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Original Investigation
May 15, 2021

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

Author Affiliations
  • 1The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 2Department of Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City
  • 3St Francis Hospital, Roslyn, New York
  • 4Cardiovascular Research Foundation, New York, New York
  • 5Division of Cardiology, University of Florida College of Medicine, Jacksonville
  • 6Mediterranea Cardiocentro, Naples, Italy
  • 7Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
  • 8Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
  • 9Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy
  • 10Department of Cardiology, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos and Complutense University, Calle del Prof Martin Lagos, Madrid, Spain
  • 11Department of Invasive Cardiology, Center of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior and Administration, Warsaw, Poland
  • 12Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, Liaoning Sheng, China
  • 13Department of Cardiology, Batra Hospital and Medical Research Centre, New Delhi, India
  • 14Department of Cardiology, Rabin Medical Center, Petach Tikva, Israel
  • 15Department of Cardiology, Duke University Medical Center–Duke Clinical Research Institute, Durham, North Carolina
  • 16Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
  • 17Department of Cardiology, Hamilton Health Sciences, Hamilton, Canada
  • 18Department of Cardiology, University of Kentucky, Lexington
  • 19Department of Cardiology, Policlinico Umberto I University, Roma, Italy
  • 20Department of Cardiology, Helios Amper-Klinikum, Dachau, Germany
  • 21Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 22Department of Cardiology, Wilhelminenhospital, Vienna, Austria
  • 23Sigmund Freud University, Medical Faculty, Vienna, Austria
JAMA Cardiol. Published online May 15, 2021. doi:10.1001/jamacardio.2021.1720
Key Points

Question  Is sex associated with differences in treatment outcomes for early aspirin withdrawal with continuation of ticagrelor after percutaneous coronary intervention (PCI) in patients at high risk for bleeding or ischemic events?

Findings  In this prespecified subgroup analysis of a randomized clinical trial including 7119 patients, women had a higher bleeding risk compared with men, which was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.

Meaning  These findings have important implications for antiplatelet regimens after PCI and should motivate dedicated studies to further explore the benefits of this approach in women.

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

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