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Vorapaxar in the Secondary Prevention of Atherothrombotic Events

Authors:
David A Morrow
David A Morrow
David A Morrow

Abstract and Figures

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
‡§ 2,112/13,056 (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
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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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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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... Vorapaxar specifically targets and inhibits PAR-1 on platelets, effectively inhibiting thrombin-induced platelet aggregation. The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis (TRAP 2P-TIMI 50) study randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral artery disease to receive either vorapaxar 2.5 mg daily or a placebo, in addition to standard aspirin therapy [47]. Over an average follow-up period of three years, those who were administered vorapaxar experienced a lower incidence of ischemic events or cardiovascular death compared to those who received the placebo. ...
... Over an average follow-up period of three years, those who were administered vorapaxar experienced a lower incidence of ischemic events or cardiovascular death compared to those who received the placebo. However, the vorapaxar group exhibited a higher occurrence of major and intracranial bleeding [47]. ...
Article
Full-text available
Purpose of Review To summarize the recent evidence and guideline recommendations on aspirin or P2Y12 inhibitor monotherapy in patients with stable ischemic heart disease and provide insights into future directions on this topic, which involves transition to a personalized assessment of bleeding and thrombotic risks. Recent Findings It has been questioned whether the evidence for aspirin as the foundational component of secondary prevention in patients with coronary artery disease aligns with contemporary pharmaco-invasive strategies. The recent HOST-EXAM study randomized patients who had received dual antiplatelet therapy for 6 to 18 months without ischemic or major bleeding events to either clopidogrel or aspirin for a further 24 months, and demonstrated that the patients in the clopidogrel arm had significantly lower rates of both thrombotic and bleeding complications compared to those in the aspirin arm. The patient-level PANTHER meta-analysis showed that in patients with established coronary artery disease, P2Y12 inhibitor monotherapy was associated with lower rates of myocardial infarction, stent thrombosis as well as gastrointestinal bleeding and hemorrhagic stroke compared to aspirin monotherapy, albeit with similar rates of all-cause mortality, cardiovascular mortality and major bleeding. Summary Long-term low-dose aspirin is recommended for secondary prevention in patients with stable ischemic heart disease, with clopidogrel monotherapy being acknowledged as a feasible alternative. Dual antiplatelet therapy for six months after percutaneous coronary intervention remains the standard recommendation for patients with stable ischemic heart disease. However, the duration of dual antiplatelet therapy may be shortened and followed by P2Y12 inhibitor monotherapy or prolonged based on individualized evaluation of the patient’s risk profile.
... Vorapaxar blocks protease-activated receptor 1 (PAR1) (encoded by F2R gene) activation on platelet membrane through reversible antagonism and inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. 1 May et al. (2023) showed that podocyte-specific activation of PAR1 leads to early severe nephrotic syndrome in mice and there might be unknown circulating factors in patients with NS that cause relapsing focal segmental glomerulosclerosis (FSGS) after kidney transplantation. 2 Anti-PAR1 treatments have also been studied in clinical trials for NS. ...
... clinicaltrials.gov ID: NCT03207451 and NCT02545933), vorapaxar protected against the primary endpoint of cardiovascular mortality, MI, or stroke compared to the placebo (Hazard ratio = 0.87, p < 0.001).1 However, to our knowledge, there is currently no available GWAS of thrombotic cardiovascular events in individuals with prior MI or PAD. ...
Preprint
Full-text available
In clinical trials, the anti-protease-activated receptor-1 (PAR1) therapy, vorapaxar, has been tested as a treatment for nephrotic syndrome (NS). This study aimed to investigate the causal relationship of PAR1 (encoded by the gene F2R) with renal phenotypes using drug-target Mendelian Randomization (MR). First, we performed colocalization analyses to confirm whether PAR1/F2R expression instruments were shared between plasma/blood and kidney tissue. We selected PAR1/F2R expression instruments from the UK Biobank-Pharma Proteomics Project (UKB-PPP), eQTLGen, and Genotype-Tissue Expression (GTEx). Kidney F2R expression data were obtained from NephQTL2. Second, given the known experimental evidence of the vorapaxar effect on PAR1 inhibition, we conducted drug-target MR to investigate the causal effects of genetically lower PAR1 protein levels or F2R expression levels on thrombotic diseases as positive controls from FinnGen, including venous thromboembolism (VTE), deep venous thrombosis (DVT), and arterial thromboembolism (AET). Finally, we performed drug-target MR to investigate the causal relationship of genetically lower PAR1 protein or F2R expression levels from plasma/blood and kidney tissues on renal diseases and function. We included five renal phenotypes as our main outcomes: CKD, microalbuminuria (MA), NS, estimated GFR (eGFR), and urinary albumin-to-creatinine ratio (uACR). Renal genome-wide association studies (GWAS) data were obtained from the CKDGen consortium, except for NS, which was obtained by meta-analysing FinnGen and a novel GWAS in the UKB. In addition, we also used serum albumin from UKB as a further outcome in a sensitivity analysis. Colocalization analyses identified shared genetic variants between blood and tubulointerstitial F2R expression (posterior probabilities are 89.1% for eQTLGen and 95.4% for GTEx) but not between plasma PAR1 and tubulointerstitial F2R expression. We present MR findings as β or odds ratios (ORs) with 95% confidence intervals (CIs) per unit decrease in plasma protein or gene expression, or per effect allele, consistent with the direction of effect when taking vorapaxar. Genetically- proxied lower PAR1 and F2R expression reduced risk of VTE with ORs of 0.84 [95% CI 0.71 to 1.00] (UKB-PPP), 0.94 [0.88 to 1.01] (eQTLGen) and 0.89 [0.75 to 1.06] (GTEx), indicating that genetically-instrumented lower PAR1 is directionally consistent with the effect of vorapaxar. Genetically-proxied lower PAR1 and F2R expression increased the risk of developing CKD (UKB- PPP: OR=1.17 [0.99 to 1.38]; eQTLGen: OR=1.12 [1.02 to 1.23]; GTEx: OR=1.24 [1.05 to 1.46]), but may decrease eGFR (eQTLGen: β=-0.02 [-0.06 to 0.01], GTEx: β=-0.04 [-0.08 to 0.01], UKB-PPP: β =-0.01, [-0.05, 0.04]). The effect of genetically-proxied PAR1 on NS was inconclusive due to lack of power. Our study suggests that genetically-proxied lower PAR1 and F2R expression reduces VTE risk, and increases CKD risk, but provides less evidence on reducing eGFR or increasing uACR. Evidence regarding NS was inconclusive. For NS patients, the decision to use anti-PAR1 treatment should be made with caution, given the potential renal implications and the current lack of conclusive evidence of its impact on NS.
... However, data on the efficacy and safety of its use remain limited, and the American guidelines emphasize that the benefits of using vorapaxar remain unclear. [30][31][32][33] Therefore, the possibility of using this agent in patients after PCI requires further studies. ...
Article
Full-text available
Introduction and purpose: aa Chronic coronary artery disease (CAD) is a prevalent condition affecting millions of people worldwide, significantly reducing quality of life and increasing the risk of myocardial infarction (MI). Percutaneous coronary intervention (PCI), often combined with stent implantation, is a cornerstone of CAD treatment. However, it induces a prothrombotic state, necessitating dual antiplatelet therapy (DAPT) to mitigate the risk of thrombosis and MI. Despite its established role, the optimal duration and specific composition of DAPT still remain under investigation. This article aims to summarise current knowledge on DAPT and highlight gaps requiring further research. Description of the state of knowledge: DAPT typically involves acetylsalicylic acid (ASA) 75 mg and clopidogrel 75 mg for 6 months after PCI. While this is effective in reducing thrombotic events, it also increases bleeding risk. Current European Society of Cardiology (ESC) guidelines recommend tailoring DAPT duration and composition based on individual patient risk factors for bleeding and ischemia. Alternatives include shortening DAPT to 1–3 months for patients with high bleeding risk or intensifying it with stronger antiplatelet agents like ticagrelor or prasugrel for those at high ischemic risk. However, evidence supporting these alternatives remains limited, and require further investigation. Emerging options, such as vorapaxar, present additional potential, but also require further validation. Summary: CAD management through PCI relies heavily on effective DAPT. Current strategies emphasize balancing ischemic and bleeding risks in optimising treatment. Although significant progress has been made, optimal DAPT regimens for specific patient groups remain uncertain, particularly in cases of shortened or intensified therapy. Continued research is crucial to refine treatment protocols and improve patient outcomes.
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The omega-3 polyunsaturated fatty acids (PUFAs) Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) exert multiple cardioprotective effects, influencing inflammation, platelet activation, endothelial function and lipid metabolism, besides their well-established triglyceride lowering properties. It is not uncommon for omega-3 PUFAs to be prescribed for hypertriglyceridemia, alongside antiplatelet therapy in cardiovascular disease (CVD) patients. In this regard, we studied the effect of EPA and DHA, in combination with antiplatelet drugs, in platelet aggregation and P-selectin and αIIbβ3 membrane expression. The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y12; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6. Both DHA and EPA displayed a dose-dependent inhibitory effect on platelet aggregation induced by AA, ADP and TRAP-6. In platelet aggregation induced by AA, DHA significantly improved acetylsalicylic acid (ASA) and triflusal’s inhibitory activity, while EPA enhanced the inhibitory effect of ASA. In combination with EPA, ASA and ticagrelor expressed an increased inhibitory effect towards ADP-induced platelet activation. Both fatty acids could not improve the inhibitory effect of vorapaxar on AA- and ADP-induced platelet aggregation. In the presence of EPA, all antiplatelet drugs displayed a stronger inhibitory effect towards TRAP-6-induced platelet activation. Both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though they had no effect on P-selectin expression induced by ADP or TRAP-6. The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αIIbβ3 membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component.
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Composite time-to-event endpoints are commonly used in cardiovascular outcome trials. For example, the IMPROVE-IT trial comparing ezetimibe+simvastatin to placebo+simvastatin in 18,144 patients with acute coronary syndrome used a primary composite endpoint with five component outcomes: (1) cardiovascular death, (2) non-fatal stroke, (3) non-fatal myocardial infarction, (4) coronary revascularization ≥30 days after randomization, and (5) unstable angina requiring hospitalization. In such settings, the traditional analysis compares treatments using the observed time to the occurrence of the first (i.e. earliest) component outcome for each patient. This approach ignores information for subsequent outcome(s), possibly leading to reduced power to demonstrate the benefit of the test versus the control treatment. We use real data examples and simulations to contrast the traditional approach with several alternative approaches that use data for all the intra-patient component outcomes, not just the first.
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BACKGROUND: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS: In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS: At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)
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Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
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BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
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BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
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Summary Background Clopidogrel was superior to aspirin in patients with previous manifestations of atherothrombotic disease in the CAPRIE study and its benefit was amplified in some high-risk subgroups of patients. We aimed to assess whether addition of aspirin to clopidogrel could have a greater benefit than clopidogrel alone in prevention of vascular events with potentially higher bleeding risk. Methods We did a randomised, double-blind, placebo-controlled trial to compare aspirin (75 mg/day) with placebo in 7599 high-risk patients with recent ischaemic stroke or transient ischaemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day. Duration of treatment and follow-up was 18 months. The primary endpoint was a composite of ischaemic stroke, myocardial infarction, vascular death, or rehospitalisation for acute ischaemia (including rehospitalisation for transient ischaemic attack, angina pectoris, or worsening of peripheral arterial disease). Analysis was by intention to treat, using logrank test and a Cox’s proportional-hazards model. Findings 596 (15.7%) patients reached the primary endpoint in the group receiving aspirin and clopidogrel compared with 636 (16·7%) in the clopidogrel alone group (relative risk reduction 6.4%, [95% CI –4·6 to 16·3]; absolute risk reduction 1% [–0·6 to 2·7]). Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (96 [2·6%] vs 49 [1·3%]; absolute risk increase 1·3% [95% CI 0·6 to 1·9]). Major bleedings were also increased in the group receiving aspirin and clopidogrel but no difference was recorded in mortality.
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TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing <60 kg. This defined 3 clinically relevant groups of patients for use of prasugrel at the studied dose regimen: group I (core clinical cohort), group II (noncore cohort), and group III (contraindicated). We assessed clinical outcomes of patients within these cohorts in the TRITON-TIMI 38 trial. Survival analysis methods were used to compare outcomes by treatment assignment (prasugrel vs clopidogrel) and by cohort (groups I and II or III). Patients in group I (n = 10,804, 79%) treated with prasugrel had a clinically significant and robust decrease in the primary end point of cardiovascular death, myocardial infarction, or stroke (8.3 vs 11.0%, hazard ratio [HR] 0.74, 95% confidence interval 0.66 to 0.84, p <0.0001), whereas patients in group II (n = 2149, 16%) had limited efficacy (15.3% vs 16.3%, HR 0.94, 0.76 to 1.18, p = 0.61, p for interaction = 0.07). For Thrombolysis In Myocardial Infarction major bleeding not related to coronary artery bypass grafting, there were tendencies to higher rates with prasugrel in group I (1.9% vs 1.5%, HR 1.24, 0.91 to 1.69, p = 0.17) and group II (4.1% vs 3.4%, HR 1.23, 0.77 to 1.97, p = 0.40); however, the absolute difference was greater for group II. The net clinical outcome (all-cause death/myocardial infarction/stroke/Thrombolysis In Myocardial Infarction major bleeding) in group I patients was highly favorable (10.2% vs 12.5%, HR 0.80, 0.71 to 0.89, p <0.0001) and neutral in group II (19.5% vs 19.7%, HR 0.98, 0.81 to 1.20, p for interaction = 0.07). Patients in group III (n = 518, 4%) did poorly with regard to efficacy and safety. In TRITON-TIMI 38 patients without previous stroke, <75 years old, and weighing >60 kg had substantial decreases in ischemic events with prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of prasugrel and limit the risk of adverse outcomes.