In TRA-2P Study, Adding Merck’s Vorapaxar to Standard of Care Significantly Reduced the Risk of Cardiovascular Events


March 24, 2012 9:10 am ET

Results Published in the Online Edition of the New England Journal of Medicine and Presented at American College of Cardiology Scientific Session

Merck Continues Discussions with External Experts to Determine Next Steps

Researchers today presented and published results from the TRA-2P (Thrombin-Receptor
Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events) TIMI 50 study of vorapaxar, Merck’s
investigational anti-thrombotic medicine, in patients with a prior
history of cardiovascular events or disease. In the study, the addition
of vorapaxar to standard of care (e.g. aspirin, or thienopyridine or
both) resulted in a significantly greater reduction in the risk of the
composite of cardiovascular (CV) death, heart attack, stroke or urgent
coronary revascularization. This is the first time that an
anti-thrombotic medicine added to the standard of care, including
aspirin, has been shown to provide an additional, significant reduction
in cardiovascular events in the secondary prevention setting, defined as
patients who previously experienced a heart attack, an ischemic stroke,
or who had documented peripheral arterial disease, or PAD. There was
also a significant increase in bleeding, including intracranial
hemorrhage (ICH), among patients taking vorapaxar in addition to
standard of care, although the risk of ICH was lower in patients without
a history of stroke.

The results of TRA-2P in 26,449 patients were presented during a
late-breaking clinical trials session at the American College of
Cardiology 61st Annual Scientific Session (ACC.12) and published
concurrently online in the New England Journal of Medicine. The
study was led by the Thrombolysis In Myocardial Infarction (TIMI) Study
Group of Brigham and Women’s Hospital in Boston, Massachusetts.

In this three-year study, the addition of vorapaxar to standard of care
in the full study population significantly reduced the risk of the
protocol-specified primary composite endpoint of cardiovascular death,
heart attack, stroke or urgent coronary revascularization by 12 percent
compared to placebo plus standard of care (11.2 percent vs. 12.4
percent, p=0.001). The addition of vorapaxar also resulted in a
significant 13 percent reduction in the protocol-specified key secondary
composite endpoint of CV death, heart attack and stroke (9.3 percent vs.
10.5 percent, p<0.001). The addition of vorapaxar significantly
increased moderate or severe bleeding, as measured by the GUSTO scale1,
(4.2 percent vs. 2.5 percent, p<0.001). There was no statistically
significant difference in the rate of fatal bleeding in the study
between the group receiving vorapaxar and the group receiving standard
of care alone (0.3 percent vs. 0.2 percent, p=0.19). Rates of
intracranial hemorrhage (ICH) were significantly greater in the
vorapaxar arm compared to placebo (1.0 percent vs. 0.5 percent,
p<0.001), primarily driven by patients with a history of stroke. In
patients without a history of stroke, the rates of ICH were numerically
greater in the vorapaxar arm compared to placebo (0.6 percent vs. 0.4
percent p=0.049).

“Results from this trial demonstrated for the first time that inhibition
of another platelet pathway in addition to standard antiplatelet therapy
reduced the risk of recurrent cardiovascular events in long-term
secondary prevention,” said David A. Morrow, M.D., MPH, senior
investigator at the TIMI Study Group and Director, Levine Cardiac
Intensive Care Unit, Brigham and Women’s Hospital. “As is the case with
other potent oral antiplatelet agents, the antithrombotic benefit of
vorapaxar must be weighed against the increased risk of bleeding, and
any potential clinical use of vorapaxar would have to be based on
appropriate patient selection.”

The presentation of the full results included patients with a prior
history of stroke, who were part of the original study design but were
discontinued from the trial following the recommendations of the Data
Safety Monitoring Board in early 2011. Among patients without a history
of stroke, the addition of vorapaxar reduced the risk of CV death, heart
attack, stroke or urgent coronary revascularization by 14 percent
compared to placebo plus standard of care (10.6 percent vs. 11.8
percent, p<0.001), and reduced the risk of CV death, heart attack or
stroke by 16 percent (8.3 percent vs. 9.6 percent, p<0.001). Also, among
patients without a history of stroke, there was a non-significant
increase in GUSTO severe bleeding (1.4 percent vs. 1.1 percent, p=0.058)
and a significant increase in GUSTO moderate bleeding (2.7 percent vs.
1.4 percent, p<0.001) in the vorapaxar group compared with the group
receiving standard of care alone.

The benefits of vorapaxar were numerically greater in patients who
qualified for the study due to a previous heart attack, which was 67
percent (n=17,779) of all patients in the study, the largest cohort. In
these patients, vorapaxar reduced the relative risk of CV death, heart
attack or stroke by 20 percent (8.1 percent vs. 9.7 percent at three
years, p<0.001). Overall, in this subgroup vorapaxar significantly
decreased the rate of heart attacks compared to standard of care alone
by 17 percent (5.2 percent vs. 6.1 percent, p=0.001).

“Despite all of the advances made in cardiovascular medicine,
significant residual risk for recurrence of cardiovascular events
remains, and that is why Merck is committed to developing medicines like
vorapaxar that are intended to provide incremental, additional
reductions in residual risk,” said Francis Plat, M.D., vice president,
Clinical Research, Therapeutic Area Head Atherosclerosis and
Cardiovascular Disease, Merck Research Laboratories. “The results from
this study showed that the addition of vorapaxar to standard of care,
including aspirin, provided an additional reduction in risk. We plan to
continue our discussions with the investigators and other outside
experts to help define the role of this investigational compound in
secondary prevention.”

TRA-2P included 26,449 stable patients at 1,032 sites in 32 countries
who had previously experienced an ischemic stroke or heart attack no
less than 2 weeks and no more than 12 months before randomization, or
who had PAD. The goal of the study was to evaluate the efficacy and
safety of vorapaxar compared with placebo in addition to standard of
care in the secondary prevention setting. In TRA-2P, vorapaxar was
administered at a 2.5 mg daily maintenance oral dose for more than one
year. The median follow-up time in the trial was 30 months.

Additional Information on the Vorapaxar Development Program

Vorapaxar has now been evaluated in two major clinical outcomes studies:
TRA-2P TIMI 50 ( identifier: NCT00526474)and
TRACER (Thrombin Receptor Antagonist for Clinical
Event Reduction in Acute Coronary Syndrome),
( identifier: NCT00527943).
TRACER was an acute care, hospital-based study of approximately 12,944
patients with non-ST-segment-elevation acute coronary syndrome. The
study was led by the Duke Clinical Research Institute, and results were
presented in 2011 at the American Heart Association Scientific Sessions
and published in the January 5, 2012 issue of The New England
Journal of Medicine
(Vol. 366, No.1). The news release can be found

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(1)GUSTO (Global Use of Strategies to Open Occluded Arteries) scale is a
criteria for classifying the severity of bleeding

Pam Eisele, 908-423-5042
Skip Irvine, 267-305-5397
Carol Ferguson, 908-423-4465

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