Although it is widely accepted that aspirin reduces the risk of myocardial infarction (MI) on average by 25%, there is considerable variation in the effect sizes reported across the trials ranging from zero to 50% relative to placebo 1. To date, factors responsible for this heterogeneity have not been well studied. One potential explanatory variable is gender. There is emerging evidence to indicate that women have an increase risk of aspirin resistance compared to men, potentially making aspirin less effective in women 2. Moreover, women who develop atherosclerosis tend to be older, have more co-morbid conditions and more extensive disease at the time of diagnosis, which might also interfere with the actions of aspirin 2. Thus, the gender mix of published trials could be an important determinant of the variability in the reported findings. The primary purpose of this study was to determine the influence of gender mix on the reported efficacy of aspirin on fatal and non-fatal MI in published clinical trials.

The original search in PUBMED yielded 637 citations. EMBASE did not contribute any additional citations. The abstracts of these articles were selected and reviewed. Of these, 61 articles were retrieved for detailed examination. From these, 23 trials were selected as they met the inclusion and exclusion criteria of the study: 21 of these trials reported on non-fatal MI, 15 trials reported on fatal MI, and 17 reported on both fatal and non-fatal MI. The selection process is depicted in Figure 1. The baseline characteristics of participants in the selected trials are summarized in Table 156789101112131415161718192021222324252627. Overall, there were 113 494 participants in the 23 included trials; 49.3% were men. The baseline mean age of the trial participants ranged between 52 and 73 years; the prevalence of current smokers varied from 11% to 60%. The duration of follow-up was from 1–10 years and the dosage of aspirin varied from 75–1500 mg per day.

The main findings of the study are summarized in Table 2. Overall, aspirin significantly reduced the risk of non-fatal MI compared with placebo (RR = 0.72, 95% CI 0.64–0.81, p < 0.001) (Figure 2). There was a trend towards lower fatal MI rates with aspirin (RR = 0.88, 95% CI 0.75–1.03, p = 0.120) (Table 2). Aspirin therapy significantly reduced the combined endpoint of fatal and non-fatal MI (RR = 0.79, 95% CI 0.72–0.87, p < 0.001) (Table 2).

In a meta-regression analysis, we observed a significant relationship between gender mix (i.e. proportionality of male or female participants in each trial) and the effectiveness of aspirin in reducing non-fatal MI rates in these trials (R² = 0.27, p = 0.017) (Figure 3). However, we failed to observe a significant impact of gender mix on the effect sizes for fatal MI (R² = 0.03, p = 0.514). The relationship between gender mix and the effectiveness of aspirin in reducing the combined end point of fatal and non-fatal MI was only marginally significant (R² = 0.21, p = 0.065). The inclusion of average age and smoking status of the trial participants made very little impact to the overall findings. For the end point of non-fatal MI, the R² value was 0.32 (p = 0.038). For fatal MI, it was 0.09 (p = 0.465) and for the combined end point of fatal and non-fatal MI, it was 0.28 (p = 0.072).

When the original trials were divided into tertile groups based on the gender mix (0–66%, 70–89%, 100% male participants in each trial), the beneficial effect of aspirin in reducing non-fatal MI was found to be the greatest in the tertile group containing the largest percentage of male participants (RR = 0.62, 95% CI 0.54–0.71), test for heterogeneity, p = 0.48). In contrast, the tertile group with the smallest percentage of male participants failed to demonstrate any benefits of aspirin in reducing non-fatal MI (RR = 0.87, 95% CI 0.71–1.06), test for heterogeneity, p = 0.26) (Table 3). Similar findings were observed in the analysis that combined non-fatal and fatal MI together (Table 3).

The findings of the present study indicate that aspirin is effective in reducing the risk for non-fatal MI. There was however considerable variation in the reported efficacy of aspirin across the trials. We found that approximately 27% of the total variation could be accounted for by considering the differences in the gender mix of the trials. In general, the trials that contained predominantly male subjects demonstrated large benefits of aspirin in reducing non-fatal MI rates. In contrast, trials that contained mostly female subjects failed to show any beneficial effect of aspirin on this end point. These data are consistent with the notion that aspirin therapy might be less effective in reducing non-fatal MI in women than in men.

Why aspirin would be less effective in reducing MI risk in women is largely a mystery. However, recent data indicate that women are more likely to demonstrate aspirin resistance compared to men. In a study by Chen and colleagues, women compared to men were 2.3 times more likely to be aspirin-resistant 29 and in the study by Gum and colleagues, women were 2.5 times more likely to demonstrate aspirin resistance 2. The mechanisms underlying these observations are uncertain.

There are also emerging data demonstrating major structural and physiological differences in coronary vasculature between men and women 30. For instance, women have smaller coronary vessels, which are generally stiffer than those in men owing to increased deposition of fibrotic tissue and remodeling of the vessel walls. Women are also more likely to demonstrate impaired vasodilatory responses to acetylcholine 31. Moreover, when women develop atherosclerosis, their lesions are usually more diffuse and extensive than those observed in men 32. Although in both men and women, the leading cause of morbidity and mortality is ischemic heart disease 33, women, especially in the younger age groups (less than 50 years of age), have short-term mortality rates that are twice those observed in men following MIs 34. Our findings in the context of the emerging literature regarding possible aspirin resistance in women suggest that clinicians should be cautious in prescribing aspirin in women especially for primary prevention. Whether or not other anti-platelet agents would be more effective for women is unclear. Future clinical studies specifically powered to evaluate sex-specific end points will be needed to determine whether other anti-platelet agents might be more effective in women compared with aspirin.

There were limitations to the present study. Firstly, we did not have access to the primary data. As such, we could not determine the influence of other risk factors such as co-morbidities that have also been associated with aspirin-resistance 35. These factors could further explain the large variation in results reported across the trials. Secondly, as with most systematic reviews, there was a possibility of publication or selection bias. To mitigate this possibility, we conducted an extensive search and included all trials that met the inclusion and exclusion criteria of the present study. Thirdly, we could not determine the mechanism by which gender modifies the efficacy of aspirin for MIs.

The present study found that the gender mix of trials accounted for a substantial proportion of the variability in the reported efficacy of aspirin in reducing MI rates. Trials that recruited predominantly men demonstrated the largest benefits; while trials that recruited mostly women failed to demonstrate any benefits. These data are consistent with the notion that aspirin is less efficacious in women (for the reduction of MIs) and raise the possibility that women are more susceptible to aspirin resistance.

This project is supported by ICEBERGS (Interdisciplinary Capacity Enhancement: Bridging Excellence in Respiratory Disease and Gender Studies), which is funded by the Canadian Institutes of Health Research (IGH/ICRH), the Canadian Lung Association, and the Heart and Stroke Foundation of Canada.

DDS is a Canada Research Chair in COPD and a senior scholar with the Michael Smith Foundation for Health Research.

All of the authors made substantial contributions to the manuscript and had full access to the data. All authors read and approved the final version of the manuscript.