Primary vascular prevention: The end of the road for aspirin?

For decades, aspirin has been regarded as a key antiplatelet agent that protects from vascular events and saves lives. Aspirin was previously advocated for primary prevention (PP) from vascular events in higher risk patients, such as individuals with diabetes. Surprisingly, however, the evidence for this management strategy was not based on solid evidence and the enthusiasm for this approach faded after a number of meta-analyses and clinical studies, mostly underpowered, questioned the clinical benefit of aspirin in PP.^1,2

Clearly, a large-scale outcome study was required to address the role of aspirin in PP and the scientific community sprung into action delivering not one but three studies that were recently published, which included over 47,000 individuals.

The ASCEND study investigated the effects of 100 mg/day aspirin against placebo in 15,480 patients with diabetes without clinical cardiovascular disease. Over a follow-up period of 7.4 years, an encouraging and significant 12% reduction in first serious vascular event was documented. ³ However, disappointment soon ensued when this was associated with a worrying 29% increase in bleeding events, mainly gastrointestinal, negating any clinical benefit. The ARRIVE study enrolled 12,546 individuals with moderate cardiovascular risk and randomised participants to 100 mg/day enteric-coated aspirin or placebo. Of note, individuals at high risk of bleeding and those with diabetes were excluded from the study. ⁴ Over a median follow-up of 5 years, there was no difference in two study arms in relation to the composite vascular outcome of cardiovascular death, coronary or cerebrovascular events, although the possible early beneficial effect of aspirin is puzzling. The ASPREE trial enrolled 19,114 healthy older individuals (>70 years of age) who were assigned to enteric-coated aspirin 100 mg daily or placebo. Over a median of 4.7 years, all-cause death was increased by a significant 14% in the aspirin group with an unexpected and significant increase in cancer death by 31%. ⁵ The cancer death was particularly confusing, given previous studies suggesting aspirin may protect from malignancy. ⁶

The investigators should be applauded for undertaking these challenging studies and the question that presents itself: is it time to dismiss aspirin from service and stop its use for PP? The answer may seem to be an easy ‘yes’ given the lack of efficacy and possible increase in mortality described above. On the other hand, studies may have placed high expectations on aspirin, beyond the capabilities of this agent, and therefore this ‘dismissal from service’ may be unfair. The design of various studies assumed that aspirin will offer vascular protection in highly heterogeneous groups of individuals, some on multiple vascular protective therapies, while using this agent at a fixed dose. Moreover, unlike other vascular protective therapies, the lack of a reliable thrombosis test prevented targeting the right individual with aspirin therapy and compromised efficacy/safety monitoring during use of this agent, which may have impacted on clinical outcome.

There are some facts to be acknowledged before passing the final judgement on aspirin in PP. First, aspirin is a relatively weak antiplatelet agent, which, admittedly, may be a safety advantage when used for PP but efficacy would be an issue in higher risk individuals. Second, aspirin has a short half-life and given increased platelet turnover in conditions such as diabetes, once daily dosing may not be adequate in some individuals. ⁷ Third, there is evidence to suggest that response to low-dose aspirin is weight-dependent and therefore those weighing more than 70 kg may not benefit. ⁸ Fourth, gastric cyclooxygenase inhibition by aspirin may be a factor in increased upper gastrointestinal bleeding ⁹ and thus can be argued that this agent should be combined with additional gastric protective therapies.

Rather the dismissal, aspirin should perhaps be allowed to take a ‘leave of absence’ from PP duties, while future studies are conducted. For example, studies using different dosing of aspirin, adjusted for weight or other measures of platelet function, and trials that include concomitant gastric protection should be considered. Also, we need to acknowledge that inhibition of a single thrombotic pathway may not be enough for PP, particularly in the era of effective preventive vascular therapies. It should be remembered that vascular occlusive disease is not only linked to enhanced platelet activation but also involves increased levels/activity of coagulation factors, which leads to impaired fibrinolysis. Indeed a recent study has shown that fibrin clot lysis is an independent predictor of cardiovascular mortality in high-risk individuals treated with dual antiplatelet therapy. ¹⁰ Therefore, instead of attempting to fully block one pathway, which is far from physiological, we need to consider partially blocking multiple pathways thus ‘normalising’ thrombosis risk without rendering the individual prone to bleeding events. For example, partial inhibition of both platelets and coagulation proteins may offer the best vascular protection by controlling the thrombotic milieu without significantly increasing bleeding risk.

Finally, we continue to treat with antiplatelet agents without biochemical efficacy or safety monitoring, which does not feel very 21st century. The development of a reliable test for thrombosis status will allow patient selection before starting antiplatelet therapy and will also help with monitoring response to treatment. This will ensure a balance is struck between reducing thrombosis while keeping bleeding risk to a minimum.

Even after conducting three large outcome studies, the debate surrounding aspirin for PP is likely to continue. Supporters of this agent will argue that even if fixed dose aspirin monotherapy is ineffective for PP, other strategies such as tailored doses or combination therapies need to be investigated. Those in opposition, however, will cite the lack of efficacy and the worrying side effect profile of aspirin, including the possible increase in cancer risk, as reasons to ‘move on’ and concentrate on alternative and modern antiplatelet agents. The outcome of this scientific quarrel is not that straightforward to predict; it may well be the end of the road for fixed dose aspirin in PP but we should not rule out the construction of a new road or ‘bypass’ that explores alternative ways for using this agent.