03 Sep 2019
ISAR REACT 5 - Ticagrelor versus prasugrel in patients with acute coronary syndrome
Reported from the European Society of Cardiology ESC Congress 2019 in Paris
At the ESC Congress 2019 in Paris, Stefanie Schuepke presented the results of the ISAR REACT 5 study. Read this analysis by Francesco Costa and view a short interview with Stefanie Schuepke.
The methodology
ISAR REACT 5 is an open-label, multicenter, randomized clinical trial to compare the efficacy and safety of ticagrelor and prasugrel in patients with acute coronary syndromes. This trial was investigator-initiated, which underscore the absence of industry funding or participation to the organization, design or conduct of the trial.
A total of 4,018 patients with acute coronary syndrome for which an invasive strategy was planned were enrolled and randomized. Depending on the clinical presentation the study protocol mandated the following conduct with drug administration: in STEMI patients all patients were randomized and treated at the time of the diagnosis; for NSTEMI or unstable angina patients, those randomized to ticagrelor were treated with the drug immediately after randomization (pre-treatment) whereas those randomized to prasugrel were treated with the drug as soon as the coronary angiography was available (no pre-treatment). In addition, patients with clinical criteria for prasugrel dose reduction (age more 75, weight <60Kg) were assigned to a prasugrel dose of 5mg qd.
The primary endpoint of the study was a composite of death, MI, or stroke at 1 year after randomization. The safety endpoint was bleeding according to the Bleeding Academic Research Consortium class 3,4 or 5 events. All events were adjudicated by a blinded clinical events committee. The primary hypothesis of the study was that ticagrelor would be superior to prasugrel in terms of the primary efficacy endpoint, with a sample size calculation selected to find a relative difference of at least 22.5% between the two treatments in favour of ticagrelor.
The study enrolled patients in a period between 2013 and 2018, 41.1% with STEMI, 46.2% with NSTEMI, and 12.7% with unstable angina. A total of 84% of patients underwent PCI, 2% underwent CABG and 14% underwent medical management alone. At discharge, roughly 80% of patients randomized to each drug was ultimately treated with the randomized drug. After 12 months, 15.2% and 12.5% of patients in the ticagrelor and prasugrel group permanently discontinued the drug at a median timing of 2.5 months and 3.5 months from randomization respectively.
What were the results?
At 12 months follow-up, the primary endpoint occurred in 9.1% of patients in the ticagrelor group and 6.8% in the prasugrel group (relative risk increase 36%, p=0.006 – Absolute risk reduction 2.3%). At Kaplan Meier curve inspection the events in the two groups appeared to progressively diverge over time. The difference in the primary endpoint was driven by a reduction of all the components of the composite endpoint, yet the only one that taken singularly reached statistical significance was myocardial infarction (relative risk increase with ticagrelor 63%). Bleeding events occurred in a similar proportion in the two groups (5.4% with ticagrelor and 4.8% with prasugrel). No heterogeneity for the primary endpoint was observed for any of the explored subgroups. In particular, the benefit for the primary endpoint was consistent in patients presenting with STEMI or with NSTEMI.
Why is this study important?
ISAR REACT 5 is the first large-sized trial which compared prasugrel and ticagrelor in ACS. The previously presented PRAGUE 18 trial was smaller and ultimately inconclusive. Hence, for the first time, we have evidence comparing the two drugs in a large scale randomized setting. Prasugrel appears as the clear winner in this comparison, with a clear reduction of MI during follow-up which importantly are not only “troponin leaks” but also a significant reduction of new STEMI. Yet it is important to underscore that this trial has not tested only two drugs but also two strategies. All patients randomized to ticagrelor were also pretreated and once again, there is no evidence that pretreatment is beneficial in any way in patients with NSTE-ACS. Ultimately it is interesting to observe that no difference in bleeding was observed in the two treatment arms, whether this is really due to a similar bleeding liability of the two treatments or to also a difference in which the two treatments were handled (pre-treatment vs. no pretreatment) it is difficult to establish.
My take on this study
While the results of the ISAR REACT are of primary importance and will likely change most clinical practice and guidelines, a series of considerations has to be done to reconcile this data with the prior trials in the literature.
First, it is difficult to understand how prasugrel which was compared to clopidogrel in 13.000 patients and showed a 19% relative risk reduction and 2.2% absolute risk reduction for the primary endpoint, and ticagrelor which was compared to clopidogrel in 18.000 patients and showed a 16% reduction and 1.9% absolute risk reduction compared with clopidogrel, were associated when compared directly together to a 36% relative risk and 2.3% absolute risk difference.
This latter point is stunning, in fact, this absolute risk reduction observed in the difference between prasugrel and ticagrelor is even bigger than those observed of other antithrombotic strategies versus placebo (e.g. the comparison of clopidogrel vs. Placebo in the CURE trial was associated with 2.1% absolute risk difference).
While the event rate in the ticagrelor group in ISAR REACT trial is similar to that observed in the PLATO trial, the event rate in the prasugrel arm was substantially lower to the event rate of prasugrel in the TRITON trial. Unfortunately, it is extremely difficult that these results will ever be replicated in the future in similar studies. A direct comparison of two competing drugs is rare, and finding fundings for this kind of research is extremely challenging. For this reason, investigator-initiated projects as ISAR REACT 5 should be commended, and despite its technical limitations, this represents the best available evidence we have between these two treatments.
Watch this short interview of Stefanie Schuepke, who presented this study at the ESC Congress 2019, providing a summary of the ISAR REACT 5 trial:
1 comment
Very clear, thank's