Over the past three decades, data from major clinical trials support the view that aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and statins each reduce cardiovascular risk significantly. Treating patients with pills from each of these classes presents a challenge due to the cost and the difficulty of taking four pills each day. As the incidence of cardiovascular disease increases in the developing world, these challenges become more profound but, if addressed adequately, can have a significant impact on the global incidence of cardiovascular disease.

The concept of a combination pill that contains a drug from each of these four classes—a polypill—has been considered since the early part of this decade. Estimates of the population effect of such a pill suggest that its use can reduce cardiovascular events in individuals without regard for prior cardiovascular disease or risk factor status by more than 80% (Wald, Law, 2003). Before a major prospective trial is undertaken, however, the efficacy of the polypill in risk factor reduction, ease of use, and tolerability must first be assessed. For this reason, a phase II, double-blind, randomized trial was designed to determine the magnitude of the effect of a combination pill on blood pressure and lipid lowering, the tolerance of such a combination pill, and possible adverse interactions among its components. In The Indian Polycaps Study (TIPS) (2009), 2053 middle-aged (54.0 + 7.9 years) individuals without previous cardiovascular disease and with one risk factor were recruited from 50 centers in India and randomized to one of nine treatment regimens: (1) 100 mg aspirin; (2) 12.5 mg thiazide; (3) 5 mg ramipril + 12.5 mg thiazide; (4) 50 mg atenolol + 12.5 mg thiazide; (5) 50 mg atenolol + 5 mg ramipril; (6) 50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide; (7) 50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide + 100 mg aspirin; (8) 20 mg simvastatin; or (9) the Polycap (50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide + 100 mg aspirin + 20 mg simvastatin). As shown in this listing, three different antihypertensive regimens were included in the trial (diuretic, angiotensin-converting enzyme inhibitor, and beta blocker) in various combinations. The active treatments were maintained for 12 weeks, and effects of the therapies on risk factors were measured at 4-week intervals, including one follow-up measurement 4 weeks after treatments were discontinued.

The principal results of the study can be summarized as follows. First, the magnitude of the reduction in blood pressure increased with increasing numbers of antihypertensive agents, with the Polycap achieving the greatest reduction (systolic pressure reduction, 7.4 mmHg; diastolic pressure reduction, 5.6 mmHg). Second, simvastatin and Polycap achieved significant reductions in LDL cholesterol, but the magnitude of reduction by Polycap was marginally significantly less than that of simvastatin used alone (27 vs. 32 mg/dL, p = .04). Third, all atenolol-containing regimens lowered heart rate by ~7 beats per minute compared with regimens not containing atenolol, and, fourth, all aspirin-containing regimens lowered 11-dehydrothromboxane B2 (a stable metabolite of platelet-derived thromboxane A2) equivalently compared with regimens not containing aspirin. Drugs were permanently discontinued in 303 patients overall (14.8%), and there appeared to be no relationship between the number of agents used in combination and the frequency of discontinuation.

These results are encouraging in that they demonstrate the short-term efficacy of a polypill, the Polycap, in reducing cardiovascular risk factors significantly and show that these effects are achieved with minimal adverse effects or intolerability. The true benefits of this approach with respect to hard clinical endpoints, long-term safety and tolerability, and overall patient adherence remain to be demonstrated in an adequately sized, prospective, longer term, randomized, controlled trial.