Barcelona, Spain - The use of low-dose aspirin in the primary prevention of cardiovascular events in healthy individuals with asymptomatic atherosclerosis is currently not warranted, according to the lead researcher of a large "real-world" study presented today at the European Society of Cardiology (ESC) 2009 Congress.
In the randomized trial of 3350 subjects deemed at high risk for cardiovascular and cerebrovascular events because of a low ankle-brachial index (ABI) (<0.95), aspirin had absolutely no effect on reducing events compared with placebo, Dr Gerry Fowkes (University of Edinburgh, Scotland) reported on behalf of the Aspirin for Asymptomatic Atherosclerosis (AAA) trialists.
However, aspirin did increase the risk of major hemorrhage.
The bleeding effect "is a real obstacle," Fowkes told heartwire. "I don't think the evidence is convincing enough as yet that aspirin should be used routinely in the general population."
The results of the trial are in conflict with findings from a meta-analysis from the Antithrombotic Trialists' (ATT) collaboration, which was published earlier this year in the Lancet [1], discussant Dr Carlo Patrono (Catholic University School of Medicine, Rome, Italy) told ESC attendees. He questioned how the results of AAA could be interpreted in light of the 12% relative risk reduction in serious cardiovascular events, largely driven by a reduction in nonfatal MI, that was seen in the ATT trial.
AAA done where the need for prevention is great
The AAA was a pragmatic trial, Fowkes explained, conducted in a deprived population in central Scotland, where rates of coronary heart disease and related mortality are high. "We wanted to get at where the problem actually existed in the population," he said.
Between 1998 and 2001, the AAA trialists invited men and women 50 to 75 years of age to undergo screening for asymptomatic atherosclerosis by measuring their ABI. A low ABI in otherwise-healthy individuals has been shown to be related to an increased risk of future cardiovascular events. Because it is simple and noninvasive, the ABI has the potential to be used as a screening test to detect high-risk individuals, Fowkes explained.
Of the more than 166 000 invitations that were sent out, the trialists ended up screening 28 980 individuals. Of this number, 3350 had a low ABI and were thus eligible to be entered into the trial.
They were randomly allocated to 100-mg enteric coated aspirin daily or to placebo and followed for a mean of 8.2 years. The primary end point of the trial was the composite of an initial fatal or nonfatal coronary event, stroke, or revascularization. Secondary end points were all vascular events, which included a composite of initial fatal or nonfatal coronary event, stroke, or revascularization, angina, intermittent claudication, transient ischemic attack, and all-cause mortality.
Patients in both groups were matched for age (mean age 62 years), gender (roughly 30% were men), and comorbidities. One-third of the study population consisted of smokers.
Aspirin had no effect in terms of reducing cardiovascular and cerebrovascular events. In all, there were 357 events, 181 (10.8%) in the aspirin group and 176 (10.5%) in the placebo group (hazard ratio 1.03, 95% CI 0.84-1.27).
Primary end-point results for aspirin vs placebo
End point
Aspirin (n=1675), n (%)
Placebo (n=1675), n (%)
Fatal coronary event
28 (1.7)
18 (1.1)
Fatal stroke
7 (0.4)
12 (0.7)
Nonfatal coronary event
62 (3.7)
68 (4.1)
Nonfatal stroke
37 (2.2)
38 (2.3)
Coronary revascularization
24 (1.4)
20 (1.2)
Peripheral revascularization
23 (1.4)
20 (1.2)
Interestingly, cancer mortality was higher in the placebo group than in the aspirin group, Fowkes noted.
Adverse events, including major hemorrhage, were greater in the aspirin group (HR 1.71, 95% CI 0.99-2.97).
Adverse events with aspirin vs placebo
Adverse event
Aspirin (n=1675), n (%)
Placebo (n=1675), n (%)
Major hemorrhage
34 (2.0)
20 (1.2)
Gastrointestinal ulcer
14 (0.8)
8 (0.5)
Fowkes pointed out that 40% of patients were noncompliant and did not take their aspirin as prescribed over the duration of the trial. Such a low compliance rate could have affected the results. "The 60% compliance rate is the typical level of compliance that you will find in the primary-prevention setting, and obviously there are many reasons that people stop taking aspirin. So whether aspirin is beneficial in clinical practice among patients who have a low ankle-brachial index and who are fully compliant with aspirin is unknown, and so our results cannot be extrapolated to that situation," he said.
heartwire asked Fowkes what he thinks may work for primary prevention in people with asymptomatic atherosclerosis, now that aspirin appears to be ineffective. "We don't have any strong evidence about what would work, but I think that given that these are high-risk individuals, it is probably reasonable to give them a statin. I think it would prove to be cost-effective to give a statin," he said. "Obviously, there is the possibility of giving a stronger antiplatelet such as clopidogrel or some of these new drugs that are being developed, but one would have to trial those properly."
AAA underpowered
Patrono said the AAA study may have been underpowered and suggested that was one reason for its negative findings. "The sample size would have to be about four times larger to achieve the power to show a 12% relative risk reduction," he said.
Other reasons: "The presence of peripheral arterial disease, whether symptomatic or asymptomatic, may render platelet activation more critically dependent on ATP than thromboxane release, and there is some experimental as well as clinical evidence supporting this possibility."
An accelerated platelet turnover associated with peripheral arterial disease—at least in some patients—may also be a cause for the discrepancy, Patrono said.
To try to dissect out potential explanations, Fowkes and Dr Colin Baigent (Oxford University, UK), lead author of the ATT trial, have agreed to see how the AAA study would fit into the ATT meta-analysis. When available, the results will be posted by the Clinical Trial Service Unit, Patrono said.
Fowkes told heartwire that there is no reason to think that the relative reduction in cardiovascular events created by aspirin should be different in the primary or secondary setting. It's just that the benefits in the secondary setting far outweigh the risks. "The absolute reduction is much higher in secondary prevention than in primary prevention, but the level of bleeding is the same. So in secondary prevention, you've got a big reduction in events and a small amount of bleeding. In primary prevention, you have a smaller amount of reduction of events, and the same amount of bleeding. These two have got to be counterbalanced in the primary-prevention situation, and that is where the concern is at the moment."
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