Aspirin for primary cardiovascular disease prevention: what we know and what we don’t know

Abstract

Aspirin has become one of the most widely prescribed medications in pharmaceutical history since its successful synthesis in the mid-to-late 19th century, having initially been utilised for its anti-inflammatory and analgesic properties. With cardiovascular disease becoming an ‘epidemic’ in the three decades after World War II, the discovery of the cyclooxygenase inhibitor properties of aspirin, and thus its antiplatelet role, led to aspirin becoming the cornerstone in the secondary prevention of cardiovascular events. Indeed, many meta-analyses have confirmed a 20–25% risk reduction in further cardiovascular events, including myocardial infarction, stroke and cardiovascular death. However, with increasing use of oral anticoagulants with newer P2Y12 inhibitor agents, aspirin is being discontinued. The key principles of pharmacotherapy for primary prevention lie in choosing a cheap and easily accessible drug with a favourable risk-to-benefit ratio in the desired population. The first large-scale aspirin for primary prevention studies were conducted in the late 1970s and early 1980s, namely, the British Doctors Study and the Physicians Health Study in the United States, published in 1988 and 1989 respectively. Although both studies demonstrated a significant reduction in non-fatal myocardial infarctions (25% and 44%, respectively), there were trends towards increased bleeding, and the effects on all-cause mortality were inconclusive. However, these findings were from an era with modestly efficacious anti-hypertensive agents, no effective lipid-modifying therapy and higher smoking rates than the contemporary population. In addition, the aspirin doses used at 500 mg daily and 325 mg alternate daily are much higher than those recommended today. Excluding studies published in 2018, nine other trials of varying sizes occurred over the subsequent three decades in total, the largest being the Women’s Health Study, which randomised almost 40 000 patients examined aspirin as a primary prevention agent. Of the 11 trials, 6 identified a statistically significant protection against non-fatal myocardial infarctions, with a pooled analysis producing a relative risk of 0.78 (95% confidence interval 0.71–0.87). Yet, the only trial that demonstrated an overall reduction in cardiovascular mortality had an exceptionally low event rate. Furthermore, subgroup analysis across the trials demonstrated that, for high-risk patients who benefitted the most from aspirin, there had been an absolute risk reduction in non-fatal myocardial infarctions of 14.3 events per 1000 person-years from a baseline risk of