Aspirin for Primary Prevention

Abstract & Commentary

By Michael H. Crawford, MD, Professor of Medicine, University of California, San Francisco; Lucie Stern Chair in Cardiology, Chief of Clinical Cardiology, University of California, San Francisco Medical Center. Dr. Crawford reports no financial relationships relevant to this field of study. This article originally appeared in the August issue of Clinical Cardiology Alert. At that time it was peer reviewed by Ethan Weiss, MD, Associate Professor of Medicine, Division of Cardiology, University of California, San Francisco, CA. Dr. Weiss is an advisory board member for Bionovo.

Source: Bartolucci AA, et al. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2011;107:1796-1801.

The use of aspirin for the primary prevention of cardiovascular (CV) disease remains controversial. In this publication, Bartolucci updates his 2006 meta-analysis by adding three new trials to the six previous ones. Since aspirin may have different effects on different CV diseases, the data were classified into several outcomes of interest compared in almost 51,000 subjects on aspirin and more than 49,000 on placebo. Individually, only two trials showed a significant decrease in CV mortality, but each trial was significant for at least one CV endpoint. For example, the Women's Health Study (WHS) was significant for stroke reduction only. The nine-trial combined results showed a decreased risk of myocardial infarction (MI; P = 0.042) and total CV events (P = 0.001, CV death, MI, and stroke). There was significant heterogeneity across trials in total coronary heart disease ([CHD] MI and death due to CHD P = 0.001 and MI P = 0.004). The combined hazard ratios for six different endpoints ranged from 0.813 to 0.956 in favor of aspirin for risk reductions of 4.4% to 18.7%. Only non-fatal CHD events, total CHD, and the combined endpoint of CV death, MI, and stroke were reduced > 10%. Stroke reduction was 8.1%, CHD mortality was 4.4%, and all-cause mortality was reduced 5.5%. The authors concluded that aspirin decreases the risk of CV events and MI, but not stroke, nor any CV cause of death or total mortality.

Commentary

I hate it when healthy people ask me if they should take an aspirin a day because I do not have the answer to this simple question. Thus, I read this latest meta-analysis with high expectations that I would get the answer. So imagine my disappointment that this question still does not have a clear answer. This analysis of nine primary prevention trials included two new trials that studied diabetics without symptomatic vascular disease. The inclusion of diabetics could mean more events and a greater chance to see differences in these higher risk subjects. Disappointingly these studies in diabetics showed that some outcomes were worse on aspirin, including CHD mortality.

The overall analysis showed a reduction in coronary events, but not stroke. No mortality endpoint was significantly reduced. This has always bothered me — how can an event be reduced, but the mortality from it not? Are such results important? Also in this analysis, the percent reductions in outcomes varied from 4% to 18%. When you weigh in the risk of gastrointestinal bleeding, even the authors admit that the net benefit is uncertain.

Despite including nine trials, almost 60% of the subjects came from the WHS and the Hypertension Optimal Treatment (HOT) study. The WHS was only positive for a reduction in stroke in older women. HOT showed reduced events, but not mortality, and overall was closer to the results of the meta-analysis. Based on these two studies, it has been concluded that aspirin prevents stroke in women and heart attack in men, but it is not as simple as that in the overall results of this meta-analysis.

What this analysis does not provide is any breakdown of the results by age, sex, or risk profile of the subjects, nor the dose of aspirin. If we are going to individualize therapy, we need to know these variables. Since there is no strong message from this analysis, therapy will need to be individualized. Also, most of these studies included only middle-aged or older subjects, but at what age do we start recommending aspirin? Based on many studies, aspirin is clearly indicated for secondary prevention in all vascular disease patients, and probably for those who probably have vascular disease based on their risk profile, but not necessarily diabetics unless they have a high-risk profile. For the true primary prevention group of low-to-intermediate risk subjects, aspirin prophylaxis probably should not be considered until age 45 in men and 55 in women since vascular events are unusual before those ages and the risks of bleeding would outweigh the potential benefit. In the older subjects at low risk — I leave the decision to the subject and if they choose to take aspirin — I recommend 81 mg of the enteric coated type. You can make a better case for the intermediate-risk patient, but we do not know if just vigorously controlling their risk factors would be enough. This type of comparative effectiveness study of aggressive risk factor control plus or minus aspirin has not, and probably will not be done, so we can only speculate on the results.