AAA: Aspirin Not Warranted in Healthy Subjects With Low ABI, Based on Population Screening

Shelley Wood

March 02, 2010

March 2, 2010 (Edinburgh, United Kingdom) — Results of the Aspirin for Asymptomatic Atherosclerosis (AAA) trial,showing no reduction in vascular events in asymptomatic subjects with a low ankle/brachial index (ABI) randomized to daily aspirin, have now been published in the March 3, 2010 issue of the Journal of the American Medical Association [1]. First presented at the ESC 2009 meeting and reported there by heartwire , the trial adds to mounting evidence that the risks of aspirin may outweigh its benefits in people without established cardiovascular disease.

According to lead author Dr F Gerald R Fowkes (University of Edinburgh, Scotland), investigators specifically looked at a population that falls within a gray area in the primary-prevention spectrum: they screened 28 980 men and women in the general population, all of whom were assumed to be healthy at the time of ABI screening, identifying 3350 with a low ABI.

"For individuals who have symptomatic peripheral vascular disease or coronary artery disease or a history of stroke, there's absolutely no doubt that aspirin is beneficial and reduces the incidence of future cardiovascular events," Fowkes told heartwire . "And in individuals with no history of CV disease at all, who are perfectly healthy, there is some debate about whether aspirin should or should not be used. . . . In our study, we're sort of halfway between those two situations, where we're looking at people who believe themselves to be totally healthy, with no history of CVD, but when they have an ABI they are found to have a low index, which indicates they are actually at increased risk. Our hope was that because these increased-risk individuals might behave in the same way as individuals with clinical cardiovascular disease, we might see a reduction [in CV events with aspirin] that was much bigger than any side effects such as bleeding. As it turned out, that wasn't the case in this trial."

AAA Trial Results

Between 1998 and 2008, the AAA trialists invited men and women, 50 to 75 years of age, living in central Scotland to undergo ABI screening for asymptomatic atherosclerosis. Of 28 980 individuals screened, 3350 had a low ABI and were randomly allocated to 100-mg enteric-coated aspirin daily or to placebo and followed for a mean of 8.2 years.

For the primary end point of the trial--a composite of an initial fatal or nonfatal coronary event, stroke, or revascularization--event rates at follow-up were no different between the aspirin and placebo groups. Event rates were also not significantly different for either of the trial's secondary end points: all vascular events (initial fatal or nonfatal coronary event, stroke, revascularization, angina, intermittent claudication, or transient ischemic attack) and all-cause mortality. Of note, however, adverse events, including major hemorrhage, were greater among aspirin-treated subjects than in the placebo group.

AAA: Event Rates per 1000 Person-Years

Outcome Aspirin Placebo HR 95% CI
Primary end point* 13.7 13.3 1.03 0.84–1.27
Vascular events 22.8 22.9 1.00 0.85–1.17
All-cause mortality 12.8 13.5 0.95 0.77–1.16
Major hemorrhage 2.5 1.5 1.71 0.99–2.97

*Initial fatal or nonfatal coronary event, stroke, or revascularization

Fowkes and colleagues write that "to their knowledge" the AAA trial is the first to address the use of aspirin in individuals with no known vascular disease identified as being potentially at risk based on ABI screening.

One of the questions raised about the trial when it was presented at the ESC meeting was whether it was adequately powered to detect a smaller effect of aspirin--a point addressed by the authors in their paper. The study was powered to detect a 25% proportional risk reduction, based on previous studies. The authors acknowledge now that this may have been an "overestimate," but as Fowkes points out, there's little point in looking for a lesser benefit. "If we had done a much bigger trial, we might have picked up smaller differences, but then you've got to say, What's the point of picking up those smaller differences, when you're getting that bleeding rate as well?"

Compliance over the course of the eight-year study was only 60%--another factor that might have weakened aspirin's ability to yield a benefit. But as Fowkes pointed out to heartwire , "That's probably fairly typical of what you would get in this population. That's why we say it's probably not worth screening the whole population and hoping you might get greater adherence, because you won't."

But interestingly, lower-than-optimal aspirin adherence did not erase the bleeding side effects of aspirin.

"I suspect [reduced aspirin adherence] is certainly contributing to the fact that we didn't get a reduction in cardiovascular events, but it wasn't severe enough to stop people from getting side effects," Fowkes commented.

Dr Jeffrey Berger (University of Pennsylvania, Philadelphia), who has also studied the role of aspirin in peripheral artery disease (PAD) patients, wrote the accompanying editorial [2]. He offers a few more possible explanations for aspirin's lack of benefit, including the use of enteric-coated aspirin, which might have resulted in lower bioavailability than regular aspirin; the higher proportion of women in the trial (70%--women are believed to derive less benefit from aspirin); or an ABI cut point (ABI <0.95) that was too high to capture the truly at-risk population. It may also be, says Berger, that aspirin offers little on top of other established primary-prevention therapies, such as statins--an explanation increasingly offered by experts who have studied aspirin over the years.

Pinpointing Those Who'd Primarily Benefit

There are a number of primary-prevention trials of aspirin still ongoing that may help identify subgroups who might benefit, but according to Fowkes, none that are looking at a very low-risk, peripheral vascular disease population identified by populationwide screening.

"I think obviously this calls into question" the value of screening in the general population, Fowkes said. "There is no point in doing population screening unless you have a suitable intervention that will lead to a reduction in events. Maybe if one did screen for an ABI and then used a statin plus perhaps a stronger antiplatelet we might obviously see some benefit, but that's just pure conjecture."

Fowkes also emphasized that the study does not speak to the use of ABI screening in a clinical setting, where there might be other good reasons for suspecting subclinical atherosclerosis.

"This trial casts some doubt on the merits of population screening for a low ankle/brachial index and then applying aspirin. Screening might work in the clinical setting targeting higher-risk groups, but of course we don't have evidence for that. If I were a cardiologist looking at a healthy patient with a slightly low ABI, I'd be thinking twice about whether to give aspirin."

Does It Come Down to Dose?

Commenting on the study for heartwire , Dr James Dalen (dean emeritus, University of Arizona College of Medicine, Tucson) expressed concern over the mounting messages to physicians that aspirin has no role in primary prevention.

"This is the seventh randomized controlled trial to show that aspirin in doses of 100 mg or less is ineffective in primary prevention, even in people with primary prevention who have risk factors, such as this case. There are two conclusions you can draw: one, aspirin doesn't work for primary prevention, or, and I think the answer is, two, they have the wrong dose."

He points to the Physicians' Health Study of 1989, a 22 000-patient trial, which showed a 44% reduction (p<0.001) in the risk of myocardial infaction among subjects taking 325 mg of aspirin every other day [3]. "I don't know why people don't accept that if you decrease the dose, it might be less effective. What do you think would happen if we cut people's dose of Plavix in half? I would suggest we'd have less effect."

Given the strength of the Physicians' Health Study, Dalen says it's impossible to draw the conclusion from smaller studies that aspirin might be ineffective or harmful. Asked if he worries that the bleeding risk would also increase at the higher dose, he points out that an analysis of bleeding risk by dose by the Aspirin Treatment Trialists found no increased risk between doses of 80 mg vs 160 mg daily. Even in the current AAA study, he notes, the difference in the rate of major hemorrhage was just one major hemorrhage for 1000 person-years: "It's statistically significant, but is it clinically significant?"

Until a trial using a 160-mg dose of aspirin is tested in primary prevention and proven not to work, Dalen says it's a "mistake" to assume aspirin should not be used in primary prevention. Acknowledging that his views are now the minority opinion, Dalen warned: "We have millions of people taking aspirin for primary prevention--are we going to tell them now to stop? I'm sure not going to tell people to stop. . . . We better be very sure before we tell them it isn't effective and they should stop taking it."

Fowkes disclosed receiving research support, lecture fees, and expenses from Bayer HealthCare and research support and honoraria from Sanofi-Aventis and Bristol-Myers Squibb. Disclosures for other authors are listed in the paper. Berger disclosed serving on an advisory board for AstraZeneca. Dalen has previously disclosed having no financial conflicts of interest.


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