TRA・CER: First-in-class
oral PAR-1 antagonist failed to reduce adverse outcomes for patients
with acute coronary syndromes
An experimental platelet thrombin receptor
antagonist didn't improve outcomes for patients with acute coronary
syndromes, according to late-breaking research presented at the
American Heart Association's Scientific Sessions 2011.
The study is simultaneously published in the New England Journal
of Medicine.
In the Thrombin Receptor Antagonist for Clinical Event Reduction
in Acute Coronary Syndrome (TRA・CER) Study, researchers compared
vorapaxar to a placebo in patients with non-ST-segment elevation
acute coronary syndrome.
Researchers enrolled 12,944 patients at 818 sites in 37 countries.
All patients received the usual medical care for their condition,
typically involving aspirin and clopidogrel, as well as procedures
such as catheterization, coronary stenting or surgery if indicated.
Half the participants also were given a 40-milligram initial dose
followed by a 2.5-milligram daily dose of vorapaxar, the first in
a new class of anti-platelet drugs, PAR-1 antagonists. The rest
of the patients received a placebo.
Participants given vorapaxar were just as likely as those given
placebo to experience at least one of five outcomes - cardiovascular-related
death, myocardial infarction, stroke, a new hospitalization for
unstable angina or urgent revascularization. After two years of
study, almost one in five patients in each group had such an outcome
(18.5 percent vorapaxar vs. 19.9 percent placebo).
Researchers also found that the patients who received vorapaxar
had more bleeding and had a three-fold increase in the risk of hemorrhagic
stroke.
Patients on vorapaxar also had a 14.7 percent risk of cardiovascular
death, heart attack or stroke, compared to 16 percent for patients
given the placebo, a difference that was not statistically significant.
Researchers said there was discordance between these findings and
their earlier Phase 2 study.
"The difference in the primary endpoint was more modest and
the bleeding risk was higher than expected," said Kenneth W.
Mahaffey, M.D., lead author of the study and co-director of cardiovascular
research at the Duke Clinical Research Institute in Durham, N.C.
"Earlier studies of vorapaxar had not identified an excess
bleeding risk, so these findings are surprising. More work is needed
to understand the bleeding risk. Whether it's related to the use
of aspirin and clopidogrel in these patients or other factors need
to be and will be examined carefully."
"We were surprised and disappointed that TRA・CER failed to
meet its primary endpoint," said Robert Harrington, M.D., chair
of the TRA・CER steering committee and director of the Duke Clinical
Research Institute. "The lower incidence of cardiovascular
death, heart attack or stroke with vorapaxar while not significant,
is promising and we look forward to seeing the data from the next
trial (TRA 2P TIMI 50) to better understand if or how to proceed
with further development of vorapaxar."
Co-authors are Pierluigi Tricoci, M.D., Ph.D.; Yuliya Lokhnygina,
Ph.D.; Paul W. Armstrong, M.D.; Phillip E. Aylward, M.D.; Edmond
Chen, M.D.; Claes Held, M.D., Ph.D.; Sergio Leonardi, M.D., M.H.S.;
Ann Kilian; David J. Moliterno, M.D.; Tyrus L. Rorick, R.N.; John
Strony, M.D.; Frans Van de Werf, M.D.; Lars Wallentin, M.D., Ph.D.;
Harvey D. White, D.Sc.; and Robert A. Harrington, M.D., for the
TRA・CER Steering Committee and TRA・CER investigators.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
Inc., funded the study.
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