Unexpected win for prasugrel in ACS
The potent P2Y12 inhibitor prasugrel significantly reduced the incidence of death, myocardial infarction (MI), or stroke in patients with acute coronary syndrome (ACS) with or without ST-segment elevation (STE) compared with ticagrelor, according to the results of the ISAR-REACT* 5 trial presented at ESC Congress 2019. Moreover, the improved anti-ischaemic efficacy of prasugrel was not accompanied by an increased bleeding risk.
The investigators hypothesized that ticagrelor would be superior to prasugrel, in view of evidence reflecting the lack of benefit and increased bleeding incidence associated with the latter drug. [N Engl J Med 2013;369:999-1010] “[Moreover,] studies showing [ticagrelor’s] stronger antiplatelet effect and potential beneficial pleiotropic effects … particularly those related to increased release of adenosine favoured the expectation of superiority of ticagrelor over prasugrel.” [N Engl J Med 2019;doi:10.1056/NEJMoa1908973]
“Contrary to our expectations, we found that prasugrel is superior to ticagrelor,” said principal investigator Professor Stefanie Schuepke from the German Heart Centre Munich in Munich, Germany.
Prasugrel recipients had a significantly lower incidence of the primary composite endpoint of death, MI, or stroke at 1 year than ticagrelor recipients (6.9 percent vs 9.3 percent, hazard ratio [HR], 1.36, 95 percent confidence interval [CI], 1.09–1.70; p=0.006), which was primarily driven by the fewer incidences of MI in the former vs the latter arm (3.0 percent vs 4.8 percent, HR, 1.63, 95 percent CI, 1.18–2.25). [ESC Congress 2019, abstract 2306]
Importantly, the fewer ischaemic events did not occur at the expense of increased bleeding risk, as evidenced by the similar rates of BARC** type 3–5 bleeding between the prasugrel and ticagrelor arms in the modified intention-to-treat analysis (4.8 percent vs 5.4 percent, HR, 1.12, 95 percent CI, 0.83–1.51; p=0.46).
A total of 4,018 patients (mean age 65 years, 24 percent women) hospitalized for ACS who were scheduled to undergo invasive evaluation were randomized 1:1 to receive prasugrel (loading dose 60 mg; maintenance dose 10 mg once daily) or ticagrelor (loading dose 180 mg; maintenance dose 90 mg twice daily). Ticagrelor loading dose was administered as soon as possible after randomization (pretreatment), while prasugrel was given either as pretreatment (STE cases) or postponed until coronary anatomy has been evaluated via diagnostic angiography (non[N]-STE cases).
“What has been missing until today is a head-to-head comparison of a ticagrelor- vs a prasugrel-based strategy in [this patient setting] in terms of 1-year clinical outcomes … The current findings show that a prasugrel-based strategy [even with] deferred loading in [NSTE-ACS] patients … was superior to a ticagrelor-based strategy with routine pretreatment,” said Schuepke. “[Therefore, our findings] support a prasugrel-based strategy – without routine pretreatment in NSTE-ACS – as first-line antiplatelet therapy for ACS patients.”
A landmark trial
“This is a very informative trial. [The findings reveal that] the one-size-fits-all strategy with ticagrelor was inferior to an individualized strategy with prasugrel … The data are consistent [across the whole spectrum of ACS] and this is good,” commented discussant Dr Gilles Montalescot from Pitié-Salpêtrière Hospital in Paris, France.
“[This is] a win for the prasugrel-based strategy – not only for the drug itself – as there was no pretreatment necessary among NSTE-ACS patients. This is an important point as majority of the patients had NSTE-ACS … Pretreatment … may be harmful,” Montalescot pointed out.
Furthermore, prasugrel dose was reduced in patients at high bleeding risk (ie, elderly), which was not the case for ticagrelor. “This may be an advantage for the prasugrel-based strategy,” he added.
“[Overall, this] is a landmark study that is going to impact our practice and the next set of guidelines,” added Montalescot. “We need to re-evaluate the way we use these drugs in our patients and to make sure that when we use one or the other drug, it is with the right strategy … [We] need to be smarter in the use of P2Y12 antagonists in ACS.”
Further analyses are underway to elucidate other issues (ie, mechanism of action, differences in half-life and toxicity profiles, drug interactions, compliance) that could further shed light on prasugrel’s win over ticagrelor, noted Schuepke.