Unexpected findings of superiority with a P2Y12 inhibitor in reducing outcomes in ACS patients

ISAR-REACT 5: Ticagrelor vs. Prasugrel in Acute Coronary Syndromes

Literature -

Presented at the ESC congress 2019 in Paris, France by: Stephanie Schüpke (Munich, Germany)

Introduction and methods

Both P2Y12 inhibitors ticagrelor and prasugrel are recommended as first year treatment for ACS patients with a class I indication. The relative benefit of ticagrelor vs. prasugrel in ACS patients with and without ST-segment elevation after one year are unknown. Therefore, a head-to-head comparison of prasugrel-based therapy vs. ticagrelor-based therapy in ACS patients with planned invasive therapy was undertaken for clinical outcomes after one year.

The ISAR-REACT 5 trial was an investigator-initiated, randomized, open-label, multicenter trial enrolling 4018 ACS patients. The investigators hypothesized that ticagrelor was superior to prasugrel with regard to clinical outcomes. There were two different loading strategies for STEMI patients and NSTEMI/unstable angina patients. Those with STEMI received a loading dose of ticagrelor or prasugrel immediately after randomization, while those with unstable angina/NSTEMI received ticagrelor after randomization and prasugrel after randomization and angiography.

The primary endpoint was a composite of death, MI or stroke after one year.

Main results

  • The number of primary endpoints with ticagrelor was higher than with prasugrel (9.3% vs. 6.9%, HR: 1.36; 95%CI:1.09-1.70, P=0.06).
  • Individual endpoints of death, MI, stroke and stent thrombosis were not different between the two groups.
  • BARC type 3-5 bleeding was not different between the two groups (5.4% for ticagrelor vs. 4.8% for prasugrel; HR: 1.12, 95%CI:0.83-1.51, P=0.46).


Prasugrel reduced the composite of death, MI, or stroke at one year in ACS patients compared to ticagrelor, without an increase in major bleeding. The findings support prasugrel as first-line antiplatelet therapy for ACS patients with or without ST-segment elevation.

Schüpke said she was absolutely surprised by the win of prasugrel. Perhaps two different loading strategies might explain the findings, or the difference in dosage. One way or the other, the investigators were very surprised. The ACCOAST results showed that bleeding was increased with pre-treatment of prasugrel. Therefore, when pre-treatment is intended, ticagrelor is given.

Mills responded that it is likely that the differences in outcome have nothing to do with loading regimes, but with effectiveness.

In response to the question whether this would result in a change in clinical practice, the answer was ‘most likely, yes’.

The investigators can not explain the mechanism of action, because they thought ticagrelor was better. Platelet function substudies will give more insights and are awaited. Schüpke mentioned that the half-lifes of the two drugs were different, ticagrelor is reversible and prasugrel irreversible, the two drugs are chemically different and side-effect profiles (and discontinuation rates) were different. Is discontinuation the driver of the findings? No said Schüpke, on treatment analysis showed no difference in findings.

- Our reporting is based on the information provided at the ESC congress -

The results of this study are simultaneously published in the N Engl J Med.

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