LOS ANGELES – A once-daily, fixed-dose combination of four cardiovascular drugs – a polypill – boosted patient adherence by 33% while meaningfully reducing both systolic blood pressure and LDL cholesterol compared with usual care in the large international UMPIRE trial.

UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) was designed to test the hypothesis that decreasing the cost and complexity of guideline-indicated medications for secondary cardiovascular prevention would improve treatment adherence and outcomes in patients with established atherosclerotic cardiovascular disease or in those at high risk for it.

And UMPIRE was a resounding success, according to Dr. Simon Thom, professor of cardiovascular medicine and pharmacology at Imperial College, London. He presented the results at the annual scientific sessions of the American Heart Association.

The study comprised 2,004 randomized patients in India, Dublin, London, and Utrecht (the Netherlands): 88% had known atherosclerotic cardiovascular disease at baseline; 29% had diabetes. Participants were randomized to the polypill – composed of 75 mg aspirin, 50 mg simvastatin, 10 mg lisinopril, and either 50 mg atenolol or 12.5 mg hydrochlorothiazide, depending upon physician preference – or to usual care, which included individual prescriptions for the same four medications. The polypill was free, while usual care was paid for in the customary local manner.

After a median 15 months of follow-up, treatment adherence was 86% in the polypill arm, compared with 65% with usual care, a relative 33% difference. Systolic blood pressure averaged 129.2 mm Hg in the polypill group, 2.6 mm Hg lower than with usual care. Mean LDL cholesterol was 84.3 mg/dL in the polypill group and 88.6 mg/dL with usual care. Diastolic blood pressure was 72.8 mm Hg with the polypill, compared with 75.2 mm Hg in the usual care group.

All of these differences were statistically significant and clinically meaningful when extrapolated to the rapidly growing global burden of cardiovascular disease. Moreover, quality of life as self-measured on a visual analog scale was significantly better in patients on the fixed-dose combination, Dr. Thom reported.

There were, however, no significant differences between the two study arms in HDL cholesterol, triglycerides, or cardiovascular event rates.

Of note, 61% of UMPIRE subjects were already on all four individual study medications at baseline. That’s an unusually high proportion in the low- and middle-income countries where the polypill will see greatest future use, and it means the UMPIRE results almost certainly underestimate the true benefits to be expected with use of the polypill in clinical practice, he continued.

Side effects were the same in both treatment arms.

Discussant Dr. Andrew M. Tonkin declared UMPIRE to be "an important trial – and the results should be taken on board not only by clinicians, but should really inform government policies and strategies."

Although there is enthusiasm in some quarters for broad use of the polypill for primary prevention – a sort of let’s-put-it-in-the-drinking-water strategy – UMPIRE was the first polypill randomized trial conducted in patients with established cardiovascular disease, and one of very few to date to run longer than about 3 months.

"I believe that UMPIRE firmly establishes the case for using the polypill in those people with manifest atherosclerotic cardiovascular disease," said Dr. Tonkin.

It’s noteworthy that patients with poor baseline adherence to the study medications were 3.4-fold more likely to benefit from use of the polypill. That’s an important finding because the polypill is expected to see its greatest future use in India, China, the Philippines, and other parts of the world where vast numbers of patients with cardiovascular disease now receive little or nothing in the way of pharmacologic secondary prevention, said Dr. Tonkin, professor of preventive medicine and head of the cardiovascular research unit at Monash Hospital in Melbourne.

Moving forward, he added, the responsibility for developing the polypill cannot rest solely with the pharmaceutical industry.

"This is a very low-margin venture using low-cost generic formulations. Major pharma doesn’t want to get interested in this," said Dr. Tonkin.

Both the World Health Organization and the European Commission are publicly on board for the polypill, he noted.

The WHO and Wellcome Trust stated in a 2002 report that demonstration of bioequivalence and improved adherence as reflected in improvements in LDL and systolic blood pressure, as seen in UMPIRE, should be sufficient for regulatory approval of the polypill.

"That, I think, will not carry water in these days, unfortunately. But a meta-analysis of clinical end point data from the various trials is planned. And there are ongoing and planned future phase III trials," Dr. Tonkin said.

While most of the clinical trials, past and present, have taken place in low-income countries, the polypill is also under study in populations in the United States, Canada, Australia, and other relatively well-off nations, he pointed out.

UMPIRE was funded by the European Commission. Dr. Thom and Dr. Tonkin reported having no financial conflicts.

Polypill Improves Cardiovascular Health in UMPIRE