Polypill Strategy for Primary Prevention of Cardiovascular Disease

Mrs. Singh is a 63-year-old woman with a history of hypertension and overweight who is in clinic for follow-up. Her systolic blood pressure (SBP) is 144 mm Hg and recent labs revealed an LDL cholesterol level of 121 mg/dL. She takes hydrochlorothiazide (25 mg) once daily for hypertension. You discuss the addition of an angiotensin converting enzyme (ACE) inhibitor for better hypertension control. She asks whether other changes in her medication regime are needed to lower her cardiovascular risk? Her calculated INTERHEART Risk Score is 17 (range, 0−48 points, with higher scores indicating greater cardiovascular risk), based on the following nine risk factors: hypertension, diabetes, hyperlipidemia, smoking, obesity, psychosocial stress, physical activity, alcohol consumption, and nutrition.

A number of trials have suggested that the use of a fixed-dose combination pill — or polypill — lowers the risk for cardiovascular events. A polypill strategy has been shown to lower SBP and low-density lipoprotein (LDL) cholesterol. In the HOPE-3 trial, fixed doses of rosuvastatin and candesartan/hydrochlorothiazide lowered the rate of future cardiovascular events in adults with intermediate risk (annual risk, ~1%), regardless of cholesterol levels, inflammatory marker status, or hypertension status. However, the addition of fixed doses of antihypertensives to the statin therapy did not lower risk unless the patient was hypertensive.

In the recently published TIPS-3 trial, conducted mostly in South and Southeast Asia, researchers randomized approximately 5700 adults (mean age, 63 years) without known cardiovascular disease to receive the polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly.

During a mean follow-up of 4.6 years, the polypill with or without aspirin lowered the risk of major cardiovascular events (including death from cardiovascular causes, myocardial infarction, and stroke). The composite outcome was significantly lower with the polypill plus aspirin versus double placebo (4.1% vs. 5.8%; hazard ratio [HR], 0.69; 95% CI, 0.5-0.97) and was nonsignificantly lower with the polypill without aspirin versus placebo (4.4% vs. 5.5%; HR, 0.79; 95% CI, 0.63-1). 

Based on these results, the recommendation for Mrs. Singh to lower her cardiovascular risk is a fixed-dose polypill containing statin and combination antihypertensive medication with aspirin.

The following NEJM Journal Watch summary provides more details of the study:

Karol E. Watson, MD, PhD, FACC reviewing Yusuf S et al. N Engl J Med 2020 Nov 13

Risk factor modification, consisting of lifestyle measures and preventive medications, is central to preventing cardiovascular disease (CVD). One possible way to improve adherence to preventive medications is the polypill, which combines several medications in one pill. Investigators tested this strategy in a 2×2 factorial study conducted almost entirely in South Asian and Southeast Asian countries (NCT01646437). The manufacturer-supplied polypill contained simvastatin 40 mg plus three antihypertensive medications (100-mg atenolol, 25-mg hydrochlorothiazide, and 10-mg ramipril).

The 5713 participants had intermediate CV risk but no known CVD and had completed a half-dose run-in phase. They were randomized to either the daily polypill or matched placebo and to either daily aspirin (75 mg) or matched placebo. At a mean of 4.6 years, the polypill lowered LDL by 19 mg/dL and systolic blood pressure by 5.8 mm Hg. In the polypill–placebo analysis, the primary cardiovascular outcome (CV death, myocardial infarction (MI), stroke, resuscitated cardiac arrest, heart failure, or revascularization) was nonsignificantly less frequent in polypill recipients than placebo recipients (4.4% and 5.5%). In the aspirin–placebo analysis, the primary outcome (CV death, MI, or stroke) was nonsignificantly less frequent in aspirin recipients than placebo recipients (4.1% and 4.7%). In the combined analysis, the primary outcome was significantly less frequent in the polypill-plus-aspirin group than the double-placebo group (4.1% vs. 5.8%; hazard ratio, 0.69). The polypill-plus-aspirin group had more hypotension and cough, but not bleeding, than the double-placebo group.

Comment: These data show that a polypill-plus-aspirin strategy lowers CV events in a primary-prevention population. The authors note that the reduction in CVD was less than they had hypothesized but that the benefit was still significant. Whether Western populations, which often have a different risk factor profile than in this study, would have the same outcomes remains unknown. Some questions have arisen about the choice of atenolol for the polypill; other medications might have yielded better results. Of note, 24% of screened participants failed the run-in phase, primarily due to side effects. Unfortunately, adherence remained suboptimal; at study's end, discontinuation of the polypill was 42% and discontinuation of aspirin was 40%. Despite the questions about adherence, these data suggest that a polypill strategy can improve CV outcomes in primary-prevention patients.

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James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.