麻豆果冻传媒影音

ORLANDO, March 30 -- Combining three antihypertensives, a statin, and an aspirin in a single, five-drug capsule appears to achieve the same benefit as giving the drugs individually, although the statin in the combination was slightly less effective, researchers said here.

While the combination did appear to blunt the potency of simvastatin -- reducing cholesterol by 27 mg/L (0.70 mmol/L) versus 32 mg/L (0.83 mmol/L) for simvastatin monotherapy (PP
Dr. Yusuf, co-chair and principal investigator of The Indian Polycap Study (TIPS), reported findings of the phase II trial today at the American College of Cardiology meeting here. The results were simultaneously published online in The Lancet.

Dr. Yusuf said the polypill reduced LDL by about 25%, compared with a 28% reduction with simvastatin monotherapy, "a difference that was statistically significant but clinically not meaningful."

The primary outcomes were reductions in blood pressure for antihypertensive drugs, LDL for the statin, heart rate for the beta blocker, and urinary 11-dehydrothromboxane B2 for antiplatelet effects of aspirin.

Dr. Yusuf estimated that the combined blood pressure and LDL reductions achieved by the polypill "could reduce heart disease by 60% and stroke by 50%."

The polypill is one of three strategies developed by the World Heart Federation to combat what has been described as a worldwide epidemic of cardiovascular disease. The first two strategies are weight loss and smoking cessation.

In a follow-up interview, Dr. Yusef said that Wellcome Trust has announced a competition to develop a polypill for primary prevention. "I've been working on the grant proposal in every spare minute," he said, "the deadline is tonight.

Wellcome Trust has limited the competition to companies in India and has said it will award £5 million to the winning company to support a clinical trial. "If it costs no more that that, the company will need to go elsewhere for funding."

"It is my fervent belief that 90% of premature cardiovascular deaths can be prevented in the next 50 years," Dr. Yusuf said.

But others were not impressed.

Robert Bonow, M.D., professor of medicine at Chicago's Feinberg School of Medicine at Northwestern University, cautioned restraint.

"We already have a polypill -- it's called exercise," Dr. Bonow said.

Dr. Bonow, who is a former president of the American Heart Association, said, however, that he did believe there was a role for a polypill in secondary prevention.

After myocardial infarction, patients should be on multiple drugs to prevent recurrent MI, he said, and "that is when compliance can be a real problem, when the patient needs to take four or five drugs so a single pill could be a big help."

Steven Nissen, M.D., director of cardiovascular research at the Cleveland Clinic Foundation, didn't mince words. "I'm not impressed," he said after listening to Dr. Yusuf's presentation.

Although he conceded that the polypill "didn't hurt anyone," he pointed out that with a mere 12 weeks of data it would be premature to endorse the polypill as safe.

"If a patient does get side-effects, how do you know which drug it is? And, you can't titrate a polypill," Dr. Nissen said.

He concluded that the polypill was probably "not approvable" in the U.S.

Whether or not Dr. Nissen's assessment of approvability is accurate, developing a polypill for use in the U.S. would be an arduous and expensive proposition.

Dr. Yusuf estimated that the phase II trial conducted in India cost about $1 million, a drop in the bucket, he said, for a clinical trial.

Attempting such a trial in the U.S. would probably cost hundreds of millions of dollars and tens of thousands of patients would need to be recruited, said Hani N. Sabbah, Ph.D., of Henry Ford Hospital in Detroit. Dr. Sabbah, who is co-chair of the ACC program committee, moderated a press conference where Dr. Yusuf discussed the results of the polypill trial.

Dr. Yusuf said the blood pressure reductions achieved with the polypill -- an average reduction of systolic BP by 7.4 mmHg and diastolic BP by 5.6 mmHg compared with controls not taking antihypertensives -- were less than the 20 mmHg/11 mmHg reductions that had been projected.

But even those more modest reductions cut the risk of coronary heart disease by 24% and stroke risk by 33%.

The trial recruited 2,053 adults (age 45 to 80) at 50 centers in India. Criteria included no history of cardiovascular disease and just one risk factor. Patients were recruited from March 5, 2007 through August 5, 2008.

Participants were randomized to the polypill -- thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg) and aspirin (100 mg), or to one of eight comparator groups: aspirin alone, simvastatin alone, thiazide alone, thiazide plus ramipril, thiazide plus atenolol, ramipril plus atenolol, all three blood pressure drugs, and all three blood pressure drugs plus aspirin.

Some 412 individuals were randomized to the polypill and 200 to each of the comparator arms. Patients were given the study drug for 12 weeks.

To lessen the risk of hypotension, patients randomized to an arm that included ramipril were initiated at a dose of 2.5 mg for seven days then titrated up to 5 mg.

Among the findings:

• The polypill reduced 11-dehydrothromboxane B2 by 283.1 ng/mmol creatinine. This was similar to reductions achieved by aspirin alone (348.8 ng/mmol creatinine) and aspirin in combination with three blood pressure drugs (350.0 ng/mmol creatinine).
• Heart rate reductions with the polypill and in treatment groups taking atenolol averaged 7 beats/min, which was significantly lower than groups not taking the beta blocker (PBP reductions increased with the number of drugs used. One drug reduced systolic pressure by an average of 2.2 mmHg and diastolic by 1.3 mmHg. With two drugs the reduction was 4.7 mmHg/3.6 mmHg, and with three, the drop was 6.3 mmHg/4.5 mmHg.

In an editorial that accompanied The Lancet paper, Christopher P. Cannon, M.D., of Harvard and a senior investigator with the TIMI Study Group, said the major appeal of the polypill is its simplicity and low cost.

That could not only translate into "broad applicability in areas of the world with less access to medical treatment", he wrote, but also "fit well in to more modern medical systems, in which large proportions of patients with risk factors are untreated."

Dr. Cannon concluded that while TIPS "does not provide all the answers, the study does take a first and crucial step forward and raises hope that, in conjunction with other global efforts to improve diet and exercise, the polypill could one day substantially reduce the burden of cardiovascular disease in the world.