Efficacy and Safety of Ticagrelor Monotherapy by Clinical Presentation: Pre-Specified Analysis of the GLOBAL LEADERS Trial

Abstract

Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

Keywords: acute coronary syndrome; all‐comers; antiplatelet therapy; coronary; intervention; stable coronary artery disease; ticagrelor.

Conflict of interest statement

Dr Vranckx discloses the following relationships: personal fees from Astra Zeneca and the Medicines Company during the conduct of the study; personal fees from Bayer Health Care, CLS‐Behring, Terumo, and Daiichi Sankyo outside the submitted work. Dr Valgimigli discloses the following relationships: personal fees from Abbott, personal fees from Chiesi, personal fees from Bayer, personal fees from Daiichi Sankyo, personal fees from Terumo, personal fees from Carbostent & Implantable Devices, personal fees from Amgen, grants from Swiss National Foundation, grants from Terumo, grants from Medicure, grants from Abbott, grants from Astra Zeneca, personal fees from Astra Zeneca, outside the submitted work. Dr Serruys discloses the following relationships: personal fees from Abbott Laboratories, Astra Zeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sino Medical Sciences Technology, Société Europa Digital Publishing, Stentys France, Svelte Medical Systems, Philips/Volcano, St Jude Medical, Qualimed, Xeltis, outside the submitted work. Dr Hamm discloses the following relationships: personal fees from AstraZeneca outside the submitted work. Dr Steg discloses the following relationships: research grant from Bayer/Janssen; grants and personal fees from Merck, Sanofi, Amarin; personal fees from Amgen, Bristol‐Myers‐Squibb, Boehringer‐Ingelheim, Pfizer, Novartis, Regeneron, Lilly, AstraZeneca; grants, personal fees, and non‐financial support from Servier, outside the submitted work. Dik Heg discloses the following relationships: affiliated with clinical trials unit Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, clinical trials unit Bern is involved in design, conduct, or analysis of clinical studies funded by not‐for‐profit and for‐profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up‐to‐date list of clinical trials unit Bern’s conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. Dr Mc Fadden discloses the following relationships: personal fees from ECRI, Rotterdam, Netherlands, during the conduct of the study; grants from Astra Zeneca; personal fees from Abbott Vascular; personal fees from Daiichi Sankyo, non‐financial support from Menarini Ireland; grants from Bayer; grants from Terumo, outside the submitted work. Dr Onuma discloses consultancy fees from Abbott Vascular. Dr Diletti discloses consultancy fees from Sanofi Aventis and Biosensors outside the submitted work. Dr Kurt Huber discloses personal fees from AstraZeneca, Sanofi Aventis, and Biosensors outside the submitted work. Dr Räber discloses the following relationships: research grants to the institution by Abbott Vascular, Boston Scientific, Heartflow, Sanofi, and Regeneron; and speaker fees from Abbott Vascular, Amgen, Astra Zeneca, Biotronic, CLS Behring, Sanofi, and Regeneron. Dr Windecker discloses the following relationships: research and educational contracts to the institution from Abbott, Amgen Inc., Bayer AG, BMS, Biotronik, Boston Scientific, CSL Behring, Edwards Lifesciences, Medtronic, St Jude Medical, Polares, and Sinomed outside the submitted work. Dr Jüni discloses the following relationships: research grants to the institution from Astra Zeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; unpaid member of the steering group of trials funded by Astra Zeneca, Biotronik, Biosensors, St. Jude Medical, and The Medicines Company; and a Tier 1 Canada Research Chair in Clinical Epidemiology of Chronic Diseases; this research was completed, in part, with funding from the Canada Research Chairs Programme. The remaining authors have no disclosures to report.

Figures

Figure 1. Caterpillar plot for key clinical outcomes by clinical presentation (acute coronary syndrome vs stable coronary artery disease).

Depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index percutaneous coronary intervention). Percentage of patients at risk. Exact censoring days used at each follow‐up, ie, events occurring up to number of days are used for the first events: 2 years=730 days. ACS indicates acute coronary syndrome; BARC, Bleeding Academic Research Consortium; MI, myocardial infarction; NACCE, composite of all‐cause mortality, stroke, any myocardial infarction or, Bleeding Academic Research Consortium 3 or 5 bleeding; and SCAD, stable coronary artery disease. §Interaction P value of modifying effect of acute coronary syndrome/stable coronary artery disease on the rate ratio comparing experimental vs reference regimen, within the specified period (df=1).

Figure 2. Caterpillar plot of landmark analyses for clinical outcomes up to 30 days (A), from 31 days to 1 year (B) and from 1 year to end of follow‐up (C) by clinical presentation (acute coronary syndrome vs stable coronary artery disease).

Top panel (A) Up to 30 days, middle panel (B) 31 days to 1 year and bottom panel (C) from 1 year to end of follow‐up. Within each landmark period, depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index percutaneous coronary intervention). Percentage of patients at risk. Exact censoring days used at each follow‐up, ie, events occurring up to number of days are used for the first events: 2 years=730 days. ACS indicates acute coronary syndrome; BARC, Bleeding Academic Research Consortium; MI, myocardial infarction; NACCE, composite of all‐cause mortality, stroke, any myocardial infarction or, Bleeding Academic Research Consortium 3 or 5 bleeding; and SCAD, stable coronary artery disease. §Interaction P value of modifying effect of acute coronary syndrome/ stable coronary artery disease on the rate ratio comparing experimental vs reference regimen, within the specified period (df=1).

Figure 3. Kaplan‒Meier curves of Bleeding Academic Research Consortium 3 or 5 bleeding up to 30 days, from 31 days to 1 year and from 1 year to end of follow‐up by clinical presentation (acute coronary syndrome vs stable coronary artery disease).

Within each landmark period, depicted are the first event per event type for each patient only (disregards multiple events of the same type within the same patient and censoring at 730 days since index percutaneous coronary intervention). Top panel: Acute coronary syndrome patients. Cumulative incidence of (A) Bleeding Academic Research Consortium 3 or 5 events (acute coronary syndrome), lower panel: (B) Bleeding Academic Research Consortium 3 or 5 events (stable coronary artery disease), (blue: experimental strategy arm; red: reference strategy arm). ACS indicates acute coronary syndrome; BARC, Bleeding Academic Research Consortium; and SCAD, stable coronary artery disease.