Aspirin for prevention of cardiovascular eventsBMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1806 (Published 16 October 2008) Cite this as: BMJ 2008;337:a1806
- William R Hiatt, professor of medicine
- 1University of Colorado Denver School of Medicine, Colorado Prevention Center, Denver, CO 80203, USA
In the linked randomised controlled trial (doi:10.1136/bmj.a1840), Belch and colleagues assess whether aspirin and antioxidants, given together or separately, reduce cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease.1
The use of aspirin for secondary prevention of cardiovascular events in patients with coronary or cerebrovascular disease is well established and is based on extensive evidence from the Antithrombotic Trialists’ Collaboration.2 That meta-analysis found that aspirin was beneficial in patients with acute myocardial infarction or ischaemic stroke; unstable or stable angina; and those with previous myocardial infarction, stroke, or cerebral ischaemia. However, not all patients with cardiovascular disease respond to aspirin, as shown by a recent meta-analysis of aspirin trials in peripheral artery disease.3
In contrast, studies evaluating the possible benefits of aspirin for primary prevention in patients without cardiovascular disease have been consistently negative. A review by the United States Food and Drug Administration (FDA) of the proposed labelling of aspirin for primary prevention in 2003 evaluated five primary prevention trials and found that they were all negative for their primary end point.4 Further examination of those trials in the higher risk subgroups (Framingham risk score greater than 8-10% a decade) and in patients with diabetes also failed to show a benefit of aspirin. On the basis of this assessment, the FDA did not extend the labelling of aspirin for primary prevention.
Subsequent to the FDA meeting, the women’s health study—a randomised trial of 39 876 healthy women treated with aspirin or placebo—also failed to show a significant improvement for the primary end point (prevention of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes; P=0.13).5 But rather than emphasising this negative conclusion, the authors focused on a subgroup analysis that led them to conclude that aspirin reduced the risk of stroke in women.
The physicians’ health study randomised 22 071 healthy men to aspirin or placebo and found no benefit for the primary end point of cardiovascular mortality, although a subgroup analysis found that aspirin prevented non-fatal myocardial infarction in men.6 The major cardiovascular event rates in these two key primary prevention studies were less than 1% a year.
Despite the consistently negative evidence from trials, guidelines provide inconsistent recommendations on the use of aspirin to prevent cardiovascular events in healthy subjects at higher risk who do not have existing cardiovascular disease, particularly patients with diabetes.7 The assumption is that the positive findings of aspirin in patients with symptomatic coronary or cerebrovascular disease can be extrapolated to these high risk populations without clinical evidence of cardiovascular disease.
Other groups at high risk include patients with markers of systemic atherosclerosis, such as peripheral artery disease. In a recent meta-analysis, an ankle brachial index of less than 0.90 (indicating peripheral artery disease) was associated with a doubling of the clinically assessed 10 year risk of major cardiovascular events after adjusting for the baseline Framingham risk score in each of the major risk groups.8 For example, women at intermediate risk with a normal ankle brachial index had an annual risk of major cardiovascular events of 1.1%, but in women with an abnormal ankle brachial index (<0.90) the risk was 2.5% a year.
In this context, Belch and colleagues’ trial compared the effects of aspirin and antioxidants (using a factorial design) on the primary prevention of fatal and non-fatal major cardiovascular events in a high risk population. Patients were eligible if they had type 1 or type 2 diabetes and evidence of asymptomatic peripheral artery disease, defined by an ankle brachial index less than 1.00. More than 1200 patients were enrolled and followed up to eight years. At baseline, participants had a mean age of 60 years and an average ankle brachial index of 0.90. The observed risk of a major cardiovascular event was 2.9% a year, much higher that that seen in the previously noted primary prevention trials (driven by age of the population and the presence of diabetes and peripheral artery disease). Patients randomised to aspirin had 116 primary fatal and non-fatal cardiovascular events compared with 117 in the control group (hazard ratio 0.98, 95% confidence interval 0.76 to 1.26). No significant difference in major cardiovascular events was seen between the antioxidant treatment group and the placebo group. Although no significant difference was seen between the rate of gastrointestinal bleeding in each group, there was a trend for a greater incidence of gastrointestinal symptoms, including dyspepsia, in patients randomised to aspirin.
Belch and colleagues’ study supports the observations from six well conducted randomised control trials that found no benefit of aspirin for primary prevention, even in higher risk groups. The findings are also consistent with the previous report of no benefit of aspirin in patients with peripheral artery disease.3 What is striking about the negative effect of aspirin is that people in Belch and colleagues’ study were at particularly high risk given their age and the presence of diabetes and asymptomatic peripheral artery disease, with an event rate of about 3% a year.
These result support the concept that risk assessment alone cannot predict which patients will benefit from aspirin. In fact, the only predictor of clinical response to aspirin is a history of a major coronary or cerebral ischaemic event, as defined by the previous meta-analysis.2 The mechanisms of this differential response to aspirin are not known but clearly suggest that patients who respond to aspirin must have a history of clinical, symptomatic cardiovascular disease. This is in sharp contrast to the evidence that statins, for reducing concentrations of low density lipoprotein cholesterol, and drugs for treating hypertension have clinical benefit that extends to all risk groups, including those with and without cardiovascular disease. In these examples, the difference between primary and secondary prevention is only in the absolute reduction in risk because primary prevention populations have a lower absolute risk of cardiovascular events but receive the same relative benefit from the treatment.
A total of seven well controlled trials now show that aspirin has no benefit for primary prevention of cardiovascular events, even in people at higher risk. Although aspirin is cheap and universally available, practitioners and authors of guidelines need to heed the evidence that aspirin should be prescribed only in patients with established symptomatic cardiovascular disease.
Cite this as: BMJ 2008;337:a1806
Competing interests: WRH served on the US Food and Drug Administration cardiovascular and renal drugs advisory committee that reviewed aspirin in 2003.
Provenance and peer review: Commissioned; not externally peer reviewed.