Women fared worse than men in terms of increased bleeding risk, but comparable to men for ischemic event rates, results of a subgroup analysis of the TWILIGHT study presented May 15 at the 70th annual meeting of the American College of Cardiology (ACC) found. However, benefits of early aspirin withdrawal and continued use of ticagrelor in this high-risk PCI population was found to be comparable between sexes.
The TWILIGHT study, published in 2019 in the New England Journal of Medicine (NEJM), and presented as a late-breaking clinical trial at TCT 2019, was a double-blind, placebo-controlled study, that found that the use of ticagrelor alone following a three-month period of dual antiplatelet therapy (DAPT) was associated with lower bleeding rates versus ticagrelor plus aspirin in high-risk PCI patients.
In the current analysis, investigators explored the differences in sex within the TWILIGHT study population to evaluate to association of sex and outcomes among patients treated with ticagrelor alone versus ticagrelor plus aspirin post-PCI. They found that women had a higher bleeding risk compared with men, which they attributed to baseline differences; however, ischemic events were found to be similar between the two sexes.
Women represented 23.9% of the 7,119 participant TWILIGHT study population and were older (mean [SD] age, 65.5 [9.6] years vs 63.4 [10.3] years), had higher rates of insulin-treated diabetes (33.5% vs. 25.1%), chronic kidney disease (21.2% vs. 14.7%), anemia (23.2% vs. 18.3%) and hypertension (76.5% vs. 71.1%) compared to men. However, women were less likely to be current smokers and to have a history of MI, PCI, or coronary artery bypass graft surgery (CABG) and were more likely to undergo PCI due to ACS compared to men.
The investigators used Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding at 12 months after randomization as the primary endpoint. The primary ischemic end point was a composite of death, MI, or stroke.
Study results showed that women had an increased bleeding rate at one year when compared with men (6.8% vs. 5.2%; hazard ratio [hr], 1.32; 95% CI, 1.06-1.64); however, no significant differences were found between the pre-specificed endpoints including all cause death, MI, or ischemic stroke in women compared with men.
“These rates were found to be significantly lower in women that were treated with ticagrelor monotherapy compared with those treated with continued DAPT, but this this was not the case in men,” said Birgit Vogel, MD, from the Icahn School of Medicine at Mount Sinai. Vogel cautioned that these results should not be considered definitive, as they were based on very few events.
While women were shown to have a heightened rate of BARC 3 or 5 bleeding compared with men (2.0% vs. 1.3%), upon multivariate adjustment, this increased bleeding risk in women was no longer significant. Ticagrelor plus placebo versus ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3 or 5 bleeding in women (5.0% vs. 8.6%) and in men (3.7% vs. 6.6%).
A relative risk reduction related to early aspirin withdrawal that was similar between the two sexes was also found. “This means a strategy of early aspirin withdrawal and continuation of ticagrelor compared to continued DAPT was not associated with an increase of ischemic risk regardless of sex,” said Vogel.
Limitations of the study included the fact that neither of the sex-specified subgroups were individually powered to draw definitive conclusions on the effect of ticagrelor monotherapy versus ticagrelor plus aspirin. Vogel also noted the many differences between men and women, which could have led to imbalances within treatment groups.
“Women notoriously have a higher bleeding risk than men. Yet in this particular study, you did not show any bleeding risk after adjusting for other confounding variables,” said Dr. Jacqueline Tamis-Holland, of the Icahn School of Medicine at Mount Sinai, during a discussion period. “In fact, one would think that the relative benefit of a treatment that is designed to decrease bleeding would be more favorable in women because women [are at a higher risk] for bleeding but you didn’t show that.”
Dr. Tamis-Holland asked Vogel whether these results could be due to rates of compliance and administration of ticagrelor. Vogel suggested that previous studies have showed an issue with medication adherence in women that could be possibly associated with a higher risk of side effect; however, she suggested that this must be explored further
“The question is why is this mortality benefit due to reduced bleeding that might be greater in women than it is in men,” said Vogel. “The reality is is that we don’t have a lot of data on that. We know about the association between bleeding and mortality very well but the impact on sex is really not well investigated.”
The TWILIGHT substudy analysis was published simultaneously in JAMA Cardiology (https://jamanetwork.com/journals/jamacardiology/fullarticle/2779977).