Aspirin versus Placebo Does Not Result in Significant Reduction in Vascular Events

In an intention-to-treat, double-blind, randomized controlled trial, researchers found that the administration of aspirin compared with placebo did not result in a significant reduction in vascular events among participants without clinical cardiovascular disease. Those participants were identified as having a low ankle-brachial index (ABI) based on screening a general population. The authors claimed the trial was the first to report on the effectiveness of aspirin in reducing major cardiovascular and cerebrovascular events in individuals from the general population who were free of clinical cardiovascular disease but at higher risk as identified by ABI screening. The results were published in the Journal of the American Medical Association [2010;303(9):841-848].

ABI is the ratio of systolic pressure at the ankle to the arm and is used in the diagnosis of peripheral artery disease affecting the legs. A low ABI is associated with concomitant coronary and cerebrovascular disease and, in healthy individuals, with an increased risk of future vascular events, independent of cardiovascular risk factors. A meta-analysis of 16 cohort studies of healthy individuals showed that the 10-year risk of a major coronary event in men with an ABI of ≤0.90 was 27% compared with 9% in those with an ABI in the normal range of 1.11 to 1.40. The figures for women were 19% and 6%, respectively.

This study, the Aspirin for Asymptomatic Atherosclerosis trial, was conducted from April 1998 to October 2008. It was a pragmatic intention-to-treat, double-blind, randomized controlled trial of once-daily low-dose aspirin (100 mg) versus placebo involving individuals free of clinical cardiovascular disease and with a low ABI. The authors wanted to determine whether screening the general population for a low ABI could identify a higher-risk group that might derive substantial benefit from aspirin therapy.

The study comprised men and women aged 50 to 75 years at baseline with no history of vascular disease. Between April 1998 and December 2001, volunteers were recruited from Lanarkshire, Glasgow, and Edinburgh in central Scotland. The authors mailed study invitations to individuals on Community Health Indexes that contain the age and sex of patients listed on the registers of general practitioners. Of that group of practitioners, 83% agreed that their patients could be invited for screening. The study was advertised in newspapers and on fliers posted in general practice offices and announced that only those who had not had a heart attack or stroke or who were not taking aspirin or warfarin could participate in the screening.

In this study, the ABI was calculated as the ratio of the lowest ankle pressure (lower of posterior tibial and dorsalis pedis and of left and right) to the higher pressure of either arm. Those with an ABI of ≤0.95 were entered into the trial unless they had a history of myocardial infarction, stroke, angina, or peripheral artery disease; currently used aspirin or other antiplatelet/anticoagulant agents; had severe indigestion; had chronic liver or kidney disease; were receiving chemotherapy; had contraindications to aspirin; and had an abnormally high or low hematocrit value (measured after the screening). Participants were randomized to receive 100 mg of enteric-coated aspirin daily or placebo.

After a mean follow-up of 8.2 years, 357 participants had a primary end point event (13.5 per 1000 person-years; 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27).

A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16).

An initial event of major hemorrhage requiring admission to the hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97).—Tim Casey