Editorial Ticagrelor versus prasugrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention: An unresolved issue Gianluigi Savarese a, ⁎, Lars H. Lund a,b a Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden b Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden article info Article history: Received 13 September 2017 Accepted 20 September 2017 The newer generation P2Y 12 inhibitors, namely prasugrel and ticagrelor, have essentially replaced clopidogrel for the treatment of pa- tients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), after the publication of TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) and PLATO (PLATelet inhibition and patient Outcomes) trials [1,2]. Thus, current European Society of Cardiology (ESC) guidelines give a IB recommendation to ticagrelor on top of aspirin, regardless of initial treatment strategy, in ACS patients, and to prasugrel on top of aspirin in P2Y 12 inhibitor-naïve patients with non-ST elevation (NSTE) ACS, or in initially conservatively managed STE ACS if indication for PCI is established, or in STE ACS patients undergoing immediate PCI [3]. Al- though ticagrelor is recommended in a broader spectrum of ACS pa- tients compared to prasugrel, there are still patients who, according to the guidelines, could equally benefit from ticagrelor or prasugrel and, currently, there is limited data comparing head-to-dead these drugs for efficacy and safety. Indeed, previously, the PRAGUE-18 trial, ran- domizing 1,230 patients with ACS referred to PCI to ticagrelor or prasugrel, could not show any difference in risk of the primary outcome (death, re-infarction, urgent target vessel revascularization, stroke, seri- ous bleeding requiring transfusion or prolonging hospitalization within 7 days) at 30 days between the treatments, but these data require con- firmation in a larger trial because of the large confidence intervals around the estimates [4]. In a “real-world” setting, Larmore et al. com- pared prasugrel vs. ticagrelor in a cohort of 16,098 patients undergoing PCI for ACS and they found out that prasugrel was associated with a reduced risk of 30-day major cardiovascular events and major bleeding, but the observational nature of these data, and in particular the evi- dence of more prasugrel use in younger and healthier patients, could not rule out the influence of residual and unmeasured confounders even after adjustments [5]. The current issue of International Journal of Cardiology reports a sys- tematic review and meta-analysis of randomized and non-randomized studies by Watti et al. aiming to compare head-to-head the 30-day safety and efficacy of prasugrel vs. ticagrelor in patients with ACS who underwent PCI [6]. They pooled 9 studies (4 randomized and 5 observa- tional) enrolling 21,360 patients (15,666 receiving prasugrel and 5,694 ticagrelor) and reported a statistically significant reduction of the risk of myocardial infarction (MI) and BARC (Bleeding Academic Research Consortium) ≥ 2 bleeding in prasugrel vs. ticagrelor arm, with no differ- ence in risk of mortality, repeat revascularization and stroke between the two agents at 30 days. Their conclusion was that prasugrel appears to be equivalent or superior to ticagrelor in patients with ACS undergo- ing PCI in 30-day follow-up, but larger randomized trials with longer follow-ups are needed to establish superiority of one agent over the other. This is the first meta-analysis attempting to perform a head-to-head comparison between prasugrel and ticagrelor in ACS patients undergo- ing PCI. Even though it enrolled a large cohort of patients, 1 of the 9 studies included, that from Larmore et al. previously described [5], accounted alone for more than the half of the population analysed and had weight 55% and 37% in the MI and bleeding outcome analyses, re- spectively, leading to conclude that had a major impact on the overall estimates. Indeed, when the analyses were repeated excluding this study, no statistically significant differences between the treatments were reported. Whether this is due to the fact that all the studies except for Larmore et al. reported only few events, and thus were underpow- ered, or to the lack of any real difference in efficacy and safety of these drugs can only be speculated. Although only a moderate heterogeneity could be observed only in the MI outcome analysis of this meta- analysis, it has to be acknowledged that the studies included varied for design, baseline cardiovascular risk factor, % of STE ACS vs. NSTE ACS patients, indication for PCI, concomitant treatments and follow- up length (ranging from 12 h to 15 months). Additionally, 5 of the 9 studies included were observational, thus there could be still room for potential influence on the results of residual and unknown confounders. All these factors, together with the few clinical events International Journal of Cardiology 249 (2017) 77–78 DOI of original article: https://doi.org/10.1016/j.ijcard.2017.07.103. ⁎ Corresponding author at: Department of Medicine, Cardiology Unit, Karolinska Institutet, S1:02, 171 76 Stockholm, Sweden. E-mail address: gianluigi.savarese@ki.se (G. Savarese). https://doi.org/10.1016/j.ijcard.2017.09.180 0167-5273/© 2017 Elsevier B.V. All rights reserved. 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