By Paul A. Gurbel, MD, and Udaya S. Tantry, PhD

Platelet Focus | As one of the oldest and most widely prescribed pharmacologic agents, aspirin is the bedrock of all antithrombotic therapies for both primary and secondary prevention of cardiovascular disease (CVD). Around 40,000 tons of aspirin (or 125 billion 325 mg tablets) are produced every year across the globe. In the United States alone, more than 50 million people, about 36% of the adult population, take about 10 to 20 billion aspirin tablets regularly for primary and secondary prevention of cardiovascular disease (CVD).^1,2

More than half a century ago, Lawrence Craven conducted informal clinical trials with aspirin for the primary prevention of myocardial infarction (MI), and the positive outcomes he saw led him to recommend aspirin therapy for primary CVD prevention in men 45-65 years old.³ These early recommendations persist in today's current guideline recommendations: the US Preventive Services Task Force recommends aspirin for men aged 45-79 to reduce risk of MI and for women aged 55-79 to reduce risk of ischemic stroke when a net benefit (based on various methods that provide estimations of coronary heart disease risk).⁴

Recently, though, after reviewing the currently available data, the FDA does not believe the current evidence base supports the general use of aspirin for primary prevention of MI and stroke, and should not be routinely used due to the serious risks of cerebral and GI bleeding. Nine major trials involving about 100,000 patients have examined the benefit of aspirin for primary prevention.

In 2009, a meta-analysis of the first six primary prevention trials performed by the Antithrombotic Trialists' (ATT) Collaboration revealed that aspirin therapy was associated with an 18% proportional reduction in any major coronary event (HR = 0.82; p = 0.00002). This was mainly driven by a 33% reduction in non-fatal MI (HR = 0.77), with no effect on stroke (HR = 0.95; p = 0.4) or vascular mortality (HR = 0.97; p = 0.7). The significant increase in major GI and other extracranial bleeding (HR = 1.54; p < 0.0001) led the authors to conclude that aspirin is of uncertain net value for primary prevention.⁵ This review also demonstrated that aspirin therapy was associated with a minor and uncertain reduction in all-cause mortality (HR = 0.96 at 20 years) and a nonsignificant difference in total cardiovascular mortality (RR = 0.85); however, aspirin therapy was associated with a significant increase in GI bleeding (RR = 1.37), major bleeding (RR = 1.62), and hemorrhagic stroke (RR = 1.38).

Ultimately, the authors concluded that the benefit of aspirin therapy for primary prevention of CVD remains statistically uncertain. Two other meta-analyses of primary prevention trials reported similar questionable benefits, but an increase in hemorrhagic stroke and major bleeding associated with aspirin therapy.^6,7

This increase in bleeding events could be attributed to improved treatments for CVD or to changes in underlying risk and lifestyle factors in recent years. There are also controversies surrounding aspirin as primary prevention in patient populations, such as those with diabetes and the elderly.

More studies are needed, particularly to address the heterogeneity in thrombotic risk; the following are currently under way:

• The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study (n = 12,500) is designed to demonstrate the efficacy and tolerability of 100 mg entericcoated aspirin versus placebo in the prevention of fatal and nonfatal MI, fatal and nonfatal stroke and cardiovascular death in a population with no history of known CVD who are at moderate risk of major coronary heart disease events
• A Study of Cardiovascular Events iN Diabetes (ASCEND) trial (n ~10,000) is designed to study the effects of aspirin and of omega-3 fatty acids in patients with diabetes
• The ASPirin in Reducing Events in the Elderly (ASPREE) trial will enroll 19,000 healthy people aged ≥70 years to determine whether low-dose aspirin (100 mg/day) will extend the duration of healthy life in an ageing population and also examine whether the potential benefits of aspirin outweigh the risks of severe bleeding in this age group
• The Japanese Primary Prevention Project (JPPP) will enroll 10,000 Japanese patients aged 60-85 years and with hypertension, hyperlipidemia, and/or diabetes patients and evaluate the ability of low-dose (100mg/day), enteric-coated aspirin to prevent CVD events.

There are serious limitations in our ability to identify patients who would benefit most from primary prevention with aspirin, as well as the optimal dose of aspirin to employ. In order to better identify these patients, we believe that a more complete assessment of cardiovascular risk—beyond commonly used demographic variables—is needed. To that end, we suggest that mechanistic substudies should be incorporated into clinical trials that provide identification of atherosclerosis burden, plaque vulnerability, inflammation, and thrombogenicity.

References

1. Warner TD, Mitchell JA. Proc Natl Acad Sci U S A. 2002;99:13371-3.
2. Campbell CL, Smyth S, Montalescot G, Steinhubl SR, et al. JAMA. 2007;297:2018-24.
3. Craven LL. Miss Valley Med J. 1953;75:38-44.
4. US Preventive Services Task Force. Ann Intern Med. 2009;150:396-404.
5. Antithrombotic Trialists' Collaboration. Lancet. 2009;373:1849-60.
6. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Arch Intern Med. 2012;172:209-16.
7. Raju N, Sobieraj-Teague M, Hirsh J, et al. Am J Med. 2011;124:621-9.

Keywords: CardioSource WorldNews Interventions

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