Two New Post-Hoc Analyses of TRA 2°P TIMI 50 Study Showed ZONTIVITY® (vorapaxar) Added to Aspirin and/or Clopidogrel Reduced Acute Limb Ischemia and Peripheral Revascularizations, Respectively, in Certain Patients with Peripheral Arterial Disease

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March 5, 2015 8:00 am ET

These and other post-hoc subgroup analyses from TRA-2°P are being presented at the 2015 American College of Cardiology Scientific Sessions

Merck (NYSE:MRK),
known as MSD outside the United States and Canada, today announced
results from two post-hoc analyses of the TRA 2°P TIMI 50 (Thrombin
Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic
Events) trial of ZONTIVITY® (vorapaxar), one of the largest secondary
prevention studies of an antiplatelet medicine. These data on additional
endpoints in subgroups of patients with peripheral arterial disease
(PAD) are being presented at the 2015 American College of Cardiology
(ACC) Scientific Sessions in San Diego from March 14-16, 2015 along with
other post-hoc subgroup analyses from the trial, with abstracts
currently available online.

ZONTIVITY is indicated for the reduction of thrombotic cardiovascular
(CV) events in patients with a history of myocardial infarction (MI) or
in patients with PAD. The May 2014 U.S. approval of ZONTIVITY was based
on the pivotal TRA 2°P TIMI 50 study, in which ZONTIVITY was shown to
reduce the rate of a combined endpoint of CV death, MI, stroke and
urgent coronary revascularization (UCR) when added to aspirin and/or
clopidogrel. The U.S. Prescribing Information for ZONTIVITY includes a
boxed warning regarding bleeding risk, which states that ZONTIVITY is
not for use in patients with a history of stroke, transient ischemic
attack (TIA) or intracranial hemorrhage (ICH), or active pathological
bleeding. Antiplatelet agents, including ZONTIVITY, increase the risk of
bleeding, including ICH and fatal bleeding.

“As treating physicians, we are always concerned about our patients with
PAD because of their risk for both systemic cardiovascular events as
well as limb vascular events including acute limb ischemia and disease
progression leading to peripheral revascularizations,” said Marc P.
Bonaca, M.D., M.P.H., investigator, TIMI Study Group and associate
physician at Brigham and Women’s Hospital and Harvard Medical School in
Boston, Mass. “Because there are limited options available to reduce the
risk of limb vascular events, these exploratory subgroup analyses raise
important hypotheses regarding the role of ZONTIVITY (vorapaxar) in the
management of PAD.”

Previously Reported Efficacy and Safety Results from the TRA 2°P
TIMI 50 Trial

The primary results of TRA 2°P TIMI 50 have been previously reported.
TRA 2°P TIMI 50 was a 26,449 patient, randomized, double-blind,
placebo-controlled trial in which participants had a history of
spontaneous MI within the prior two weeks to twelve months, ischemic
stroke, or documented (symptomatic) PAD. Patients were followed for up
to four years, with a median follow-up of 2.5 years. ZONTIVITY, when
used daily with standard of care that included aspirin and/or a
thienopyridine (principally clopidogrel), was superior to standard of
care alone in reducing the incidence of both the primary combined
endpoint of CV death, MI, stroke, and UCR and a key secondary composite
endpoint of CV death, MI, and stroke.

In the overall study population, patients with a history of stroke or
TIA showed an increased risk of ICH. Consequently, the approved use of
ZONTIVITY is based on the study population with a history of MI or with
PAD and without a history of stroke or TIA. Among those patients, 10,080
were randomized to treatment with ZONTIVITY and 10,090 were randomized
to treatment with placebo. In post-MI or PAD patients without a history
of stroke or TIA, the study showed a 17% relative risk reduction through
three years for the composite primary efficacy endpoint of CV death, MI,
stroke, and UCR (10.1% in the group randomized to ZONTIVITY vs. 11.8% in
the placebo group; hazard ratio [HR] 0.83, p<0.001). For the key
secondary composite efficacy endpoint of CV death, MI, and stroke, the
study showed a 20% relative risk reduction through three years (7.9% in
the group randomized to ZONTIVITY vs. 9.5% in the placebo group; HR
0.80, p<0.001).

Among randomized post-MI or PAD patients without a history of stroke or
TIA who were treated with ZONTIVITY (n=10,059) or placebo (n=10,049),
adding ZONTIVITY to standard of care (including aspirin and/or a
thienopyridine) was associated with an increased rate of GUSTO moderate
or severe bleeding1 through three years (3.7%) compared to
adding placebo (2.4%) (HR 1.55, 95% confidence interval [CI] 1.30-1.86).
GUSTO severe bleeding occurred at a rate of 1.3% for ZONTIVITY versus
1.0% for placebo (HR 1.24, 95% CI 0.92-1.66). Any GUSTO bleeding
(severe/moderate/mild) occurred at a rate of 27.7% for ZONTIVITY
(vorapaxar) versus 19.8% for placebo (HR 1.52, 95% CI 1.43-1.61). The
three-year rate of ICH was numerically higher for patients adding
ZONTIVITY to standard of care, 0.6%, compared to 0.4% for patients
adding placebo (HR 1.46; 95% CI 0.92-2.31). Fatal bleeding occurred at a
three-year rate of 0.2% in both the ZONTIVITY and placebo groups, with a
hazard ratio of 1.15 favoring the placebo group (95% CI 0.56-2.36).
Clinically significant bleeding2 occurred at a three-year
rate of 15.5% in the group taking ZONTIVITY, compared with 10.9% in the
placebo group (HR 1.47, 95% CI 1.35-1.60).

There is no experience with ZONTIVITY as the only administered
antiplatelet agent, because ZONTIVITY was studied only as an addition to
aspirin and/or clopidogrel.

New post-hoc analyses results from the TRA 2°P
TIMI 50 Trial

Data being presented at ACC include two post-hoc subgroup analyses that
explored the use of ZONTIVITY in certain patients with established PAD.
PAD is generally defined as obstruction of arteries supplying the lower
extremities, most commonly due to atherosclerosis. People with PAD are
at increased risk for heart attack, stroke, and CV death. People with
PAD are also at risk for complications from ischemia involving the lower
extremities, and this was the focus of the two subgroup analyses being
presented. More specifically, these exploratory analyses looked at rates
of:

1. acute limb ischemia (ALI), a serious condition caused by an abrupt
interruption of blood flow to a limb due to embolic or thrombotic
vascular occlusion, which can result in limb loss.

2. peripheral artery revascularization (PR), either a percutaneous
(generally with stenting) or surgical procedure that restores blood flow
to a limb that is supplied by blocked arteries.

Subgroup analyses should be interpreted cautiously as differences can
reflect the play of chance among a large number of analyses. The
following are more specific details on the two presentations at ACC:

  • (Abstract #1131M-11) Moderated Poster Session: Vorapaxar and
    Acute Limb Ischemia: Insights from the Thrombin Receptor Antagonist in
    Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50
    Trial. A. Guitierrez

    • Among the 3,787 patients whose qualifying diagnosis for the TRA
      2°P TIMI 50 trial was symptomatic PAD (including 514
      patients with a history of stroke or TIA in whom use of ZONTIVITY
      (vorapaxar) is contraindicated), a total of 109 ALI events
      occurred during the trial. The majority of ALI events were due to
      acute surgical graft thrombosis (54%) or in situ thrombosis in a
      native vessel (27%). In this post-hoc subgroup analysis,
      researchers found that in patients with symptomatic PAD, adding
      ZONTIVITY to standard care (which included aspirin and/or
      clopidogrel) yielded a 42% relative risk reduction in the
      incidence of ALI versus aspirin and/or clopidogrel alone (3-yr
      event rates 2.3% vs. 3.9%, respectively; HR: 0.58, 95% CI
      0.39–0.86).
    • Saturday, March 14; 11:00 AM-11:10 AM PT. Location: Vascular
      Medicine Moderated Poster Theater, Poster Hall B1.
  • (Abstract #1131M-05) Vorapaxar and Peripheral Revascularization:
    Insights from the TRA2P-TIMI 50 Trial. I. Gilchrist.

    • In this post-hoc subgroup analysis of 5,845 patients in TRA 2ºP
      with a history of PAD (regardless of primary enrollment stratum),
      ZONTIVITY vs. placebo, added to aspirin and/or clopidogrel, showed
      a consistent pattern of reduction in the need for peripheral
      revascularization (PR) (via percutaneous or surgical procedures)
      among the various indications for PR captured by the analysis.
      This included a reduction in PR for the treatment of claudication
      (event rates 11.6% for placebo and 9.4% for ZONTIVITY; HR 0.84,
      95% CI 0.71-0.99). Adding ZONTIVITY also reduced the rate of
      surgical PR procedures (event rates 7.7% for placebo and 4.5% for
      ZONTIVITY; HR 0.59, 95% CI 0.47-0.74). Approximately 20% of the
      5,845 patients included in this analysis had a history of stroke
      or TIA, which are contraindications to use of ZONTIVITY.
    • Saturday, March 14; 10:15 AM-10:25 AM PT. Location: Vascular
      Medicine Moderated Poster Theater, Poster Hall B1.

These exploratory subgroup analysis abstracts in PAD patients do not
include information about bleeding. In the overall trial population,
among the subgroup of patients who qualified for the trial based on a
diagnosis of PAD and who had no history of stroke or TIA, the annualized
rate of GUSTO moderate or severe bleeding was 2.3% for those receiving
ZONTIVITY compared with 1.5% for those receiving placebo (HR 1.60, 95%
CI 1.15-2.21).

Additional subgroup analyses also being presented at ACC include:

  • (Abstract #905-04) Poster Session: The role of Vorapaxar in
    Patients with Coronary Artery Bypass Grafting: Findings from the TRA
    2P-TIMI 50 Trial. E. Kosova.

    • In this post-hoc subgroup analysis of 2,942 post-MI or PAD
      patients with no history of stroke or TIA who had undergone
      coronary artery bypass grafting (CABG) prior to the trial, adding
      ZONTIVITY to aspirin and/or clopidogrel reduced the risk of CV
      death, myocardial infarction or stroke (event rate 11.9% for
      ZONTIVITY vs. 15.6% for placebo; HR 0.71, 95% CI 0.58-0.88). In
      these patients, ZONTIVITY increased the risk of GUSTO moderate or
      severe bleeding (6.8% for ZONTIVITY vs. 3.7% for placebo; HR 1.87,
      95% CI 1.28-2.72). In another subgroup analysis, among 319 post-MI
      or PAD patients with no history of stroke or TIA who underwent a
      new CABG during the trial, the rates of TIMI major bleeding
      3
      within 30 days of surgery were 6.0% for ZONTIVITY and 4.2% for
      placebo (HR 1.43, 95% CI 0.53-3.84).The authors state that the
      increased bleeding risk with ZONTIVITY in this small group
      undergoing CABG was similar to the increase in bleeding risk with
      ZONTIVITY in the overall study population.
    • Sunday, March 15; 10:57 AM-11:08 AM PT. Location: Room 7B.

About ZONTIVITY (vorapaxar)

ZONTIVITY is indicated for the reduction of thrombotic CV events in
patients with a history of MI or with PAD. ZONTIVITY has been shown to
reduce the rate of a combined endpoint of CV death, MI, stroke, and UCR.
ZONTIVITY inhibits the protease-activated receptor-1 (PAR-1), the
primary receptor for thrombin, which is considered to be the most potent
activator of platelets. The PAR-1 pathway participates in the formation
of blood clots through the activation and aggregation of platelets.

ZONTIVITY is a once-daily tablet containing 2.08 mg vorapaxar,
equivalent to 2.5 mg vorapaxar sulfate. ZONTIVITY was studied only as an
addition to aspirin and/or clopidogrel and should be used with aspirin
and/or clopidogrel according to their indications or standard of care.
There is no experience with use of ZONTIVITY alone as the only
administered antiplatelet agent.

Additional selected safety information about ZONTIVITY

ZONTIVITY is contraindicated in patients with a history of stroke, TIA,
or ICH and in patients with active pathological bleeding such as ICH or
peptic ulcer. Discontinue ZONTIVITY (vorapaxar) in patients who
experience a stroke, TIA, or ICH.

Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding,
including ICH and fatal bleeding. ZONTIVITY increases the risk of
bleeding in proportion to the patient’s underlying bleeding risk.
Physicians should consider the underlying risk of bleeding before
initiating ZONTIVITY.

General risk factors for bleeding include older age, low body weight,
reduced renal or hepatic function, and history of bleeding disorders.
Use of certain concomitant medications (e.g., anticoagulants,
fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs,
selective serotonin reuptake inhibitors, serotonin norepinephrine
reuptake inhibitors) also increases the risk of bleeding. Avoid
concomitant use of warfarin or other anticoagulants.

Withholding ZONTIVITY for a brief period will not be useful in managing
an acute bleeding event because, due to its long half-life, significant
inhibition of platelet aggregation remains four weeks after
discontinuation. There is no known treatment to reverse the antiplatelet
effect of ZONTIVITY.

Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY
exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A4
inhibitors or inducers.

Based on the increased inherent risk of bleeding in patients with severe
hepatic impairment, ZONTIVITY is not recommended in these patients.

Bleeding, including life-threatening and fatal bleeding, is the most
commonly reported adverse reaction with ZONTIVITY.

Background antiplatelet therapies among PAD patients in the TRA-2P
study

In TRA-2ºP, 88% of all patients who qualified for the trial with PAD
were receiving background therapy with aspirin at enrollment, 37% were
receiving a thienopyridine (principally clopidogrel), and 28% were
receiving both. Among PAD patients with no history of stroke or TIA, 88%
were receiving background therapy with aspirin at enrollment, 35% were
receiving a thienopyridine (principally clopidogrel), and 27% were
receiving both.

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subject to significant risks and uncertainties. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
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Please see Prescribing Information, including Boxed Warning, for
ZONTIVITY (vorapaxar) at
http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf
and Medication Guide for ZONTIVITY (vorapaxar) at
http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_mg.pdf

ZONTIVITY® is a trademark of Merck, Sharp &
Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA.

______________________________

1 GUSTO severe bleeding: fatal, intracranial, or bleeding
with hemodynamic compromise requiring intervention. GUSTO moderate
bleeding: bleeding requiring transfusion of whole blood or packed
red blood cells without hemodynamic compromise. (GUSTO: Global
Utilization of Streptokinase and Tissue Plasminogen Activator for
Occluded Arteries.)
2 Clinically significant bleeding: bleeding requiring
medical attention including ICH, or clinically significant overt
signs of hemorrhage with a drop in Hgb ≥3 g/dL (or, when Hgb is not
available, an absolute drop in Hct ≥9%).
3 CABG-related TIMI major bleeding: fatal bleeding,
perioperative ICH, reoperation for bleeding, transfusion of ≥5 units
of whole blood or packed red blood cells within a 48-hour period, or
chest tube output ≥2 L within a 24-hour period. (TIMI: Thrombolysis
in Myocardial Infarction Study Group.)

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