FDA committee votes not to approve aspirin for the primary prevention of MI

Gaithersburg, MD - The evidence supporting the use of aspirin for the primary prevention of MI failed to hold up to the scrutiny of the FDA's Cardiovascular and Renal Drugs Advisory Committee at its most recent December 8, 2003 meeting.

The committee voted overwhelmingly11 votes against and three votes for approvalto reject the petition sought by Bayer Corp to approve aspirin for the reduction of the risk of a first MI in moderate-risk patients, those with a 10-year coronary heart disease risk >10%.

Despite the existing data, which consisted of five major clinical trials, the committee felt the evidence supporting the extended label for aspirin was inconsistent at best or lacking at worst.

"My vote of no is not a vote that is based on my conclusion that we've established lack of favorable benefit to risk in this setting," said Dr Thomas Fleming (University of Washington, Seattle). "It is rather based on the fact that there is a paucity of data in the setting in which we are truly asked to make a judgment."

During the meeting, committee members considered evidence from a meta-analysis of five major clinical trials examining the role of aspirin in the primary prevention of cardiovascular events. The available evidence consisted of more than 55000 low- to high-risk patients enrolled in primary-prevention trials.

However, of the studies presented, including the Physician's Health Study (PHS), the British Doctor's Trial, (BDT), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) trial, and the Primary Prevention Project (PPP), only TPT studied moderate-risk patients, the patient population under consideration for the extended label.

Moreover, while the studies were large, most failed to meet their primary end point. Adverse events were also infrequent, with patients treated for only an average of 3.8 years, forcing the FDA to extrapolate benefit and risk from the trials.

According to evidence presented on behalf of the sponsor, treating 1000 moderate-risk patientsthose with a 10-year risk of CHD >10%would be expected to prevent 14 MIs over 5 years. In this same population, the rate of 0 to 2 hemorrhagic strokes and 2 to 4 gastrointestinal bleeds would be expected per 1000 patients receiving aspirin therapy.

"We are being asked to opine on a group of trials that were largely negative on their primary end point," said Dr Steve Nissen (Cleveland Clinic, OH). "The minute you start to go there, you're in some trouble. It's a very slippery slope when you try to interpret data from trials negative on their primary end point, picking out some things that looked pretty good and choosing to emphasize the benefits from those secondary analyses."

While the five studies showed about a 32% reduction in nonfatal MI, the results were not consistent for fatal MI, with a clear reduction in only one study. There was also no beneficial effect on cardiovascular deaths and a potential increase in the risk of stroke. Concerns were also raised about the definition of MI, with only one trial selecting silent non-Q-wave MI as a secondary end point.

"In a certain sense, I would consider silent MIs to be a level of surrogate less clinically relevant in this continuum," said Fleming. "But when I see nonfatal MI trends that aren't translating into other domains of benefit, and then I see the single study that looks at silent MIs and [the results] go in the wrong direction, then I begin to wonder whether our measurement of who had an MI or not is capturing the essence of overall cardiovascular influence that we're having on these individuals."

Dr Eric Topol (Cleveland Clinic), who spoke on behalf of Bayer, said the most salient aspect of the trials was the greater than 30% reduction in nonfatal MIa reduction equivalent to results seen in the secondary-prevention studiesand took exception to the FDA's focus on silent MI as an end point.

"The issue about silent MI is somewhat disturbing to me because the trials did not use silent MI as their primary end point and from the very outset it has never been part of the outcome data of these trials," said Topol. Available silent MI data are also compromised by lack of time to event and lack of ability to define the infarctions, said Topol.

However, to unequivocally answer the question about aspirin's benefit in primary prevention, without extrapolating from low-risk patient populations, Fleming said further study is still needed. A seven-year trial with approximately 15000 patients would be able to assess aspirin's benefit in preventing future cardiovascular events in moderate-risk patients.

With the meta-analysis having failed to provide clear evidence supporting the extension of aspirin into primary prevention, Nissen agreed that a prospective clinical trial is needed.

"Given all the extrapolation that one has to do, I have no idea about what to say about women, the elderly, or people with concomitant hypertension," said Nissen. "How do I write a reasonable or meaningful label for such a use?"

Dr Beverly Lorell (Harvard University, Boston, MA) also voted against approving aspirin for the primary prevention of MI in moderate-risk patients, although she does see benefit in reducing the risk of nonfatal MI.

"I do think the evidence in its totality supports the use of aspirin for primary prevention of nonfatal MI, and that is how I would answer that question," said Lorell, adding that the data "remain ambiguous on the end point of fatal MI and all-cause mortality." Despite the recognition that further trials are needed to establish the patient population in which the benefit-to-risk ratio could be firmly established, Lorell doubts such a trial is possible.

"I think it would be profoundly difficult in the US in the year 2004 to do any study except to revisit low-risk patients and those patients who sit right on the border between low and moderate risk," said Lorell.

Dr Alan T Hirsch (University of Minnesota Medical School, Minneapolis), who voted yes for the extended indication, admitted he was not overly impressed by the data.

Still, Hirsch said he believes the studies do show a strong benefit toward reducing nonfatal MI, despite concerns about silent non-Q-wave infarctions. While there was adequate information to recommend the approval of aspirin in the primary prevention of MI, he said it is difficult to identify the patient population for whom the benefit exceeds the risk. The signal of benefit, however, remains strong enough to vote for approving the extended label, he said.

What plagued the FDA committee throughout the session was its inability to completely rule out harm, particularly the risk of hemorrhagic stroke, even if that effect was only modest.

"Stroke is an increasingly important end point," said Nissen. "Particularly among older patients and among hypertensive patients, I worry about hemorrhagic stroke because I know what the consequences of that are and it is a far worse outcome than an MI for most patients."

According to Fleming, the evidence remaining for the FDA to sift through showed effects that did not parallel those seen in the primary-prevention setting, especially with regard to important end points such as fatal MI and all-cause mortality.

"It leaves me in the end with a sense that it just may be that there is a positive benefit to risk if we can target the right population," said Fleming. "The question today isn't does aspirin work. We know it works."

However, in a primary-prevention setting, Fleming said he remains unconvinced about targeting a high-enough-risk group where the benefit would offset the known and constant negative effects.

Panel advisory member Dr Edward Pritchett (Duke University Medical Center, Durham, NC) summed up the discordance between the recommendations of the FDA and the practice, or at least the instincts, of a majority of cardiologists.

While he said the evidence simply wasn't sufficient to approve the extended label for aspirin, he said he takes an aspirin everyday and recommends his patients do so too.

Heartwire from Medscape © 2003 

Cite this: FDA committee votes not to approve aspirin for the primary prevention of MI - Medscape - Dec 09, 2003.