TY - JOUR
T1 - Comparative Methodological Assessment of the Randomized GLOBAL LEADERS Trial Using Total Ischemic and Bleeding Events
AU - Hara, Hironori
AU - van Klaveren, David
AU - Takahashi, Kuniaki
AU - Kogame, Norihiro
AU - Chichareon, Ply
AU - Modolo, Rodrigo
AU - Tomaniak, Mariusz
AU - Ono, Masafumi
AU - Kawashima, Hideyuki
AU - Wang, Rutao
AU - Gao, Chao
AU - Niethammer, Margit
AU - GLOBAL LEADERS Trial Investigators
AU - Fontos, Geza
AU - Angioi, Michael
AU - Ribeiro, Vasco Gama
AU - Barbato, Emanuele
AU - Leandro, Sergio
AU - Hamm, Christian
AU - Valgimigli, Marco
AU - Windecker, Stephan
AU - Jüni, Peter
AU - Steg, Philippe Gabriel
AU - Verbeeck, Johan
AU - Tijssen, Jan G. P.
AU - Sharif, Faisal
AU - Onuma, Yoshinobu
AU - Serruys, Patrick W.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - aspirin
KW - mortality
KW - myocardial infarction
KW - percutaneous coronary intervention
KW - ticagrelor
UR - http://www.scopus.com/inward/record.url?scp=85089768264&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/CIRCOUTCOMES.120.006660
DO - https://doi.org/10.1161/CIRCOUTCOMES.120.006660
M3 - Article
C2 - 32762446
SN - 1941-7713
VL - 13
SP - 526
EP - 537
JO - Circulation. Cardiovascular quality and outcomes
JF - Circulation. Cardiovascular quality and outcomes
IS - 8
ER -