A three-component polypill designed to reduce cardiovascular risk could merit consideration for approval in the United States if it was determined to be both safe and effective, a Food and Drug Administration advisory committee has agreed.
Just what form that determination would take remains a big unknown, however.
Dr. Sanjay Kaul
No such pill exists in the United States. But at a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the committee members considered a hypothetical polypill that would include at least one antihypertensive, a statin, and aspirin. The members envisioned it to be used as a secondary prevention measure in patients who are both hyperlipidemic and hypertensive. Some committee members suggested that the indication should be restricted to high-risk patients, including those who have had a heart attack.
The strongest reason for such a pill would be to improve compliance in patients who are taking cardiovascular drugs but aren’t reaching their goals. A polypill could also be useful for patients who can’t or won’t comply with follow-up visits necessary for titrating blood pressure medications.
"The concept is very appealing, but the current body of evidence doesn’t appear to guarantee" that the benefits of such a pill would outweigh the benefits of the individual components, committee member Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said at the meeting. "A key question to me is to make sure that there would not be pharmacokinetic or pharmacodynamics issues" in the combination that might affect the proven safety of each ingredient. "We are interested not just in improving outcomes, but in maintaining safety."
Many patients are already taking all of these individual drugs simultaneously, and no pharmaceutical company has brought a combination pill forward to the FDA. Some companies have told the agency, however, that they might create one if there were a good chance of approval.
Similar drugs are available in other countries – including India, where a large phase II trial showed that it resulted in significant reductions in blood pressure and lipids, compared with the individual components alone (Lancet 2009;373:1341-51).
A U.S. observational study of a similar concept found very encouraging results. The 2010 Kaiser Permanente ALL/PHASE protocol utilized a bundle of aspirin, lisinopril, and a statin, said Dr. James Dudl, an endocrinologist at Kaiser. More than 170,000 patients, 78% of whom had diabetes and 50% of whom had coronary artery disease, were followed for 3 years. Full data were available on 47,000. The patients were split into a high-exposure group, with a mean compliance of 68%, and a low-exposure group.
Cardiovascular events were reduced by 15/1,000 patients in the high-exposure group. The outcome was driven by stroke alone, with no benefit in heart attack. Since then, Kaiser has continued the bundle recommendation, which Dr. Dudl said costs about 25 cents per day.
The American Heart Association supports the concept of a polypill – with some caveats. "It might be aneffective way to improve adherence and reduce cardiovascular disease," Dr. Niteesh Choudhry of the AHA told the committee. "But we do have lingering concerns about the efficacy and safety of a combined agent. We believe more data are needed from a clinical trial of sufficient duration and power to identify clinically relevant outcomes – particularly blood pressure and LDL cholesterol – and safety, and to identify subgroups" that might particularly benefit from the pill, or who might experience some untoward effects of it. Postmarketing surveillance should be a requirement, added Dr. Choudhry, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.
Although many patients are already taking all the components of a polypill simultaneously, many of the committee members believed strongly that safety and efficacy studies would be a requirement. Some thought those data could be gathered from existing studies conducted in the United States and other countries; others felt that a prospective, or even a randomized, study should be part of any approval request.
"I want to see an observational trial in a real-world setting," said Dr. Stuart Rich, professor of medicine at the University of Chicago. "A clinical trial is not a real-world setting, and what might be shown in a clinical trial won’t translate in terms of the most meaningful outcome: adherence. I would also ask that there be a measure of health care cost savings."
Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas, disagreed. "It would be a mistake to demand outcomes studies that would be small, underpowered, and maybe give incorrect answers. The way to do this would be to license it and get it out there and evaluate it."