Aspirin therapy for secondary prevention of atherosclerotic cardiovascular disease: should we be tailoring according to sex?

The role of aspirin therapy for secondary prevention of major adverse cardiac events (MACE) in patients with atherosclerotic cardiovascular disease (ASCVD) is well established (1-3). However, male and female patients are known to differ in terms of platelet reactivity (4,5). Yet, no society guidelines have established sex-specific recommendations regarding aspirin therapy for the secondary prevention of ASCVD, as women are generally underrepresented in antiplatelet trials.

The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial was an open-label randomized controlled trial that reported no significant differences in the effectiveness and safety of two aspirin dosing regimens, 81 vs. 325 mg daily, in patients with ASCVD (6). Recently, a secondary analysis of this trial investigated whether there were any sex differences in safety or effectiveness (7).

This study included 15,076 patients (31.3% female) with a median follow-up of 26 months. While female participants were on average slightly younger than their male counterparts, they had a higher average body mass index (BMI), as well as more comorbidities and ASCVD risk factors. Despite this, they were less likely to be treated with aspirin or a P2Y12 inhibitor at baseline.

The primary effectiveness outcome of all-cause death or hospitalization for myocardial infarction or stroke occurred in 379 female (8.1%) and 780 male participants (7.1%) [adjusted hazard ratio (aHR) =1.01; 95% confidence interval (CI): 0.89–1.15], with no significant interaction between sex and aspirin dose. However, when analyzing the components of the primary outcome female participants were at a higher risk for stroke hospitalization for stroke (aHR =1.72; 95% CI: 1.27–2.33), but not myocardial infarction or all-cause death. There was no significant interaction between sex and the primary safety outcome of hospitalization for major bleeding associated with blood transfusion. However, this outcome occurred at a rate of less than 1% overall. Again, there was no interaction between sex and aspiring dose.

While the need for sex-specific antiplatelet therapy remains uncertain, it is well established that sex-specific differences in platelet reactivity, clinical management and outcomes (4,5,8). Women tend to exhibit increased platelet reactivity, which is mitigated before menopause by higher estrogen levels. This heightened reactivity is attributed to several factors, including (I) greater adenosine diphosphate (ADP)- and collagen-induced platelet activation; (II) increased surface expression of GPIb-IX-V; and (III) elevated integrin αIIbβ3 expression, along with higher levels of inflammatory markers (8-11). Women also exhibit increased aspirin resistance, which is attributed to (I) reduced inhibition of indirect platelet activation pathways; and (II) diminished inhibition of COX-1, likely due to elevated concentrations of 11-dehydrothromboxane B2 (4,5).

This sub-analysis of the ADAPTABLE trial represents a significant advance in determining whether sex-specific recommendations regarding aspirin therapy for secondary prevention in ASCVD patients are necessary. While the results do not indicate that tailoring aspirin according to sex is required, there remain several important considerations to discuss. First, only 30% of patients enrolled were female, which would limit the power to detect sex differences if they existed. Additionally, the authors reported difficulty recruiting women in this study. This may stem from clinicians possibly avoiding the inclusion of females perceived to be at higher bleeding risk. The younger age of female participants may reflect such a tendency, as women tend to manifest symptoms of ASCVD later than men. Moreover, lower rates of antithrombotic therapy at baseline suggests either lower than expected a priori risk compared to real-world female ASCVD patients or reflects a general tendency to undertreat female patients compared to male counterparts that has been well documented in cardiology. Second, the long-term comparative effectiveness and safety of 81 or 325 mg of aspirin according to sex remains unknown. Third, adherence rates were low with high rates of cross-over or discontinuation, especially in the 325 mg group, although a sensitivity analysis suggests that this did not significantly impact the outcome (7). Fourth, the primary safety outcome required transfusion, which is a rather stringent criterion. Not all clinically significant bleeding events require transfusions. It may be that the true combined effect of aspirin dose and sex on clinically significant bleeding is underestimated in this report. Finally, several relevant confounders were not assessed or included in the adjusted Cox proportional hazard models, such as oral anticoagulant therapy and dose, which could have affected the conclusions on both primary effectiveness and safety outcomes. Therefore, while these findings presently uphold the status quo of not considering sex when determining the indication for and dose of aspirin in secondary prevention, further study of the subject is warranted.

In an Antithrombotic Trialist Collaboration meta-analysis of 16 secondary prevention trials, daily aspirin reduced major coronary events in men [odds ratio (OR) =0.82; 95% CI: 0.72–9.2], but not women (OR =0.73; 95% CI: 0.51–1.03), and did not significantly reduce the risk of stroke in either women or men (12). Similarly, when analyzing primary prevention trials, aspirin again reduced coronary events in men (OR =0.77; 95% CI: 0.67–0.89), but not women, but reduced the incidence of stroke in women (OR =0.77; 95% CI: 0.59–0.99) but men (12). However, we must acknowledge that all trials, like the ADAPTABLE trial, investigating the role of aspirin for primary and secondary prevention of ASCVD included a strong majority of men. Due to the underrepresentation of women, some trials might have been underpowered to detect sex differences (13). Therefore, any observed sex differences are intriguing but also insufficient to draw definitive conclusions. This historical selection bias must therefore be addressed through properly designed trials that ensure adequate representation of women or even trials solely dedicated to the study of women’s cardiovascular health.

While both obstacles and facilitating factors to the participation of women in clinical trials remain poorly defined, atypical clinical presentations, multi-comorbidity, competing responsibilities, and the older age of women with ASCVD have been suggested as potential explanations (14). Interventions encouraging the participation of females in trials and increasing researchers’ awareness of the fundamental importance of equitable representation in trials should be undertaken.

Despite physiologic differences in platelet reactivity, neither the recent sub-analysis of ADAPTABLE nor other studies do not support differing recommendations based on sex, and current guidelines do not advocate for a sex-specific approach. In spite of this, female patients continue to be exposed to sex-related disparities in diagnostic approach, medical treatment prescription, and the use of invasive therapies, suggesting that women with ASCVD may well not be receiving equitable care (8). While we await further data regarding the possibility of sex-specific differences in response to aspirin therapy, it stands to reason that ensuring equitable care for women will improve cardiovascular outcomes for our patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-211/prf

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