PLoS: Jury still out on polypill

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A polypill, which combines cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol, achieved sizeable reductions in systolic blood pressure (BP) and LDL cholesterol but caused side effects in about one in six people, according to a study published May 25 in PLoS One. Ultimately, the study authors suggested that the benefits may outweigh the risks, especially for those patients at higher risk.

To assess the much-discussed polypill, the PILL Collaborative Group conducted a randomized, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year cardiovascular disease risk over 7.5 percent.

The trial tested the effectiveness and tolerability of the polypill in 378 people with raised risk of cardiovascular disease who did not necessarily have high BP or cholesterol, against a placebo. The participants came from the U.K., Australia, Brazil, India, New Zealand, the Netherlands and the U.S.

The primary outcomes were systolic BP, LDL cholesterol and tolerability (proportion discontinued randomized therapy) at 12 weeks follow-up.

At baseline, mean BP was 134/81 mmHg and mean LDL cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced systolic BP by 9.9 mmHg and LDL cholesterol by 0.8 mmol/L.

According to the researchers, the discontinuation rates in the polypill group compared with placebo were 23 versus 18 percent. There was an excess of side effects known to the component medicines (58 vs. 42 percent), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment.

The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, the authors concluded that the substantial net benefits would be expected among patients at high risk.

"The results show a halving in heart disease and stroke can be expected for people taking this polypill long-term," said Anthony Rodgers, MD, professor of global health at the George Institute for International Health, based in Sydney, Australia. "We know from other trials that long-term there would also be a 25 to 50 percent lower death rate from colon cancer, plus reductions in other major cancers, heart failure and renal failure. These benefits would take several years to ‘kick in,’ but of course one of the hopes with a polypill is it helps people take medicines long-term."

The authors noted that the benefits, while large, were not as massive as previous researchers have suggested, and the side effects also were not as rare as first thought. In the short-term about one in six people experienced a side effect. Most were mild but about one in 20 overall stopped treatment due to side effects, indicating that treatment is best targeted to those at raised risk of disease.

"We now need to conduct larger trials to test whether these medicines are best provided in the form of a polypill, or as separate medicines, and whether this combination strategy improves patient adherence to cardiovascular medication," said Simon A. McG. Thom, MD, of Imperial College London, who led the U.K. arm of the trial.

The trial was funded by The Wellcome Trust, the Health Research Council of New Zealand, the National Heart Foundation of New Zealand, the National Health and Medical Research Council of Australia, the Brazilian Ministry of Health (Projeto Hospitais de Excelencia) and the British Heart Foundation.