Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Abstract

Aim: A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS. Methods: Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n 92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort. Results: Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p 0.013). There were no deaths or any other MACE. Conclusion: SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI. J Atheroscler Thromb, 2010; 17:156-164.

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].…”

Platelet Function Measured Using a Whole Blood Aggregometer Can Predict Bleeding Events

“…Several investigators reported that increasing the dose or adding antiplatelet agents resulted in stronger platelet inhibition without increasing the number of bleeding complications 8,10,19,20) . This seems slightly different from our major finding mentioned above.…”

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).…”