The association of body mass index with long-term clinical outcomes after ticagrelor monotherapy following abbreviated dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: a prespecified sub-analysis of the GLOBAL LEADERS Trial

Masafumi Ono, Ply Chichareon, Mariusz Tomaniak, Hideyuki Kawashima, Kuniaki Takahashi, Norihiro Kogame, Rodrigo Modolo, Hironori Hara, Chao Gao, Rutao Wang, Simon Walsh, Harry Suryapranata, Pedro Canas da Silva, James Cotton, René Koning, Ibrahim Akin, Benno J W M Rensing, Scot Garg, Joanna J Wykrzykowska, Jan J Piek, Peter Jüni, Christian Hamm, Philippe Gabriel Steg, Marco Valgimigli, Stephan Windecker, Robert F Storey, Yoshinobu Onuma, Pascal Vranckx, Patrick W Serruys, Masafumi Ono, Ply Chichareon, Mariusz Tomaniak, Hideyuki Kawashima, Kuniaki Takahashi, Norihiro Kogame, Rodrigo Modolo, Hironori Hara, Chao Gao, Rutao Wang, Simon Walsh, Harry Suryapranata, Pedro Canas da Silva, James Cotton, René Koning, Ibrahim Akin, Benno J W M Rensing, Scot Garg, Joanna J Wykrzykowska, Jan J Piek, Peter Jüni, Christian Hamm, Philippe Gabriel Steg, Marco Valgimigli, Stephan Windecker, Robert F Storey, Yoshinobu Onuma, Pascal Vranckx, Patrick W Serruys

Abstract

Background: The efficacy of antiplatelet therapies following percutaneous coronary intervention (PCI) may be affected by body mass index (BMI).

Methods and results: This is a prespecified subgroup analysis of the GLOBAL LEADERS trial, a prospective, multicenter, open-label, randomized controlled trial in an all-comer population undergoing PCI, comparing the experimental strategy (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with a reference regimen (12-month aspirin monotherapy following 12-month DAPT). A total of 15,968 patients were stratified by baseline BMI with prespecified threshold of 27 kg/m2. Of those, 6973 (43.7%) patients with a BMI < 27 kg/m2 had a higher risk of all-cause mortality at 2 years than those with BMI ≥ 27 kg/m2 (adjusted HR 1.24, 95% CI 1.02-1.49). At 2 years, the rates of the primary endpoint (all-cause mortality or new Q-wave myocardial infarction) were similar between treatment strategies in either BMI group (pinteraction = 0.51). In acute coronary syndrome, however, the experimental strategy was associated with significant reduction of the primary endpoint compared to the reference strategy in patients with BMI < 27 kg/m2 (HR 0.69, 95% CI 0.51-0.94), but not in the ones with BMI ≥ 27 kg/m2 (pinteraction = 0.047). In chronic coronary syndrome, there was no between-group difference in the efficacy and safety of the two antiplatelet strategies.

Conclusions: Overall, BMI did not influence the treatment effect seen with ticagrelor monotherapy; however, a beneficial effect of ticagrelor monotherapy was seen in ACS patients with BMI < 27 kg/m2.

Trial registration: The trial has been registered with ClinicalTrials.gov, Number NCT01813435.

Keywords: Acute coronary syndrome; Body mass index; Drug-eluting stent; Dual antiplatelet therapy; Percutaneous coronary intervention; Ticagrelor monotherapy.

Conflict of interest statement

Dr. Chichareon reports research grant from Biosensors outside the submitted work. Dr. Modolo received research grant from the Sao Paulo Research Foundation (FAPESP Grant Numer 2017/22013–8) and Biosensors. Dr. Piek reports personal fees and non-financial support from Philips/Volcano, outside the submitted work. Dr. Hamm reports personal fees from AstraZeneca, outside the submitted work. Dr. Steg reports grants and personal fees from Bayer/Janssen, grants and personal fees from Merck, grants and personal fees from Sanofi, grants and personal fees from Amarin, personal fees from Amgen, personal fees from Bristol Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Pfizer, personal fees from Novartis, personal fees from Regeneron, personal fees from Lilly, personal fees from AstraZeneca, and grants and personal fees from Servier, outside the submitted work. Dr. Jüni reports research grants to the institution from Astra Zeneca, Biotronik, Biosensors International, Eli Lilly and The Medicines Company, and serves as unpaid member of the steering group of trials funded by Astra Zeneca, Biotronik, Biosensors, St. Jude Medical and The Medicines Company. Dr. Storey reports personal fees from Bayer, personal fees from Bristol-Myers Squibb/Pfizer, grants and personal fees from AstraZeneca, personal fees from Novartis, personal fees from Idorsia, grants and personal fees from Thromboserin, personal fees from Haemonetics, personal fees from Amgen, grants and personal fees from Glycardial Diagnostics, personal fees from Portola, and personal fees from Medscape, outside the submitted work. Dr. Valgimigli reports personal fees from Astra Zeneca, grants and personal fees from Terumo, personal fees from Alvimedica/CID, personal fees from Abbott Vascular, personal fees from Daiichi Sankyo, personal fees from Opsens, personal fees from Bayer, personal fees from CoreFLOW, personal fees from IDORSIA PHARMACEUTICALS LTD, personal fees from Universität Basel | Dept. Klinische Forschung, personal fees from Vifor, personal fees from Bristol Myers Squib SA, and personal fees from iVascular, outside the submitted work. Dr. de Windecker received research and educational grants to the institution from Amgen, Abbott, Boston Scientific, Biotronik, Bayer, BMS, CSL Behring, Medtronic, Edwards Lifesciences, and Polares and Sinomed, outside the submitted work. Dr. Vranckx received personal fees from Astra Zeneca, personal fees from Bayer Health Care, personal fees from Daiichi Sankio, personal fees from Terumo, and personal fees from CLS Behring, outside the submitted work. Dr. Serruys reports personal fees from Biosensors, personal fees from Medtronic, personal fees from Micel Technologies, personal fees from Sinomedical Sciences Technology, personal fees from Philips/Volcano, personal fees from Xeltis, and personal fees from HeartFlow, outside the submitted work. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the present study. Among 15,966 patients included in this analysis, 6973 (43.7%) had BMI 2 and 8993 patients (56.3%) had BMI ≥ 27 kg/m2. Outcomes were assessed between experimental strategy and reference strategy in all-comers population, and furthermore in each clinical presentation (ACS and CCS). BMI body mass index, ACS acute coronary syndrome, CCS chronic coronary syndrome, ASA acetylsalicylic acid
Fig. 2
Fig. 2
Histogram of BMI stratified by clinical presentation with adjusted hazard ratio for adverse events according to BMI. Blue and red bar graphs indicate the number of patients with BMI 2 and ≥ 27 kg/m2 in the setting of ACS, respectively. Similarly, sky blue and orange bar graphs indicate the number of patients with BMI < 27 kg/m2 and ≥ 27 kg/m2 in the setting of CCS, respectively. Blue curve with light blue area indicates adjusted hazard ratio with 95% CI for composite of all-cause mortality and new Q-wave MI at 2-year according to BMI with reference of 27 kg/m2. Red curve with light red area indicates adjusted hazard ratio with 95% CI for BARC type 3 or 5 bleeding according to BMI with reference of 27 kg/m2. The number of knots for the cubic spline curves were three in each model. Adjusted covariates for all-cause mortality or new Q-wave MI are age (years), sex, clinical presentation (ACS or CCS), diabetes mellitus, hypertension, hypercholesteremia, PVD, COPD, renal impairment, previous MI, previous PCI, and previous CABG. Adjusted covariates for BARC type 3 or 5 bleeding are age (years), sex, clinical presentation (ACS or CCS), diabetes mellitus, previous bleeding, renal impairment, anemia according to WHO classification, and radial access in the index procedure. BMI body mass index, ACS acute coronary syndromes, CCS chronic coronary syndromes, HR hazard ratio, CI confidence interval, MI myocardial infarction, BARC Bleeding Academic Research Consortium, PVD peripheral vascular disease, COPD chronic obstructive pulmonary disease, PCI percutaneous coronary intervention, CABG coronary artery bypass graft, WHO World Health Organization
Fig. 3
Fig. 3
Clinical outcomes at 2-year and forest plots in comparison of patients stratified according to BMI with threshold of 27 kg/m2. The squares indicate estimated hazard ratio, and the horizontal lines indicate 95% CI. There was no statistically significant difference in any clinical outcomes between experimental strategy and reference strategy in each BMI group (BMI < 27 kg/m2 or ≥ 27 kg/m2). pinteraction values were derived from Cox regression model. Abbreviations as in Fig. 2
Fig. 4
Fig. 4
The 1-year landmark analysis and Kaplan–Meier curves in patients with ACS and either BMI 2 or BMI ≥ 27 kg/m2. The 1-year landmark analyses of primary endpoint (all-cause mortality or new Q-wave MI), all-cause mortality, and secondary safety endpoint (BARC type 3, or 5 bleeding) have demonstrated that the reduced risks of adverse events in experimental arm compared to reference arm were largely obtained at 1 year in patients with ACS and BMI < 27 kg/m2. However, in patients with ACS and BMI ≥ 27 kg/m2, no treatment benefits were seen in terms of primary endpoint, all-cause mortality, and BARC type 3 or 5 bleeding, either in the first-year and up to 2 years from 1 year. Abbreviations as in Fig. 2

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Drug Interventions

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