Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study

Role of Vorapaxar After Coronary Revascularization

“…Consistent with the results from main phase III trials, vorapaxar led to significantly increased risk of major bleeding events, including ICH [11,12]. In the phase II studies involving patients undergoing PCI, vorapaxar demonstrated a trend towards lesser thrombotic events compared to placebo without exposing to an increase in bleeding risk [6,9]. It was postulated that while inhibiting thrombin-mediated platelet activation, PAR1 antagonism might not interfere with the hemostatic pathway and, thus, not predispose to a higher bleeding risk [6,9].…”

“…In the phase II studies involving patients undergoing PCI, vorapaxar demonstrated a trend towards lesser thrombotic events compared to placebo without exposing to an increase in bleeding risk [6,9]. It was postulated that while inhibiting thrombin-mediated platelet activation, PAR1 antagonism might not interfere with the hemostatic pathway and, thus, not predispose to a higher bleeding risk [6,9]. However, in phase 3 trials, the magnitude M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 7 of the increased bleeding rates was much higher than expected on the basis of the preclinical and phases 2 trials, which suggested that vorapaxar did not significantly increase the risk of bleeding, over and above that of standard DAPT with aspirin and clopidogrel [6][7][8][9][10].…”

“…It was postulated that while inhibiting thrombin-mediated platelet activation, PAR1 antagonism might not interfere with the hemostatic pathway and, thus, not predispose to a higher bleeding risk [6,9]. However, in phase 3 trials, the magnitude M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 7 of the increased bleeding rates was much higher than expected on the basis of the preclinical and phases 2 trials, which suggested that vorapaxar did not significantly increase the risk of bleeding, over and above that of standard DAPT with aspirin and clopidogrel [6][7][8][9][10]. In fact, the TRACER trial was terminated early because of the observed significant increase in major bleeding, [12] and in the TRA-2P TIMI 50 trial, the data and safety monitoring board recommended the discontinuation of vorapaxar in patients with a history of stroke on the basis of an excess of ICH in such patients [11].…”

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

“…Two phase II clinical trials showed that addition of vorapaxar to DAPT was associated with a reduction in adverse cardiac events without major side effects (57,58). However, in the phase III TRACER trial, vorapaxar significantly increased the risk of major bleeding and intracranial haemorrhage and was therefore stopped early (59).…”

Perioperative handling of antiplatelet therapy: watching the two sides of the coin

“…The new PAR-1 antagonists, currently in phase III clinical testing, have given promising preclinical and preliminary clinical results, showing an effective antiplatelet action without any associated significant bleeding, and future novel approaches may provide further options in this sense [12,13].…”