But first a word of caution, says Gilles Montalescot from the University Hospital of Pitié-Salpètrière in Paris.The major risk of aspirin, as with all NSAIDs, is bleeding.
The major risk of aspirin, as with other non-steroidal anti-inflammatory drugs, is the risk of bleeding. The most striking side effect is an increased risk of hemorrhagic stroke of 0.2 events per 1000 patient-years. A stroke is more likely to result in long-term disability than any other non-fatal vascular event. Thus, if the net cerebrovascular benefit is in favour of aspirin in secondary prevention, it is a different story in primary prevention where the protection against ischemic stroke is offset by the risk of intracranial bleeding.
The majority of the increased bleeding has a gastrointestinal tract aetiology. All aspirin dosages are associated with an increased bleeding risk, although a moderate but significant relationship between aspirin dose and bleeding has been demonstrated in clinical trials. In the Women’s Health Study, even a 100 mg dose of aspirin on alternate days was associated with an increased risk of gastrointestinal bleeding compared with placebo. However, enteric-coated or buffered aspirin preparations do not appear to influence the risk of major bleeding in the upper GI tract. Upper GI tract symptoms would prompt up to 12% of patients to interrupt treatment, a major concern in high risk coronary patients.
Numerous studies using a wide variety of ex-vivo tests have found significant variability in individual response to aspirin, with some trials suggesting a correlation between non-responsiveness and clinical outcomes. Whether higher doses and/or several takes a day of aspirin would improve clinical outcome remains so far unknown. Measuring aspirin responsiveness with bedside tests and tailoring the dose is an attractive strategy which still needs testing to demonstrate any impact on clinical outcome.
Allergies are also well known side effects of aspirin: aspirin-induced asthma, aspirin-exacerbated respiratory disease, sinusitis, aspirin-induced urticaria and/or angioedema, including laryngeal oedemas, are among the most frequent (and feared) allergic reactions reported and all can turn out to be vital complications in some patients. Although desensitisation to aspirin is possible in many patients, it remains a serious limitation for such a widely used drug.
There is conflicting data suggesting that the efficacy of aspirin may be sex- and or age-dependent. In a meta-analysis of primary prevention trials, aspirin was associated with a significant reduction in MI among men with no effect on stroke, while women experienced a lower stroke rate with no effect on MI. These findings were not confirmed in a more recent meta-analysis, especially in secondary prevention. Although the elderly and women are more exposed to bleeding in general, they do not represent a particular safety concern for aspirin prescription.
In secondary prevention, many interventions (statins, other antiplatelet agents, revascularization) can now decrease the risk of further vascular events. Subsequently, the absolute benefit of adding aspirin to these interventions may appear limited. However, in secondary prevention the net benefit of adding aspirin clearly exceeds the bleeding hazards, irrespective of age or sex. In contrast, the benefit is more uncertain in primary prevention.
While the benefits of aspirin exceed the risks of bleeding in most patients with overt arterial disease, the risk/benefit ratio is marginal in low-risk populations, says Carlo Patrono from the Catholic University School of Medicine in Rome.
The efficacy and safety of aspirin in cardiovascular prevention have been evaluated in several populations, ranging from apparently healthy persons at low risk to patients presenting with an acute MI or ischaemic stroke. Among patients with occlusive vascular disease, both individual studies and a meta-analysis of all randomised trials show that low-dose aspirin (in a range of 75-162 mg daily in most trials) reduces the risk of a serious vascular event by approximately 25%.
This figure represents a composite of a one-third reduction in non-fatal MI, a one-fourth reduction in non-fatal stroke, and a reduction by one-sixth in death from a vascular or unknown cause.
In an acute ischaemic event, a very substantial benefit is achieved after a few weeks of therapy. Thus, in acute MI and acute ischemic stroke one month of treatment prevents 40 and ten major vascular events, respectively, for every 1000 patients. Long-term aspirin therapy among a wide range of patients with vascular disease, in whom the annual risk of a serious vascular event ranges from 4 to 8%, typically prevents at least ten to 20 fatal and non-fatal vascular events for every 1000 patients treated for one year.
In the recently published ATT collaborative meta-analysis of six 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 one fifth in non-fatal MI. The net effect on stroke and vascular mortality was not significant.
In both primary and secondary prevention trials the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women, and for people below and above the age of 65. However, the size of the absolute benefit of aspirin in the primary prevention trials was about 25 times smaller than that found in the secondary prevention trials. Whereas the benefits of aspirin exceed the risks of bleeding in most patients with clinically overt arterial disease, the risk/benefit ratio is marginal in low-risk populations.
At least four new trials are ongoing to identify some particular category of individual in whom primary prevention with aspirin may be of definite net benefit. One such category might be adults with diabetes but no known vascular disease, for whom aspirin is presently recommended in the absence of convincing evidence for its efficacy and safety. ASCEND and ACCEPT-D investigators are now recruiting 15000 patients with diabetes into placebo-controlled aspirin trials, with expected completion in around five years.
Additional benefits of long-term aspirin therapy in preventing other serious outcomes, such as colorectal cancer, are not yet established by randomised clinical trials. However, the demonstrated efficacy of low-dose aspirin in reducing the risk of recurrence of sporadic colorectal adenomas is promising in this respect; aspirin warrants further investigation into its chemopreventive properties.
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