Characterizing high-risk enrollment criteria and impact on clinical outcomes in a large randomized clinical trial: Insights from the TWILIGHT trial - 18/02/25

Doi : 10.1016/j.ahj.2025.01.016

Philippe Gabriel Steg, MD ^a,^{⁎
Contributed equally in the writing of this manuscript}, Johny Nicolas, MD, MSc ^b,^{⁎
Contributed equally in the writing of this manuscript}, Usman Baber, MD, MS ^c, Samantha Sartori, PhD ^b, Zhongjie Zhang, MPH ^b, Yihan Feng, MS ^b, Dominick J. Angiolillo, MD, PhD ^d, Carlo Briguori, MD, PhD ^e, David J. Cohen, MD, MSc ^f,^g, Timothy Collier, MSc ^h, George Dangas, MD,PhD ^b, Dariusz Dudek, MD, PhD ⁱ, Javier Escaned, MD, PhD ^j, C. Michael Gibson, MD, MSc ^k, Ya-Ling Han, MD, PhD ^l, Kurt Huber, MD ^m,ⁿ, Adnan Kastrati, MD ^o, Upendra Kaul, MD ^p, Steven O. Marx, MD ^q, Ran Kornowski, MD ^r, Vijay Kunadian, MBBS, MD ^s,^t, Birgit Vogel, MD ^b, Angelo Oliva, MD ^b, Shamir R. Mehta, MD ^u, David Moliterno, MD ^v, Gennaro Sardella, MD ^w, Mitchell Krucoff, MD ^x, Richard A. Shlofmitz, MD ^g, Samin Sharma, MD ^b, Stuart Pocock, PhD ^h, Roxana Mehran, MD ^b,^⁎
^a Université Paris-Cité, INSERM-UMR1148, 22 Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, French Alliance for Cardiovascular Trials, and 23 Institut Universitaire de France, Paris
^b Icahn School of Medicine at Mount Sinai, The Zena and Michael A. Wiener Cardiovascular Institute, New York, NY
^c Department of Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK
^d Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL
^e Mediterranea Cardiocentro, Naples, Italy
^f Cardiovascular Research Foundation, New York, NY
^g St. Francis Hospital, Roslyn, NY
^h Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
ⁱ Jagiellonian University Medical College, Krakow, Poland
^j Hospital Clínico San Carlos IDISCC, Complutense University of Madrid, Madrid, Spain
^k Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
^l General Hospital of Northern Theater Command, Shenyang, China
^m Third Department Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria
ⁿ Medical Faculty, Sigmund Freud University, Vienna, Austria
^o Deutsches Herzzentrum München, Munich, Germany
^p Batra Hospital and Medical Research Centre, New Delhi, India
^q Department of Pharmacology and Molecular Signaling, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
^r Rabin Medical Center, Petach Tikva, Israel
^s Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
^t Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^u Hamilton Health Sciences, Hamilton, Ontario, Canada
^v Division of Cardiovascular Medicine, University of Kentucky
^w Policlinico Umberto I University, Rome, Italy
^x Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC

^†Reprint requests: Roxana Mehran, MD, Center for Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, New York 10029-6574.Center for Interventional Cardiovascular Research and Clinical TrialsThe Zena and Michael A. Wiener Cardiovascular InstituteIcahn School of Medicine at Mount SinaiOne Gustave L. Levy Place, Box 1030New YorkNew York10029-6574

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 18 February 2025

ABSTRACT

Background

The TWILIGHT trial showed that, among high-risk patients who underwent percutaneous coronary intervention (PCI) and were event-free at 3 months, ticagrelor monotherapy versus ticagrelor plus aspirin reduced bleeding without increasing ischemic events.

Methods

This posthoc analysis describes the risk profiles and outcomes of patients enrolled in the TWILIGHT trial. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, and the key secondary outcome was a composite of death, myocardial infarction, or stroke within 1 year after randomization.

Results

The proportion of patients (n = 7,119) fulfilling ≤ 3, 4, 5, or ≥ 6 risk factors was 21.5%, 32.7%, 27.4%, and 18.4%, respectively. Troponin-positive acute coronary syndrome (ACS) was the most prevalent clinical criterion (64.9%), and multivessel disease (MVD) was the most prevalent angiographic criterion (66.5%). The most frequent intersection of criteria was the combination of troponin-positive ACS, atherosclerotic vascular disease, MVD, left main or proximal anterior descending lesion, and stent length > 30 mm. A stepwise increase in ischemic but not in bleeding risk was noted with an increasing number of high-risk criteria. Compared with ticagrelor plus aspirin, ticagrelor monotherapy reduced bleeding regardless of the number of risk factors (≤ 3-RF: 3.5% vs 5.8%, HR 0.59, 95% CI [0.38-0.93]; 4-RF: 3.7% vs 6.4%, HR 0.57, 95% CI [0.37-0.86]; 5-RF: 3.8% vs 8.6%, HR 0.44, 95% CI [0.29-0.66]; ≥ 6-RF: 5.3% vs 7.9%, HR 0.65, 95% CI [0.44-0.96]; p-interaction = .56) without significantly increasing the ischemic risk (≤ 3-RF: 1.6% vs 2.1%, HR 0.75, 95% CI [0.38-1.50]; 4-RF: 3.5% vs 2.2%, HR 1.58, 95% CI [0.91-2.75]; 5-RF: 4.1% vs 5.0%, HR 0.80, 95% CI [0.51-1.24]; ≥ 6-RF: 6.7% vs 6.9%, HR 0.98, 95% CI [0.67-1.43]; p-interaction = .22).

Conclusions

In the TWILIGHT trial, the high-risk features correlated more strongly with ischemic than with bleeding risk. Nonetheless, the benefits of ticagrelor compared with ticagrelor plus aspirin were consistent, irrespective of the number of high-risk features. These findings are only applicable to patients who are event-free at 3 months after PCI.