ISAR-REACT 5: Prasugrel Bests Ticagrelor in ACS

Marlene Busko

September 02, 2019

PARIS — Among patients hospitalized for acute coronary syndrome (ACS) and scheduled to have invasive coronary angiography, those who received an antiplatelet treatment strategy with prasugrel (Effient/Efient, Eli Lilly/Daiichi Sankyo) rather than ticagrelor (Brilinta/Brilique, AstraZeneca) had better 1-year outcomes — the opposite of what had been expected.

Stefanie Schüpke, MD, Deutsches Herzzentrum München, Munich, Germany presented these "counterintuitive" findings from the ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial here at the European Society of Cardiology (ESC) Congress 2019. The study was simultaneously published online September 1 in the New England Journal of Medicine.

Patients who received prasugrel rather than ticagrelor were less likely to die or have a myocardial infarction (MI) or stroke after a year of antiplatelet therapy, the primary efficacy outcome, and there was no difference in bleeding risk, the primary safety outcome.

The trial compared two types of patients with ACS , those with ST-segment elevation MI (STEMI) and those with non-STEMI or unstable angina; two types of antiplatelet therapy, ticagrelor and prasugrel; and two treatment strategies, an antiplatelet loading dose before or after angiography.

"The results of the trial support a prasugrel-based strategy — without routine pretreatment in non-STEMI ACS — as the first-line antiplatelet therapy for ACS patients," Schüpke said in a press briefing.

"We were surprised" with these results, she added, "because we...assumed that ticagrelor would be superior, and we found just the opposite."

This was a "landmark study," said the assigned discussant at the hotline session, Gilles Montalescot, MD, PhD, Pitié-Salpêtrière University Hospital, Paris, France.

It showed that a one-size-fits-all treatment strategy with ticagrelor was inferior to an individualized treatment strategy with prasugrel, he noted.

"Two drugs, two strategies, with different ways of treating patients — before angiography, after angiography, STEMI, non-STEMI — that to me is a little bit confusing," press briefing co-moderator Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York City, told | Medscape Cardiology.

Nevertheless, this was a real-world, important study, she said, and more head-to-head comparisons such as this one are needed.  

"I think many people will look at this and say [prasugrel] is cheaper, it's a once-a-day drug, I'm going to use it, and it's not going to be harmful,'" she said, noting that the researchers "did have a pathway for the older patients at a lower dose, which hasn't been looked at before."

"This head-to-head comparison is much needed," Nicholas L. Mills, MD, PhD, University of Edinburgh, United Kingdom, agreed. The findings, though "counterintuitive...seem very clear," he told | Medscape Cardiology.

"I've always had concerns about real-world adherence to antiplatelet drugs following stenting," Mills added. "I think the advantage of [prasugrel of] having a longer half-life and a single dosing strategy may have been relevant in this trial."  

It remains to be determined, he added, whether some patients should continue to be managed with the earlier-generation antiplatelet agent clopidogrel, which is still widely used.

At his center, clinicians use clopidogrel and ticagrelor, and "we'll need to reflect on the outcomes of this trial before determining exactly what policy we adopt," he said.

First Head-to-Head Trial of Newer Antiplatelet Agents

Prasugrel and ticagrelor each have a class 1 recommendation for 1-year treatment of patients with ACS, Schüpke said.

However, the researchers hypothesized that in such patients, ticagrelor treatment would top prasugrel, on the basis of several considerations.

First, pretreatment with ticagrelor was associated with an early benefit over clopidogrel in PLATO (Study of Platelet Inhibition and Platelet Outcomes). 

In another trial, pretreatment with prasugrel was not beneficial in patients who had ACS without STEMI, and it was associated with an increased incidence of major bleeding.

And in the TRILOGY ACS (Targeted Platelet Inhibition to Clarify optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, prasugrel was not superior to clopidogrel in patients who had ACS without STEMI and did not undergo revascularization.

ISAR-REACT 5 was an open-label trial to assess whether ticagrelor was superior to prasugrel in patients with ACS using a planned invasive strategy.

The researchers randomly assigned 4018 patients with ACS at 21 centers in Germany and 2 centers in Italy (who were about to undergo coronary angiography) to receive therapy with prasugrel or ticagrelor.

Close to half of the patients had a suspected diagnosis of STEMI (41% of patients) and the remaining patients had a suspected diagnosis of non-STEMI (46.2%) or, less often, unstable angina (12.7%).  

Patients who were randomly assigned to receive ticagrelor were given a loading dose of 180 mg as soon as possible after randomization, followed by a maintenance dose of 90 mg twice daily.

Patients who were randomly assigned to receive prasugrel were given a loading dose of 60 mg as soon as possible if they had STEMI, but they were given this loading dose after angiography only if they had non-STEMI or unstable angina.

After percutaneous coronary intervention (PCI), they received a maintenance dose of 10 mg/day, or 5 mg/day if they were age 75 years or older or weighed less than 60 kg.   

The patients received the antiplatelet therapy for 12 months along with concomitant aspirin at a dose of 75 to 150 mg/day.

The patients had a mean age of 64 years, and 24% were women. Eighty-four percent of patients underwent PCI and 2.1% of patients underwent coronary artery bypass grafting.

At 1 year, 15.2% of patients who were receiving ticagrelor when they were discharged from the hospital and 12.5% of patients who were receiving prasugrel at hospital discharge had discontinued the trial therapy (P = .03).

Surprising Results

The researchers had assumed that the composite endpoint (death, MI, or stroke at 1 year) would occur in 10% in the ticagrelor group and 12.9% in the prasugrel group, so they would need a sample size of 4000 to show superiority of ticagrelor.

In fact, the primary composite endpoint occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.8%) in the prasugrel group (P = .006).

At 1 year, the rate of death from any cause was 4.5% vs 3.7%, the rate of MI was 4.8% vs 3.0%, and the rate of stroke was 1.1% vs 1.0% for patients in the ticagrelor vs prasugrel groups, respectively.

The rate of definite stent thrombosis was also lower in patients in the prasugrel group (0.6% vs 1.1%, respectively).

At the same time, among patients who had received at least one dose of the randomly assigned drugs, the rate of major bleeding (Bleeding Academic Research Consortium [BARC] types 3 through 5) was 5.4% for patients in the ticagrelor group vs 4.8% for patients in the prasugrel group, which was not significantly different (P = .46).

"The lower incidence of the composite endpoint was primarily driven by fewer myocardial infarctions in the prasugrel group than in the ticagrelor group, and the benefit of fewer ischemic events with prasugrel did not occur at the expense of an increased risk of bleeding," the researchers summarize.

The trial did not simply compare two antiplatelet drugs, they stress. Rather, it compared two antiplatelet treatment strategies for two types of patients with ACS involving two different drugs.

It remains to be seen exactly how these new findings will be incorporated into European society treatment guidelines that are currently being updated, Montalescot said.

The study was supported by a grant from the German Center for Cardiovascular Research and Deutsches Herzzentrum München. Schüpke reports receiving a grant from the Else Kröner Fresenius Stiftung and consulting fees from Bayer.

European Society of Cardiology (ESC) Congress 2019. Presented September 1, 2019.

N Engl J Med. Published online September 1, 2019. Article

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