Women Bleed More Than Men After PCI, GLOBAL LEADERS Affirms

Women may have similar ischemic outcomes after contemporary PCI compared with men, but they continue to have increased bleeding risks regardless of their assigned antiplatelet regimen, a subgroup analysis of the GLOBAL LEADERS trial shows.

Through the 2 years of follow-up in the neutral trial, the risk of all-cause mortality/new Q-wave MI (primary efficacy endpoint) did not differ by sex after accounting for baseline differences. Women, however, were more likely than men to develop BARC type 3 or 5 bleeding and hemorrhagic stroke, the investigators report.

Sex did not significantly interact with the relative safety and efficacy of the different antiplatelet regimens evaluated in the trial.

The clinical message “is that when you prescribe antiplatelet treatment to women you can expect more bleeding, so as a physician I will be certainly paying attention to that,” senior author Patrick Serruys, MD, PhD (Imperial College London, England), told TCTMD. “For that reason, I would certainly look carefully to the body mass index and this kind of thing to see if there is a way . . . to maintain the anti-ischemic effect without increasing the bleeding risk.”

Having said that, “it’s not easy to tailor anything in the field. You give or you don’t give the pills,” he said, suggesting that using a lower dose of ticagrelor, for instance, might be a solution. “But beyond that, you just have to warn the women that they are more prone to bleeding than men and as a physician be more careful about that.”

Sex Doesn’t Interact With Treatment Effects

Published last year, the main results of GLOBAL LEADERS, the largest contemporary trial of PCI in all-comers, showed that continuing with ticagrelor alone after 1 month of ticagrelor plus aspirin was not superior to dual antiplatelet therapy (DAPT) with aspirin plus either clopidogrel (in stable patients) or ticagrelor (in ACS patients) for 12 months followed by a year of aspirin monotherapy in terms of the primary endpoint of all-cause death or new Q-wave MI at 2 years.

Prior studies have indicated that women have worse ischemic outcomes and more bleeding after PCI compared with men. So in a prespecified subgroup analysis, published online November 6, 2019, ahead of print in JAMA Cardiology with lead author Ply Chichareon, MD (Amsterdam UMC, the Netherlands), the GLOBAL LEADERS investigators explored whether sex had an impact on the results.

Of the 15,968 patients included in the analysis, 23.3% were women. Women were older on average, more likely to have diabetes, hypertension, and impaired renal function, and less likely to smoke or to have had a prior MI, PCI, or CABG.

After accounting for those and other baseline differences, women did not have a higher risk of all-cause mortality/new Q-wave MI at 2 years compared with men (adjusted HR 1.00; 95% CI 0.83-1.20). There were also no differences for a variety of other clinical outcomes.

Women, however, did have higher risks of BARC type 3 or 5 bleeding (2.99% vs 1.85%; adjusted HR 1.32; 95% CI 1.04-1.67) and hemorrhagic stroke (0.36% vs 0.08%; adjusted HR 4.76; 95% CI 1.92-11.81). Those elevated risks were mostly evident during the first year of follow-up, disappearing between 1 and 2 years.

“Women bleed more after PCI whatever the treatment is and that increased risk is not negligible,” Serruys said.

Women bleed more after PCI whatever the treatment is and that increased risk is not negligible. Patrick Serruys

Throughout the entire 2-year follow-up, patient sex did not interact with the relative efficacy and safety of the antiplatelet strategies compared in the trial. But at 1 year, ticagrelor monotherapy was associated with a lower risk of BARC type 3 or 5 bleeding compared with DAPT in men (HR 0.72; 95% CI 0.53-0.98) but not in women (HR 1.23; 95% CI 0.80-1.89; P = 0.045 for interaction by sex).

That interaction was mostly due to a higher bleeding risk in women with stable CAD who were receiving ticagrelor monotherapy, the authors note. “Although the evidence supporting routine use of potent P2Y12 inhibitors in stable CAD is lacking, off-label prescription has been reported to be as high as 34%,” they write. “The 2017 European Society of Cardiology focused update on DAPT gave [a] class IIb recommendation for the consideration of [a] potent P2Y12 inhibitor in patients with stable CAD undergoing PCI after taking into account the ischemic and bleeding risk. Our study suggests that potent P2Y12 inhibitors should be used with caution in women who present with stable CAD.”

Time to Update Bleeding Risk Scores?

The researchers also investigated treatment adherence, finding that women were less likely to be compliant from 3 months and beyond. At 2 years, adherence was 85.9% in men and 83.5% in women (P < 0.001).

The authors point out that that difference is consistent with prior registry studies showing that cessation of antiplatelet therapy was more common in women, driven by bleeding or dyspnea, both of which were more frequently observed in female patients in GLOBAL LEADERS. “This observation should encourage physicians to carefully weigh the risk and benefit of using ticagrelor in women,” Chichareon et al say.

They point out that even though female sex has been identified as an independent predictor of bleeding after PCI, risk scores designed to predict bleeding—like the PARIS and PRECISE DAPT tools—do not include it as a variable.

This new analysis confirms, the authors say, that even in the setting of potent P2Y12 inhibition, female sex remains associated with major bleeding after PCI. “Therefore, our findings question the predictive ability of bleeding risk scores where sex is not included and emphasizes the need for external validation of bleeding risk scores in contemporary PCI practice,” they write.

For Serruys, the scores should be updated to include female sex as a variable. “It’s quite amazing for me that gender is not part of it,” he said.