Sex-specific approach to only optimize acetylsalicylic acid dosing for secondary prevention in cardiovascular disease is definitely questionable—insights from the ADAPTABLE trial and beyond

The ADAPTABLE trial (1) sought to address a long-standing question in cardiology, namely what the optimal acetylsalicylic acid (ASA) dose for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD) is. It is well-known that the effects of ASA vary significantly with the dose, influencing its pharmacodynamic and clinical outcomes (2). In Table 1, we provide a brief summary of these dose-dependent effects and pharmacodynamic actions to contextualize the findings of this analysis. Therefore, as a cornerstone therapy for preventing recurrent cardiovascular events, ASA’s ideal dosing has been extensively debated.

The primary objective of the ADAPTABLE trial was to compare the effects of 81 vs. 325 mg ASA in participants with established ASCVD, examining key outcomes such as mortality, stroke, myocardial infarction (MI), and major bleeding events. No significant differences in the primary outcomes have been shown between the two ASA doses. However, some confirmations of well-known patterns emerged from the sex-specific analysis, particularly concerning stroke recurrence and coronary revascularization rates.

Building on these primary findings, this secondary analysis carried on by Benziger and colleagues (4) delves deeper into the trial data to explore potential sex-based differences in ASA’s effects, particularly in terms of safety and effectiveness. By focusing on sex-stratified outcomes and further evaluating variables that may interact with sex, such as age and comorbidities, this analysis aims to provide a more nuanced understanding of ASA dosing and its clinical implications across diverse populations.

Sex-specific cardiovascular risk profiles

The ADAPTABLE trial enrolled over 15,000 participants, with 31.3% being women: this represents a relatively higher proportion of female participants compared to many previous cardiovascular trials, which have often underrepresented women. This more inclusive design is critical because women with ASCVD often present with distinct risk profiles compared to men, including higher rates of diabetes, heart failure, and prior cerebrovascular disease. These differences have been noted in multiple studies, including the EUROASPIRE IV survey (5), which highlighted sex-specific disparities in cardiovascular risk factors and treatment approaches. These findings are consistent with observations from the ADAPTABLE trial survey, which similarly highlighted that woman with cardiovascular disease (CVD) tend to have more complex comorbid profiles, placing them at higher overall risk for adverse outcomes.

Additionally, a larger percentage of women in the trial were smokers, and there was greater representation from minority groups, both of which are important factors that may have influenced cardiovascular outcomes and the effectiveness of ASA treatment. In particular, the INTERHEART study found that women who smoked had a disproportionately higher risk of MI compared to men who smoked, highlighting the need for more tailored prevention strategies in smokers (6).

Moreover, undertreatment in women is compounded by their higher burden of non-cardiovascular comorbidities such as depression and autoimmune diseases, which can complicate both diagnosis and management. The Women’s Health Initiative (7) also underscored that women with CVD have more complex health needs, further reinforcing the importance of a holistic approach to treatment that considers both cardiovascular and non-cardiovascular factors.

These findings underline current sex-specific disparities in cardiovascular care, an issue extensively investigated in the literature. While increased awareness has led to a greater focus on women’s cardiovascular health, future efforts should aim on refining trial designs and developing treatment guidelines focused on distinct risk factors and treatment responses observed in women.

Effectiveness outcomes: stroke and coronary revascularization

Building on the ADAPTABLE trial’s finding that women with ASCVD have more complex comorbid profiles, the effectiveness outcomes of the trial provided further evidence of sex-specific differences in cardiovascular events. While no significant differences were observed in overall mortality or MI rates between men and women, the trial revealed that women had a higher rate of rehospitalization for stroke compared to men [adjusted hazard ratio (aHR) 1.72; 95% confidence interval (CI): 1.27–2.33]. This finding underscores the potential differences in ASA’s effectiveness for stroke prevention and aligns with prior studies such as the Women’s Health Study, which found that low-dose ASA was more effective in preventing ischemic stroke in women, but not MI (8). This higher stroke rate in women could be attributed to factors like sex-specific vascular biology, differences in platelet reactivity, or a higher prevalence of comorbid conditions such as hypertension and diabetes, both of which are known to increase stroke risk disproportionately in women.

The ADAPTABLE trial also revealed a lower rate of coronary revascularization procedures among women (5.0% vs. 6.6% in men—aHR 0.79; 95% CI: 0.68–0.92), continuing a trend that has been observed in multiple studies. Despite having similar or even greater clinical indications for invasive procedures, women are less likely than men to undergo coronary interventions such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This disparity may reflect ongoing biases or differences in the presentation of symptoms. For instance, women are more likely to experience atypical angina symptoms, which can lead to delayed or less aggressive treatment strategies. As Titterington and colleagues reported, women with coronary artery disease (CAD) are often undertreated, which may contribute to worse long-term outcomes (9). This underutilization of invasive procedures is further supported by data from an US registry (10), which showed that even after adjusting for clinical factors women were less likely to receive coronary angiography [adjusted odds ratio (aOR), 0.92; 95% CI: 0.91–0.93] and PCI (aOR, 0.82; 95% CI: 0.81–0.83) compared with men.

This disparity is critical because coronary revascularization is a cornerstone of managing advanced ASCVD. Without timely intervention, women may face worse long-term outcomes. Studies have also found that women with similar or greater clinical need for revascularization compared to men are still less likely to receive these procedures (11). These trends call for increased awareness and proactive strategies to ensure that women receive equitable care, including interventions that are crucial for improving outcomes in ASCVD.

Therefore, the ADAPTABLE trial reinforces the need to address sex-specific differences in both stroke prevention and the use of invasive procedures in managing ASCVD. Women’s higher stroke risk and lower likelihood of receiving revascularization indicate that sex-specific guidelines are necessary to optimize care for female patients with cardiovascular disease.

ASA dosing and bleeding risk

The trial’s lack of significant differences in major bleeding events between the two ASA doses in both sexes was somewhat surprising. Higher doses of ASA (325 mg) have historically been associated with increased bleeding risk, particularly gastrointestinal bleeding. For example, the ASPREE trial demonstrated that higher ASA doses in elderly populations lead to greater bleeding risks without significant cardiovascular benefit, prompting recent guideline revisions against the routine use of ASA for primary prevention in older adults (12).

However, the ADAPTABLE trial showed that bleeding events were relatively low across both dosage groups. While women in the 81 mg ASA group experienced slightly higher bleeding rates than those in the 325 mg group, this difference was not statistically significant. Given the large cohort size, this finding should be interpreted with caution, as the lack of statistical significance may limit its clinical relevance. Nonetheless, it is worth noting that lower doses are generally expected to reduce bleeding risk, making this an interesting observation. It also contrasts with findings from the meta-analysis of gender differences in antithrombotic therapy, which showed that women tend to experience higher bleeding rates with ASA than men, even at lower doses (13). This discrepancy could reflect differences in study design, participant characteristics, or adherence rates, but it certainly warrants further investigation.

Moreover, women are known to have different bleeding risk profiles compared to men, particularly when it comes to antithrombotic therapies. Multiple studies have shown that women may be at a higher risk for gastrointestinal and other major bleeding events when on ASA or dual antiplatelet therapy (DAPT) (14). This is thought to be due to biological factors, such as lower body weight, differences in platelet reactivity, and hormonal influences, which may alter the pharmacokinetics and pharmacodynamics of ASA and other antithrombotic drugs. For example, in the CURRENT-OASIS 7 trial, higher ASA doses in women led to more bleeding events compared to men, despite similar efficacy in preventing cardiovascular events (15).

Additionally, some analyses suggest that women may be more sensitive to ASA’s gastrointestinal side effects than men. The TRANSLATE-ACS study explored outcomes related to ASA dosing after acute coronary syndrome and found that while higher doses were linked to increased bleeding risk in both men and women, women had a disproportionately higher risk of major bleeding, particularly when also taking P2Y12 inhibitors (16). This underscores the need for more sex-specific research on ASA dosing to optimize both effectiveness and safety in secondary prevention, especially considering the higher baseline bleeding risk in women.

Moreover, recent studies on sex differences in post-PCI bleeding complications found no conclusive evidence to support sex-specific therapies. Women, despite showing up to 20% higher baseline platelet responsiveness than men, had no significant difference in long-term bleeding risks. However, in the acute phase, women exhibited a 1.5–2 times higher risk of major bleeding. Age, renal function, and body weight should be considered when tailoring antiplatelet therapy for women. In addition, direct oral anticoagulants (DOACs) appear to reduce bleeding risk in women compared to warfarin, but the optimal duration and regimen of triple antithrombotic therapy (TAT) for women with atrial fibrillation post-PCI remain uncertain (17).

Growing evidence highlights sex differences in drug metabolism and adverse effects. Women have a 1.6 times higher risk of complications from anti-inflammatory drugs, with selective and non-selective COX inhibitors showing stronger anti-thrombotic activity in men. Women are more sensitive to corticosteroids, particularly when estradiol levels are high, such as those using hormonal contraception (18). These findings seem to suggest potential sex-specific differences in COX-1 inhibition and subsequent thromboxane pathways that could reflect the discrepancies with the male population.

Therefore, while the ADAPTABLE trial did not show significant differences in bleeding outcomes between doses, the potential for sex-specific variations in ASA’s safety profile remains an important area for further investigation. Certain conditions unique to women—such as pregnancy, the puerperium period, contraceptive use, hormone therapy, and heavy menstrual bleeding—may influence ASA’s effects and bleeding risk. Future trials should consider these factors when evaluating optimal ASA dosing, as some subpopulations of women may still require tailored dosing strategies.

Adherence and dose switching: two reasons to question the rationale of the study

One of the most significant challenges in interpreting the ADAPTABLE trial’s results is the high rate of dose switching, particularly in the 325 mg group. More than 51% of women and 42.4% of men in this group switched to the 81 mg dose during the trial. This high crossover rate in both sexes may have diluted any potential differences in outcomes between the two dosage groups, making it difficult to draw definitive conclusions about the impact of ASA dosing. The ADAPTABLE trial’s open-label, pragmatic design—while beneficial for generalizability—may have exacerbated adherence problems. In blinded trials, participants are less likely to know what dose they are receiving and are often more compliant. However, in open-label designs, participants who experience side effects are more likely to switch or discontinue the medication altogether, as they are aware of the higher dose and the associated risks. This reality highlights a key trade-off between the external validity of pragmatic trials and the internal validity of more controlled randomized trials.

Dose switching in clinical trials is a common challenge that can compromise the ability to detect meaningful differences between treatment arms, as seen in the ADAPTABLE trial. This switch can undermine the trial’s statistical power and, as in this case, may confound the comparison of dose-specific effects. This issue is not unique to the ADAPTABLE trial. The EUCLID trial, which evaluated antiplatelet therapy for peripheral artery disease, also faced substantial challenges with adherence and dose switching, limiting its ability to draw definitive conclusions about the superiority of one antiplatelet strategy over another (19). Similar to ADAPTABLE, EUCLID’s real-world design reflected patients’ behaviors such as switching or discontinuing medications due to side effects or patients’ preferences, which diluted the effects of the treatment and complicated the analysis of the outcomes. In both trials, the high rate of dose switching indicates a pragmatic limitation when studying ASA and other therapies in the real-world setting.

The dose switching and adherence issues observed in the ADAPTABLE trial definitely present a significant limitation to the interpretation of its results, particularly when analyzing the differential effects of ASA dosing. However, it is important to consider that the high rate of switching from 325 to 81 mg may reflect a sound judgment by patients and clinicians. This shift aligns with evidence suggesting that lower doses of ASA (81 mg) offer comparable efficacy with a lower risk of complications, such as bleeding, especially in women, who often have lower body weight and height compared to men (3,20). This perspective is supported by prior findings that indicate a benefit in adjusting doses based on patient characteristics, such as weight, genetic factors, and interactions with other medications (21,22).

This high rate of dose switching raises serious concerns about adherence and the practicality of prescribing higher doses of ASA in routine clinical practice, especially given that lower doses are generally perceived as safer by both patients and clinicians (13). Participants switching from a higher to a lower dose may do so due to perceived or actual adverse effects, such as gastrointestinal discomfort or bleeding risk, which are known concerns with higher doses of ASA. For women, who are already at an increased risk of bleeding, dose switching might reflect a desire to mitigate these risks. Moreover, a recent meta-analysis showed a tendency in a lower prescription rate of ASA in women with established cardiovascular disease (OR 0.89, 95% CI: 0.84–0.94), also highlighting the uncertainty of clinicians (23). These issues are a clear limit to the reliability of the results presented by the ADAPTABLE trial but reflects a real existing issue in this field.

Adherence was another significant challenge in the ADAPTABLE trial, potentially influencing its findings. Variations in adherence, driven by perceived side effects, healthcare access disparities, and medication tolerance, may have hindered the ability to draw definitive conclusions on sex-specific responses to aspirin dosing. Future studies should incorporate electronic adherence monitoring, such as digital pill tracking or pharmacy refill data, to capture real-world adherence more accurately. Additionally, blinded trial designs could help mitigate bias related to perceived side effects, which often affect adherence in women. Implementing these strategies would enhance data reliability and provide a clearer understanding of optimal antithrombotic therapy across sexes.

Rather than focusing solely on adherence, future cardiovascular trials might benefit more from optimizing the rationale behind dose selection. For example, individualized dosing strategies should consider patient-specific factors like body weight, genetic resistance to ASA, or potential interactions with concurrent medications. Such approaches would align better with real-world clinical practice, where the goal is not necessarily to enforce high-dose regimens but to tailor therapy to maximize efficacy while minimizing adverse effects.

From trial insight to implications for clinical practice and guidelines

Rather than suggesting that women require a different aspirin dose, the ADAPTABLE trial’s findings point to the importance of a more tailored cardiovascular prevention strategy, especially given the frequent dose switching observed during the study. Current guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) do not provide sex-specific recommendations for ASA dosing, even though women may have different risk profiles for stroke, MI, and bleeding (24). Moreover, international guidelines from AHA and the European Society of cardiology (ESC) highlight the importance of personalized cardiovascular strategies but do not specifically address sex-based differences in antiplatelet therapy. These broad recommendations do not have a firm answer to the differences highlighted by trials like ADAPTABLE. However, AHA is currently inviting to better highlight potential sex specific differences, advocating for more sex-comparative comparative studies (25).

The higher stroke rate in women observed in the ADAPTABLE trial aligns with prior research indicating that women may be more prone to stroke in both primary and secondary prevention settings. This suggests that clinicians should consider a more individualized approach to cardiovascular risk management that goes beyond adjusting aspirin dose.

While the ADAPTABLE trial did not find a significant interaction between sex and ASA dose for most outcomes, the trends in stroke and bleeding risk, particularly in women, highlight the need for further research into personalized cardiovascular prevention strategies rather than a one-size-fits-all method. This includes not only optimizing ASA use but also integrating other preventive measures that address women’s unique risk profiles. This approach aligns with emerging trends in precision medicine, where treatments are increasingly customized to patient-specific factors, rather than relying on generalized dosing strategies.

Similar findings have been noted in studies such as the CURRENT-OASIS 7 trial, which compared high and low doses of ASA in patients with acute coronary syndromes. The trial found no significant differences in outcomes between the doses, but it emphasized the value of shared decision-making, particularly for women, to better address their specific risk (15). Likewise, the TRITON-TIMI 38 study, which investigated antiplatelet therapy in combination with ASA, did not find significant differences in outcomes between high and low doses in women but stressed the importance of considering sex-based variations in bleeding and cardiovascular events (26).

These findings underscore the importance of shared decision-making between patients and clinicians, especially when prescribing ASA for secondary prevention. Instead of focusing solely on adjusting ASA doses for women, clinicians should engage in informed discussions about a broader range of preventive strategies, such as smoking cessation, blood pressure control, and monitoring bleeding risks.

In conclusion, the results of the ADAPTABLE trial contribute to the growing recognition that cardiovascular prevention should not rely solely on standardized ASA dosing. Women and men may benefit from a more nuanced approach that carefully balances their cardiovascular risk through a comprehensive strategy. Despite being hindered by severe issues like high dose-switching rates and adherence problems, ADAPTABLE trial findings underscore the necessity for a more tailored approach in women: clinicians should consider patient-specific factors, such as weight, bleeding risk, and genetic predisposition when prescribing aspirin for secondary prevention in women. However, given the observed differences in cardiovascular risk profiles and adherence patterns, future guidelines should emphasize individualized cardiovascular prevention strategies rather than focusing only on aspirin dosing regimen.

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-24-241/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-241/coif). A.S. reports honoraria from Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Novartis, Viatris, Sanofi, Werfen, Boehringer-Ingelheim, Alexion, and Roche. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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