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In the past 20 years, major adverse cardiovascular outcomes (MACE) in ST-segment elevation myocardial infarction (STEMI) have improved, but a sex disparity has remained in both short-term and long-term MACE. While clinical trial and registry studies agree that women with STEMI have higher MACE rates than men, there is controversy regarding whether this difference persists after adjusting for the higher cardiovascular risk profile in women . Women with STEMI are more likely to have longer delays to reperfusion, develop bleeding complications, and less likely to receive guideline-recommended pharmacotherapy. Is there a true sex difference in STEMI biology or is the higher MACE rate confounded by sex differences in baseline characteristics and treatment?
In this issue of CCI, Yu et al. compare the baseline characteristics, treatment, and 3-year clinical outcomes in women versus men with STEMI in the HORIZONS-AMI trial, which randomized 3,602 patients (23.4% women) with STEMI to bivalirudin or heparin plus glycoprotein IIb/IIIa inhibitors and to percutaneous coronary intervention (PCI) with drug-eluting or bare metal stents. The results confirm previously reported data that women with STEMI have higher risk characteristics including age, hypertension, hyperlipidemia, diabetes, congestive heart failure, anemia, chronic kidney disease at presentation. Women were more likely to be treated with medical management alone (6.9% vs. 4.7%) and had significantly longer symptom-onset-to-balloon time (237.5 min vs. 218 min), driven by longer symptom-onset-to-door time. Compared to men, women had higher rates of major bleeding and MACE in-hospital, at 30 days and at 3 years. However, female sex was not an independent predictor of long-term MACE at 3 years after adjusting for differences in baseline and treatment characteristics, while it remained an independent predictor of major bleeding at 3 years.
Consistent with prior studies, the authors conclude that increased long-term MACE in women with STEMI is largely explained by adverse comorbidities and treatment differences. How do we close this gender gap? Female sex is an easily identifiable phenotype that should alert clinicians to apply evidence-based guidelines for cardiovascular risk assessment, currently used less often in women. Can we improve the cardiovascular risk profile of women with early detection and prevention? Despite having more comorbidities than men, women with acute coronary syndrome have less obstructive coronary artery disease but similar number of angiographically culprit lesions and plaque burden as men . In addition, while the increased comorbidities in women may be related to older age, studies indicate that young women (age <65 years) with STEMI have worse survival compared to similarly aged men despite multivariable adjustment, potentially due to sex differences in the pathophysiology of ischemic heart disease, including plaque erosion and abnormal coronary vasoreactivity . Novel strategies for identifying cardiovascular risk factors in young women, such as adverse pregnancy outcomes and coronary microvascular dysfunction, may improve risk stratification.
Strategies for tailoring treatment to sex are also needed to improve prognosis in women. The delay in symptom-onset-to-door presentation is confounded by sex-specific heightened pain perception and somatic awareness in women, which may hasten the symptom onset of STEMI compared to men . However, hospital and community education regarding female-pattern and “non-classic” angina symptoms is needed to improve symptom-onset-to-balloon time. Studies demonstrate that employment of standardized protocols and improving volume-driven technical proficiency can reduce discrepancies in therapy and time to treatment (as noted in the HORIZONS-AMI trial) and thus lead to better patient outcomes . Sex-specific treatment protocols should also be designed to promote use of radial access, careful antithrombotic dosing taking consideration of patient size/age/renal function, management of heart failure, and referral for post-STEMI cardiac rehabilitation in women.
Ischemic heart disease remains the number one killer of women; nearly 30% of all STEMI patients are women. Although female sex may not be an independent MACE predictor, women nevertheless continue to have worse outcomes than men following STEMI. Yu et al.’s excellent study highlights the complex interactions contributing to gender inequity in STEMI.
Conflict of interest: Nothing to report.