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Delayed ticagrelor noninferior to clopidogrel for major bleeding after fibrinolytic therapy
ORLANDO, Fla. — In the TREAT trial, delayed administration of ticagrelor following fibrinolytic therapy was noninferior to clopidogrel for major bleeding at 30 days among patients with STEMI aged younger than 75 years.
However, ticagrelor (Brilinta, AstraZeneca) was associated with increased minor bleeding and there was no benefit on efficacy outcomes, Otavio Berwanger, MD, PhD, cardiologist and clinical epidemiologist at the Brazilian Clinical Research, Sao Paulo, said during a presentation at the American Heart Association Scientific Session.
“In several settings, immediate access to a 24-hour cath lab capable of performing primary angioplasty or transfer to a hospital capable of performing such a procedure in a timely manner is not available,” Berwanger said. “In this regard, a large portion of STEMI patients end up receiving fibrinolytics as the main reperfusion therapy. To date, no large-scale trial evaluating the safety and efficacy of ticagrelor in STEMI patients treated with fibrinolytic therapy has been published.”
To address these questions, Berwanger and colleagues enrolled 3,799 patients aged younger than 75 years in the TREAT trial. All patients had STEMI and were receiving fibrinolytic therapy at 152 sites in 10 countries from November 2015 to November 2017. At a median of 11 hours after fibrinolytic therapy, patients were randomly assigned to receive ticagrelor at a 180-mg loading dose followed by 90 mg twice daily or to clopidogrel at a 300- to 600-mg loading dose followed by 75 mg daily.
The primary endpoint — TIMI major bleeding through 30 days — occurred in 0.73% of patients treated with ticagrelor vs. 0.69% treated with clopidogrel (absolute difference, 0.04%; 95% CI, -0.49 to 0.58; P < .001 for noninferiority).
PLATO major bleeding and BARC type 3-5 bleeding occurred in 1.2% of the ticagrelor group vs. 1.38% of the clopidogrel group (absolute difference, –0.18%; 95% CI, –0.89 to 0.54; P = .001 for noninferiority). Fatal (0.16% vs. 0.11%; P = .67) and intracranial bleeding (0.42% vs. 0.37%; P = .82). The researchers also evaluated minimal bleeding, which was more common with ticagrelor treatment (2.46% vs. 1.59%; 95% CI, -0.03 to 1.76).
“The rates of minor, minimal and total bleeding events were numerically higher with ticagrelor than with clopidogrel. Because most of the included patients were pretreated with clopidogrel, these findings reflect mostly the noninferiority of switching from clopidogrel to ticagrelor in patients already treated with clopidogrel,” the researchers wrote in JAMA Cardiology.
In other findings, a composite outcome of death from vascular causes, MI or stroke occurred in 4% of the ticagrelor group vs. 4.3% of the clopidogrel group (HR = 0.91; 95% CI, 0.67-1.25).
The researchers noted that 90% of patients enrolled in TREAT received clopidogrel before randomization.
“In this regard, given that patients who received fibrinolytic therapy in the previous 24 hours were excluded from the PLATO trial and that STEMI guidelines recommend that ticagrelor should only be initiated after 48 hours after fibrinolysis, we believe that our trial adds new safety information to practicing physicians,” Berwanger and colleagues wrote.
Clyde W. Yancy, MD, MSc, and Robert A. Harrington, MD, discussed the findings in a related editorial. They noted that “lytic therapy remains a standard of care in much of the world, especially in the 10 countries within the TREAT trial,” thus it is important to evaluate best practices associated with improved outcomes.”
“The TREAT trial attempts to address the questions of safety and efficacy of ticagrelor use for STEMI management in the setting of fibrinolytic therapy. This trial answers some questions, but critical others remain. Converting to ticagrelor late after initial exposure to clopidogrel appears safe, as defined by a noninferior difference in major bleeding (using a wide inferiority margin). But we also await further data addressing short-term and long-term outcomes in this lower-risk population of patients with STEMI.
“The crucial question that needs to be addressed — concomitant use of ticagrelor with lytic therapy for acute revascularization — remains unanswered in this trial. Given the worldwide burden of acute coronary syndromes and the recognized exigencies which preclude the ubiquitous availability of PCI, we believe this question needs urgent attention. We await future trials,” Yancy, from Feinberg School of Medicine, and Harrington, from Stanford University and deputy editor of JAMA Cardiology, wrote. – by Dave Quaile
References:
Berwanger O. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Berwanger, W, et al. JAMA Cardiol. 2018;10. 10.1001/jamacardio.2018.0644.
Yancy CW, et al. JAMA Cardiol. 2018;doi: 10.1001/jamacardio.2018.0644.
Disclosures: The TREAT trial was funded by AstraZeneca. Berwanger reports no relevant financial disclosures. Harrington reports that he receives grants from AstraZeneca, Bristol-Myers Squibb, CSL Limited, Janssen, Novartis, Portola, Sanofi and The Medicines Company; personal fees from Amgen, Bayer, Element Science, Gilead, MyoKardia and The Medicines Company; and serves on the board of directors of the American Heart Association and Stanford Health Care. Yancy reports no relevant financial disclosures.