List of Authors:
FGR Fowkes, JF Price, MCW Stewart, I Butcher, GC Leng, ACH Pell, PAG Sandercock, KAA Fox, GDO Lowe, GD Murray for the Aspirin for Asymptomatic Atherosclerosis trialists, University of Edinburgh
The effectiveness of antiplatelet therapy in preventing major vascular events in patients with known cardiovascular disease is well established but the value of antiplatelets in primary prevention remains unclear. The ankle brachial index (ABI) which is the ratio of systolic pressure at the ankle to that in the arm is an indicator of subclinical atherosclerosis and has been shown convincingly in many cohort studies of healthy populations to predict the risk of major vascular events independently of established cardiovascular risk factors. Thus individuals free of clinical cardiovascular disease but with a low ABI may be a high risk group that could benefit from antiplatelet therapy in a similar way to those with established clinical disease. Since the ABI is a simple, inexpensive, non-invasive test, it has the potential to be used in cardiovascular screening programmes, but whether those with a low ABI should be prescribed antiplatelets such as aspirin is unknown.
From April 1998 to December 2001, 28,980 men and women aged 50 to 80 years and free of cardiovascular disease were recruited from GP age sex registers in Lanarkshire, Glasgow and Edinburgh in Scotland and had an ABI screening test. 3350 with a low ABI (=0.95) were entered into the trial and randomised to 100mg enteric coated aspirin or matching placebo. The sample size of 3350 gave 80% power at 5% significance level (2 sided) to detect a reduction in the proportion of patients with at least one primary endpoint from 12% on placebo to 9% on aspirin.
Subjects entered into the trial had a clinic follow up visit at 3 months and 1 year. Subsequent follow up for a mean of 8.2 years was annually by telephone with an intervening 6 monthly letter. Contact has been maintained with 95% of survivors. At 5 years, 2557 subjects (85% of survivors) had a detailed clinical follow up examination. Cardiovascular events and deaths have also been ascertained by flagging of GP notes, review of hospital discharges in Scotland using record linkage, and flagging of deaths at NHS Central Registry. The Outcome Events Committee provided confirmation of events by review of medical records and death certificates.
The primary endpoint was a composite of initial fatal or nonfatal coronary event or stroke or revascularisation. The two secondary endpoints were (1) all initial vascular events defined as a composite of a primary endpoint event or angina, intermittent claudication or transient ischaemic attack; and (2) all cause mortality.
A total of 357 participants had a primary endpoint event (13.5 per 1000 person years, 95%CI 12.2 to 15.0). No statistically significant difference was found between those allocated to aspirin or placebo (181 v 176 events) (hazard ratio [HR] 1.03, 95% CI 0.84 to 1.27). A vascular event comprising the secondary endpoint occurred in 578 participants (22.8 per 1000 person years, 95% CI 21.0 to 24.8) and no statistically significant difference was found between the aspirin and placebo groups (288 v 290 events) (HR 1.00, 95% CI 0.85 to 1.17). All cause mortality was similar in both groups (176 v 186 deaths) (HR 0.95 95% CI 0.77 to 1.16). An initial event of major haemorrhage requiring admission to hospital occurred in 34 (2%) of participants in the aspirin group and 20 (1.2%) in the placebo group. (HR 1.71, 95% CI 0.99 to 2.97).
These findings do not support the routine use of aspirin for the prevention of vascular events in the context of ABI screening in the general population.
A low ankle brachial index (ABI) indicates peripheral atherosclerosis in the legs and an increased risk of cardiovascular and cerebrovascular events. Some guidelines recommend antiplatelet prophylaxis for asymptomatic individuals with a low ABI, in the absence of direct trial evidence. The aim of the AAA trial was to determine the efficacy and safety of low-dose aspirin in preventing major vascular events in subjects with no history of vascular disease but with asymptomatic atherosclerosis as indicated by an ABI ≤0.95.
The primary end-point of the study was a composite of initial fatal or non fatal coronary event or stroke or revascularization. The trial was powered to detect a 25% proportional risk reduction in major vascular events. After ABI screening, 3350 men and women (about 70%) aged 50 to 75 years (mean age, 62 yr) were allocated randomly to enteric coated aspirin 100 mg once daily or placebo. The mean duration of follow-up was 8.2 years. Overall, participants were assessed as compliant with the study medication for 60% of participant years of follow-up.
A total of 357 subjects had one or more validated primary endpoint events, resulting in an incidence of 1.4 per 100 person years. No statistically significant difference was found between the aspirin and placebo groups (181 vs 176 events, HR 1.03, 95%CI 0.84 to 1.27). All cause mortality was similar in both groups. An initial event of major bleeding requiring hospital admission occurred in 34 (2%) of participants in the aspirin group and 20 (1.2%) in the placebo group (HR 1.71, 95%CI 0.99 to 2.97).
How are these apparently negative findings to be interpreted in the light of the recent Antithrombotic Trialists’ (ATT) collaborative meta-analysis of aspirin trials? In the 6 primary prevention trials among 95000 individuals at low average risk, aspirin allocation yielded a 12% proportional reduction in serious vascular events, due mainly to a reduction of about a fifth in non fatal myocardial infarction. The net effect on stroke was not significant and vascular mortality did not differ significantly. Aspirin allocation increased major gastrointestinal and extracranial bleeds by about 50%.
If the true effect of aspirin in people with asymptomatic atherosclerosis was a 12% reduction in risk (as in the ATT meta-analysis), then the sample size of the AAA trial would have had to be about 4 times larger to achieve the intended statistical power. For each outcome, there was substantial overlap between the AAA and ATT primary prevention results, so lack of power (amplified by relatively poor compliance) does seem to provide a reasonable explanation for the AAA null findings. In fact, an updated meta-analysis that includes the major vascular events from the AAA trial does not indicate any definite evidence of heterogeneity between the AAA and the other 6 trials for any single endpoint (ATT Collaboration, unpublished).
Other explanations may help interpreting the AAA results. Thus, it has been suggested that the presence of peripheral arterial disease (PAD), whether symptomatic or asymptomatic, may render platelet activation more critically dependent on ADP than TXA2 release. Moreover, accelerated platelet turn-over associated with PAD may be responsible for faster renewal of unacetylated platelet COX-1, thereby blunting the antiplatelet effect of low-dose aspirin given once daily. Until additional information is available, perhaps the most reliable estimate of aspirin effects on particular vascular outcomes in people with asymptomatic atherosclerosis may be derived from the updated ATT meta-analysis.