A baby aspirin a day keeps a heart attack away. This widely accepted health practice was seriously undermined at an advisory committee meeting of the Food and Drug Administration (FDA, held in December 2003. The FDA advisory committee voted overwhelmingly to reject a petition from the Bayer Corp. to approve aspirin for reducing the risk of a first heart attack.

Though an estimated 20 million Americans already take low-dose aspirin daily to prevent a heart attack, this is an off-label use—that is, the aspirin manufacturers have not received FDA approval for this particular indication. FDA approval is required, however, once an aspirin manufacturer plans to advertise the drug for this use. And once approval is granted, the drug’s packet insert must be rewritten to inform consumers of the new indication.

Bayer’s petition made the FDA Cardiovascular and Renal Drugs Advisory Committee take a critical look at the five trials (One trial compared aspirin with vitamin E) in which people without heart disease took either aspirin or a placebo (a dummy pill). Altogether there were more than 55,000 participants at anywhere from low to high risk for a heart attack. Here is what the cardiologists and other experts on the committee found in the way of benefit: Aspirin produced about a 32% reduction in non-fatal heart attacks. [Translation: An estimated 3% of all moderate-risk people will have a heart attack in the next five years. Daily low-dose aspirin therapy will reduce their odds to about 2%.] The benefit is given in terms of a five-year period because the trials lasted four to seven years.

Several things troubled the FDA committee members about the results of these trials: Aspirin did not have any mortality reduction benefit; nor did it reduce the odds of having an ischemic stroke, which is, arguably, the most feared consequence of heart disease. Yet aspirin has the potential for causing another, less common type of stroke called hemorrhagic stroke, which is a rupture of a blood vessel in the brain.

One committee member who voted to reject Bayer’s petition is Steven Nissen, MD, Medical Director of the Cleveland Clinic Cardiovascular Coordinating Center. In a telephone interview, Dr. Nissen explained, “The data [from the five trials] were terribly weak.” You always have to weigh the trade- offs , he said, referring to hemorrhagic stroke as the major concern.

But the aforementioned 32% reduction in non-fatal heart attacks applies to the combined total of all the study participants, most of whom were men with differing levels of risk. The committee hit a snag once it came to individuals. Dr. Nissen said that he and other committee members were concerned that daily aspirin, if taken by people at a low enough risk, could cause more harm than good. Asked to define “low enough risk,” he explained that there was too much uncertainty to answer the question. “No one in the world can answer the question of who benefits and who doesn’t, and if there is no answer, then how could I vote to approve?” he asked.

The fact that women were underrepresented in the five trials (only 20% of all participants) also troubled Dr. Nissen. “It may be that the risks exceed the benefit for women,” he said, “but we simply don’t know—there is not enough data.” Still, Dr. Nissen was careful to stress that he was not against aspirin therapy for everyone, suggesting that people talk over the decision with their physicians. The FDA advisory committee “took a lot of heat,” said Dr. Nissen, referring to its decision to turn down Bayer’s petition and thus reject the prevailing medical view that aspirin therapy is good for just about everyone. “We were called flat earthers ,” he said.

The FDA is not obligated to follow the decisions made by its advisory committees, but the agency usually does. The committee’s decision, though entirely appropriate, illustrates how the current system works against consumers who want to become fully informed before they go on lifelong drug therapy. Approval would have meant a rewrite of the drug’s packet insert to include the new indication. And this, in turn, would have compelled the advisory committee to identify the appropriate group of people for whom the benefit of aspirin therapy clearly outweighs the risks. The evidence from the five trials did not provide the answer; therefore, 20 million people will continue to take daily aspirin without knowing anything about the uncertainties of the supporting research.

The advisory committee’s concerns can be contrasted with the practice guidelines aimed at physicians and published in 2002 by the U.S. Preventive Services Task Force. The Task Force concluded that the number of “cardiac events” prevented by aspirin therapy far exceeded the number of hemorrhagic strokes caused by aspirin therapy. This, too, is based on the combined results of the same five trials. When the Task Force tried to break things down for individuals, it came up with this estimation for moderate-risk men and women: “For 1,000 patients with a 3% risk of having a heart attack in the next five years, aspirin would prevent eight heart attacks but would cause one hemorrhagic stroke and three major gastrointestinal bleeding events.”

Where it concerns low-risk people, the Task Force is in agreement with the FDA advisory committee: MMMM
“…patients at low risk for coronary heart disease probably do not benefit from and may even be harmed by aspirin because the risk for adverse events may exceed the benefits…” (Annals of Internal Medicine, 1/15/02).

For More Information:

• Go to www.med-decisions.com to see one method used by the Task Force to identify different levels of risk for a heart attack. The Task Force used an additional assessment tool based on the risk information from the Framingham Heart Study, which has since become outdated.
• The transcript of the December 8-9, 2003 meeting of the Cardiovascular and Renal Drugs Advisory Committee is likely to be posted on the Internet in February or March. Go to www.fda.gov and click into “Advisory Committees.” Then go to this specific committee and its meeting date.

Maryann Napoli
January 2004