Aspirin for Everyone?

Abstract & Commentary

By Allan J. Wilke, MD, Professor, Department of Introduction to Clinical Medicine, Ross University School of Medicine, Commonwealth of Dominica.

This article originally appeared in the March 15, 2012, issue of Internal Medicine Alert. At that time it was peer reviewed by Gerald Roberts, MD, Assistant Clinical Professor of Medicine, Albert Einstein College of Medicine, New York, NY. Dr. Wilke and Dr. Roberts report no financial relationships relevant to this field of study.

Synopsis: Aspirin can reduce the risk of nonfatal myocardial infarction, but not mortality, in people without coronary vascular disease, at the expense of increased risk of bleeding. It should not be routinely recommended.

Sources: Seshasai SR, et al. Effect of aspirin on vascular and nonvascular outcomes: Meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:209-216. Mora S. Aspirin therapy in primary prevention: Comment on "Effect of aspirin on vascular and nonvascular outcomes." Arch Intern Med 2012;172:217-218.

Since 2009, the U.S. Preventive Services Task Force (USPSTF) has recommended the use of aspirin (ASA) "for men age 45 to 79 years when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage" and "for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage."1 These recommendations were based on a systematic review published in the Annals of Internal Medicine. Use of ASA for the secondary prevention of cardiovascular disease (CVD) is well established, but its use for primary prevention is less certain. There is an increased risk for gastrointestinal (GI) bleeding that accompanies ASA use that must be factored into the risk-benefit analysis. Since the 2009 publication, three additional articles have been published that were not included in the review.4-6 Seshasai and colleagues have now performed a meta-analysis of randomized controlled trials (RCTs) that includes the newer data. They also looked at the evidence for ASA's role in the prevention of nonvascular disorders (e.g., cancer).

Seshasai et al searched MEDLINE and the Cochrane Library of Clinical Trials for RCTs that had at least 1000 participants with no history of coronary heart disease (CHD) or stroke. In addition, the studies' designs had to include at least 1 year of follow-up and provide data regarding CHD, stroke, cerebrovascular disease, heart failure, peripheral vascular disease, and bleeding events. Since the initial studies often did not report data on nonvascular outcomes, they searched for subsequent analyses of secondary outcomes that included cancer and other nonvascular endpoints. They also went back to the original investigators for unpublished data on secondary outcomes. Because the original investigators used different definitions of bleeding, Seshasai et al devised a category of "clinically non-trivial bleeding" encompassing fatal bleeding, cerebrovascular or retinal bleeding, GI bleeding, and bleeding requiring hospitalization or transfusion.

Their initial search produced 680 potentially relevant articles, which were narrowed down to nine after appropriate exclusion. These nine studies include 102,621 subjects and were published between 1988 and 2010. Three of the studies enrolled medical and nursing professionals and most of the subjects resided in Western nations. Average age of the subjects was 57 years, and 54% were female. Most of the RCTs enrolled people at increased risk for CHD. Average follow-up was 6 years, during which 2169 CHD events occurred. Nonfatal myocardial infarction (MI) accounted for 1540 CHD events; 592 MIs were fatal. There were 1504 strokes and 1512 cancer deaths. There were 40,712 bleeding events, of which 10,049 were nontrivial. ASA use reduced total CVD events by 10% (odds ratio [OR] 0.90; 95% confidence interval [CI], 0.85-0.96). Nonfatal MI was the largest contributor to this with a 20% reduction in risk (OR 0.80; 95% CI, 0.67-0.96), number-needed-to-treat (NNT) 162. There was no significant reduction in fatal MI, stroke, CVD death, or all-cause mortality. There was no reduction in cancer deaths. ASA increased the risk of total bleeding events by 70% (OR 1.70; 95% CI, 1.17-2.46) and nontrivial bleeding events by 31% (OR 1.31; 95% CI, 1.14-1.50), number-needed-to-harm (NNH) 73.

Commentary

One way to view the conclusions of this meta-analysis is to look at the NNT for nonfatal MI events and the NNH for nontrivial bleeding events. Is treating 162 individuals with ASA to prevent one nonfatal MI worth at least two nontrivial bleeding events? The answer to this question depends on how you (and your patients) value MI prevention (hard to prove a negative) vs nontrivial bleeding (usually very apparent when it occurs). While there is good evidence for prescribing ASA for secondary prevention of CHD, the tradeoff of increased nontrivial bleeding for reduction of nonfatal MI (and no mortality benefit) may make primary prevention less appealing. Perhaps our other methods of primary prevention (e.g., smoking cessation, following a healthy diet and exercise program, control of hypertension, statin use, psychosocial stress management, aggressive diabetes treatment) are more effective and have made ASA less valuable.

Limitations of this meta-analysis include the inclusion of studies done among health professionals, who may not represent the average person in your practice. Strengths include the very large sample size and the timeliness of the studies that comprise the meta-analysis.

The USPSTF recommendations include a table that indicates by age when the risks of CHD for men and the risk of stroke for women exceed the risk of GI harms.7 It also includes links to risk calculators to help you quantify your patient's risk. Some doctors may find this time consuming, and there is no evidence to date that there are subgroups that would benefit from primary prevention. However, as Mora's commentary concludes, "it is reasonable to consider using aspirin for primary prevention in higher-risk individuals without known CVD (above 1% CVD event rate per year) if they are deemed to have a greater benefit to risk ratio and after taking into account patient preferences."8 I think I'll put away my bottle of baby aspirin.

References

1. http://www.uspreventiveservicestaskforce.org/uspstf/uspsasmi.htm. Accessed Feb. 20, 2012.

2. Wolff T, et al. Aspirin for the primary prevention of cardiovascular events: An update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2009;150:405-410.

3. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-1860.

4. Belch J, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.

5. Ogawa H, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial. JAMA 2008;300:2134-2141.

6. Fowkes FG, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: A randomized controlled trial. JAMA 2010;303:841-848.

7. http://www.uspreventiveservicestaskforce.org/uspstf09/aspirincvd/aspcvdsum.htm. Accessed Feb. 20, 2012.

8. Mora S. Aspirin therapy in primary prevention: Comment on "Effect of aspirin on vascular and nonvascular outcomes." Arch Intern Med 2012;172:217-218.