Chronic aspirin therapy for the prevention of cardiovascular events: a waste of time, or worse?

John GF Cleland  About the author

Few therapies in cardiovascular medicine have been studied so intently and adopted so widely into clinical practice as aspirin, especially with so little evidence of long-term benefit for people with or at risk of coronary artery disease. A series of studies has shown that long-term aspirin therapy is ineffective, or worse, for the primary, secondary or tertiary prevention of cardiovascular events; however, distorted reporting of these studies, in a way that would not be tolerated for other pharmacologic agents, has led many readers to misinterpret neutral studies as showing benefit with aspirin (see Supplementary Table 1 online for a list of these investigations). To the dismay of some, but fuelled by evidence, debate about the efficacy and safety of aspirin is growing within the cardiology community. Admitting that previous advice could have been wrong is unappealing, but the need to be correct should be stronger than the desire to be consistent. International guidelines have started to recommend withdrawal of aspirin, albeit in specific populations of high-risk patients with heart disease, because of the increase in adverse effects with this drug and its failure to reduce vascular events.^{1, 2} In this Viewpoint, I will discuss why I believe that these recommendations should be extended to many other patients groups with or at risk of cardiovascular disease in whom aspirin has failed to show long-term benefit.

Why is aspirin so popular in the management of cardiovascular disease? Aspirin's popularity is a recent phenomenon—in 1986 the ISIS-1 study randomized patients to a control or intravenous-atenolol-therapy group and reported that at hospital discharge only 5% of patients were receiving antiplatelet therapy.² Two pieces of information led to a change in attitude towards aspirin. First, the ISIS-2 study—a large, robust double-blind trial—reported that a 5-week course of aspirin after a myocardial infarction reduced the risk of reinfarction and death compared with placebo.⁴ This study formed the basis for recommending short-term aspirin therapy after myocardial infarction but provided no evidence that treatment should extend beyond 5 weeks. Aspirin withdrawal studies have shown that, as with antibiotics and thrombolytic therapy, a short course of treatment can have long-term benefits.^{2, 5} Trials comparing short-term with long-term aspirin treatment are therefore required. The second major contributing factor was the meta-analysis by the Antiplatelet Trialists' Collaboration, which was state-of-the-art for its time but not robust by modern standards.⁶ This meta-analysis reanalyzed data from published trials and showed consistent bias in favor of aspirin (although later reports corrected the most extreme examples).⁷ The findings of the meta-analysis were driven largely by data from small positive trials, with a dearth of small negative trials.^{2, 3, 4} Most clinicians agree that meta-analysis is useful for confirming robust clinical trial results—which are lacking for long-term aspirin therapy—or calculating the size of trial required to provide a robust result; however, proof depending on meta-analysis alone is now generally considered weak.

Aspirin inhibits cyclo-oxygenase irreversibly in platelets. Aspirin also blocks the production of prostaglandins in the vessel wall, where they act as antithrombotics and vasodilators, and in the gastric mucosa, where they are responsible for maintaining mucosal integrity. Although inhibition of vessel-wall cyclo-oxygenase is reversible, in patients with heart disease the effects on the vasculature of even low-dose aspirin can be prolonged.^{2, 5, 8} In the setting of an acute vascular event, inhibition of platelet adhesion to the damaged endothelium appears to outweigh the risk of inhibiting vascular defence mechanisms. At other times the balance of risk and benefit can change, making treatment with aspirin futile, and might even increase the rate of myocardial infarction (see Supplementary Table 1 online).² In patients such as those with heart failure who are critically dependent on upregulation of vascular-wall vasodilator prostaglandins, aspirin is likely to be deleterious.⁸ Population studies have shown that low-dose aspirin use is a common cause of dyspepsia and chronic anemia, and is associated with an excess need for renal dialysis.^{2, 5, 9, 10} To date, patients with a history or increased risk of such problems have been excluded from clinical trials, which therefore cannot assess the true risk associated with aspirin use. Aspirin also attenuates the benefit of angiotensin-converting-enzyme inhibitors, and possibly -blockers—agents for which there is robust evidence of cardiovascular benefit.² Accordingly, on existing evidence, aspirin should only be given to carefully selected patients, for a few weeks after a vascular event.

Because older aspirin trials studied very-high-dose aspirin, it has been argued that they are not relevant to modern practice. No substantial long-term trial, however, has ever used less than 300 mg aspirin daily after myocardial infarction. Only one sizable long-term secondary prevention study used 75 mg aspirin daily, and that studied patients with chronic angina, excluding patients who had had a myocardial infarction.⁷ The study showed benefits with aspirin on nonfatal outcomes but, again, failed to show an effect on mortality. Only one substantial study, conducted in patients who had had a neurologic event, suggested a mortality reduction with long-term aspirin;⁷ however, the dose was 975 mg aspirin daily. Long-term studies using contemporary doses of aspirin following stroke showed no difference in mortality between aspirin and placebo, and only a modest reduction in nonfatal events, with no evidence of reduced disability. Studies comparing doses of aspirin and finding no difference in outcome were underpowered, and the lack of difference reported can readily be explained by no tested dose being effective. Short-term aspirin therapy (2–4 weeks) early after a stroke has shown a small benefit in mortality and disability⁷.

The rationale for prescribing aspirin to patients with or at risk of vascular disease is to try to reduce the risk of events that cause morbidity and mortality; however, morbidity needs to be defined and ranked in terms of importance. For example, preventing chronic debility resulting from a major stroke or heart failure is of great importance; avoiding the morbidity of dyspepsia and gastrointestinal bleeding might be seen as of secondary importance. So how should a minor neurologic event that resolves within 48 h, a small and uncomplicated myocardial infarction requiring hospitalization, or the development of new Q-waves indicating silent myocardial infarction be viewed? Surely preventing chronic disability rather than preventing transient events should be given priority. After all, many people are willing to suffer the pain and anxiety of surgery to overcome chronic disability. The ability to prevent short-lived events that do not result in long-term disability or death could be viewed as unimpressive for a treatment that is not entirely benign.

Aspirin should be used to treat or prevent medical problems only when the effective dose and duration of therapy is known—that is, for short-term treatment of acute vascular events and relief of pain. Aspirin should not be given to patients to achieve misguided health-service targets. International guidelines now recommend aspirin withdrawal in some patients with coronary disease, and such recommendations should be extended to other patient groups after scientific review of the relevant evidence.¹ Sensible, adequately sized trials focusing on disability and death will then be required to establish whether aspirin really works.

Competing interests

JGF Cleland was on the steering committee of the Warfarin/Aspirin Study in Heart Failure (WASH) and Warfarin and Antiplatelet Therapy in Chronic Heart Failure Trial (WATCH), which were partly funded by Dupont, Sanofi and Bristol-Myers Squibb.

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