September 3, 2019 — Results from the ISAR-REACT 5 trial have been causing much discussion since they were presented at a Hot Line Session and simultaneously published in the New England Journal of Medicine.1
According to current clinical practice guidelines, prasugrel and ticagrelor have equal, Class I recommendations for use following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS), with and without ST-segment elevation. But, as presenter Professor Stefanie Schüpke (Deutsches Herzzentrum München, Munich, Germany), explains, “It was not clear to us what the relative merits of the two different treatments were. In the emergency room, we found ourselves faced with the dilemma of which of the two drugs we should use.” The group embarked on a head-to-head comparison of the two agents in a randomised setting in an investigator-initiated study funded by the DZHK (German Centre for Cardiovascular Research) and the Deutsches Herzzentrum München.
This was an open-label multicentre trial, enrolling patients admitted for ACS and planned invasive strategy from 23 centres in Germany and Italy. Patients randomised to ticagrelor received a loading dose as soon as possible after randomisation and before coronary angiography. With prasugrel, study drug initiation depended on clinical presentation: it was administered as soon as possible after randomisation for patients with ST-elevation myocardial infarction (STEMI) but after the coronary anatomy was known (and before PCI) in patients with non-ST-elevation (NSTE)-ACS.
The primary endpoint was a composite of death, myocardial infarction (MI) or stroke within 12 months after randomisation. Secondary endpoints included the individual components of the composite, type 3–5 bleeding (according to the hierarchical Bleeding Academic Research Consortium classification [BARC]) and stent thrombosis. Hazard ratios (HRs) represent the comparison of ticagrelor in relation to prasugrel.
The composite of death, MI or stroke at 12 months was higher with ticagrelor compared with prasugrel (9.3% vs 6.9%; HR 1.36; 95% confidence interval [CI] 1.09–1.70; p=0.006).
The difference in the effects of the two treatments on the primary endpoint was primarily driven by rates of MI, which were 4.8% with ticagrelor and 3.0% with prasugrel (HR 1.63; 95% CI 1.18–2.25). There were no significant differences between ticagrelor and prasugrel in rates of overall mortality (4.5% and 3.7%, respectively) and stroke (1.1% and 1.0%, respectively). Rates of definite or probable stent thrombosis were 1.3% and 1.0% while rates of definite stent thrombosis were 1.1% and 0.6%, with ticagrelor and prasugrel, respectively.
“The benefit of prasugrel over ticagrelor did not come at the expense of an increased bleeding risk,” says Prof. Schüpke. There was no difference between treatments in BARC type 3–5 bleeding, with rates of 5.4% with ticagrelor and 4.8% with prasugrel (HR 1.12; 95% CI 0.83–1.51; p=0.46).
“The results very clearly demonstrate the superiority of prasugrel over ticagrelor,” says Prof. Schüpke. “This actually came as a surprise to us. When we planned the trial, we assumed that ticagrelor would be superior to prasugrel, but results show us that the opposite is true. At the moment, we do not yet know why prasugrel is superior to ticagrelor. Possibilities include issues related to the reversibility of platelet inhibition, treatment half-lives, drug–drug interactions and side effects leading to higher rates of discontinuation with ticagrelor, but this needs more investigation. We have performed substudies on platelet function that may help to provide some of the answers.”
Prof. Schüpke thinks that the results of the trial will have an impact on clinical practice. “Because prasugrel and ticagrelor have equal recommendation in the guidelines, some hospitals had opted to prescribe just one of the two drugs. In the light of the strong evidence from our trial that prasugrel is superior to ticagrelor, clinicians and hospitals may reconsider their treatment choices.” Further, she adds, “The ISAR-REACT 5 trial not only tested two drugs, but also two strategies, i.e. pretreatment vs no pretreatment in NSTE-ACS. The question of whether patients with ACS need pre-treatment with P2Y12 antagonists before reaching the cath lab has not been fully elucidated to date. Its clarification is particularly important for patients with NSTE-ACS, where the interval between presentation and invasive evaluation is usually longer than for STEMI patients. The results of the ISAR-REACT 5 trial support a prasugrel-based strategy that does not include pre-treatment in NSTE-ACS patients.”
1. Schüpke S et al. N Engl J Med 2019. doi.org/10.1056/NEJMoa1908973