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Jan 17, 2013

PAR-1 inhibitors increase chances of bleeding


PAR-1 inhibitors are new class of antplatlet agents. Thrombin is potent platelet aggregator, PAR-1 inhibitors target thrombin-induced platelet aggregation, thrombin receptor signaling in platelets is mediated by protease-activated receptor PAR-1 and PAR-4,

Vorapaxar and Atopaxar are two clinically available PAR-1 inhibitors Vorapaxar has entered phase 3 trials and atopaxar into phase 2 trial.

Vorapaxar

Vorapaxar is reversible PAR-1 inhibitors.

Phase 2 study, TRA-PCI (Thrombin Receptor Antagonist in PCI) was done in elective PCI 1038 patients on clopidogrel and aspirin were randomized to Vorapaxar 10mg, 20mg and 40mg. The primary endpoint TIMI major and minor bleeding was similar in both groups and ischemic events were numerically less in Vorapaxar group compared to placebo. Japanese study in CVA patients also showed similar results

Phase 3study, Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, 13000 patients with NSTEMI most were on aspirin and clopidogrel were randomized to Vorapaxar and placebo. Study was terminated early do increased bleeding in Vorapaxar patients (7.2% vs. 5.2%; P value less than 0.001). With median follow-up of two years, there was no difference in the incidence of the composite primary endpoint of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalisation, and/or urgent coronary revascularization. Incidence of intracranial bleeding was higher in Vorapaxar group i.e. 1.1% vs. 0.2%; P value less than 0.001

Another phase 3 trial  TRA2P-TIMI 50 trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events -Thrombolysis in Myocardial Infarction 50 trial). In this trial patients who had MI, stroke  peripheral atherosclerotic artery disease, more 2 weeks and less than 2 years were to randomized to receive Vorapaxar and placebo above their aspirin and clopidogrel, some patients were  also on dipyridamole . Patients of CVA developed intracranial bleed with Vorapaxar group so they were discontinued from the study, but others were continued. In others ischemic events were less Vorapaxar versus placebo 11.2% versus 12.4% P = 0.001 patients with MI were most benefited, but this reduced ischemic events was at expense of increased bleeding Vorapaxar versus placebo 4.2% vs. 2.5%, P less than 0.001. The major limitation of this trail is one year continuation of dual antplatlet therapy, CHARISMA trial had shown no benfit of dual antplatalet therapy beyond one year.

Atopaxar

This is reversible PAR1 – inhibitor with shorter period of inhibition as compared to Vorapaxar
This drug in phase 2 trial did not show benfit and was associated with increased bleeding. Two trail of atopaxar are LANCELOT-ACS and LANCELOT-CAD. Done in ACS and CAD patients who were on aspirin were randomized to atopaxar and placebo. Atopaxar group had increased chance of bleeding with  decreasing ischemic events.

Conclusion

PAR-1 inhibitors Vorapaxar and atopaxar are having increased chance of bleeding without much benfit in reduction is ischemic events.

Vorapaxar in phase 2 trail showed benfit but not in phase 3 trails