Mechanistic insights into the superior clinical efficacy of prasugrel over ticagrelor

This editorial refers to ‘Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study’†, by B. Schnorbus et al., on page 3144. In patients with acute coronary syndrome (ACS), a dual antiplatelet regimen with a platelet P2Y12 receptor antagonist in addition to the cyclooxygenase inhibitor acetylsalicylic acid (ASA) represents an essential treatment component to prevent subsequent thrombotic vascular events.1–4 The third-generation thienopyridine prasugrel5 and the cyclopentyl-triazolo-pyrimidine ticagrelor provide a greater, more rapid, and consistent platelet inhibition compared with the predecessor thienopyridine clopidogrel.6 While prasugrel—like clopidogrel—blocks the ADP-binding site of the P2Y12 receptor irreversibly, ticagrelor reversibly inhibits binding of ADP to the P2Y12 receptor in a non-competitive manner.7 Both drugs have been tested against clopidogrel in large, randomized, double-blind clinical trials of ACS patients.5 , 8 In the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial of patients with ACS undergoing percutaneous coronary intervention (PCI), prasugrel compared with clopidogrel resulted in a significant reduction in the composite ischaemic endpoint of cardiovascular death, myocardial infarction, or stroke.5 In the PLATelet inhibition and patient Outcomes (PLATO) trial of ACS patients treated either conservatively or with an invasive strategy, ticagrelor compared with clopidogrel was also associated with a significant reduction in the composite of vascular death, myocardial infarction, or stroke.8 Based on the advantages of ticagrelor and prasugrel over clopidogrel in the two landmark studies, both drugs received a class I recommendation for their use in ACS patients, including patients with ST-segment elevation myocardial infarction (STEMI)2 and non-ST-segment elevation acute coronary syndromes (NSTE-ACS).1 Although both ticagrelor and prasugrel have been used in millions of patients with ACS during the last decade, there has been a dramatic lack of dedicated comparative studies of their clinical efficacy and safety in these patients for many years. However, several studies have compared pharmacodynamic effects of ticagrelor and prasugrel, often showing discordant results.9–14 Part of the variability in the results has also been attributed to the different testing methods used in these studies. For example, it has been reported that the vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay may overestimate the pharmacodynamic effect of ticagrelor.15 One important lesson is learnt from these studies: ticagrelor and prasugrel exert multiple effects that might be relevant to their performance in the clinical setting, and the isolated evaluation of platelet inhibition by these drugs is not sufficient to understand the mechanisms underlying their relative merits in clinical practice (Figure 1). Therefore, there is a specific need for studies that aim at filling this gap in our knowledge by simultaneously assessing various properties of the P2Y12 receptor antagonists. Possible mechanisms underlying the effect of P2Y12 receptor antagonists on clinical outcomes in patients with coronary artery disease. In this issue of the European Heart Journal, Schnorbus and colleagues16 report on the results of an industry-independent, randomized drug study. They compared the effects of clopidogrel, prasugrel, and ticagrelor on vascular function by assessing flow-mediated dilation (FMD) of the radial artery, on markers of inflammation by measuring interleukin (IL)-6 and other plasma biomarkers, and on platelet function by analysing ADP-induced platelet aggregation in NSTE-ACS patients undergoing everolimus-eluting stent implantation. Several limitations should be taken into account during the interpretation of the results of this study. Overall, a total of 90 patients were enrolled in the trial and randomly assigned to one of the three treatment groups. The trial was prematurely stopped for slow recruitment after a 4-year period of enrolment. Because of the small sample size, differences in subgroups defined by clinical presentation (NSTEMI vs. unstable angina) or timing of study drug administration (before angiography or after PCI) should be considered with great caution. Markers of inflammation were assessed only in the first 56 patients, at a variable number of visits, and the P-values were not adjusted for multiple testing. The study also lacks the advantage of a double-blind design. However, this design would have required the use of placebo pills, whose availability is unlikely to be feasible without the support of the respective drug companies. Notwithstanding these drawbacks, the study provides interesting results. Prasugrel was superior not only to clopidogrel but also to ticagrelor in terms of vascular function. In addition, prasugrel reduced markers of inflammation and provided stronger inhibition of ADP-induced platelet aggregation compared with both clopidogrel and ticagrelor. The main strength of the study is the industry-independent, head to head comparison of prasugrel vs. ticagrelor. Although industry-independent, head to head trials are well received by the medical community, some experts are inclined to accept their results only if they are in line with indirect comparisons derived from separate industry-sponsored studies. They follow the logic of the transitive law: ‘If therapy a and therapy b show a comparable advantage over therapy c in separate studies, then therapy a is equivalent to therapy b.’ Several examples in medicine show the failure of this logic. Sirolimus-eluting stents and paclitaxel-eluting stents showed comparable advantages over bare-metal stents in industry-sponsored trials including patients with coronary artery disease,17 , 18 but only industry-independent, head to head comparisons were able to show that they were not equivalent.19 , 20 Limus-eluting stents are currently the standard drug-eluting stent for PCIs. The importance of the findings of Schnorbus and colleagues16 should also be considered in the context of the recently reported clinical outcomes of patients with a broad spectrum of ACS treated with either a ticagrelor- or prasugrel-based strategy in the setting of the randomized Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial.21 In this trial, at 12 months after randomization, prasugrel was associated with a 26% risk reduction for the composite endpoint of death, myocardial infarction, or stroke compared with ticagrelor.21 While there was a numeric reduction in all three components of the primary endpoint with prasugrel, the benefit was primarily driven by fewer myocardial infarctions. The observation that definite stent thrombosis occurred in 12 patients assigned to prasugrel vs. 22 patients assigned to ticagrelor supports a greater antithrombotic efficacy of prasugrel. Notwithstanding the clear and consistent clinical results in favour of prasugrel in the ISAR-REACT 5 trial, the mechanism underlying it could not easily be elucidated. Reversibility of the P2Y12 receptor antagonism by ticagrelor might render the stability of platelet inhibition more vulnerable to short-term patient non-adherence, especially with a drug given twice daily. On the other hand, the patient adherence is more likely to be compromised for a drug associated with more side effects, as in the case of ticagrelor. Dyspnoea, dizziness, syncope, elevation of creatinine, and elevation of uric acid and consequent exacerbation of gout are unique side effects of ticagrelor. These reasons may explain part of the difference in efficacy between prasugrel and ticagrelor shown in the ISAR-REACT 5 trial.21 In this regard, the study of Schnorbus and colleagues16 suggests additional plausible mechanisms related to the differential response of vascular function and inflammation to prasugrel and ticagrelor. Although cardiologists who care for patients with ACS usually do not wait for the full elucidation of the mechanisms underlying differences in drug efficacy before adopting the results of a large randomized trial, findings of mechanistic studies such as this of Schnorbus and colleagues16 may well facilitate changes in practice. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.