Vorapaxar in the secondary prevention of atherothrombotic events

Article (PDF Available)inNew England Journal of Medicine 366(15):1404-13 · March 2012with253 Reads
DOI: 10.1056/NEJMoa1200933 · Source: PubMed
Abstract
Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

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original article
Vorapaxar in the Secondary Prevention
of Atherothrombotic Events
David A. Morrow, M.D., M.P.H., Eugene Braunwald, M.D., Marc P. Bonaca, M.D.,
Sebastian F. Ameriso, M.D., Anthony J. Dalby, M.B., Ch.B., Mary Polly Fish, B.A.,
Keith A.A. Fox, M.B., Ch.B., Leslie J. Lipka, M.D., Ph.D., Xuan Liu, Ph.D.,
José Carlos Nicolau, M.D., Ph.D., A.J. Oude Ophuis, M.D., Ph.D.,
Ernesto Paolasso, M.D., Benjamin M. Scirica, M.D., M.P.H.,
Jindrich Spinar, M.D., Ph.D., Pierre Theroux, C.M., M.D.,
Stephen D. Wiviott, M.D., John Strony, M.D., and Sabina A. Murphy, M.P.H.,
for the TRA 2P–TIMI 50 Steering Committee and Investigators*
The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr.
Morrow at the TIMI Study Group, Cardio-
vascular Division, Brigham and Women’s
Hospital, 75 Francis St., Boston, MA 02115,
or at dmorrow@partners.org.
*Members of the Thrombin Receptor
Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events
(TRA 2P)–Thrombolysis in Myocardial
Infarction (TIMI) 50 steering commit-
tee, as well as other committee mem-
bers and investigators, are listed in the
Supplementary Appendix, available at
NEJM.org.
This article (10.1056/NEJMoa1200933)
was published on March 24, 2012, at
NEJM.org.
N Engl J Med 2012.
Copyright © 2012 Massachusetts Medical Society.
A bs t r ac t
Background
Thrombin potently activates platelets through the protease-activated receptor PAR-1.
Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of
thrombin through antagonism of PAR-1.
Methods
We randomly assigned 26,449 patients who had a history of myocardial infarction,
ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or
matching placebo and followed them for a median of 30 months. The primary effi-
cacy end point was the composite of death from cardiovascular causes, myocardial
infarction, or stroke. After 2 years, the data and safety monitoring board recom-
mended discontinuation of the study treatment in patients with a history of stroke
owing to the risk of intracranial hemorrhage.
Results
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vora-
paxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the
vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardio-
vascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascu-
larization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients
(12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001).
Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar
and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93;
P<0.001). There was an increase in the rate of intracranial hemorrhage in the vora-
paxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Conclusions
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or isch-
emic events in patients with stable atherosclerosis who were receiving standard ther-
apy. However, it increased the risk of moderate or severe bleeding, including intra-
cranial hemorrhage. (Funded by Merck; TRA 2P–TIMI 50 ClinicalTrials.gov number,
NCT00526474.)
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P
latelets play a central role in ath-
erothrombosis and are an important target
for pharmacotherapy. In patients with acute
coronary syndromes, the use of potent platelet
inhibitors has been shown to reduce the rate of
thrombotic events at the cost of increased bleed-
ing.
1-3
In contrast, among patients with stable
atherosclerosis, a reduced rate of thrombotic events
with antiplatelet therapy in addition to aspirin ther-
apy has not been established.
4
Thrombin is a serine protease that is critical
in thrombosis. In addition to generating fibrin,
thrombin is a potent agonist of platelets through
interaction with protease-activated receptors
(PARs).
5
Vorapaxar (SCH 530348, Merck) is a com-
petitive and selective antagonist of PAR-1, the ma-
jor thrombin receptor on human platelets. Vora-
paxar potently inhibits thrombin-induced platelet
aggregation.
6,7
This study, called the Thrombin
Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events (TRA 2P)
Thrombolysis in Myocardial Infarction (TIMI) 50
trial, was designed to evaluate the efficacy and
safety of vorapaxar in reducing atherothrombotic
events in patients with established atherosclerosis
who were receiving standard therapy. In addition
to investigating vorapaxar specifically, the trial
more broadly tested the hypothesis that the in-
tensification of antiplatelet therapy by adding an
agent with a different pharmacologic target is ben-
eficial for secondary prevention in patients with
stable disease and a history of myocardial infarc-
tion, ischemic stroke, or peripheral arterial disease.
Methods
Study Design and Oversight
The TRA 2P–TIMI 50 trial was a multinational,
double-blind, placebo-controlled trial
8
that was
conducted at 1032 sites in 32 countries (see the
Supplementary Appendix, available with the full
text of this article at NEJM.org). The trial was spon-
sored by Merck and was designed by the TIMI Study
Group in conjunction with the steering commit-
tee and trial sponsor. The protocol was approved by
the relevant ethics committees at all participating
centers. The raw database was provided to the TIMI
Study Group, which carried out the data analyses
independently of the sponsor, prepared this report,
and made the decision to submit the manuscript
for publication. The members of the TIMI Study
Group assume responsibility for the accuracy and
completeness of the data and all analyses and for
the fidelity of this report to the study protocol,
which is available at NEJM.org.
Study Population
Eligible patients had a history of atherosclerosis,
which was defined as a spontaneous myocardial
infarction or ischemic stroke within the previous
2 weeks to 12 months or peripheral arterial dis-
ease associated with a history of intermittent
claudication in conjunction with either an ankle–
brachial index of less than 0.85 or previous revas-
cularization for limb ischemia. By design, enroll-
ment of patients with a qualifying diagnosis of
either stroke or peripheral arterial disease was to
end when the number enrolled reached approxi-
mately 15% of the total anticipated sample size.
Patients were ineligible if they were planning
to undergo a revascularization procedure, had a
history of bleeding diathesis, had recent active ab-
normal bleeding, were receiving ongoing treatment
with warfarin, or had active hepatobiliary disease.
The full eligibility criteria have been reported previ-
ously.
8
Written informed consent was obtained
from all patients.
Randomization and Study Treatment
Eligible patients were randomly assigned in a 1:1
ratio to receive either vorapaxar (2.5 mg daily) or
matched placebo by a central computerized system
with hierarchical stratification according to the
qualifying diagnosis (myocardial infarction, stroke,
or peripheral arterial disease) and the responsible
physician’s intent to administer a thienopyridine
(see the Methods section in the Supplementary Ap-
pendix). Vorapaxar and placebo were administered
orally in a blinded fashion once daily until the end
of follow-up. Study therapy was to be interrupted
if the patient required treatment with either a
potent inhibitor of the cytochrome P-450 3A4
(
CYP3A4) enzyme system or warfarin in conjunc-
tion with a thienopyridine. All concomitant medi-
cal therapy, including the use of other antiplate-
let agents, was managed by the clinicians at the
study sites who were responsible for the care of
the patients, according to local standards of care.
In January 2011, after completion of enrollment
and a median of 24 months of follow-up, the data
and safety monitoring board reported an excess of
intracranial hemorrhage in patients with a history
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Vor apa xar and Pre vention of atheros cler otic e vents
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3
of stroke in the vorapaxar group and recommend-
ed discontinuation of the drug in all patients with
previous stroke, including those with a new stroke
during the trial. The board also recommended
continuation of the trial in patients without a
history of stroke. The protocol was amended ac-
cordingly (see the Methods section in the Supple-
mentary Appendix).
End Points
The protocol-defined primary efficacy end point
was a composite of cardiovascular death, myocar-
dial infarction, stroke, or recurrent ischemia lead-
ing to urgent coronary revascularization. The major
secondary end point was a composite of cardio-
vascular death, myocardial infarction, or stroke.
Before the database was locked and during blind-
ed treatment, the investigators reviewed data from
the newly completed Thrombin Receptor Antag-
onist for Clinical Event Reduction in Acute Coro-
nary Syndrome (TRACER) trial (ClinicalTrials.gov
number, NCT00527943).
9
On the basis of data from
that trial, the steering committee amended the
main data-analysis plan to reorder the hierarchy
of efficacy analyses, defining as the primary end
point the composite of cardiovascular death, myo-
cardial infarction, or stroke. The composite of car-
diovascular death, myocardial infarction, stroke,
or urgent coronary revascularization became the
major secondary end point. Definitions of the com-
ponents of these composite end points are provided
in the Supplementary Appendix.
We assessed bleeding using the Global Use of
Strategies to Open Occluded Coronary Arteries
(GUSTO) classification system and the TIMI clas-
sification system, with GUSTO moderate or severe
bleeding defined as the safety end point of pri-
mary interest. A clinical-events committee whose
members were unaware of the study-group as-
signments adjudicated all components of the pri-
mary and major secondary efficacy end points and
bleeding episodes.
Statistical Analysis
We calculated that 2279 events would be required
to provide a power of at least 90% to detect a 15%
relative risk reduction in the composite end point of
cardiovascular death, myocardial infarction, stroke,
or urgent coronary revascularization in the vora-
paxar group, as compared with the placebo group.
We estimated that 1400 events would be required
to provide a power of at least 85% to detect the
same relative treatment effect with respect to the
composite end point of cardiovascular death, myo-
cardial infarction, or stroke.
The primary efficacy analysis was conducted on
an intention-to-treat basis among all patients who
underwent randomization. After the data and
safety monitoring board recommended discon-
tinuation of vorapaxar in all patients with previ-
ous stroke, the protocol was amended to include
supplementary evaluation of efficacy in patients
who qualified for the trial with a diagnosis of
myocardial infarction or peripheral arterial dis-
ease without a history of stroke before random-
ization. In addition, an analysis of efficacy that was
restricted to patients with the qualifying diagno-
sis of myocardial infarction alone was specified in
the original analysis plan before the board’s rec-
ommendation.
The efficacy analyses were performed with the
use of a Cox proportional-hazards model, with the
study group and stratification factors at random-
ization as covariates. Cumulative event rates were
calculated with the use of the Kaplan–Meier meth-
od at 3 years. Safety analyses were performed
among patients who received one or more doses of
a study drug and included events through 60 days
after premature cessation of study therapy or
30 days after a final visit at the conclusion of the
trial. On the basis of one planned interim analysis
of efficacy, a P value of less than 0.049 was con-
sidered to indicate statistical significance for the
final analysis,
8
and a P value of less than 0.05 was
deemed to indicate a significant interaction. All
reported P values are two-sided.
Results
Study Patients and Follow-up
From September 26, 2007, through November 13,
2009, a total of 26,449 patients were enrolled in
the trial. Of these, 13,225 were randomly assigned
to receive vorapaxar, and 13,244 to receive placebo
(Fig. S1 in the Supplementary Appendix).
Baseline characteristics of the patients are
shown in
Table 1
. The qualifying diagnosis for
enrollment was myocardial infarction in two thirds
of the patients, stroke in 18%, and peripheral arte-
rial disease in 14%. A total of 94% of the patients
were treated with aspirin. At baseline, a thieno-
pyridine was being administered in a majority of
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patients with a qualifying diagnosis of myocardial
infarction but in only a minority of patients with
a qualifying diagnosis of stroke or peripheral ar-
terial disease. Only 177 patients (0.7%) received
prasugrel during the study.
The longest duration of follow-up was 49
months, with a median follow-up of 30 months
(interquartile range, 24 to 36). Details of follow-
up and loss to follow-up are provided in the Sup-
plementary Appendix. The last date of patient
Table 1. Baseline Characteristics of the Patients.*
Characteristic Vorapaxar
(N = 13,225) Placebo
(N = 13,224)
Demographic
Age
Median — yr 61 61
Interquartile range — yr 53–69 53–69
≥75 yr — no. (%) 1,514 (11.4) 1,506 (11.4)
Female sex — no. (%) 3,154 (23.8) 3,172 (24.0)
White race — no./total no. (%)† 11,562/13,218 (87.5) 11,524/13,219 (87.2)
Qualifying type of atherosclerosis — no. (%)
Myocardial infarction 8,898 (67.3) 8,881 (67.2)
Ischemic stroke 2,435 (18.4) 2,448 (18.5)
Peripheral arterial disease 1,892 (14.3) 1,895 (14.3)
Selected clinical characteristics — no./total no. (%)
Diabetes mellitus 3,368/13,224 (25.5) 3,356/13,220 (25.4)
Hypertension 9,047/13,225 (68.4) 9,127/13,219 (69.0)
Hyperlipidemia 10,983/13,224 (83.1) 11,011/13,220 (83.3)
Current smoker 2,748/13,225 (20.8) 2,750/13,220 (20.8)
Any coronary artery disease 10,329/13,223 (78.1) 10,362/13,215 (78.4)
Previous coronary revascularization 8,641/13,223 (65.3) 8,620/13,218 (65.2)
Any peripheral arterial disease 2,901/13,224 (21.9) 2,944/13,218 (22.3)
Previous cerebrovascular event 3,139/13,223 (23.7) 3,129/13,220 (23.7)
Estimated glomerular filtration rate <60 ml/min/1.73 m
2
ठ2,112/13,056 (16.2) 1,972/13,057 (15.1)
Use of antiplatelet agents — no./total no. (%)
Qualifying myocardial infarction
Aspirin 8,732/8,898 (98.1) 8,716/8,881 (98.1)
Thienopyridine 6,934/8,898 (77.9) 6,960/8,881 (78.4)
Qualifying peripheral arterial disease
Aspirin 1,661/1,892 (87.8) 1,671/1,895 (88.2)
Thienopyridine 696/1,892 (36.8) 698/1,895 (36.8)
Qualifying stroke
Aspirin 1,978/2,435 (81.2) 1,976/2,448 (80.7)
Thienopyridine 574/2,435 (23.6) 580/2,448 (23.7)
Dipyridamole 475/2,435 (19.5) 474/2,448 (19.4)
Use of other medications — no. (%)
Lipid-lowering agent§ 12,032 (91.0) 12,131 (91.7)
Angiotensin-converting–enzyme inhibitor or angiotensin-
receptor blocker§ 9,714 (73.5) 9,871 (74.6)
* There were no significant differences between the two study groups, except as indicated.
† Race was self-reported.
‡ The glomerular filtration rate was estimated with the use of the Modification of Diet in Renal Disease (MDRD) formula.
§ P<0.05.
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Vor apa xar and Pre vention of atheros cler otic e vents
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contact was December 23, 2011, and the trial data-
base was locked on January 9, 2012.
Efficacy End Points
At 3 years, the primary end point of cardiovascular
death, myocardial infarction, or stroke had oc-
curred in 1028 patients (9.3%) in the vorapaxar
group, as compared with 1176 patients (10.5%) in
the placebo group (hazard ratio, 0.87; 95% confi-
dence interval [CI], 0.80 to 0.94; P<0.001) (
Table
2
and Fig. 1A). The major secondary end point of
cardiovascular death, myocardial infarction, stroke,
or urgent coronary revascularization occurred in
1259 patients (11.2%) in the vorapaxar group, as
compared with 1417 patients (12.4%) in the placebo
group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95;
P = 0.001) (
Table 2
and Fig. 1B). The rate of cardio-
vascular death or myocardial infarction was re-
duced from 8.2% among patients in the placebo
group to 7.3% among patients in the vorapaxar
group (P = 0.002) (
Table 2,
and Fig. S2 in the Sup-
plementary Appendix). Individual components of
these composite end points are also shown in
Table 2
. The rate of death from any cause did not
differ significantly between the vorapaxar group
and the placebo group (5.0% and 5.3%, respec-
tively; hazard ratio, 0.95; 95% CI, 0.85 to 1.07;
P = 0.41). (Additional prespecified efficacy end
points are shown in Tables S1 and S2 in the Sup-
plementary Appendix.)
Among patients with no history of stroke, the
primary end point occurred in 8.3% of patients in
the vorapaxar group, as compared with 9.6% of
those in the placebo group (hazard ratio, 0.84;
95% CI, 0.76 to 0.93; P<0.001) (Table S3 in the
Supplementary Appendix). There was no signifi-
cant heterogeneity for the benefit of vorapaxar on
the rate of cardiovascular death, myocardial infarc-
tion, or stroke across most of the major subgroups
examined, including those defined according to
the use or nonuse of a thienopyridine (Fig. S3 in
the Supplementary Appendix). However, among
patients who weighed less than 60 kg, the use of
vorapaxar did not have a favorable influence on
this outcome (P = 0.03 for interaction). Additional
analyses of efficacy in subgroups that were de-
fined according to the qualifying diagnosis of
atherosclerosis (myocardial infarction, stroke, or
peripheral arterial disease) and the presence or
absence of a history of stroke are provided in Ta-
ble S3 and Figure S3 in the Supplementary Ap-
pendix.
Safety End Points
The major safety end point of moderate or severe
bleeding (according to GUSTO criteria) occurred
in 438 patients (4.2%) in the vorapaxar group, as
compared with 267 patients (2.5%) in the place-
bo group (hazard ratio, 1.66; 95% CI, 1.43 to
1.93; P<0.001) (
Table 2
and Fig. 2A). There was
no evidence of heterogeneity in the effect of vora-
paxar on moderate or severe bleeding in major
subgroups (Fig. S4 in the Supplementary Appen-
dix). Rates of TIMI clinically significant bleeding
(Fig. 2B) and rates of TIMI major bleeding not re-
lated to coronary-artery bypass grafting were also
both significantly increased in the vorapaxar group
as compared with the placebo group (P<0.001)
(
Table 2
).
Overall, intracranial hemorrhage occurred in
102 patients (1.0%) in the vorapaxar group, as
compared with 53 patients (0.5%) in the placebo
group (hazard ratio, 1.94; 95% CI, 1.39 to 2.70;
P<0.001) (
Table 2,
and Fig. S5 in the Supplementary
Appendix). Fatal bleeding occurred in 29 patients
(0.3%) in the vorapaxar group, as compared with
20 patients (0.2%) in the placebo group (hazard
ratio, 1.46; 95% CI, 0.82 to 2.58; P = 0.19). Among
patients with a history of stroke, the rate of intra-
cranial hemorrhage in the vorapaxar group was
2.4%, as compared with 0.9% in the placebo group
(P<0.001), with corresponding rates of fatal bleed-
ing of 0.5% and 0.3% (P = 0.46) (Table S3 in the
Supplementary Appendix). Among patients with-
out a history of stroke, the rates of intracranial
hemorrhage were lower in the two study groups
(0.6% in the vorapaxar group and 0.4% in the pla-
cebo group, P = 0.049), as were the rates of fatal
bleeding (0.3% and 0.2%, respectively; P = 0.30).
Additional safety analyses are shown in Tables S3
and S4 in the Supplementary Appendix.
Net Clinical Outcome
A composite end point termed net clinical outcome,
comprising the primary efficacy and safety end
points, was prespecified (
Table 2
). The composite
of cardiovascular death, myocardial infarction,
stroke, or GUSTO moderate or severe bleeding
occurred in 1315 patients (11.7%) in the vora-
paxar group and in 1358 patients (12.1%) in the
placebo group (hazard ratio, 0.97; 95% CI, 0.90 to
1.04; P = 0.40). Other net clinical outcomes in all
patients and in patients without stroke are re-
ported in
Table 2,
and Table S4 in the Supple-
mentary Appendix.
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Discussion
In previous studies, it has not been established
whether the addition of another antiplatelet agent
to aspirin therapy would reduce the rate of throm-
botic events in patients with stable atherosclerotic
disease.
4
In our large randomized trial, the PAR-1
antagonist vorapaxar significantly reduced the
rate of cardiovascular death, myocardial infarction,
or stroke in patients with a history of athero-
thrombosis who were receiving standard therapy.
However, the reduction in cardiovascular events
came at the cost of increased bleeding. This ben-
efit and risk emerged early and continued to accrue
throughout follow-up. Our findings show that in-
hibition of another platelet pathway in addition to
Table 2. Efficacy and Bleeding End Points at 3 Years.*
End Point Vorapaxar Placebo Hazard Ratio
(95% CI) P Value
number (percent)
Efficacy 13,225 13,224
Cardiovascular death, myocardial infarction,
or stroke 1028 (9.3) 1176 (10.5) 0.87 (0.80–0.94) <0.001
Cardiovascular death, myocardial infarction, stroke,
or urgent coronary revascularization 1259 (11.2) 1417 (12.4) 0.88 (0.82–0.95) 0.001
Cardiovascular death or myocardial infarction 789 (7.3) 913 (8.2) 0.86 (0.78–0.94) 0.002
Cardiovascular death 285 (2.7) 319 (3.0) 0.89 (0.76–1.04) 0.15
Myocardial infarction 564 (5.2) 673 (6.1) 0.83 (0.74–0.93) 0.001
Stroke
Any stroke 315 (2.8) 324 (2.8) 0.97 (0.83–1.14) 0.73
Ischemic stroke 250 (2.2) 294 (2.6) 0.85 (0.72–1.01) 0.06
Urgent coronary revascularization 279 (2.5) 316 (2.6) 0.88 (0.75–1.03) 0.11
Death from any cause 540 (5.0) 565 (5.3) 0.95 (0.85–1.07) 0.41
Bleeding 13,186 13,166
GUSTO moderate or severe 438 (4.2) 267 (2.5) 1.66 (1.43–1.93) <0.001
TIMI
Clinically significant 1759 (15.8) 1241 (11.1) 1.46 (1.36–1.57) <0.001
Non–CABG-related major 287 (2.8) 198 (1.8) 1.46 (1.22–1.75) <0.001
CABG-related major† 11 (7.6) 10 (6.1) 1.13 (0.48–2.66) 0.79
Fatal 29 (0.3) 20 (0.2) 1.46 (0.82–2.58) 0.19
Intracranial 102 (1.0) 53 (0.5) 1.94 (1.39–2.70) <0.001
Intracerebral 89 (0.8) 41 (0.4) 2.19 (1.51–3.17) <0.001
Subdural or epidural 12 (0.1) 10 (0.1) 1.20 (0.52–2.79) 0.67
Unknown 1 (<0.1) 2 (<0.1)
Net clinical outcome 13,186 13,166
Cardiovascular death, myocardial infarction, stroke,
or GUSTO moderate or severe bleeding 1315 (11.7) 1358 (12.1) 0.97 (0.90–1.04) 0.40
Cardiovascular death, myocardial infarction, stroke,
urgent coronary revascularization, or
GUSTO moderate or severe bleeding
1526 (13.4) 1593 (14.0) 0.96 (0.89–1.02) 0.20
Death from any cause, myocardial infarction, stroke,
or GUSTO severe bleeding 1322 (11.9) 1436 (12.8) 0.92 (0.85–0.99) 0.02
* Percentages are cumulative Kaplan–Meier event rates at 3 years. The stroke component in all efficacy end points in-
cluded all ischemic and hemorrhagic strokes, unless otherwise specified. Urgent coronary revascularization was defined
by recurrent ischemia leading to urgent coronary revascularization. CABG denotes coronary-artery bypass grafting,
GUSTO Global Use of Strategies to Open Occluded Coronary Arteries, and TIMI Thrombolysis in Myocardial Infarction.
† CABG-related major bleeding was assessed in 175 patients in the vorapaxar group and 201 patients in the placebo group.
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Vor apa xar and Pre vention of atheros cler otic e vents
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7
that targeted by standard antiplatelet therapy for
secondary prevention reduces the risk of recurrent
thrombotic events in patients with previous athero-
thrombosis. This benefit was evident particularly in
those whose qualifying diagnosis for participation
in the trial was myocardial infarction.
The results of our study establish that interrup-
tion of the platelet-directed cellular actions of
Event Rate (%)
100
80
90
70
60
40
30
10
50
20
0
0 12060 240180 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Days since Randomization
BDeath from Cardiovascular Causes, Myocardial Infarction, Stroke, or Recurrent Ischemia Leading to Urgent Coronary
Revascularization
ADeath from Cardiovascular Causes, Myocardial Infarction, or Stroke
Hazard ratio, 0.87 (95% CI, 0.80–0.94)
P<0.001
14
12
8
6
2
10
4
0
0 120 240 360 480 600 720 840 960 1080
No. at Risk
Placebo
Vorapaxar
13,224
13,225
12,727
12,784
12,365
12,479
12,013
12,162
9,366
9,463
6,239
6,287
Placebo
Vorapaxar
10.5
9.3
Event Rate (%)
100
80
90
70
60
40
30
10
50
20
0
0 12060 240180 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Days since Randomization
Hazard ratio, 0.88 (95% CI, 0.82–0.95)
P= 0.001
14
12
8
6
2
10
4
0
0 120 240 360 480 600 720 840 960 1080
No. at Risk
Placebo
Vorapaxar
13,224
13,225
12,631
12,720
12,207
12,364
11,824
12,003
9,180
9,295
6,104
6,147
Placebo
Vorapaxar
12.4
11.2
Figure 1. Kaplan–Meier Rates of Cardiovascular Events.
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The
ne w engl an d jour na l
o f
me di ci ne
10.1056/nejmoa1200933  nejm.org
8
Event Rate (%)
100
80
90
70
60
40
30
10
50
20
0
0 12060 240180 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Days since Randomization
BTIMI Clinically Significant Bleeding
AGUSTO Moderate or Severe Bleeding
Hazard ratio, 1.66 (95% CI, 1.43–1.93)
P<0.001
6
5
3
2
4
1
0
0 120 240 360 480 600 720 840 960 1080
No. at Risk
Placebo
Vorapaxar
13,166
13,186
12,311
12,235
11,620
11,570
11,120
10,997
9,334
9,174
6,039
5,963
Placebo
Vorapaxar
4.2
2.5
Event Rate (%)
100
80
90
70
60
40
30
10
50
20
0
0 12060 240180 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
Days since Randomization
Hazard ratio, 1.46 (95% CI, 1.36–1.57)
P<0.001
18
14
16
12
8
6
2
10
4
0
0 120 240 360 480 600 720 840 960 1080
No. at Risk
Placebo
Vorapaxar
13,166
13,186
11,995
11,730
11,135
10,885
10,529
10,200
8,748
8,393
5,606
5,366
Placebo
Vorapaxar
15.8
11.1
Figure 2. Kaplan–Meier Rates of Bleeding.
Panel A shows the estimated rates of moderate or severe bleeding, according to Global Use of Strategies to Open
Occluded Coronary Arteries (GUSTO) criteria. Panel B shows the rates of clinically significant bleeding, according to
Thrombolysis in Myocardial Infarction (TIMI) criteria, defined as any clinically overt bleeding that requires unplanned
treatment or laboratory evaluation or that meets the criteria for TIMI minor or major bleeding.
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Vor apa xar and Pre vention of atheros cler otic e vents
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9
thrombin, suggested in preclinical studies to be
pivotal to thrombosis,
10
translates into a clinical
effect on major thrombotic events. In our study,
antagonism of PAR-1 was complementary to inhi-
bition of the thromboxane A
2
and P2Y
12
-receptor
pathways with aspirin and thienopyridines, with
respect to the protective effect against recurrent
thrombosis. We did not find evidence of signifi-
cant heterogeneity of the effect of vorapaxar on
the basis of treatment with clopidogrel. When
vorapaxar was studied in the TRACER trial for the
management of acute coronary syndromes, there
was a nonsignificant trend toward a reduction in
the rate of cardiovascular death, myocardial infarc-
tion, stroke, recurrent ischemia with hospitaliza-
tion, or urgent coronary revascularization and an
exploratory finding of a reduction in the rate of
cardiovascular death, myocardial infarction, or
stroke, along with a significant increase in the
risk of intracranial hemorrhage.
9
Previous small-
er phase 2 trials of vorapaxar
11,12
and of atopax-
ar,
13,14
another PAR-1 antagonist, have also re-
vealed trends toward reductions in recurrent
thrombotic events but without evidence of an in-
creased risk of intracranial hemorrhage.
During the trial, the data and safety monitor-
ing board recommended the discontinuation of
vorapaxar in patients with a history of stroke on
the basis of an excess of intracranial hemorrhage
in such patients. We therefore carried out a sepa-
rate analysis that was confined to patients without
a history of stroke and found a significant benefit
in this subgroup. In addition, in a prespecified
analysis involving patients with a qualifying diag-
nosis of myocardial infarction, vorapaxar reduced
the relative risk of the primary end point by 20%.
In the largest previous placebo-controlled trial of
antiplatelet therapy for secondary prevention in
patients with stable atherothrombosis or at high
risk for vascular disease, clopidogrel plus aspirin
was no better than aspirin alone in the overall
cohort.
4
Nevertheless, in an exploratory analysis
involving 3846 patients with previous myocardial
infarction in that trial, the addition of clopidogrel
reduced the risk of cardiovascular death, myocar-
dial infarction, or stroke by 23%.
15
Our trial in-
volving a substantially larger number of patients
with a history of myocardial infarction shows that
the addition of another antiplatelet agent to aspirin
therapy over the long term can achieve further
reductions in recurrent atherothrombotic events in
this population.
The reduction in thrombotic events with vora-
paxar came with significant increases in bleeding.
Although our findings show that additional reduc-
tions in atherothrombosis can be achieved, this
benefit must be weighed against the increase in
bleeding risk. In the overall trial cohort, there was
no significant between-group difference in the
prespecified net clinical outcome (including both
thrombotic end points and moderate or severe
bleeding). However, weighed against the risk of
severe bleeding, particularly in patients without
a history of stroke, the net clinical outcome was
improved in patients receiving vorapaxar.
The results of our study also add to the accu-
mulating evidence of a heightened risk of intra-
cranial hemorrhage among patients with a history
of stroke who are treated with potent antiplatelet
therapy.
2,16,17
As with the use of third-generation
P2Y
12
inhibitors, such as prasugrel, any clinical
use of vorapaxar would have to be based on an
appropriate selection of patients, with the risk of
bleeding balanced against that of recurrent throm-
botic events. We have previously identified crite-
ria for selecting patients who are more likely to
have improved net clinical outcomes with potent
antiplatelet therapy.
2,18
In our study, the relative
risk of bleeding, including intracranial hemor-
rhage, showed a similar significant increase in the
vorapaxar group among patients with and those
without a history of stroke. However, the absolute
rate of intracranial hemorrhage (0.2% per year)
among patients without a history of stroke was
substantially lower than that among patients with
such a history (0.8% per year). The rate of fatal
bleeding was not significantly increased in the
vorapaxar group.
In conclusion, the addition of vorapaxar to stan-
dard therapy reduced the risk of cardiovascular
death, myocardial infarction, or stroke among pa-
tients with stable atherosclerosis, a benefit that
was most apparent in patients with a history of
myocardial infarction. Vorapaxar also increased
the risk of moderate or severe bleeding, including
intracranial hemorrhage, with the latter occurring
most frequently in patients with a history of stroke.
Supported by Merck.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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10
Vor apa xar and Pre vention of atheros cler otic e vents
Appendix
The authors’ affiliations are as follows: the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Depart-
ment of Medicine, Brigham and Women’s Hospital, Boston (D.A.M., E.B., M.P.B., M.P.F., B.M.S., S.D.W., S.A.M.); the Institute for
Neurological Research, FLENI, Buenos Aires (S.F.A.); Milpark Hospital, Johannesburg (A.J.D.); the Division of Cardiovascular Research,
University of Edinburgh, Edinburgh (K.A.A.F.); Merck Research Laboratories, Rahway, NJ (L.J.L., X.L., J. Strony); the Heart Institute
(InCor)–University of São Paulo Medical School, São Paulo (J.C.N.); Canisius–Wilhelmina Hospital, Nijmegen, the Netherlands
(A.J.O.O.); Instituto de Investigaciones Clínicas Rosario, Rosario, Argentina (E.P.); University Hospital Brno, Masaryk University, Brno,
Czech Republic (J. Spinar); and Montreal Heart Institute and University of Montreal, Montreal (P.T.).
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    • "The percutaneous shuttling device can then be passed via percutaneous anteromedial,8 superior medial or posterior medial access points shown in Figure 2. The safety of these access points has been previously described.5-7,9-11 The posterior medial access point can be used for large tear with posteromedial retraction. "
    [Show abstract] [Hide abstract] ABSTRACT: Most arthroscopic rotator cuff repairs utilize suture passing devices placed through arthroscopic cannulas. These devices are limited by the size of the passing device where the suture is passed through the tendon. An alternative technique has been used in the senior author's practice for the past ten years, where sutures are placed through the rotator cuff tendon using percutaneous passing devices. This technique, dubbed the global percutaneous shuttling technique of rotator cuff repair, affords the placement of sutures from nearly any angle and location in the shoulder, and has the potential advantage of larger suture bites through the tendon edge. These advantages may increase the area of tendon available to compress to the rotator cuff footprint and improve tendon healing and outcomes. The aim of this study is to describe the global percutaneous shuttling (GPS) technique and report our results using this method. The GPS technique can be used for any full thickness rotator cuff tear and is particularly useful for massive cuff tears with poor tissue quality. We recently followed up 22 patients with an average follow up of 32 months to validate its usefulness. American Shoulder and Elbow Surgeons scores improved significantly from 37 preoperatively to 90 postoperatively (P<0.0001). This data supports the use of the GPS technique for arthroscopic rotator cuff repair. Further biomechanical studies are currently being performed to assess the improvements in tendon footprint area with this technique.
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    • "These findings clearly put selective PAR-1 inhibition on center stage as a promising target to interfere with atherosclerosis. Interestingly, while PAR-1 inhibition reduces the risk of cardiovascular death or ischemic events with stable atherosclerosis [50], such effects have not been witnessed so far for acute coronary syndromes [51]. Both studies revealed that PAR-1 inhibition leads to an increased risk of moderate and severe bleeding, including intracranial hemorrhage, thus highlighting the need to optimize the therapeutic regimen to specifically interfere with thrombin’s contribution to the initiation, formation, progression, and destabilization of atherosclerotic plaques. "
    [Show abstract] [Hide abstract] ABSTRACT: Thrombin is the protease involved in blood coagulation. Its deregulation can lead to hemostatic abnormalities, which range from subtle subclinical to serious life-threatening coagulopathies, i.e., during septicemia. Additionally, thrombin plays important roles in many (patho)physiological conditions that reach far beyond its well-established role in stemming blood loss and thrombosis, including embryonic development and angiogenesis but also extending to inflammatory processes, complement activation, and even tumor biology. In this review, we will address thrombin's broad roles in diverse (patho)physiological processes in an integrative way. We will also discuss thrombin as an emerging major target for novel therapies.
    Article · Aug 2013
    • "To date many PAR1 antagonists have been synthesized and characterized [7]–[10] and the high affinity non-peptide PAR1 antagonist, Vorapaxar, completed phase III clinical trials. The Vorapaxar TRA-CER trial was terminated due to an association of treatment with an increased risk of bleeding including intracranial hemorrhage however, the TRA-2P-TIMI 50 trial, excluding patients presenting with previous stroke, was completed and showed that PAR1 antagonism is effective in reducing cardiovascular death and ischemic events [11]–[13]. PAR4 as the low affinity thrombin receptor is consequently engaged by high concentrations of thrombin and thus subject to differential temporal engagement by thrombin. Our lab and others have documented signaling differences between PAR1 and PAR4 indicating that although activated by the same endogenous agonist and purportedly couple to the same G-proteins, platelet thrombin receptor signaling is fundamentally distinct [14]–[19]. "
    [Show abstract] [Hide abstract] ABSTRACT: Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a novel series of indole-based PAR4 antagonists also necessitated the development of a platelet based high-throughput screening assay. Screening and subsequent structure activity relationship analysis yielded several selective PAR4 antagonists as well as possible new scaffolds for future antagonist development.
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