Don’t use aspirin for primary prevention of cardiovascular disease

The clinical problem

Cardiovascular disease accounted for around two million deaths in the European Union in 2000.1 Daily low dose aspirin is established in the secondary prevention of cardiovascular disease.1 2 3 4 In primary prevention, however, use of low dose aspirin is unlicensed in the United Kingdom, and published evidence does not support the assumption that the benefits clearly outweigh the harms. So the routine practice of starting patients on such treatment for primary prevention of cardiovascular disease should be abandoned.

The evidence for change

Whether the benefits of aspirin in people with no history of cardiovascular disease outweigh the risks has been doubted.2 5This is partly because long term, low dose aspirin therapy substantially increases the likelihood of gastrointestinal haemorrhage.6 Also, published evidence has never unequivocally supported the use of aspirin in this setting, and accumulating data have further undermined such practice.

A meta-analysis of six randomised controlled trials (involving a total of 95 000 participants) investigated aspirin for the primary prevention of cardiovascular disease.5 Aspirin use reduced serious vascular events by about 0.07% per year (0.51% per year with aspirin v 0.57% per year with control treatment, P=0.0001). This was due mainly to an absolute reduction of about 0.05% in the likelihood of non-fatal myocardial infarction (0.18% per year v 0.23% per year with control treatment, P<0.0001; number needed to treat per year around 2000). However, aspirin resulted in an absolute increase in major gastrointestinal or other extracranial bleeding of about 0.03% per year (0.10% per year v 0.07% per year, P<0.0001; number needed to harm per year around 3300). Rates of all cause mortality, death due to coronary heart disease, and stroke did not differ significantly between the aspirin and the control groups. The proportional reduction in serious vascular events did not depend significantly on age, sex, blood pressure, history of diabetes, or predicted risk of coronary heart disease.

Other systematic reviews and a recently published randomised trial support these findings.7 8 9 10 In a sex specific meta-analysis of the six primary prevention trials included in the Antithrombotic Trialists’ Collaboration meta-analysis,5 aspirin treatment for a mean of 6.4 years resulted in an average absolute benefit of around 3 cardiovascular events prevented per 1000 women and 4 cardiovascular events prevented per 1000 men.7 This was offset by an additional 2.5 major bleeding events per 1000 women and 3 major bleeding events per 1000 men. A review that assessed five randomised controlled trials of antiplatelet agents for primary or secondary prevention in people with hypertension found that aspirin did not reduce the likelihood of stroke or “all cardiovascular events” compared with placebo in patients with raised blood pressure and no prior cardiovascular disease. Overall, the magnitude of benefit with aspirin was similar to the magnitude of harm.8 A third review assessed six randomised controlled trials of aspirin that included people with diabetes and no pre-existing cardiovascular disease; it found no reduction in the likelihood of major cardiovascular events or all cause mortality with aspirin as primary prevention in people with diabetes.9

The Aspirin for Asymptomatic Atherosclerosis trial10 randomised 3350 people aged 50-75 without clinically evident cardiovascular disease, but with an ankle brachial index of 0.95 or less detected on screening (a risk factor for cardiovascular events), to receive enteric coated aspirin 100 mg daily or placebo. At a mean follow-up of 8.2 years, aspirin was no more effective than placebo at reducing the primary endpoint of fatal or non-fatal coronary event, stroke, or revascularisation.

With aspirin for primary prevention, the overall absolute reduction in disabling or fatal cardiovascular events seems small and at least partially offset by an increase in serious intracranial and extracranial bleeds.11 Currently available trials do not seem to justify general guidelines advocating the routine use of aspirin for primary prevention in apparently healthy people, and this conclusion holds regardless of such individuals’ gender, blood pressure, or predicted risk of cardiovascular disease, or of whether they have a history of diabetes.11

Barriers to change

Several guidelines published between 2005 and 2008 recommended aspirin for the primary prevention of cardiovascular disease in various groups of patients, including certain patients with type 2 diabetes,3 4 12 those with a cardiovascular disease risk of 20% or more over 10 years,3 4 and those with a 10 year risk of cardiovascular disease mortality over 10%.1 The Scottish Intercollegiate Guidelines Network’s recently published guideline on management of diabetes states that low dose aspirin is not recommended for primary prevention of vascular disease in patients with diabetes.13 However, the British Hypertension Society has recently reaffirmed its guidance promoting aspirin for primary prevention.14 These guidelines, coupled with the acceptance that low dose aspirin is useful for secondary prevention, may have led to widespread prescribing of aspirin for primary prevention, as well as over the counter purchases of the drug for self medication. It is also worth noting that risk factors that predict vascular events also predict haemorrhagic events,5 so patients who will benefit from aspirin can be identified on the basis of risk scores only if they have already had a vascular event.

How should we change our practice?

Low dose aspirin should not be routinely used for primary prevention of cardiovascular disease. Current evidence has not identified a worthwhile net benefit from such treatment, even in specific subgroups such as patients with raised blood pressure or diabetes. Furthermore, such treatment is associated with a potential risk of serious bleeds. All those currently taking aspirin for primary prevention should be reviewed individually, and the decision to stop or continue treatment should be made with these patients after fully informing them of the available evidence.