Ticagrelor Monotherapy’s Benefits Extend to Women in TWILIGHT

Women tend to bleed more often than men following PCI, but the advantages of early aspirin withdrawal—with continued ticagrelor monotherapy—are similar regardless of sex, according to a prespecified subanalysis of the TWILIGHT trial.

“Our findings should motivate dedicated studies to further explore the benefits of early aspirin withdrawal in women,” said Birgit Vogel, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the results today during a late-breaking clinical trial session at the virtual American College of Cardiology 2021 Scientific Session.

Video Interview

Sex-Specific Outcomes in TWILIGHT: Ticagrelor With or Without Aspirin After PCI

May 24, 2021

More Bleeding, Same Benefit for Women

TWILIGHT, presented during TCT 2019, found a 3.1% absolute reduction in BARC 2, 3, or 5 bleeding with no increase in death, MI, or stroke among a population of 7,119 high-risk patients randomized to either ticagrelor (Brilinta; AstraZeneca) monotherapy at 3 months post-PCI or to ticagrelor and continued aspirin.

Today’s prespecified subanalysis, simultaneously published in JAMA Cardiology, zeroed in on women, who made up 23.9% of the cohort and tended to be older and have a higher prevalence of chronic kidney disease.

In this group, the primary endpoint of BARC 2, 3, or 5 bleeding at 1 year occurred more often than it did in men (HR 1.32; 95% CI 1.06-1.64), but this seemed to be due to differences in baseline characteristics, because the relationship disappeared after multivariate adjustment (adjusted HR 1.20; 95% CI 0.95-1.52). There was no difference in death, MI, or stroke (HR 0.86; 95% CI 0.65-1.15) or other ischemic endpoints between the sexes before or after adjustment.

We need bleeding reduction strategies especially in women, and we need trials that are statistically robust to answer these questions. Birgit Vogel

The bleeding benefit seen with dropping aspirin at 3 months over continued dual antiplatelet therapy (DAPT) in the main findings of the trial were confirmed in both women (adjusted HR 0.62; 95% CI 0.42-0.92) and men (adjusted HR 0.57; 95% CI 0.44-0.73; P for interaction = 0.69). Ischemic endpoints were again similar between the study arms in both sexes, with the exception that there was less all-cause death among women but not men in the ticagrelor monotherapy arm compared with those who continued DAPT (P for interaction = 0.03).

In terms of absolute risk reduction, women and men were 3.6% and 2.9%, respectively, less likely to report BARC 2, 3, or 5 bleeding within a year after dropping aspirin at 3 months compared to continuing on both agents.

Of note, the study was not powered to show sex specific differences, and randomization was not stratified by sex, Vogel stressed. Additionally, the findings can only be applied to PCI patients at high risk for bleeding or ischemic events who can tolerate 3 months of DAPT without major adverse events.

Sex-Based Randomization Needed

Commenting on the study for TCTMD, J. Dawn Abbott, MD (Brown University, Providence, RI), said, “The key take home from this sex-specific analysis of the TWILIGHT study is that the findings in the overall randomized population hold true in women, meaning that in women at high risk of bleeding or ischemia that underwent PCI with a drug-eluting stent and were prescribed DAPT with Brilinta and aspirin, an abbreviated 3-month course of aspirin resulted in lower rates of bleeding without increasing ischemia. This suggests that early aspirin discontinuation at 3 months should be considered as a routine strategy in women undergoing PCI that met inclusion for the study.”

Specifically, Abbott continued, “based on this analysis, I would be more likely to discontinue aspirin and go to ticagrelor monotherapy in women than men.”

Women notoriously have higher bleeding risk than men. Jacqueline Tamis-Holland

Discussing the study following the presentation, Jacqueline Tamis-Holland, MD (Icahn School of Medicine at Mount Sinai), said what is known—and what this analysis confirms—“is that women notoriously have higher bleeding risk than men.” As such, the lack of a difference after adjustment for confounding variables is somewhat unexpected, she said, prompting the question of whether compliance may have been a factor.

Vogel, in response, said there may be unknown factors that contribute to bleeding risk, and that women did, in fact, have slightly lower adherence than men to both study drugs, although the difference was not significant.

“Therefore, I don't think that it had any impact on our results,” she said. “We know about the association between bleeding and mortality very well, but the impact on sex on this is really not well investigated. We have a few analyses that are showing conflicting results, and I think that it would be worthwhile investigating this further to come up with bleeding reduction strategies in women, because this is really important.”

Vogel stressed to TCTMD that, going forward, it’s important to keep in mind that women are at higher risk for bleeding post-PCI. “We need bleeding reduction strategies especially in women, and we need trials that are statistically robust to answer these questions,” she said.

Likewise, Abbott said she “would encourage investigators performing RCTs to stratify randomization according to sex” in order to better tailor care.

Note: Several co-authors are faculty members of the Cardiovascular Research Foundation, the publisher of TCTMD.