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
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
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.
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.
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
Labels: For Doctors, Intermediate Level, Ischemic Heart Disease