The Polypill and Heart Disease
The Polypill and Heart Disease
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.
Synopsis: A polypill consisting of low doses of thiazide, atenolol, ramipril, simvastatin, and aspirin administered to 2053 subjects in 50 centers in India was effective in reducing multiple risk factors and cardiovascular risk.
Source: Yusuf S, 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;373:1341-1351.
It has been clearly demonstrated that aspirin,1 beta-blockers,2 angiotensin-converting-enzyme inhibitors,3 and statins4 reduce the incidence of cardiovascular disease. Combining drugs to treat the many cardiac risk factors in one pill has been estimated to be capable of reducing cardiovascular disease worldwide by more than 80%5 if the polypill would be administered to all individuals 55 years and older irrespective of previous cardiovascular disease or risk factors.
The Indian Polycap Study (TIPS) is a large randomized phase II trial that assessed the effects of 9 different pills containing either a single agent or combination of 2, 3, 4, or 5 drugs (the polypill) to measure their effect on risk factors such as blood pressure and cholesterol concentrations. The study was conducted as a double-blind trial in 50 centers in India in 2053 individuals without cardiovascular disease who were aged 45-80 years with 1 cardiovascular risk factor. The study tested the feasibility and tolerability of administering a single pill to a relatively unselected group of patients. Polycaps consisting of low doses of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day were administered to 412 subjects, and 8 other groups of 200 subjects were given either aspirin alone, simvastatin alone, hydrochlorothiazide alone, 3 combinations of 2 blood pressure-lowering drugs, 3 blood pressure-lowering drugs alone, or 3 blood pressure-lowering drugs plus aspirin. The Polycap reduced systolic and diastolic blood pressures to the same degree as did the 3 blood pressure-lowering drugs with or without aspirin. It reduced the LDL-cholesterol to a lesser degree than the group that received simvastatin alone, but the reductions were greater in both simvastatin groups than they were in subjects who did not receive simvastatin. The tolerability of the Polycap was similar to that of other treatments with no evidence of increasing intolerability with increasing numbers of active components in one pill. The authors from the Population Health Research Institute in Hamilton, Canada, concluded that the Polycap formulation was practical and should be considered for use mainly to reduce multiple risk factors and cardiovascular risk worldwide.
Commentary
It is most important to recognize that the TIPS study was focused on determining the possibility and feasibility of reducing worldwide cardiovascular events with a single, carefully formulated polypill and was not an outcomes trial to demonstrate that a polypill could reduce mortality or recurrent myocardial infarctions in patients who had previously suffered an acute myocardial infarction or who were afflicted with hypertension and/or hyperlipidemia. The study demonstrated that the Polycap was not inferior to its individual components in lowering blood pressure and heart rate. In fact, each of the components of the polypill did what it was intended to do: The statin reduced cholesterol, the 3 antihypertensives reduced blood pressure (and the more of them, the greater the reduction), and aspirin reduced the clotting ability of the blood. However, because the lowering of the LDL-cholesterol in the Polycap group was less than when simvastatin alone was used, it is clear that the effects of the polypill cannot be assumed to be equal to the combined effects of its individual components. The effect of the Polycap on LDL-cholesterol was greater in participants with diabetes, suggesting that the potential relative and absolute benefits of the Polycap on chemical outcomes are likely to be larger in high-risk subjects than in low-risk subgroups but are still important in the latter group of subjects. Finally, in any new trials of the use of a polypill to reduce cardiovascular diseases, the simvastatin dosage may have to be increased to 40 mg or the drug selected may have to be changed to a more potent statin given at a more moderate dose.
Obviously, a large phase III trial with longer follow-up is needed to assess the feasibility and effectiveness of a single magic bullet for the prevention of heart disease. Currently, for combination pills, regulatory authorities require that the pill be available in every dose combination of each drug so that the combination pill will not limit treatment. This approach would not be feasible if a pill with 5 or 6 components had to have 2-4 different dose ranges, which obviously would alter the simple single-dose concept into a complicated prescribing morass. If effectiveness is proven in a properly designed large-scale trial, the polypill concept would be attractive because both its simplicity and low cost would obviously improve compliance and in all likelihood would prove to be effective in large populations throughout the world where risk factors are usually untreated.6 Obviously, lifestyle activities such as exercise, weight control, and consuming an appropriate diet would have to be continuously encouraged even if the preventive polypill concept for cardiovascular disease control is utilized. In summary, the authors of the TIPS study should be complemented for performing this extremely complex study which, even though it does not provide all the answers, does take a first and quite crucial step forward to raise hope that, in conjunction with other global efforts to improve diet and exercise, the polypill could one day significantly contribute to reducing the burden of cardiovascular disease in the world.
Reference
1. Antithrombotic Trialists' Collaboration. Collaborated meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
2. Yusuf S, et al. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-371.
3. Yusuf S, et al. Effects of angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
4. Baigent C, et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278.
5. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-1424.
6. Kotseva K, et al; EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: A comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009;373:929-940.
A polypill consisting of low doses of thiazide, atenolol, ramipril, simvastatin, and aspirin administered to 2053 subjects in 50 centers in India was effective in reducing multiple risk factors and cardiovascular risk.Subscribe Now for Access
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