GLOBAL LEADERS: no sex-difference in mortality or MI rates two years after PCI, but bleeding risk higher in women than men

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Senior author Patrick Serruys

A prespecified subgroup analysis of the GLOBAL LEADERS trial has found no between-sex difference in the risk of two-year all-cause mortality or new Q-wave myocardial infarction (MI) following percutaneous coronary intervention (PCI). Published online in JAMA Cardiology, the study also found that the risks of bleeding and haemorrhagic stroke were higher in women than men, and that ticagrelor monotherapy was associated with a lower risk of bleeding than dual antiplatelet therapy at one year in men, but not in women.

GLOBAL LEADERS was an investigator-initiated, prospective, randomised, multicentre, multicontinental, open-label trial to evaluate two antiplatelet therapy strategies after PCI using uniformly bivalirudin and biolimus A9–eluting stents (Biomatrix) in an all-comers population with no restrictions on clinical presentation, complexity of lesions, or number of stents used.

The current analysis, by Ply Chichareon (Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands, and Prince of Songkla University, Songkhla, Thailand) et al, aimed to assess the association of sex with patient outcomes, and with the efficacy and safety of two antiplatelet strategies.

They explain: “Considering that the ischaemic and bleeding risk of women undergoing PCI may differ from men, it follows that the safety and efficacy of long-term ticagrelor monotherapy after PCI may differ between the sexes. Therefore, we aimed to compare the two-year outcomes between women and men undergoing contemporary PCI and to assess the association of sex with the efficacy and safety of antiplatelet strategy in the GLOBAL LEADERS study.”

The main study enrolled 15,991 unselected patients undergoing PCI between July 2013 and November 2015. Patients had an outpatient clinic visit at 30 days and at three, six, 12, 18, and 24 months after the index procedure. Patients were randomised to either the experimental antiplatelet strategy—one month DAPT followed by 23 months of ticagrelor monotherapy—or to the reference strategy, which consisted of 12 months of DAPT followed by 12 months of aspirin monotherapy. The primary efficacy endpoint was a composite of all-cause mortality and new Q-wave MI at two years, with a secondary safety endpoint of Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding.

In all, 23.3% (3,714) of patients in the study were women. The risk of the primary endpoint at two years was similar between women and men (adjusted hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.83–1.2). At two years, women had a higher risk of both BARC 3 or 5 bleeding (adjusted HR 1.32, 95% CI 1.04–1.67) and haemorrhagic stroke (adjusted HR 4.76, 95% CI 1.92–11.81) than men. There was no between-sex difference in the efficacy and safety of the two antiplatelet strategies at two years, and at one year, ticagrelor monotherapy was associated with a lower risk of bleeding than DAPT in men (HR 0.72, 95% CI 0.53–0.98) but not in women (HR 1.23, 95% CI 0.8–1.89, p for interaction = 0.045).

Chichareon and colleagues point out: “In this study, women were older and had higher prevalence of diabetes, hypertension, and impaired renal function than men, and the unadjusted analysis shows the higher risk of primary endpoint and other ischemic outcomes in women. However, the differences were no longer evident in the adjusted models, suggesting that the differences in ischaemic risk between women and men were attributed to confounders and not associated with sex, per se. Furthermore, it could be speculated that the sex gap may have been diminished by contemporary PCI practice, with the use of newer-generation DES [drug eluting stents], potent antiplatelet agents, and optimal medical therapy.”

They add: “This study reveals that women undergoing PCI are at higher risk of major bleeding and haemorrhagic stroke than men. This difference persists after adjustment for confounders, confirming that sex is an independent predictor for major bleeding after PCI. Therefore, our findings question the predictive ability of bleeding risk scores where sex is not included and emphasises the need for external validation of bleeding risk scores in contemporary PCI practice.”

However, the researchers acknowledge the risk of a type II error in the analysis as the randomisation in GLOBAL LEADERS was not stratified by sex, and there were less women enrolled in the study than men. In addition, they note that the analyses are exploratory, with no statistical adjustment for multiple testing. “Therefore,” they say, “the difference in the effect of antiplatelet strategy on bleeding between sexes could be a play of chance and should be regarded as hypothesis-generating.”


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