Sex Differences Among Patients With High Risk Receiving Ticagrelor With or Without Aspirin After Percutaneous Coronary Intervention: A Subgroup Analysis of the TWILIGHT Randomized Clinical Trial

Abstract

Importance: Shortened dual antiplatelet therapy followed by potent P2Y12 receptor inhibitor monotherapy reduces bleeding without increasing ischemic events after percutaneous coronary intervention (PCI).

Objective: To explore sex differences and evaluate the association of sex with outcomes among patients treated with ticagrelor monotherapy vs ticagrelor plus aspirin.

Design, setting, and participants: This was a prespecified secondary analysis of TWILIGHT, an investigator-initiated, placebo-controlled randomized clinical trial conducted at 187 sites across 11 countries. Study participants included patients who underwent successful PCI with drug-eluting stents, were planned for discharge with ticagrelor plus aspirin, and who had at least 1 clinical and at least 1 angiographic feature associated with high risk of ischemic or bleeding events. Data were analyzed from May to July 2020.

Interventions: At 3 months after PCI, patients adherent to ticagrelor and aspirin without major adverse event were randomized to either aspirin or placebo for an additional 12 months along with ticagrelor.

Main outcomes and measures: The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding at 12 months after randomization. The primary ischemic end point was a composite of death, myocardial infarction, or stroke.

Results: Of 9006 enrolled patients, 7119 underwent randomization (mean [SD] age, 63.9 [10.2] years; 5421 [76.1%] men). Women were older (mean [SD] age, 65.5 [9.6] years in women vs 63.4 [10.3] years in men) with higher prevalence of chronic kidney disease (347 women [21.2%] vs 764 men [14.7%]). The primary bleeding end point occurred more often in women than men (hazard ratio [HR], 1.32; 95% CI, 1.06-1.64; P = .01). After multivariate adjustment, incremental bleeding risk associated with female sex was no longer significant (adjusted HR, 1.20; 95% CI, 0.95-1.52; P = .12). Ischemic end points were similar between sexes. Ticagrelor plus placebo vs ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3, or 5 bleeding in women (adjusted HR, 0.62; 95% CI, 0.42-0.92; P = .02) and men (adjusted HR, 0.57; 95% CI, 0.44-0.73; P < .001; P for interaction = .69). Ischemic end points were similar between treatment groups in both sexes.

Conclusions and relevance: These findings suggest that the higher bleeding risk in women compared with men was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, the benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.

Trial registration: ClinicalTrials.gov Identifier: NCT02270242.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Baber reported receiving personal fees from Amgen, AstraZeneca, and Boston Scientific during the conduct of the study. Dr Cohen reported receiving grants and personal fees from AstraZeneca, Medtronic, and Abbott Vascular and grants from Boston Scientific outside the submitted work. Dr Sharma reported receiving personal fees from Abbott Vascular, Boston Scientific, and Cardiovascular Systems and serving on an advisory board for Boston Scientific outside the submitted work. Dr Angiolillo reported receiving grants and personal fees from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, CeloNova, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; personal fees from St Jude Medical; and grants (paid to his institution) from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Briguori reported receiving grants from Mount Sinai during the conduct of the study. Dr Collier reported serving on data monitoring committees sponsored by AstraZeneca, Boston Scientific, Daiichi-Sankyo, Devax, Infraredx, Medtronic, Pfizer, and Zoll. Dr Dangas reported receiving grants from AstraZeneca, personal fees from AstraZeneca and Biosensors, and owning stock in Medtronic outside the submitted work. Dr Escaned reported receiving personal fees from Abbott, Philips, Boston Scientific, Medtronic, Abiomed, Terumo, and Biosensors. Dr Krucoff reported receiving grants and personal fees from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Medtronic, OrbusNeich. Dr Kunadian reports receiving personal fees/honoraria from Bayer, AstraZeneca, Abbott, Amgen, Daichii Sankyo. Dr Mehta reported receiving grants from AstraZeneca during the conduct of the study. Dr Moliterno reported receiving grants from AstraZeneca during the conduct of the study. Dr Ohman reported receiving grants from Chiesi and Portola and personal fees from Cytokinetics, Abiomed, Pfizer, 3D Communications, ACI Clinical, Biotie, Cara Therapeutics, Cardinal Health, Faculty Connection, Imbria, Impulse Medical, Janssen Pharmaceuticals, Medscape, Milestone Pharmaceuticals, XyloCor, and Otsuka outside the submitted work. Dr Witzenbichler reported personal fees from Mount Sinai Hospital during the conduct of the study. Dr Gibson reported receiving grants and personal fees from Angel Medical, Bayer, CSL Behring, Johnson & Johnson, Janssen, AstraZeneca, Portola Pharmaceuticals, personal fees from the Medicines Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somahlution, Verreseon Corporation, Boston Scientific, Impact Bio, MedImmume, Medtelligence, MicroPort, PERT Consortium, and GE Healthcare; owning stock in nference; serving as chief executive officer of Baim Institute, and receiving grants (paid to Baim Institute) from Bristol Myers Squibb. Dr Pocock reported receiving grants and personal fees from AstraZeneca outside the submitted work. Dr Huber reported receiving personal fees from AstraZeneca and Bayer. Dr Mehran reported receiving grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, American College of Cardiology, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Bleeding Events and Ischemic Events by Sex at 12 Months After Randomization

Men were used as the reference category. Adjusted hazard ratios (HRs) were adjusted for age (years), non-White race, region of enrollment, insulin-treated diabetes, chronic kidney disease, anemia, current smoker, hypertension, previous myocardial infarction, previous coronary revascularization (previous percutaneous coronary intervention or previous coronary artery bypass graft), multivessel coronary artery disease, indication for percutaneous coronary intervention, radial artery access, whether left anterior descending coronary artery was treated, whether left circumflex coronary artery was treated, number of lesions treated, and minimum stent diameter (mm). Bleeding outcomes were performed in the intention-to-treat cohort, and ischemic outcomes were performed in the per-protocol cohort. BARC indicates Bleeding Academic Research Consortium; CV, cardiovascular; GUSTO, Global Utilization of Streptokinase and TPA for Occluded Arteries; ISTH, International Society on Thrombosis and Hemostasis; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

Figure 2.. Primary Bleeding and Ischemic End Points by Sex and Randomized Treatment Assignment

Kaplan-Meier estimates and adjusted hazard ratios (HRs) for Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding among the intention-to-treat cohort (A) and for death, myocardial infarction, or stroke among the per-protocol cohort (B) at 12 months after randomization. aAdjusted for age (years), non-White race, region of enrollment, insulin-treated diabetes, chronic kidney disease, current smoking, hypercholesterolemia, previous percutaneous coronary intervention, multivessel coronary artery disease, indication for percutaneous coronary intervention, and lesion calcification.