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Antiplatelets Go Head-to-Head in ACS, With Unexpected Result

— Assumption that ticagrelor would be superior upended in ISAR-REACT 5

MedpageToday

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PARIS -- In a large head-to-head trial of two P2Y12 Inhibitors, prasugrel (Effient) significantly lowered rates of ischemic events versus ticagrelor (Brilinta) for patients with acute coronary syndrome (ACS), and without an increase in major bleeds.

Among more than 4,000 patients in the open-label trial, the combined 1-year rate of stroke, MI, or death was 9.3% in the group randomized to ticagrelor compared to 6.9% in the prasugrel group (HR 1.36, 95% CI 1.09-1.70, P=0.006), Stefanie Schüpke, MD, of Deutsches Herzzentrum in Munich, reported here at the 2019 European Society of Cardiology congress.

Rates of major bleeds, defined as Bleeding Academic Research Consortium (BARC) type 3 to 5, among those who received at least one dose of the study drugs were similar between the two arms, 5.4% in the ticagrelor group and 4.8% with prasugrel (HR 1.12, 95% CI 0.83-1.51). An intent-to-treat analysis also showed no difference (5.8% vs 5.6%).

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

Yet investigators had designed ISAR-REACT 5 with the hypothesis that the ticagrelor-based strategy would be superior. Results from the multicenter trial were simultaneously published in the .

"I am very surprised," said session chair Roxana Mehran, MD, of Mount Sinai Hospital in New York City. "The devil is in the details."

The trial used two different strategies for ST-segment elevation myocardial infarction (STEMI) and non-ST-elevation MI (NSTEMI), and different protocols for administering ticagrelor and prasugrel.

Following randomization, the ticagrelor group received their loading dose as soon as possible. In the prasugrel group, only patients with ST-segment elevation received the loading dose as soon as possible, while those without ST-segment elevation had this initial dose postponed until their coronary anatomy could be assessed as requiring intervention.

"When you go into a trial designed for superiority and then you come out with a completely different result, I don't know how one is to interpret that," Mehran said.

Schüpke said she believes the results will change clinical practice.

"I guess this will be discussed in the various guideline steering committees," said press briefing moderator Steen Kristensen, MD, of Aarhus University in Denmark.

Numerically higher rates for each component of the primary endpoint were seen with ticagrelor versus prasugrel:

  • Stroke: 1.1% vs 1.0%
  • MI: 4.8% vs 3.0%
  • Death: 4.5% vs 3.7%

Schüpke's group randomized 2,006 ACS patients to prasugrel and 2,012 to ticagrelor at two centers in Italy and 21 centers in Germany. The cohorts had a mean age of about 65 years and roughly 24% were women. Clinical follow-up was scheduled at 1, 6, and 12 months.

All patients had been hospitalized for an ACS -- unstable angina (12.7%), STEMI (41.1%), and NSTEMI (46.2%) -- and scheduled to be evaluated using coronary angiography. The treatment strategy was percutaneous coronary intervention for about 84%.

Treatment with prasugrel was initiated with a loading dose of 60 mg and continued at a maintenance dose of 10 mg once daily. For patients who weighed less than 132 lbs or were age 75 or older, a reduced maintenance dose of 5 mg daily was recommended.

For the ticagrelor cohort, therapy was initiated at a loading dose of 180 mg and continued with a maintenance dose of 90 mg twice daily. Patients in the ticagrelor cohort received the loading dose shortly after randomization.

Exclusion criteria were use of oral anticoagulation, chronic kidney disease that required dialysis, use of either study drug within 5 days of randomization, and history of intracranial bleeding, stroke, or transient ischemic attack.

One limitation was that follow-up was largely done by telephone.

Disclosures

The study was supported by Deutsches Herzzentrum München and the German Center for Cardiovascular Research.

Kristensen disclosed relationships with Aspen, AstraZeneca, Bayer, BMS, and Pfizer.

Primary Source

New England Journal of Medicine

Schüpke S, et al "Ticagrelor or prasugrel in patients with acute coronary syndromes" N Engl J Med 2019; DOI: 10.1056/NEJMoa1908973.