clin Hypertens 2020; 22(2): 261-9.
[http://dx.doi.org/10.1111/jch.13774] [PMID: 32003938]
[20]
Marazzi G, Pelliccia F, Campolongo G, et al. Greater cardiovascular risk reduction with once-daily fixed combination of three antihypertensive agents and statin versus free-drug combination: The ALL-IN-ONE trial. Int J Cardiol 2016; 222: 885-7.
[http://dx.doi.org/10.1016/j.ijcard.2016.07.163] [PMID: 27522394]
[21]
Park JS, Shin JH, Hong TJ, et al. Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: An 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong). Drug Des Devel Ther 2016; 10: 2599-609.
[http://dx.doi.org/10.2147/DDDT.S112873] [PMID: 27574399]
[22]
Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: The UMPIRE randomized clinical trial. JAMA 2013; 310(9): 918-29.
[http://dx.doi.org/10.1001/jama.2013.277064] [PMID: 24002278]
[23]
Muñoz D, Uzoije P, Reynolds C, et al. Polypill for cardiovascular disease prevention in an underserved population. N Engl J Med 2019; 381(12): 1114-23.
[http://dx.doi.org/10.1056/NEJMoa1815359] [PMID: 31532959]
[24]
Soliman EZ, Mendis S, Dissanayake WP, et al. A polypill for primary prevention of cardiovascular disease: A feasibility study of the world health organization. Trials 2011; 12(1): 3.
[http://dx.doi.org/10.1186/1745-6215-12-3] [PMID: 21205325]
[25]
Mariani J, Rosende A, De Abreu M, et al. Multicap to improve adherence after acute coronary syndromes: Results of a randomized controlled clinical trial. Ther Adv Cardiovasc Dis 2020; 14.
[http://dx.doi.org/10.1177/1753944720912071] [PMID: 32186246]
[26]
Ros-Castelló V, Natera-Villalba E, Gómez-López A, et al. Use of the cardiovascular polypill in secondary prevention of cerebrovascular disease: A real-life tertiary hospital cohort study of 104 patients. Cerebrovasc Dis Extra 2020; 10(3): 166-73.
[http://dx.doi.org/10.1159/000511064] [PMID: 33176324]
[27]
Castellano JM, Sanz G, Peñalvo JL, et al. A polypill strategy to improve adherence: Results from the FOCUS project. J Am Coll Cardiol 2014; 64(20): 2071-82.
[http://dx.doi.org/10.1016/j.jacc.2014.08.021] [PMID: 25193393]
[28]
Lafeber M, Grobbee DE, Schrover IM, et al. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; A randomized crossover trial. Int J Cardiol 2015; 181: 193-9.
[http://dx.doi.org/10.1016/j.ijcard.2014.11.176] [PMID: 25528311]
[29]
Mostaza JM, Suárez-Fernández C, Cosín-Sales J, et al. Safety and efficacy of a cardiovascular polypill in people at high and very high risk without a previous cardiovascular event: The international VULCANO randomised clinical trial. BMC Cardiovasc Disord 2022; 22(1): 560.
[http://dx.doi.org/10.1186/s12872-022-03013-w] [PMID: 36550424]
[30]
Castellano JM, Pocock SJ, Bhatt DL, et al. Polypill strategy in secondary cardiovascular prevention. N Engl J Med 2022; 387(11): 967-77.
[http://dx.doi.org/10.1056/NEJMoa2208275] [PMID: 36018037]
[31]
Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS One 2012; 7(7): e41297.
[http://dx.doi.org/10.1371/journal.pone.0041297] [PMID: 22815989]
[32]
Rodgers A, Patel A, Berwanger O, et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. In: Wright JM, Ed. PLoS One. 2011; 6: p. (5)e19857.
[http://dx.doi.org/10.1371/journal.pone.0019857] [PMID: 21647425]
[33]
Kim SH, Jo SH, Lee SC, et al. Blood pressure and cholesterol-lowering efficacy of a fixed-dose combination with irbesartan and atorvastatin in patients with hypertension and hypercholesterolemia: A randomized, double-blind, factorial, multicenter phase III study. Clin Ther 2016; 38(10): 2171-84.
[http://dx.doi.org/10.1016/j.clinthera.2016.09.005] [PMID: 27742464]
[34]
Neutel JM, Bestermann WH, Dyess EM, et al. The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: A randomized, placebo-controlled, multicenter study. J Clin Hypertens 2009; 11(1): 22-30.
[http://dx.doi.org/10.1111/j.1751-7176.2008.00058.x] [PMID: 19125855]
[35]
Malekzadeh F, Marshall T, Pourshams A, et al. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy (‘polypill’) on cardiovascular risk factors. Int J Clin Pract 2010; 64(9): 1220-7.
[http://dx.doi.org/10.1111/j.1742-1241.2010.02412.x] [PMID: 20653798]
[36]
Gong C, Huang SL, Huang JF, et al. Effects of combined therapy of Xuezhikang capsule and valsartan on hypertensive left ventricular hypertrophy and heart rate turbulence. Chin J Integr Med 2010; 16(2): 114-8.
[http://dx.doi.org/10.1007/s11655-010-0114-z] [PMID: 20473735]
[37]
Liu H, Massi L, Laba TL, et al. Patients’ and providers’ perspectives of a polypill strategy to improve cardiovascular prevention in Australian primary health care: A qualitative study set within a pragmatic randomized, controlled trial. Circ Cardiovasc Qual Outcomes 2015; 8(3): 301-8.
[http://dx.doi.org/10.1161/CIRCOUTCOMES.115.001483] [PMID: 25944629]
[38]
Hobbs FDR, Gensini G, Mancini GBJ, et al. International open-label studies to assess the efficacy and safety of single-pill amlodipine/atorvastatin in attaining blood pressure and lipid targets recommended by country-specific guidelines: The JEWEL programme. Eur J Cardiovasc Prev Rehabil 2009; 16(4): 472-80.
[http://dx.doi.org/10.1097/HJR.0b013e32832b63f5] [PMID: 19407658]
[39]
Sergienko IV, Ansheles AA, Drapkina OM, et al. ANICHKOV study: The effect of combined hypotensive and lipid-lowering therapy on cardiovascular complications in patients of high and very high risk. Ter Arkh 2019; 91(4): 90-8.
[http://dx.doi.org/10.26442/00403660.2019.04.000104] [PMID: 31094482]
[40]
Sirenko Y, Radchenko G. Impact of statin therapy on the blood pressure-lowering efficacy of a single-pill perindopril/amlodipine combination in hypertensive patients with hypercholesterolemia. High Blood Press Cardiovasc Prev 2017; 24(1): 85-93.
[http://dx.doi.org/10.1007/s40292-017-0184-5] [PMID: 28150140]
[41]
Zeymer U, Jünger C, Zahn R, et al. Effects of a secondary prevention combination therapy with an aspirin, an ACE inhibitor and a statin on 1-year mortality of patients with acute myocardial infarction treated with a beta-blocker. Support for a polypill approach. Curr Med Res Opin 2011; 27(8): 1563-70.
[http://dx.doi.org/10.1185/03007995.2011.590969] [PMID: 21682553]
[42]
Mohamed MMG, Osman M, Kheiri B, Saleem M, Lacasse A, Alkhouli M. Polypill for cardiovascular disease prevention: Systematic review and meta-analysis of randomized controlled trials. Int J Cardiol 2022; 360: 91-8.
[http://dx.doi.org/10.1016/j.ijcard.2022.04.085] [PMID: 35641323]
[43]
Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: An individual participant data meta-analysis. Lancet 2021; 398(10306): 1133-46.
[http://dx.doi.org/10.1016/S0140-6736(21)01827-4] [PMID: 34469765]
[44]
Bahiru E, de Cates AN, Farr MRB, et al. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases. Cochrane Libr 2017; 2017(3): CD009868.
[http://dx.doi.org/10.1002/14651858.CD009868.pub3] [PMID: 28263370]
[45]
de Cates AN, Farr MR, Wright N, et al. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2014; 4(4): CD009868.
[http://dx.doi.org/10.1002/14651858.CD009868.pub2] [PMID: 24737108]
[46]
Segar MW, Patel KV, Vaduganathan M, et al. Development and validation of optimal phenomapping methods to estimate long-term atherosclerotic cardiovascular disease risk in patients with type 2 diabetes. Diabetologia 2021; 64(7): 1583-94.
[http://dx.doi.org/10.1007/s00125-021-05426-2] [PMID: 33715025]
[47]
Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380(9841): 581-90.
[http://dx.doi.org/10.1016/S0140-6736(12)60367-5] [PMID: 22607822]
[48]
Rose G. Sick individuals and sick populations. Int J Epidemiol 1985; 14(1): 32-8.
[http://dx.doi.org/10.1093/ije/14.1.32] [PMID: 3872850]
[49]
Lee YM, Kim RB, Lee HJ, et al. Relationships among medication adherence, lifestyle modification, and health-related quality of life in patients with acute myocardial infarction: A cross-sectional study. Health Qual Life Outcomes 2018; 16(1): 100.
[http://dx.doi.org/10.1186/s12955-018-0921-z] [PMID: 29788961]
[50]
Elley CR, Gupta AK, Webster R, et al. The efficacy and tolerability of ‘polypills’: Meta-analysis of randomised controlled trials. PLoS One 2012; 7(12): e52145.
[http://dx.doi.org/10.1371/journal.pone.0052145] [PMID: 23284906]
[51]
Hennawi HA, Ashraf MT, Zohaib M, et al. Polypill therapy in cardiovascular disease: A meta-analysis of randomized controlled trials. Curr Probl Cardiol 2023; 48(8): 101735.
[http://dx.doi.org/10.1016/j.cpcardiol.2023.101735] [PMID: 37044270]
[52]
Hayıroğlu Mİ. Telemedicine: Current concepts and future perceptions. Anatol J Cardiol 2019; 22 (Suppl. 2): 21-2.
[http://dx.doi.org/10.14744/AnatolJCardiol.2019.12525] [PMID: 31670712]
[53]
Tekkeşin Aİ, Hayıroğlu Mİ, Çinier G, et al. Lifestyle intervention using mobile technology and smart devices in patients with high cardiovascular risk: A pragmatic randomised clinical trial. Atherosclerosis 2021; 319: 21-7.
[http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.020] [PMID: 33465658]
[54]
Hayıroğlu Mİ, Çinier G, Yüksel G, et al. Effect of a mobile application and smart devices on heart rate variability in diabetic patients with high cardiovascular risk: A sub-study of the LIGHT randomized clinical trial. Kardiol Pol 2021; 79(11): 1239-44.
[http://dx.doi.org/10.33963/KP.a2021.0112] [PMID: 34599495]
[55]
Hayıroğlu Mİ, Altay S. The role of artificial intelligence in coronary artery disease and atrial fibrillation. Balkan Med J 2023; 40(3): 151-2.
[http://dx.doi.org/10.4274/balkanmedj.galenos.2023.06042023] [PMID: 37025078]

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