Comparative Methodological Assessment of the Randomized GLOBAL LEADERS Trial Using Total Ischemic and Bleeding Events
Journal article

Comparative Methodological Assessment of the Randomized GLOBAL LEADERS Trial Using Total Ischemic and Bleeding Events

  • Hara, Hironori Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • van Klaveren, David Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (D.v.K.).
  • Takahashi, Kuniaki Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • Kogame, Norihiro Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • Chichareon, Ply Cardiology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Thailand (P.C.).
  • Modolo, Rodrigo Cardiology Division, Department of Internal Medicine, University of Campinas (UNICAMP), Brazil (R.M.).
  • Tomaniak, Mariusz First Department of Cardiology, Medical University of Warsaw, Poland (M.T.).
  • Ono, Masafumi Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • Kawashima, Hideyuki Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • Wang, Rutao Department of Cardiology, Radboud University, Nijmegen, the Netherlands (R.W., C.G.).
  • Gao, Chao Department of Cardiology, Radboud University, Nijmegen, the Netherlands (R.W., C.G.).
  • Niethammer, Margit Medizinische Klinik I, Herz-Thorax Zentrum, Klinikum Fulda, Germany (M.N.).
  • Fontos, Geza
  • Angioi, Michael Department of Interventional Cardiology Clinique Louis Pasteur Essey-les-Nancy, France (M.A.).
  • Ribeiro, Vasco Gama Cardiology Department, Gaia Hospital Center, Portugal (V.G.R.).
  • Barbato, Emanuele Division of Cardiology, Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy (E.B.).
  • Leandro, Sergio Instituto Nacional De Cardiologia, Rio de Janeiro, Brazil (S.L.).
  • Hamm, Christian Kerckhoff Heart Center, Campus University of Giessen, Bad Nauheim, Germany (C.H.).
  • Valgimigli, Marco Department of Cardiology, Bern University Hospital, Inselspital, University of Bern, Switzerland (M.V., S.W.).
  • Windecker, Stephan Department of Cardiology, Bern University Hospital, Inselspital, University of Bern, Switzerland (M.V., S.W.).
  • Jüni, Peter Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department of Medicine and the Institute of Health Policy, Management and Evaluation at the University of Toronto, Canada (P.J.).
  • Steg, Philippe Gabriel Imperial College, Royal Brompton Hospital, London, United Kingdom (P.G.S.).
  • Verbeeck, Johan I-Biostat, University of Hasselt, Belgium (J.V.).
  • Tijssen, Jan G.P. Department of Cardiology, Academic Medical Center, University of Amsterdam, the Netherlands (H.H., K.T., N.K., P.C., R.M., M.O., H.K., J.G.P.T.).
  • Sharif, Faisal Department of Cardiology, National University of Ireland, Galway (NUIG), Ireland (F.S., Y.O., P.W.S.).
  • Onuma, Yoshinobu Department of Cardiology, National University of Ireland, Galway (NUIG), Ireland (F.S., Y.O., P.W.S.).
  • Serruys, Patrick W. ORCID NHLI, Imperial College London, United Kingdom (P.W.S.).
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Published in:
  • Circulation: Cardiovascular Quality and Outcomes. - Ovid Technologies (Wolters Kluwer Health). - 2020, vol. 13, no. 8
English
Background:
Time-to-first-event analysis considers only the first event irrespective of its severity. There are several methods to assess trial outcomes beyond time-to-first-event analysis, such as analyzing total events and ranking outcomes. In the GLOBAL LEADERS study, time-to-first-event analysis did not show superiority of ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention to conventional 12-month DAPT followed by aspirin monotherapy in the reduction of the primary composite end point of all-cause mortality or new Q-wave myocardial infarction. This study sought to explore various analytical approaches in assessing total ischemic and bleeding events after percutaneous coronary intervention in the GLOBAL LEADERS study.


Methods and Results:

Total ischemic and bleeding events were defined as all-cause mortality, any stroke, any myocardial infarction, any revascularization, or Bleeding Academic Research Consortium grade 2 or 3 bleeding. We used various analytical approaches to analyze the benefit of ticagrelor monotherapy over conventional DAPT. For ischemic and bleeding events at 2 years after percutaneous coronary intervention, ticagrelor monotherapy demonstrated a 6% risk reduction, compared with conventional 12-month DAPT in time-to-first-event analysis (hazard ratio, 0.94 [95% CI, 0.88–1.01]; log-rank
P
=0.10). In win ratio analysis, win ratio was 1.05 (95% CI, 0.97–1.13;
P
=0.20). Negative binomial regression and Andersen-Gill analyses which include repeated events showed statistically significant advantage for ticagrelor monotherapy (rate ratio, 0.92 [95% CI, 0.85–0.99;
P
=0.020] and hazard ratio, 0.92 [95% CI, 0.85–0.99;
P
=0.028], respectively), although in weighted composite end point analysis, the hazard ratio was 0.93 (95% CI, 0.84–1.04; log-rank
P
=0.22).



Conclusions:
Statistical analyses considering repeated events or event severity showed that ticagrelor monotherapy consistently reduced ischemic and bleeding events by 5% to 8%, compared with conventional 1-year DAPT. Applying multiple statistical methods could emphasize the multiple facets of a trial and result in accurate and more appropriate analyses. Considering the recurrence of ischemic and bleeding events, ticagrelor monotherapy appeared to be beneficial after percutaneous coronary intervention.


Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01813435.

Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.rero.ch/global/documents/60109
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