South Asian Experience with the Polypill
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomized trial. Lancet. 2009;373:1341-1351.
Six years ago, Wild and Law, two British physicians, proposed that a single pill with multiple active components could profoundly reduce cardiac risk (CV). They suggested that this polypill might contain antihypertensives, a statin, an aspirin, and folic acid. No data were available to test this concept until the recent release of the TIPS trial, also known as The Indian Polycap Study. TIPS sought to test the hypothesis that a multiple (poly) pill regimen, consisting of appropriate risk factor medications at low doses, would improve CV outcomes. TIPS was carried out in 50 centers in India, each testing a different regimen in men, 45-80 years old, without clinical cardiovascular disease and with one risk factor (diabetes, hypertension, abnormal LDL, smokers, obesity) over a 12-week period. The main components of this polypill included three drugs for hypertension (atenolol, a thiazide, an angiotensin inhibitor) simvastatin, and aspirin. The primary outcomes were LDL cholesterol, blood pressure, and rates of drug discontinuation. Also measured were urinary dehydrothromboxane B2, an aspirin metabolite, which was included to test the degree of aspirin antiplatelet effect. TIPS also tested the effects of each drug class alone, and the three antihypertensive drugs with or without aspirin alone, to assess whether the polypill produced additive effects over each component. Thus, aspirin 100 mg, hydrochlorothiazide 12.5 mg, ramipril 5 mg, simvastatin 20 mg, and atenolol 20 mg were assessed in eight groups.
Several questions were raised by the investigators. Can a single pill be formulated to reproduce the appropriate results? What level of blood pressure and lipid lowering can be achieved in people with normal levels of risk factors? Will a five-component pill be tolerated? Would there be unexpected and unwanted drug interactions with any combination of low-dose vasoproactive drugs? Does aspirin affect the levels of the other components (i.e., antihypertensive drugs)?
Results: A total of 412 patients were randomly assigned to the Polycap group and 200 to each of the other eight groups. Discontinuation rates ranged between 12 % and 24 %, with no pattern and mostly due to drop outs. As compared to the groups not receiving antihypertensive medications, the polypill reduced systolic blood pressure by 7 mmHg and diastolic by 5 mmHg, which was similar to the reductions seen with the antihypertensive drug combination with or without aspirin. In the single antihypertensive drug studies, blood pressure was incrementally lowered by adding more drugs (2, 4, 6 mmHg). LDL cholesterol was reduced 0.70 mmol/L by the polypill, but 0.83 by simvastatin alone. Any group given aspirin exhibited similar reductions in 11-dehydrothromboxame B2. Surprisingly, tolerability was similar in all groups and didn't decrease significantly with the number of drugs. The authors concluded that the polypill could potentially reduce heart disease by 60% and stroke by 18%.
Commentary
This report deserves the attention of health care workers, physicians, epidemiologists, and all interested in decreasing athersclerotic heart disease. The polypill concept was first postulated in a report from Great Britain (Wild, Law. BMJ. 2003) which intrigued many physicians and health care workers. Salim Yusuf et al in India (50 institutions) are to be congratulated on conducting this large and complicated trial to test this hypothesis. While it is unlikely to have an immediate effect on CV risk lowering, the data from the individuals enrolled in TIPS are "proof of concept." The safety of this approach seems reasonable; the administration of low doses of all agents tested (aspirin, atenolol, thiazide, simvastatin, ramipril) is reassuring, although more data would be necessary if dosages were to increase. The polypill would be particularly appropriate for utilization in many countries devoid of adequate health care access, and certainly for Americans who struggle with health care costs. TIPS provides a fascinating beginning for an issue affecting all of us. Much needs to be explored with this approach, and there will be resistance. Nevertheless, I urge Dr. Yusuf et al and other institutions to pursue the possibility and feasibility of a larger and longer study. An editorial by Chris Cannon in the same issue of Lancet is sensible and sets out the steps to be taken for success.1 Interested readers should pursue further discussion and look for many studies testing a multiple drug pill per pill in the near future!
Reference
1. Cannon CP. Can the polypill save the world from heart disease? Lancet. 2009;373:1313-1314.
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