Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction: A Randomized Clinical Trial

Abstract

Importance: The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain.

Objective: To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy.

Design, setting and participants: We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%.

Interventions: Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel.

Main outcomes and measures: The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days.

Results: The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57).

Conclusions and relevance: In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days.

Trial registration: clinicaltrials.gov Identifier: NCT02298088.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Berwanger reports grants from AstraZeneca, Amgen, Bayer, Novo Nordisk, Boehringer Ingelheim, and Roche Diagnosis; personal fees from AstraZeneca, Bayer, Roche Diagnosis, and Sanofi. Dr Damiani reports grants from AstraZeneca. Dr De Luca reports grants from AstraZeneca, Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Dr Gabriel Melo de Barros e Silva reports personal fees from Daiichi Sankyo and Boehringer Ingelheim. Dr Goodman reports grants for the current work from Research Institute, Heart Hospital; grants from AstraZeneca, Lilly, and Sanofi outside the submitted work; and personal fees from AstraZeneca, Lilly, and Sanofi outside the submitted work. Dr Lopes reports grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer and personal fees from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Dr Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, the Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience and personal fees from AstraZeneca, Anthera, Eli Lilly, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr Nicolau reports grants from AstraZeneca and personal fees from Sanofi. Dr Parkhomenko reports grants and personal fees from Pfizer, Bayer, Janssen, Sanofi-Aventis, MSD, and AstraZeneca. Dr Saraiva reports personal fees for the current work from AstraZeneca, Boehringer, Janssen, Pfizer, Bristol-Myers Squibb, Novartis, Amgen, Sanofi, and Merck Sharp and Dohme and personal fees from AstraZeneca, Boehringer, Pfizer, and Novartis outside the submitted work. Dr White reports personal fees from AstraZeneca for the current work; grants from Eli Lilly and the National Institutes of Health outside the submitted work, and personal fees from Eli Lilly and Omthera Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in TREAT Trial

For most included patients, randomized treatment did not begin immediately but rather hours after initiation of fibrinolytic therapy. In this sense, patients randomized to ticagrelor received the first dose of ticagrelor several hours after initiation of fibrinolytic therapy (median, 11.4 hours), and 90% were pretreated with clopidogrel.

Figure 2.. Major Bleeding (Thrombolysis in Myocardial Infarction [TIMI], Platelet Inhibition and Patient Outcomes [PLATO], and Bleeding Academic Research Consortium [BARC] Definitions) at 30 Days

Difference (in percentage) presented as bilateral 95% confidence interval. 1% Absolute difference margin noninferiority test. Noninferiority test was done considering a 1-sided test.