TREAT: Ticagrelor Safe in STEMI Patients After Fibrinolysis

Susan Jeffrey

March 11, 2018

ORLANDO, FL — A new trial shows that delayed administration of ticagrelor (Brilinta/Brilique, AstraZeneca) was noninferior to clopidogrel in terms of major bleeding risk at 30 days in patients younger than 75 years with an ST-segment elevation myocardial infarction (STEMI).

Although rates of fatal and intracranial bleeding were also similar between the groups, rates of minor and minimal bleeding were higher with ticagrelor vs clopidogrel, the authors reported.

"Because most of the included patients were pretreated with clopidogrel," they note, "these findings reflect mostly the noninferiority of switching from clopidogrel to ticagrelor in patients already treated with clopidogrel."

The results, from the Ticagrelor in Patients With ST-Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis (TREAT) trial, were published online March 11 in JAMA Cardiology, to coincide with their presentation here at the American College of Cardiology (ACC) 2018 Annual Scientific Session.

Otavio Berwanger, MD, PhD, from the Research Institute, Heart Hospital, São Paulo, Brazil, reported the results on behalf of the TREAT investigators in 10 countries.

Percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for STEMI patients, but in many parts of the world, timely access to primary PCI is not available, the researchers point out in their article.

"One of the main concerns of physicians in using more potent antiplatelet therapy like ticagrelor is bleeding, and the population who received fibrinolytic therapy in the past 24 hours were included from the pivotal Platelet Inhibition and Patient Outcomes (PLATO) trial," Berwanger told a press conference here. "So in order to address this concern, we designed this study."

The randomized, open-label trial with blinded endpoint adjudication enrolled 3799 patients younger than 75 years of age with STEMI who received fibrinolytic therapy at 152 sites from November 2015 through November 2017.

Patients were randomly assigned to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter), "the same scheme used in the PLATO trial," he noted. They were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel.

The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%.

"This trial is a story in two parts," he said. The first part is safety, and the primary outcome was thrombolysis in myocardial infarction major bleeding through 30 days. They also reported bleeding according to other classifications, and an exploratory analysis of efficacy outcomes.

"We also plan to report the outcomes at 12 months in terms of efficacy," Berwanger noted.

The mean age was 58 years, 77.1% were men, and 57.3% were white.

At 30 days, thrombolysis in myocardial infarction major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel, meeting their criterion for noninferiority (absolute difference, 0.04%; 95% confidence interval, −0.49% to 0.58%; P < .001 for noninferiority).

Major bleeding defined by the PLATO criteria and by the Bleeding Academic Research Consortium (BARC) types 3 to 5 bleeding, which are more sensitive measures, he said, occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group, also meeting noninferiority thresholds (absolute difference, −0.18%; 95% confidence interval, −0.89% to 0.54; P = .001 for noninferiority).

As expected, the closer to the lytic therapy patients received treatment, the higher the bleeding rates, but still without a significant difference between groups.

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.

There was no difference seen in the composite of death from vascular causes, MI, or stroke, occurring in 76 patients (4.0%) treated with ticagrelor and 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% confidence interval, 0.67 - 1.25; P = .57).

"But we should wait for the 12-month results to have a clearer picture," Berwanger noted.

Critical Questions Remain

In an editor's note accompanying the publication, Clyde W Yancy, MD, from the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and Robert A Harrington, MD, from Stanford University, California, deputy editors of JAMA Cardiology, write that TREAT answers some questions about the use of ticagrelor for STEMI management in the setting of fibrinolytic therapy, "but critical others remain."

Commenting here for | Medscape Cardiology, Yancy pointed out that lytic therapy is still the preferred approach in many outside-US countries, "and so this question of what is the best antiplatelet therapy that would accompany lytic therapy is actually quite pressing. Because in the absence of PCI as we exercise it in this country, many patients worldwide really do resort to medical therapies to facilitate early reperfusion and to maintain patency."

He called the trial an "iterative step, telling us at least when ticagrelor is initiated late after lytic therapy — late by our standards — there does appear to be some modest advantage over time."

In this study, however, patients received clopidogrel first and then were converted to ticagrelor, he noted. "That's not the question we really think needs to be answered," he said. "We think the question that needs to be answered is clopidogrel vs ticagrelor in the acute onset of an MI necessitating some sort of a reperfusion therapy."

Yancy pointed out that in preparation for writing the editorial, he performed a literature review looking at this question of the differential use of PCI vs lytics in the United States and worldwide, "and quite frankly, it's extraordinary that in this country, most MI victims are within a reasonable distance of a PCI center," he said.

"As well, our guidelines really make it clear that what you should do is preferentially ship those patients that have acute MI rather than give them lytic therapy," he added. "We believe the benefit of PCI is so much more superior, so yes, I think this is a uniquely outside-the-US issue."

However, Craig Beavers, PharmD, from the University of Kentucky College of Pharmacy, Lexington, who commented on the findings during a press briefing here, said that at their institution, where they serve a lot of rural patients, "you might have some instances where they may not be able to get treated with PCI, depending on a variety of variables, weather, etc, and we end up getting a couple of those patients a month, or one a week," he said.

In those cases, the patients have been treated with lytics and transferred, usually already loaded with clopidogrel, and the question becomes whether it's safe to switch them to ticagrelor, which is something that clinicians may want to do for a variety of reasons, such as a high residual thrombotic risk or genetic predisposition against clopidogrel response.

"Historically, we've had no data to guide that decision, and we've just done it and hoped for the best," Beavers told | Medscape Cardiology. Although these data can't be extrapolated to older patient populations, "at least these data tell us that in the acute phase, if we do that, there's not an increased safety risk."

But there are still more questions to be answered, he said, "and I definitely want to see the ischemic outcomes at 12 months."

The TREAT trial was an investigator-initiated trial funded by AstraZeneca. Berwanger reports grants from AstraZeneca, Amgen, Bayer, Novo Nordisk, Boehringer Ingelheim, and Roche Diagnosis, and personal fees from AstraZeneca, Bayer, Roche Diagnosis, and Sanofi. Harrington reports receiving grants from Astra, Bristol-Myers Squibb, Janssen, Novartis, Portola, the Medicines Company, Sanofi, and CSL Limited; receiving personal fees from Amgen, Bayer, Element Science, Gilead, MyoKardia, and the Medicines Company; and serving on the board of directors of the American Heart Association and Stanford Health Care.

American College of Cardiology (ACC) 2018 Annual Scientific Session: Presentation 404-12. Presented March 11, 2018.

JAMA Cardiol. Published online March 11, 2018. Article full text, Editor's note full text

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