Interventions to promote healthy lifestyles and simplify pharmacotherapy regimens are available, however, implementation of the concepts remain challenging. Historically, this has been driven by limited access to medical care, cost of treatment, lack of healthcare coverage, and patient related factors (e.g., poor adherence, poor health literacy, polypharmacy).¹ As such, the notion of a fixed-drug combination in one pill – "the polypill" – represents a potential strategy to enhance cardiovascular prevention efforts at a population level.² Traditionally, polypills combine lipid and blood pressure lowering therapy (with or without aspirin) and have been tested in low/middle income populations at increased risk of cardiovascular disease³ (CVD) (Table 1).

Table 1: Polypill Studies Comparison^4-11
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Recently, The International Polycap Study 3 (TIPS-3) sought to investigate the safety and efficacy of a once-daily polypill (n=2,816) (atenolol 100 mg + ramipril 10 mg + hydrochlorothiazide [HCTZ] 25 mg + simvastatin 40 mg) versus placebo (n=2,852) among those at intermediate risk of CVD.¹¹ Patients were also randomized to aspirin 75 mg daily versus placebo. The trial found that the polypill was superior to placebo in reducing systolic blood pressure (BP) [mean difference: 5.8 mm Hg (5.1-6.4 mm Hg)], low-density lipoprotein cholesterol (LDL-C) [mean difference: 19 mg/dl (17.3-20.8 mg/dl)], and the primary composite outcome (major cardiovascular events plus heart failure, resuscitated cardiac arrest, and arterial revascularization) [(4.4% vs. 5.5% (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-1.0)] at approximately 5 years.¹¹ The addition of aspirin to the polypill showed a greater reduction in CVD events compared with double placebo [(4.1% vs. 5.8%, HR (95%CI): 0.69 (0.50-0.97)]. Notably, adherence to the polypill/aspirin combination was low at 43%, but similar to polypill alone, aspirin alone, and double placebo: 43%, 43%, and 42%, respectively. Rates of bleeding causing permanent discontinuation of therapy in the aspirin versus placebo group were similarly low (<3% for each).

Prior studies comparing polypill to placebo (Table 1) have also demonstrated superiority of the polypill for BP and LDL-C reduction, but perhaps at the expense of increased risk of adverse events (namely hypotension and dizziness) at higher doses. These trials also found varying degrees of adherence which are likely related to the specific formulations of polypills that were used (for example, 43% in TIPS-3 vs. 81% in PolyIran). As noted in Table 1, the PILL study (aspirin 75mg + lisinopril 10mg + HCTZ 12.5mg + simvastatin 20mg) showed higher rates of discontinuation in the polypill group compared to placebo (23 % vs. 18%, respectively, RR 1.33, 95% CI 0.89-2.00, p=0.2).⁹ The leading reasons for stopping in each group were gastric irritation (3% vs. 1%, p=0.06) and hypotension (4% vs. 1%, p=0.09). Alternatively, the polypill formulation in the study by Muñoz (atorvastatin 10mg + amlodipine 2.5mg + losartan 25mg + HCTZ 12.5mg) had an 86% adherence rate.⁷ All of the polypill formulations studied had some rate of discontinuation due to hypotension or dizziness (Table 1), possibly because of the diuretic combinations used.

Polypill therapy with aspirin has shown greater reductions in CVD risk compared to placebo alone.^4,6,9,10 However, the addition of aspirin is controversial considering recent evidence noting a balanced reduction in CVD risk with aspirin, but at an increased risk of major bleeding events.^12-14 Although there were similar rates of bleeding in the aspirin versus placebo groups in TIPS-3, this risk may have been underestimated given poor pharmacotherapy adherence in the total population.¹¹ In PolyIran, for example, no significant increase in the risk of major bleeding was seen in the polypill group, however individuals at elevated risk of bleeding were excluded from the trial.¹⁰ Alternatively, evidence suggests that coronary artery calcium (CAC) imaging may be used as a decision aid to guide aspirin use; a CAC ≥100 supports the use daily low dose aspirin among individuals at intermediate risk of atherosclerotic cardiovascular disease (ASCVD) who are at lower bleeding risk.^15-17 Indeed, when participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were classified according to inclusion criteria of four polypill studies (TIPS, PolyIran, Wald's, and PILL) higher CVD event rates were found in the CAC >100 group who were also eligible for polypill treatment, suggesting a net benefit for the addition of aspirin.^4-6,9,11,18

TIPS-3 follows a growing number of polypill studies that demonstrate benefit and tolerability of a variety of formulations. These studies have focused largely on populations of low/medium socioeconomic status considering higher rates of modifiable risk factors and ASCVD that are driven in part by inadequate access to health care, environmental factors, economic barriers, and varying levels of educational attainment.^19-21 Therefore, polypill therapy targeting multiple risk factors concurrently represents an intuitive strategy that can mitigate individual ASCVD risk and overall population burden, respectively, and will likely be cost effective overall.^22,23

Widespread uptake of a population-based approach to prevent CVD has been slow amid concerns of overmedicating a large number of low-ASCVD-risk individuals. Additionally, individuals can have a varied response to the same medication;²⁴ this is an important consideration as optimizing risk factors correlates with improved survival. Therefore, it may be difficult to titrate polypill dosages when BP, for example, is treated to goal and LDL-C levels are not. This issue is further compounded when considering the potential side effects of the various components of the polypill such as myalgias, orthostatic hypotension, or bleeding (Table 1).²¹

Ultimately, implementation of prevention efforts may be optimally achieved by a hybrid approach to patient care: identifying high-risk communities and applying precision medicine to reconcile those who receive maximum benefit and minimal harm.²³ Polypills may serve as a foundational therapy or as an adjunct to existing preventative care. Any improvement in risk factors sufficient to reduce CVD burden may justify continuation of the same dosage of polypill.^21,24 With several formulations of the polypill on the market, it may be possible to assign therapy based on prespecified criteria including clinical risk factors, patient values, and preferences.⁶ CAC testing and machine learning algorithms, respectively, could be used to identify a subset of truly high-risk patients who would benefit from initiation/intensification of pharmacotherapy and aggressive risk factor interventions, however implementation may be cost prohibitive, particularly in low/medium socioeconomic populations.¹⁸

Conclusion
Fixed-dose combination therapy (polypill) with or without aspirin is associated with greater reductions in cardiovascular risk factors and major cardiovascular events when compared to usual care, placebo, or active comparators. These benefits are offset, to some degree, by the fact that polypills may not be well tolerated in some individuals. Barriers to polypill implementation may be overcome with a hybrid approach, marrying population-based and risk-based strategies (with the addition of imaging) for the prevention of CVD.

References

1. Sanz G, Fuster V. Prevention: Polypills for cardiovascular prevention: a step forward? Nat Rev Cardiol 2013;10:683-84.
2. Singh K, Crossan C, Laba TL, et al. Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: within-trial cost-effectiveness analysis of the UMPIRE trial. Int J Cardiol 2018;262:71-78.
3. Cimmaruta D, Lombardi N, Borghi C, Rosano G, Rossi F, Mugelli A. Polypill, hypertension and medication adherence: the solution strategy? Int J Cardiol 2018;252:181-86.
4. Indian Polycap Study (TIPS), Yusuf S, Pais P, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009;373:1341-51.
5. Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS One 2012;7:e41297.
6. Yusuf S, Pais P, Sigamani A, et al. Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: The Second Indian Polycap Study (TIPS-2) investigators. Circ Cardiovasc Qual Outcomes 2012;5:463-71.
7. Muñoz D, Uzoije P, Reynolds C, et al. Polypill for cardiovascular disease prevention in an underserved population. N Engl J Med 2019;381:1114-23.
8. Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374:2032-43.
9. PILL Collaborative Group, Rodgers A, Patel A, et al. Correction: An international randomised placebo-controlled trial of a four-component combination pill ("polypill") in people with raised cardiovascular risk. PLoS One 2019;14:e0225924.
10. Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet 2019;394:672-83.
11. Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med 2021;384:216-28.
12. Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA 2019;321:277-87.
13. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1428-29.
14. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.
15. Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014;7:453-460.
16. Ajufo E, Ayers CR, Vigen R, et al. Value of coronary artery calcium scanning in association with the net benefit of aspirin in primary prevention of atherosclerotic cardiovascular disease. JAMA Cardiol 2021;6:179-87.
17. Cainzos-Achirica M, Miedema MD, McEvoy JW, et al. Coronary artery calcium for personalized allocation of aspirin in primary prevention of cardiovascular disease in 2019: the MESA Study (Multi-Ethnic Study of Atherosclerosis). Circulation 2020;141:1541-53.
18. Bittencourt MS, Blaha MJ, Blankstein R, et al. Polypill therapy, subclinical atherosclerosis, and cardiovascular events-implications for the use of preventive pharmacotherapy: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2014;63:434-43.
19. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA 2014;311:1406-15.
20. Schultz WM, Kelli HM, Lisko JC, et al. Socioeconomic status and cardiovascular outcomes: challenges and interventions. Circulation 2018;137:2166-78.
21. Muñoz D, Wang TJ. The polypill revisited: why we still need population-based approaches in the precision medicine era. Circulation 2019;140:1776-78.
22. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356:2388-98.
23. Leopold JA, Loscalzo J. Emerging role of precision medicine in cardiovascular disease. Circ Res 2018;122:1302-15.
24. Huffman MD, de Cates AN, Ebrahim S. Fixed-dose combination therapy (polypill) for the prevention of cardiovascular disease. JAMA 2014;312:2030-31.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Statins, Acute Heart Failure

Keywords: Primary Prevention, Cholesterol, LDL, Lisinopril, Atenolol, Calcium, Ramipril, Aspirin, Diuretics, Simvastatin, Blood Pressure, Losartan, Cost-Benefit Analysis, Hypotension, Orthostatic, Polypharmacy, Dizziness, Cardiovascular Diseases, Coronary Vessels, Confidence Intervals, Health Literacy, Myalgia, Drug Combinations, Hydrochlorothiazide, Heart Failure, Amlodipine, Risk Factors, Patient Care, Atherosclerosis, Health Care Costs, Heart Arrest, Algorithms, Health Services Accessibility, Social Class, Socioeconomic Factors, Decision Support Techniques

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