Benefit and Risks of Aspirin in Addition to Ticagrelor in Acute Coronary Syndromes: A Post Hoc Analysis of the Randomized GLOBAL LEADERS Trial

Abstract

Importance: The role of aspirin as part of antiplatelet regimens in acute coronary syndromes (ACS) needs to be clarified in the context of newer potent P2Y12 antagonists.

Objective: To evaluate the benefit and risks of aspirin in addition to ticagrelor among patients with ACS beyond 1 month after percutaneous coronary intervention (PCI).

Design, setting, and participants: This is a nonprespecified, post hoc analysis of GLOBAL LEADERS, a randomized, open-label superiority trial comparing 2 antiplatelet treatment strategies after PCI. The trial included 130 secondary/tertiary care hospitals in different countries, with 15 991 unselected patients with stable coronary artery disease or ACS undergoing PCI. Patients had outpatient visits at 1, 3, 6, 12, 18, and 24 months after index procedure.

Interventions: The experimental group received aspirin plus ticagrelor for 1 month followed by 23-month ticagrelor monotherapy; the reference group received aspirin plus either clopidogrel (stable coronary artery disease) or ticagrelor (ACS) for 12 months, followed by 12-month aspirin monotherapy. In this analysis, we examined the clinical outcomes occurring between 31 days and 365 days after randomization, specifically in patients with ACS who, within this time frame, were assigned to receive either ticagrelor alone or ticagrelor and aspirin.

Main outcomes and measures: The primary outcome was the composite of all-cause death or new Q-wave myocardial infarction.

Results: Of 15 968 participants, there were 7487 patients with ACS enrolled; 3750 patients were assigned to the experimental group and 3737 patients to the reference group. Between 31 and 365 days after randomization, the primary outcome occurred in 55 patients (1.5%) in the experimental group and in 75 patients (2.0%) in the reference group (hazard ratio [HR], 0.73; 95% CI, 0.51-1.03; P = .07); investigator-reported Bleeding Academic Research Consortium-defined bleeding type 3 or 5 occurred in 28 patients (0.8%) in the experimental group and in 54 patients (1.5%) in the reference arm (HR, 0.52; 95% CI, 0.33-0.81; P = .004).

Conclusions and relevance: Between 1 month and 12 months after PCI in ACS, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. These findings should be interpreted as exploratory and hypothesis generating; however, they pave the way for further trials evaluating aspirin-free antiplatelet strategies after PCI.

Trial registration: ClinicalTrials.gov identifier: NCT01813435.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tomaniak reports lecture fees from AstraZeneca outside the submitted work. Dr Chichareon reports grants from Biosensors outside the submitted work. Dr Onuma has served as a member of the advisory board of Abbott Vascular. Dr Deliargyris is Chief Medical Officer and full-time employee of PLx Pharma Inc, New Jersey. Dr Modolo reports grants from Biosensor outside the submitted work. Dr Storey reports grants and personal fees from PlaqueTec; personal fees from Amgen, Bayer, Novartis, Idorsia, Thromboserin, Haemonetics, GlyCardial Diagnostics, and Bristol-Myers Squibb/Pfizer; and grants, personal fees, and other support from AstraZeneca outside the submitted work; In addition, Dr Storey has patent PCT/GB2017/050692 pending. Dr Dangas reports personal fees from AstraZeneca, Biosensors, and Sanofi and grants and personal fees from Bayer and Abbott outside the submitted work. Dr Bhatt reports grants from AstraZeneca during the conduct of the study; grants from Amarin, Roche, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, Ironwood, Abbott, Regeneron, Idorsia, Synaptic, and The Medicines Company; other support from FlowCo, Fractyl, Novo Nordisk, VA, Clinical Cardiology, PLx Pharma, Bayer, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, St Jude Medical (now Abbott), Biotronik, Cardax, Merck, Boston Scientific, Svelte, and Takeda; personal fees from Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Bayer, Medtelligence/Reach MD, HMP Global, Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, and Elsevier; personal fees, nonfinancial support, and other support from American College of Cardiology; personal fees and nonfinancial support from Society of Cardiovascular Patient Care; nonfinancial support from American Heart Association; grants and other support from PhaseBio; and personal fees and other support from Boehringer Ingelheim outside the submitted work. Dr Angiolillo reports grants and personal fees from Amgen, AstraZeneca, Biosensors, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, Sanofi, CeloNova, The Medicines Company; personal fees from Aralez, Bristol-Myers Squibb, the National Institutes of Health, Bayer, Haemonetics, PhaseBio, PlX Pharma, Pfizer, and St Jude; grants from CSL Behring, Novartis, Matsutani Chemical Industry Co, Renal Guard Solutions, Osprey Medical, Boehringer Inghelheim, Eisai, Gilead, Scott R. MacKenzie Foundation, and Idorsia outside the submitted work. Dr Hamm reports personal fees from AstraZeneca during the conduct of the study. Dr Valgimigli reports grants and personal fees from AstraZeneca, Abbott, and Terumo; personal fees from Chiesi, Bayer, Daiichi Sankyo, Amgen, Alvimedica, Biosensors, and Idorsia; and grants from Medicure outside the submitted work. Dr Windecker reports grants from Amgen, Abbott, BMS, Boston Scientific, Biotronik, Medtronic, Bayer, Edwards Lifesciences, and SINOMED outside the submitted work. Dr Steg reports grants and personal fees from Bayer/Janssen, Servier, Merck, Sanofi, and Amarin and personal fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron, Lilly, and AstraZeneca outside the submitted work. Dr Vranckx reports personal fees from AstraZeneca and The Medicines Company during the conduct of the study and personal fees from Bayer Health Care, Terumo, and Daiichi Sankyo outside the submitted work. Dr Serruys reports personal fees from Abbott Laboratories, AstraZeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sino Medical Sciences Technology, Société Europa Digital Publishing, Stentys France, Svelte Medical Systems, Philips Volcano, St Jude Medical, QualiMed, and Xeltis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Design, Patient Population, and Randomized Treatment in the GLOBAL LEADERS Trial

In this investigation, we evaluated the clinical outcomes specifically in patients with acute coronary syndrome (ACS) who, according to the study protocol, between 31 and 365 days after randomization were to receive either ticagrelor alone or ticagrelor and aspirin (ASA) at a dose of 75 mg to 100 mg daily. CAD indicates coronary artery disease; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.

Figure 2.. Clinical Events in Acute Coronary Syndrome Patients Between 31 Days and 365 Daysa

All-cause mortality (A), Bleeding Academic Research Consortium (BARC)–defined bleeding type 3 or 5 (B), patient-oriented composite end points (POCE) (C), and net-adverse clinical events (NACE) (D). Patient-oriented composite endpoint (POCE) included all-cause mortality or any stroke, myocardial infarction, or revascularization, whereas net-adverse clinical events (NACE) comprised POCE and BARC type 3 or 5 bleeding. Patients who were alive at 31 days of follow-up and did not encounter event of the specific type nor were censored prior to the landmark of 30 days have been included in this analysis. HR indicates hazard ratio. aIn these time frames, according to the study protocol, the experimental regimen is ticagrelor monotherapy and the reference regimen is ticagrelor plus aspirin.

Figure 3.. Bleeding Academic Research Consortium (BARC)–Defined Bleeding Events Type 2 (A) and Type 3 (B) Between 31 and 365 Days in Patients With Acute Coronary Syndromea

aIn these time frames, according to the study protocol, the experimental regimen is ticagrelor monotherapy and the reference regimen is ticagrelor plus aspirin. HR indicates hazard ratio.