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Clinical Trials of Polypills for CVD Begin

Posted: Thursday, January 25, 2007

Polypill will contain aspirin, lisinopril, simvastatin, and atenolol, and will cost 2 dollars a month.

Raghu Cidambi (Dr Reddy's Laboratories, Hyderabad, India) stated that, the company hopes to gain Indian approval of this version of the polypill for secondary prevention on the basis of this trial, which has already completed enrol lment.

"We believe that we don't need an elaborate outcomes trial for secondary prevention," he said. "It is our understanding that as long as there is solid evidence of no drug-drug interaction and that the pill achieves its goals of reducing blood pressure and cholesterol, it will be approved in India"

The concept of a polypill was born in 2003, when British professors from the Wolfson Institute of Preventive Medicine in London, UK, Nick J Wald and Malcolm R Law, proposed a polypill containing six constituents in the BMJ [1].

To determine the ideal combination, Wald and Law reviewed 750 drug trials (representing 400 000 participants) to identify agents that substantially modified these risk factors. They settled on a hypothetical pill combining a statin; three blood-pressure-lowering drugs, each at a half-standard dose (potentially a thiazide, beta blocker, and ACE inhibitor); 0.8-mg folic acid; and 75-mg aspirin. Such a product could slash the risk of cardiovascular events by 80% or more and benefit one in three people if everyone over the age of 55 were to take the pill, they calculated. And by including only half-doses of the antihypertensives, the risk of adverse effects would be minimized, they said.

Three strengths of the secondary-prevention version of the polypill have been developed, with trial participants beginning with the lowest dose. If their blood-pressure and lipid goals are not reached, they then move up to use the medium dose and then the higher dose of the polypill. It is designed as one pill, to be taken once a day. Constituents of secondary-prevention polypill

Aspirin dose (mg)

Simvastatin dose (mg)

Low-dose

5

25

75

20

High-dose

10

50

Regarding the constituents of the pill, he said the company's principal advisor on this has been Dr Anthony Rodgers (University of Auckland, New Zealand). "We also consulted a number of doctors and carefully reviewed the dosing regimen (twice a day vs once a day), the pharmacokinetics, tolerability, how much the pill is used in various markets, etc, to determine the choice of agent.

"We believe that two [antihypertensive] agents will be adequate in many cases to treat to goal and also adhere to the treatment guidelines. It may also be easier to find acceptance of a two-antihypertensive combination by doctors, rather than three, particularly in cases of mild to moderate hypertension," he added. Folic acid was left out because of the lack of evidence of benefit in cardiovascular trials so far, he noted.

Cidambi also believes there is a market for the polypill in the West, where people must take numerous tablets per day for secondary prevention. Such polypills would improve compliance and help prevent many secondary events, he says.

Dr Reddy's Laboratories is also hoping to begin a pilot trial of a primary-prevention polypill in the second quarter of this year. There will also be three strengths of this version of the pill, in which the beta blocker atenolol is replaced by the thiazide diuretic hydrochlorothiazide.

The study is being led by Rodgers and will be conducted on five continents, including patients from Australia, Brazil, India, South Africa, the US, and UK.

It will recruit 600 people at high risk of MI or stroke and will randomize participants to the polypill or placebo. Once again, patients will begin on the lowest-dose version of the polypill but "upgrade" to the medium or high dose if their blood-pressure and cholesterol goals are not met. If this is successful, a full-scale trial is planned in 5000 people.

Rodgers is also planning a separate trial in New Zealand in people at high risk of MI and stroke, which will enroll 300 Maori and 300 non-Maoris. Constituents of primary-prevention polypill

Aspirin dose (mg)

Simvastatin dose (mg)

Low-dose

5

12.5

75

20

High-dose

10

12.5