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R&D INSIGHT REPORT
Vorapaxar: First Global Approval
Raewyn M. Poole • Shelley Elkinson
Published online: 25 June 2014
� Springer International Publishing Switzerland 2014
Abstract Vorapaxar [Zontivity� (US)], an orally active
protease-activated receptor-1 (PAR-1) receptor antagonist,
has been developed by Merck & Co for the reduction of
thrombotic cardiovascular events in patients with a history
of myocardial infarction (MI) or peripheral arterial disease
(PAD). Vorapaxar has received its first global approval for
this indication in the US. This article summarizes the
milestones in the development of vorapaxar leading to this
first approval for the reduction of thrombotic cardiovas-
cular events in patients with a prior MI or PAD.
1 Introduction
Patients with atherothrombosis have a high risk of recur-
rent ischaemic events and therefore require aggressive
secondary prevention therapy [1]. Platelets have a central
role in atherothrombosis, and antiplatelet therapy is there-
fore a mainstay of recommended secondary prevention
measures [2, 3]. Combining antiplatelet agents with dif-
ferent mechanisms of action, for example aspirin and the
thienopyridine clopidogrel, provides greater inhibition of
platelet activation and increased clinical benefit compared
with monotherapy [4]. However, the risk of recurrent
ischaemic events remains high despite the use of dual
antiplatelet therapy with aspirin plus a platelet P2Y12
inhibitor [4–6]. While this risk has been reduced with the
use of more potent antiplatelet agents than clopidogrel,
such as prasugrel and ticagrelor, this has been at the cost of
increased bleeding risk [4, 7]. Furthermore, the relatively
modest reduction in ischaemic events (approximately
20 %) with the more potent P2Y12 inhibitors versus
clopidogrel suggests an alternative mechanism of platelet
inhibition may be required [7].
Thrombin receptor antagonists are a new class of anti-
platelet agents under investigation for use in secondary pre-
vention [4, 6]. Thrombin stimulates protease-activated
receptors (PARs), specific G-protein-coupled cell receptors
that are involved in proliferative and pro-inflammatory pro-
cesses that may have implications in thrombosis and ath-
erosclerosis. Of the four PAR subtypes, only PAR-1 and
PAR-4 are expressed on human platelets [6]. PAR-1 mediates
platelet activation at low thrombin concentrations and is
involved in atherosclerosis, thrombosis and inflammation;
furthermore, it does not appear to be essential for protective
homeostasis [4–6]. These properties make PAR-1 an attrac-
tive target for the development of new antiplatelet agents.
Vorapaxar [Zontivity� (US)] is a first-in-class thrombin
and PAR-1 receptor antagonist developed by Merck & Co
for the secondary prevention of arterial thrombosis. Vora-
paxar received its first global approval in the US on 8 May
2014 as a once-daily tablet for the reduction of thrombotic
cardiovascular events in patients with a history of myo-
cardial infarction (MI) or peripheral arterial disease (PAD)
[8]. The approved labelling includes a black box warning
regarding the increased risk of bleeding, including intra-
cranial haemorrhage (ICH) and fatal bleeding, in patients
This profile has been extracted and modified from the Adis R&D
Insight drug pipeline database. Adis R&D Insight tracks drug
development worldwide through the entire development process,
from discovery, through pre-clinical and clinical studies to market
launch.
R. M. Poole
Adis, Auckland, New Zealand
S. Elkinson (&)
Adis, Level 1, 5 The Warehouse Way, Northcote 0627; Private
Bag 65901, Mairangi Bay 0754, Auckland, New Zealand
e-mail: [email protected]
Drugs (2014) 74:1153–1163
DOI 10.1007/s40265-014-0252-2
taking vorapaxar. Vorapaxar is contraindicated in patients
with a history of stroke, transient ischaemic attack (TIA) or
ICH, and those with active pathological bleeding (includ-
ing ICH or peptic ulcer) [8, 9]. Vorapaxar is to be
administered as a tablet containing vorapaxar sulfate
2.5 mg (vorapaxar base 2.08 mg), once daily in addition to
aspirin and/or clopidogrel given according to their indica-
tions or standard of care [9].
The approval is based on data from TRA 2�P-TIMI
50 (NCT00526474; P04737), a multinational phase III
trial that evaluated the efficacy of vorapaxar, given in
addition to the current standard of care, in reducing the
combined endpoint of cardiovascular death, MI or stroke
in [26,000 patients with a history of MI, ischaemic
stroke or documented PAD. The administration of vo-
rapaxar to patients with ischaemic stroke in this trial
was discontinued in January 2011 following recom-
mendations by the Data and Safety Monitoring Board
(DSMB), and the trial was completed in patients with
MI and PAD only (approximately 75 % of enrolled
patients) [10, 11].
Vorapaxar is awaiting approval for the prevention of
arterial thromboembolism in the EU [12]. It is also in phase
III development globally for this indication.
Chemical structure of vorapaxar
N
O
H
NH
HH
H
H H
H
O
O
O
F
Features and properties of vorapaxar
Alternative names MK 5348; MK-5348; SCH 530348; SCH530348; TRA-SCH 530348; Zontivity�
Class 3-ring-heterocyclic-compounds, carbamates, lactones, pyridines
Mechanism of action PAR-1 receptor antagonists; thrombin receptor antagonists
Route of administration Oral
Pharmacodynamics Prolonged, dose-related inhibition of platelet aggregation at therapeutic doses; no
clinically significant effects on coagulation markers
Pharmacokinetics Dose-dependent pharmacokinetics; tmax 1 h; mean Vd *424 L, C99 % plasma protein
binding; multi-exponential disposition with effective t1/2 of 3–4 days, apparent terminal
elimination t1/2 8 days; steady-state reached within 21 days of once-daily dosing, 5- to 6-fold
accumulation. Main route of elimination is by metabolism with CYP3A4 and CYP2J2
involvement; primarily faecal elimination. Concomitant use of strong CYP3A inducers and
inhibitors should be avoided
Adverse events
Most frequent Haemorrhage
Occasional Anaemia, depression, skin reactions, iron deficiency, retinopathy or retinal disorder,
diplopia/oculomotor disturbances
ATC codes
WHO ATC code B01A-X (other antithrombotic agents)
EphMRA ATC code B1X (other antithrombotic agents)
Chemical name Carbamic acid, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[2-[5-(3-Fluorophenyl)pyridin-
2-yl]ethen-1-yl]-1-methyl-3-oxodecahydronaphtho-[2,3-c]furan-6-yl]-, ethyl ester
1154 R. M. Poole, S. Elkinson
1.1 Company Agreements
Vorapaxar was originally being developed by Schering
Plough, which merged with Merck & Co in November
2009 [13].
2 Scientific Summary
2.1 Pharmacodynamics
Vorapaxar is a reversible PAR-1 antagonist, although it is
effectively irreversible due to its long half-life [9]. Vora-
paxar inhibited thrombin-induced and thrombin receptor
agonist peptide (TRAP)- induced platelet aggregation in
in vitro studies, but did not affect adenosine diphosphate
(ADP)-, collagen- or thromboxane mimetic-induced
platelet aggregation.
In studies in healthy volunteers, vorapaxar inhibited
TRAP-induced platelet aggregation by C80 % after
1 week of treatment at the recommended dose, with dose-
and concentration-dependent duration of antiplatelet
activity [9]. TRAP-induced platelet aggregation continued
to be inhibited by 50 % 4 weeks after discontinuation of
treatment with vorapaxar 2.5 mg. There were no changes
in platelet P-selectin and soluble CD40 ligand (sCD40L)
expression or measures of coagulation after single or
multiple doses of vorapaxar.
Vorapaxar produced rapid and prolonged dose-depen-
dent inhibition of platelet aggregation in studies in healthy
volunteers [14, 15]. In two randomized, placebo-controlled
studies, healthy volunteers received either single ascending
doses of vorapaxar 0.25–40 mg or placebo (n = 50),
multiple ascending doses of 1–5 mg/day or placebo for
28 days (n = 36), or a loading dose of 10 or 20 mg then
maintenance doses of 1 mg once daily for 6 days or pla-
cebo (n = 12) [15]. Complete (C80 %) inhibition of
TRAP-induced platelet aggregation was observed with
single vorapaxar doses of 20 and 40 mg, with effects sus-
tained for C72 h post-dose. Complete inhibition was
achieved with multiple doses of vorapaxar 5 mg/day from
day 1 and vorapaxar 1 and 3 mg/day on day 7. No sig-
nificant increases in soluble P-selectin or sCD40L con-
centrations were observed. In a randomized, open-label
study in 111 healthy volunteers, single loading doses of
vorapaxar 20 mg and 40 mg inhibited TRAP-induced
platelet aggregation by 80 % at 1 h, although the 40 mg
dose was required to achieve this in most volunteers [14].
Consistent 80 % platelet inhibition was seen with a 2.5 mg/
day maintenance dose from day 7, but not with mainte-
nance doses of 0.5 or 1 mg/day. Dose-dependent recovery
of platelet function was observed within days or weeks
after stopping treatment with vorapaxar after 28 days.
A pharmacodynamic substudy of the TRACER trial
showed that vorapaxar significantly reduced PAR-1-medi-
ated platelet aggregation compared with placebo [16]. In a
subset of 249 patients with non-ST-segment elevation
acute coronary syndrome (NSTE ACS) enrolled in TRA-
CER, PAR-1-mediated platelet aggregation, as measured
by light transmittance aggregometry (LTA) and VerifyNow
assays, was rapidly and significantly inhibited by vora-
paxar. Inhibition of ADP was significantly greater for vo-
rapaxar versus placebo at 4 h and at 1 month (P \ 0.01),
and the number of PAR-1 receptors was significantly
reduced from baseline in the vorapaxar group (179 vs. 225;
P = 0.004) but not the placebo group.
2.1.1 Effects on QTc Interval
Vorapaxar did not cause significant QT/QTc interval
prolongation in a randomized, double-blind, placebo- and
positive-controlled study in 120 healthy volunteers [17].
Male and female volunteers aged 18–50 years were ran-
domized to receive a single dose of vorapaxar 120 mg or
placebo (double-blind) or moxifloxacin 400 mg (open-
label). Vorapaxar had no significant effect on QTc inter-
val with Fridericia’s correction for heart rate (QTcF), with
the upper bound of the 95 % confidence interval (CI) for
the difference from placebo being B3.8 ms at all time
points during the 23-h post-dose evaluation period. In
contrast, a mean increase in QTcF of [10 ms was seen
with moxifloxacin compared with placebo at 1, 1.5 and 2
h post-dose.
2.2 Pharmacokinetics
Elimination of vorapaxar is via metabolism, which is pri-
marily catalyzed by the cytochrome P450 (CYP) enzymes
CYP3A4 and CYP2J2 [9, 18]. Vorapaxar is metabolized to
a major excreted inactive amine metabolite (M19) by
carbamate cleavage and to the monohydroxy metabolite
(M20) [18]. M20 is the major circulating metabolite of
vorapaxar at steady state and has comparable potency to
the parent compound. The main route of elimination is
faecal (58 % of administered dose), followed by urinary
excretion (25 %) [9].
The pharmacokinetics of vorapaxar are dose-dependent
and steady-state is reached within 21 days of once-daily
administration with 5- to 6-fold accumulation [9]. Vora-
paxar has multi-exponential disposition, with an effective
half-life (t1/2) of 3–4 days and apparent terminal elimina-
tion t1/2 of 8 days. The mean absolute bioavailability of
vorapaxar is 100 %. The mean peak plasma concentration
(Cmax) of vorapaxar occurred 1 hour after administration of
a single 2.5 mg dose under fasted conditions. Vorapaxar
has a mean volume of distribution of approximately 424 L
Vorapaxar: First Global Approval 1155
and, along with the active metabolite M20, is almost
completely bound to plasma proteins (C99 %).
In a study in healthy volunteers (n = 111) who received
vorapaxar (loading dose of 5, 10, 20 or 40 mg then main-
tenance doses of 0.5, 1 or 2.5 mg/day for 28 days), expo-
sure was dose-related and the mean terminal t1/2 of
vorapaxar ranged from 165 to 311 h [14]. Vorapaxar also
demonstrated dose-dependent pharmacokinetics in two
studies in healthy volunteers [15]. After administration of
single doses of 0.25–40 mg, the mean Cmax of vorapaxar
ranged from 2.2 to 376.0 ng/mL, time to Cmax (tmax) from
0.8 to 1.5 h, and AUC0-72h from 34 to 6028 ng�h/mL. In
volunteers receiving daily doses of 1, 3 or 5 mg, mean Cmax
ranged from 24.6 to 131.0 ng/mL and AUC from 363 to
1910 ng�h/mL; tmax was 1.0 h for all doses. Vorapaxar had a
long elimination half-life of 126–269 h after administration
of single 20 and 40 mg doses and 173–269 h after multiple
doses of 1–5 mg/day. Mean accumulation ratio (R) ranged
from 4.72 to 6.37. Steady state plasma concentrations were
reached within 21 days in these studies.
Food, concomitant administration of a strong antacid
and older age had modest effects on the pharmacokinetics
of vorapaxar in a randomized, open-label study in healthy
volunteers, although the differences were not considered
clinically significant [19]. A total of 83 healthy volunteers
aged 18–45 years received a single oral dose of vorapaxar
40 mg after a 10-h fast (n = 22), within 5 min of an extra-
strength antacid after a 10-h fast (n = 20), with food
(n = 20), 1 h after food (n = 11) or 2 h after food
(n = 10); in addition, 18 volunteers aged [65 years
received vorapaxar 40 mg after fasting. Vorapaxar had a
median tmax of 1 h in the fasted state; tmax increased to 2–3
h when given with or 1 or 2 h after food. After food, the
area under the plasma concentration time curve (AUC?)
and Cmax increased by 43 and 31 %, respectively. When
given with antacid, AUC? and Cmax decreased by 15 and
38 %, respectively, and the median tmax increased to 2 h.
The AUC? and Cmax of vorapaxar were increased by 41
and 23 %, respectively, in elderly versus younger volun-
teers, but the median tmax was unchanged. The mean t1/2
was also longer in elderly volunteers (370 vs. 240 h for
younger volunteers). The increased exposure in elderly
volunteers was due to decreased clearance (mean 1618 vs.
2280 mL/h for younger volunteers) and a longer t1/2 (370
vs. 240 h for younger volunteers). An open-label two-
period crossover study in 16 healthy volunteers also
showed that food did not significantly affect the pharma-
cokinetics of a single oral dose of vorapaxar 2.5 mg [20].
Geometric mean ratios (GMRs) for the AUC0–72 h and
Cmax of vorapaxar in the fed and fasted states were 96.9
(90 % CI 92.2–102) and 79.1 (90 % CI 67.6–92.5),
respectively; both 90 % CIs were within the pre-specified
range for comparability of 0.50–2.00.
The pharmacokinetics and pharmacodynamics of vora-
paxar do not appear to be affected by ethnicity. There were
no clinically meaningful differences in pharmacokinetics or
inhibition of platelet aggregation with vorapaxar between
age-, sex-, height-, and bodyweight-matched Japanese and
Caucasian volunteers [21]. The pharmacokinetics of vora-
paxar and its major active metabolite, M20, were also
similar in Chinese and US healthy volunteers [22].
2.2.1 Effects of Renal or Hepatic Impairment
No dose adjustment is required in patients with renal
impairment or mild or moderate hepatic impairment [9].
However, the use of vorapaxar in patients with severe hepatic
impairment is not recommended due to the increased risk of
bleeding. Hepatic impairment did not have a clinically
meaningful effect on the pharmacokinetics of vorapaxar
(40 mg) in a single-dose study in patients with mild (Child–
Pugh 5–6; n = 6), moderate (Child–Pugh 7–9; n = 6) or
severe (Child–Pugh 10–15; n = 4) hepatic impairment and
age-, sex-, height- and bodyweight-matched healthy volun-
teers (n = 16) [23]. Exposure to vorapaxar or its active
metabolite M20 and t1/2 values did not appear to correlate
with the severity of hepatic impairment. Mean AUCfinal and
Cmax values for vorapaxar ranged from 14,200 to
18,000 ng�h/mL and 206–279 ng/mL, respectively; although
the lowest values occurred in patients with severe hepatic
impairment, the 90 % CIs for the GMRs for AUCfinal and
Cmax included 100 and no trend between increased GMR and
increased hepatic impairment was observed. The median tmax
ranged from 1.0 to 1.75 h, and mean t1/2 from 298 to 366 h.
End-stage renal disease had no clinically significant
effects on the pharmacokinetics or pharmacodynamics of a
single oral dose of vorapaxar 10 mg in an open-label study
in eight patients on haemodialysis and seven matched
healthy volunteers [24].
2.2.2 Interactions with Other Drugs
Concomitant treatment with strong CYP3A inhibitors (C5-
fold increase in AUC of substrate or [80 % decrease in
clearance), such as ketoconazole itraconazole, posaconaz-
ole, clarithromycin, telithromycin, nefadozone, ritonavir,
saquinavir, nelfinavir, indinavir, boceprevir, telaprevir and
conivaptan, and strong CYP inducers (C80 % decrease in
substrate AUC), such as rifampin carbamazepine, phenyt-
oin and St. John’s Wort, should be avoided in patients
receiving vorapaxar [9]. However, no increase in bleeding
risk or reduction in the efficacy of vorapaxar was observed
in patients taking weak or moderate CYP3A inhibitors in
phase III studies, and dose adjustment is not considered
necessary for concomitant administration of these drugs
with vorapaxar [9].
1156 R. M. Poole, S. Elkinson
No dose adjustment is required for vorapaxar in patients
treated with antacids or proton pump inhibitors or rosig-
litazone [9]. No significant pharmacokinetic interaction
between vorapaxar and prasugrel was observed after mul-
tiple-dose administration at steady-state, and dose adjust-
ment is not considered necessary; however, clinical
experience of vorapaxar in patients treated with prasugrel
is limited. Although there has been no study of the phar-
macokinetic interaction between vorapaxar and clopido-
grel, concomitant use is supported by the results of the
TRA 2�P-TIMI 50 and TRACER studies.
The effects of ketoconazole (400 mg once daily for
28 days) and rifampin (600 mg once daily for 28 days) on
the pharmacokinetics of vorapaxar (20 mg on day 7 then
2.5 mg/day once daily for 21 days) were examined in an
open-label, placebo-controlled, parallel-group study in
healthy volunteers [25]. Compared with placebo, concomi-
tant administration of ketoconazole 400 mg once daily
increased the steady state AUC0–24 and Cmax of vorapaxar by
196 and 193 %, respectively, whereas concomitant admin-
istration of rifampin reduced the AUC0–24 and Cmax of
vorapaxar to 45.5 and 61.4 % of control, respectively.
Although no significant pharmacokinetic or pharmaco-
dynamic interaction between vorapaxar and warfarin was
observed in a study in healthy volunteers, concomitant use
should be avoided due to the increased risk of bleeding
events [9]. In an open-label, two-period crossover study in
12 healthy male volunteers, concomitant administration of
vorapaxar (2.5 mg/day on days 1–6) with warfarin 25 mg
did not significantly affect exposure to R- or S-warfarin,
prothrombin time (PT) or international normalized ratio
(INR) [26]. Compared with warfarin 25 mg alone, GMRs
were 108 and 105, respectively, for the AUC? of R- and
S-warfarin; corresponding values for Cmax were 105 and
105. Estimated GMRs for the AUC0-120h for PT and INR
were 97 and 96, respectively.
Vorapaxar also showed no clinically significant inter-
action with digoxin in a study in healthy volunteers [27]. In
this open-label, fixed-sequence, two-period crossover
study, 18 volunteers received digoxin 0.5 mg on day 1 or
vorapaxar 2.5 mg/day on days 1–6 and a single dose of
vorapaxar 40 mg plus digoxin 0.5 mg on day 7, with a
washout period of C8 days in between treatments.
Although the Cmax of digoxin was increased (GMR of 154),
the AUCfinal and tmax and the pharmacodynamics of
digoxin, as evaluated by changes in electrocardiogram
(ECG) parameters (ventricular rate, QRS, PR, QT and QTc
intervals), were similar for the two treatments.
2.3 Therapeutic Trials
Vorapaxar has been evaluated in two major multinational
randomized, double-blind, placebo-controlled phase III
trials, TRA 2�P-TIMI 50 (NCT00526474) in patients with
MI, PAD or ischaemic stroke and TRACER
(NCT00527943) in patients with NSTE ACS. These studies
assessed the effects of adding vorapaxar to standard ther-
apy on ischaemic outcomes and bleeding risk, as assessed
by GUSTO (Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Arteries) and TIMI
(Thrombolysis In Myocardial Infarction) criteria.
2.3.1 TRA 2�P-TIMI 50 Trial
Vorapaxar significantly reduced the risk of cardiovascular
death or ischaemic events in patients with a history of MI
or ischaemic stroke (within the previous 2–52 weeks) or
PAD in the TRA 2�P-TIMI 50 trial [11]. This trial enrolled
26,449 patients who were randomized to receive vorapaxar
2.5 mg (n = 13,225) or placebo (n = 13,224), once daily
in addition to standard therapy. In January 2011, after a
median follow-up duration of 24 months, study medication
was discontinued for all patients with a history of ischae-
mic stroke (including new strokes occurring during the
trial) after the DSMB reported an excess of ICH in this
population; treatment was continued for patients with no
history of stroke, as per the DSMB recommendations. The
primary endpoint of the study was originally the composite
of cardiovascular death, MI, stroke or urgent coronary
revascularization (UCR); however, this became the main
secondary endpoint and the primary endpoint was changed
to the composite of cardiovascular death, MI or stroke after
a review of data from the TRACER trial (NCT00527943)
by the TRA 2�P-TIMI 50 investigators before the database
was locked and while blinded treatment was ongoing.
In the intention-to-treat (ITT) population, including
patients with stroke, a significant reduction in the primary
endpoint of cardiovascular death, MI or stroke was
observed with vorapaxar, compared with placebo [9.3 vs.
10.5 %; hazard ratio (HR) 0.87; 95 % CI 0.80–0.94;
P \ 0.001] at 3 years [11]. Significant reductions were
observed with vorapaxar versus placebo for the main sec-
ondary endpoint (11.2 vs. 12.4 %; HR 0.88, 95 % CI
0.82–0.95; P = 0.001), and cardiovascular death or MI
(7.3 vs. 8.2 %; HR 0.86, 95 % CI 0.78–0.94; P = 0.002)
and MI (5.2 vs. 6.1 %; HR 0.83, 95 % CI 0.74–0.93;
P = 0.001). However, there were no significant differences
in the rates of cardiovascular death, all-cause mortality, any
stroke, ischaemic stroke and UCR. Data from patients with
no history of stroke also showed that vorapaxar signifi-
cantly reduced the primary composite endpoint (8.3 vs.
9.6 %; HR 0.84, 95 % CI 0.76–0.93; P \ 0.001). Arterial
revascularization rates were significantly reduced with
vorapaxar at 3 years (13.6 vs. 15.5 %; HR 0.89, 95 % CI
0.83–0.95; P \ 0.001) [28]. Significant reductions were
seen in both peripheral and coronary revascularization,
Vorapaxar: First Global Approval 1157
including CABG surgery, and elective revascularizations
(P \ 0.05 for all).
No significant heterogeneity was observed for the pri-
mary endpoint across most major patient subgroups, with
the exception of bodyweight (P = 0.03 for interaction)
[11]. The HR for the primary endpoint in patients weighing
C60 kg was 0.85 (95 % CI 0.78–0.92), whereas in patients
weighing \60 kg it was 1.22 (95 % CI 0.88–1.69).
The efficacy of vorapaxar in reducing the primary
endpoint was independent of thienopyridine therapy [29].
Thienopyridine therapy was planned for 15,356 (58 %) of
the 26,449 patients enrolled in the study and 24,734 (94 %)
received aspirin (recommended dose B162 mg). Signifi-
cant and similar reductions in the primary endpoint were
seen regardless of whether thienopyridine therapy was
planned (p value for interaction 0.64) or whether it was
used at baseline or at 18 months (p values for interaction
0.76 and 0.99, respectively).
Analysis of net clinical outcomes, which included
bleeding as well as efficacy endpoints, showed a significant
difference for vorapaxar versus placebo for all-cause
mortality, MI, stroke or GUSTO severe bleeding (11.9 vs.
12.8 %; HR 0.92, 95 % CI 0.85–0.99; P = 0.02) in the ITT
population [11]. However, no significant differences were
seen for the net clinical outcomes of cardiovascular death,
MI, stroke or GUSTO moderate or severe bleeding (11.7
vs. 12.1 %; HR 0.97, 95 % CI 0.90–1.04; P = 0.40) and
cardiovascular death, MI, stroke, UCR or GUSTO mod-
erate or severe bleeding (13.4 vs. 14.0 %; HR 0.96, 95 %
CI 0.89–1.02; P = 0.20).
A pre-specified subgroup analysis of patients with a
prior MI as the qualifying event for enrolment
(n = 17,779) showed a significant reduction in the primary
endpoint with vorapaxar compared with placebo [30]. After
a median follow-up of 2.5 years, primary endpoint events
had occurred in 610 of 8,898 vorapaxar recipients, com-
pared with 750 of 8,881 patients in the placebo group,
corresponding to 3-year Kaplan–Meier estimates of 8.1 and
9.7 %, respectively (HR 0.80, 95 % CI 0.72–0.89;
P \ 0.0001). Vorapaxar was also associated with signifi-
cant reductions in the risk of the main secondary endpoint
(10.5 vs. 12.1 %; HR 0.83, 95 % CI 0.76–0.92;
P = 0.0001) and the individual endpoints of MI (5.7 vs.
7.0 %; HR 0.79, 95 % CI 0.70–0.90; P = 0.0003) and
ischaemic stroke (1.0 vs. 1.4 %; HR 0.66, 95 % CI
0.48–0.89; P = 0.006) at 3 years. However, there were no
significant differences in cardiovascular death or all-cause
mortality rates. Reductions in the primary endpoint with
vorapaxar were independent of aspirin dose (\100 mg,
100–162 mg or [162 mg; p value for interaction 0.98)
[31]. Vorapaxar also had comparable efficacy in patients
who qualified with MI whether or not they had diabetes
mellitus, with significant reductions in the primary
endpoint in both those with diabetes (12.6 vs. 15.7 %;
P = 0.004) and those without diabetes (6.8 vs. 7.9 %;
P = 0.005) [32].
A pre-specified analysis of patients with a prior
ischaemic stroke (n = 4883) showed no significant
reduction in the primary endpoint with vorapaxar com-
pared with placebo (13.0 vs. 11.7 %; HR 1.03, 95 % CI
0.85–1.25; P = 0.75) [33]. There were also no significant
differences in secondary efficacy endpoints, including
recurrent ischaemic stroke.
A subgroup analysis of patients with PAD (n = 3787)
also showed no significant reduction in the primary end-
point (11.3 vs. 11.9 %; HR 0.94, 95 % CI 0.78–1.14;
P = 0.53) or the main secondary endpoint (12.7 vs.
13.4 %; HR 0.95, 95 % CI 0.79–1.14; P = 0.57) with
vorapaxar [34]. However, in patients with PAD vorapaxar
was associated with reduced rates of hospitalization for
acute limb ischaemia (2.3 vs. 3.9 %; HR 0.58, 95 % CI
0.39–0.86; P = 0.006) and peripheral artery revasculari-
zation (18.4 vs. 22.2 %; HR 0.84, 95 % CI 0.73–0.97;
P = 0.017) than placebo; both urgent and elective
peripheral revascularization were significantly reduced in
the vorapaxar group (P \ 0.05 for both). The rates of the
composite endpoints of cardiovascular death, MI, stroke or
urgent vascular hospitalization and cardiovascular death,
MI, stroke, urgent vascular hospitalization and revascu-
larization were also significantly reduced with vorapaxar
compared with placebo (both P \ 0.05). Patients in the
PAD subgroup of this study were required to have a history
of intermittent claudication and an ankle-brachial index of
\0.85 or previous revascularization for limb ischaemia.
More than half (57 %) of the patients in this subgroup also
had coronary artery disease (CAD), and 14 % had a history
of stroke or TIA.
Treatment with vorapaxar was associated with a sig-
nificant reduction in the risk of definite stent thrombosis,
according to Academic Research Consortium criteria [35].
A total of 14,042 (53 %) patients had undergone a prior
coronary stent placement, and another 449 patients
received a stent during the follow-up period. After 3 years,
definite stent thrombosis had occurred in 1.1 % of vora-
paxar recipients, compared with 1.4 % of placebo-treated
patients (HR 0.71; P = 0.40). Similar results were seen
when patients who qualified for the study with MI and had
undergone stent placement before or during the study
(13,489 of 17,779; 76 %) were analysed separately, with
3-year definite stent thrombosis rates of 1.1 and 1.4 %,
respectively for the vorapaxar and placebo groups (HR
0.71; P = 0.46).
An analysis of strokes occurring during the study in
patients with no prior history of cerebrovascular disease
showed that vorapaxar significantly reduced the risk of
ischaemic stroke compared with placebo (HR 0.57, 95 %
1158 R. M. Poole, S. Elkinson
CI 0.43–0.75; P \ 0.001) [36]. Haemorrhagic stroke
occurred more frequently in patients treated with vorapaxar
(HR 2.78, 95 % CI 1.00–7.73; P = 0.049); however, due
to the reduction in ischaemic stroke the overall stroke risk
was lower for vorapaxar than placebo (HR 0.68, 95 % CI
0.52–0.80; P = 0.001). There were no significant differ-
ences between vorapaxar and placebo in the risk of
haemorrhagic conversion and death among patients with a
first ischaemic stroke.
2.3.2 TRACER Trial
The addition of vorapaxar to standard therapy did not
significantly reduce the primary endpoint of cardiovascular
death, MI, stroke, rehospitalization due to recurrent
ischaemia or UCR in patients with NSTE ACS in the
TRACER study [37]. In this trial, 12,944 patients were
randomized to receive vorapaxar (40 mg loading dose then
2.5 mg once daily maintenance dose) or placebo in addi-
tion to standard therapy. Follow-up was terminated early
on the recommendation of the study’s DSMB after a safety
review; at this time the target number of primary endpoint
events specified in the study protocol had been reached.
Two-year Kaplan–Meier rates of the primary endpoint in
the vorapaxar and placebo groups were 18.5 and 19.9 %,
respectively (HR 0.92, 95 % CI 0.85–1.01; P = 0.07). A
significant reduction in the main secondary endpoint of
cardiovascular death, MI or stroke was seen with vorapaxar
compared with placebo (14.7 vs. 16.4 %; HR 0.89, 95 %
CI 0.81–0.98; P = 0.02) and the composite endpoint of
cardiovascular death or MI was also reduced with vora-
paxar (HR 0.90, 95 % CI 0.81–0.99; P = 0.03). Results
were consistent across patient subgroups, including age
[38], presence or absence of PAD [39], aspirin dose [40],
glycoprotein (GP) IIb/IIIa inhibitor use [41], or CYP2C19
genotype or paraoxonase-1 activity [42].
Vorapaxar reduced the risk of a first MI (HR 0.88, 95 %
CI 0.79–0.98; P = 0.021) and first and subsequent MIs
(HR 0.86, 95 % CI 0.77–0.97; P = 0.014) compared with
placebo [43]. Analysis by type of MI showed that the most
frequent were type 1 MI (related to ischaemia caused by
atherothrombosis), which accounted for 1,025 of 1,580 MIs
occurring during the follow-up period, and that vorapaxar
significantly reduced the risk of this type of MI (HR 0.83,
95 % CI 0.73–0.95; P = 0.007). The second most common
type of MI was percutaneous coronary intervention (PCI)-
related (type 4a), with 352 (22.3 %) of the total MIs being
of this type; vorapaxar did not significantly reduce the risk
of PCI-related MI (HR 0.90, 95 % CI 0.73–1.12;
P = 0.35).
Analysis of net clinical outcomes for the main secondary
endpoint showed that, when offset by the risk of GUSTO
severe bleeding or TIMI major bleeding, the net clinical
benefit with vorapaxar at 1 year was 0.34 % [44]. When
patients were stratified according to the risks of ischaemic
events ([13 vs. B13 %) and major bleeding ([5 vs.
B5 %), those with high ischaemic risk and low bleeding
risk had a net benefit (2.8 %); however, negative benefits
were seen for those with high bleeding and low ischaemic
risk (-2.93 %), high bleeding and high ischaemic risk
(-3.08 %), and low bleeding and low ischaemic risk
(-0.10 %).
Results for medically managed patients (n = 4194)
were consistent with those for the overall population, with
no significant difference in the primary composite endpoint
with vorapaxar versus placebo [45]. Although there was
also no significant difference for the main secondary end-
point, the rate of MI was significantly reduced with vora-
paxar (HR 0.79, 95 % CI 0.63–0.99).
There were no significant differences in the primary
endpoint or the main secondary endpoint for vorapaxar
versus placebo in the subgroup of patients who underwent
PCI during the index hospitalization (n = 7,479) [46]. In
contrast, a pre-specified subgroup analysis showed that
vorapaxar was associated with a significant 45% reduction
in the risk of the primary endpoint in patients who under-
went CABG surgery during the index hospitalization
(n = 1312) [47]. Primary endpoint events occurred in
8.2 % of vorapaxar recipients and 12.9 % of placebo
recipients in the CABG subgroup (HR 0.55, 95 % CI
0.36–0.83; P = 0.005), with no significant increase in
CABG-related TIMI major bleeding (HR 1.36, 95 % CI
0.92–2.02; P = 0.12).
2.3.3 Phase II Trials
Vorapaxar was associated with a non-significant reduction
in the risk of death or major adverse cardiac events
(MACE) in patients with symptoms of CAD undergoing
non-urgent PCI or angiography with intent to perform PCI
in the TRA-PCI trial (NCT00132912) [48]. This random-
ized, double-blind, multinational study enrolled a total of
1030 patients who were randomized to receive a single
loading dose of vorapaxar 10, 20 or 40 mg or placebo at
least 1 hour before PCI; those who subsequently underwent
PCI then received a maintenance dose of vorapaxar 0.5, 1
or 2 mg/day or placebo for 60 days. Among the patients
who underwent PCI, the 60-day rates of death or MACE
were 9 % for placebo recipients, compared with 6 % for
patients receiving vorapaxar (range 5–8 % for loading
doses of 10, 20 or 40 mg).
Vorapaxar significantly reduced the risk of peri-proce-
dural MI in Japanese patients with NSTE ACS undergoing
planned PCI in a randomized, double-blind multicentre
phase II study (NCT00684203) [49]. This study enrolled
117 patients who were randomized 4:1 to receive
Vorapaxar: First Global Approval 1159
vorapaxar 20 or 40 mg loading dose or placebo, followed
by vorapaxar 1 or 2.5 mg/day maintenance dose or placebo
for 60 days for those who underwent PCI, in addition to the
standard of care (aspirin, ticlopidine and heparin). There
were no deaths or MACE other than MI among patients
who underwent PCI during 60 days’ follow-up. Non-fatal
peri-procedural MI occurred in 16.9 % of vorapaxar
recipients compared with 42.9 % of patients who received
only the standard of care (P = 0.013); the incidences of MI
in the vorapaxar 20 and 40 mg loading dose cohorts were
similar.
2.4 Adverse Events
Vorapaxar is associated with an increased risk of bleeding,
including serious and potentially fatal bleeding events [9].
The increase in bleeding risk is proportional to patients’
underlying risk of bleeding, with known risk factors
including renal or hepatic impairment, older age, lower
bodyweight, prior history of bleeding disorders, and con-
comitant use of certain medications (including anticoagu-
lants and fibrinolytics). Vorapaxar is contraindicated in
patients with a prior history of stroke, TIA or ICH due to
their increased risk of ICH; it is also contraindicated in
patients with active pathological bleeding, including ICH
and peptic ulcers.
Bleeding was assessed in the TRA 2�P-TIMI 50 trial
according to GUSTO and TIMI criteria, with GUSTO
moderate or severe bleeding being the primary safety
endpoint of the study [11]. In the ITT population (including
patients with a history of stroke), vorapaxar was associated
with increased rates of GUSTO moderate or severe
bleeding (4.2 vs. 2.5 %; HR 1.43–1.93; P \ 0.001) and
TIMI clinically significant bleeding 15.8 vs. 11.1 %; HR
1.46, 95 % CI 1.36–1.57; P \ 0.001) compared with pla-
cebo. The increased risk of GUSTO moderate or severe
bleeding was seen across the major patient subgroups.
Although non-CABG-related TIMI major bleeding was
significantly increased in the vorapaxar group compared
with the placebo group (2.8 vs. 1.8 %; HR 1.46, 95 % CI
1.22–1.75; P \ 0.001), the difference in CABG-related
TIMI major bleeding was not statistically significant (7.6
vs. 6.1 %; HR 1.13, 95 % CI 0.48–2.66; P = 0.79). ICH
occurred in 102 (1.0 %) patients in the vorapaxar group,
compared with 53 (0.5 %) in the placebo group (HR 1.94,
95 % CI 1.39–2.70; P \ 0.001); this included a significant
increase in the risk of intracerebral bleeding (0.8 vs. 0.4 %;
HR 2.19, 95 % CI 1.51–3.17; P \ 0.001). Rates of fatal
bleeding were not significantly different for vorapaxar and
placebo (0.3 vs. 0.2 %; HR 1.46, 95 % CI 0.82–2.58;
P = 0.19). In patients with a history of stroke, ICH
occurred in 2.4 % of vorapaxar recipients, compared with
0.9 % of patients in the placebo group (P \ 0.001) but
fatal bleeding rates were not significantly different (0.5 vs.
0.3 %; P = 0.46). ICH and fatal bleeding rates in patients
with no history of stroke treated with vorapaxar and pla-
cebo were 0.6 vs. 0.4 % (P = 0.049) and 0.3 vs. 0.2 %
(P = 0.30), respectively.
Analysis of bleeding rates in the 20,108 patients who
qualified for the TRA 2�P-TIMI 50 study with MI or PAD
and had no history of stroke showed an increased risk of
GUSTO moderate or severe bleeding with vorapaxar
compared with placebo, with Kaplan-Meier estimates of
3.7 vs. 2.4 % at 1080 days (HR 1.55, 95 % CI 1.30–1.86)
[9]. Although vorapaxar was associated with higher rates of
ICH and fatal bleeding than placebo, the increases were not
statistically significant (HR 1.46, 95 % CI 0.92–2.31 and
HR 1.15, 95 % CI 0.56–2.36, respectively). However, rates
of clinically significant bleeding (HR 1.47, 95 % CI
1.35–1.60), including gastrointestinal bleeding (HR 1.37,
95 % CI 1.18–1.59) were increased with vorapaxar. When
patients who qualified for study with PAD (n = 3,787) and
Clinical trials of vorapaxar in the secondary prevention of arterial thrombosis conducted by Merck & Co
Drugs Patient subgroup Study
phase
Status Location Trial identifiers
Vorapaxar ? SOC Patients with atherosclerosis III Completed Multinational NCT00526474; P04737
(TRA 2�P-TIMI 50)
Vorapaxar ? SOC (e.g. aspirin,
clopidogrel)
Patients with ACS III Terminated Multinational NCT00527943; P04736
(TRACER)
Vorapaxar ? SOC Assessment of long-term ocular safety
in study NCT00526474
III Completed Multinational NCT00617123; P05183
Vorapaxar ? SOC Patients undergoing non-emergent
PCI
II Completed Multinational NCT00132912; P03573
(TRA-PCI)
Vorapaxar ? aspirin ? clopidogrel Patients with ACS II Completed Japan NCT00684203; P04772
Vorapaxar ? aspirin Patients with cerebral infarction
(safety study)
II Completed Japan NCT00684515; P05005
ACS Acute coronary syndrome, SOC standard of care
1160 R. M. Poole, S. Elkinson
MI (n = 17,779) were analysed separately, rates of
GUSTO moderate or severe bleeding were significantly
increased with vorapaxar versus placebo for both patients
with PAD (7.4 vs. 4.5 %; HR 1.62, 95 % CI 1.21–2.18;
P = 0.001) and those with MI (3.4 vs. 2.1 %; HR 1.61,
95 % CI 1.31–1.97; P \ 0.0001) [30, 34]. However, rates
of GUSTO severe bleeding, fatal bleeding and ICH were
not significantly different for vorapaxar and placebo in
either of these subgroups.
A pre-specified analysis of patients who qualified for the
TRA 2�P-TIMI 50 study with a prior ischaemic stroke
showed that, compared with placebo, vorapaxar was
associated with significant increases in the rates of GUSTO
moderate or severe bleeding (4.2 vs. 2.4 %; HR 1.93, 95 %
CI 1.33–2.79; P \ 0.001), GUSTO severe bleeding (3.0 vs.
1.6 %; HR 2.09, 95 % CI 1.31–3.34; P = 0.002) and ICH
(2.5 vs. 1.9 %; HR 2.52, 95 % CI 1.46–4.36; P \ 0.001)
[33]. Rates of TIMI clinically significant bleeding, TIMI
non-CABG major bleeding and intracerebral haemorrhage
were also significantly higher for vorapaxar than placebo;
however, the difference in fatal bleeding rates was not
statistically significant.
In the TRACER study in patients with NSTE ACS,
vorapaxar was associated with significant increases in the
rates of GUSTO moderate or severe bleeding (7.2 vs.
5.2 %; HR 1.35, 95 % CI 1.16–1.58; P \ 0.001) and TIMI
clinically significant bleeding (20.2 vs. 14.6 %; HR 1.43,
95 % CI 1.31–1.57; P \ 0.001) compared with placebo
[37]. The rates of GUSTO severe bleeding (2.9 vs. 1.6 %;
HR 1.66, 95 % CI 1.27–2.16; P \ 0.001), ICH (1.1 vs.
0.2 %; HR 3.39, 95 % CI 1.78–6.45; P \ 0.001) and TIMI
major bleeding (4.0 vs. 2.5 %; HR 1.53, 95 % CI
1.24–1.90; P \ 0.001) were also significantly higher for
vorapaxar versus placebo. However, there were no signif-
icant differences between vorapaxar and placebo with
respect to fatal bleeding and CABG-related bleeding dur-
ing the index hospitalization. While GUSTO moderate or
severe bleeding rates were increased with vorapaxar in
most patient subgroups, the risk was higher for patients
who were receiving a thienopyridine at baseline than those
who were not (P = 0.04 for interaction) and for patients
whose bodyweight was below the median than for those
with higher bodyweight (P = 0.03 for interaction).
Examination of patient and clinical characteristics associ-
ated with major bleeding found that age, history of PAD,
past and present tobacco use, creatinine clearance, hae-
moglobin level at presentation, T-wave inversion on ECG,
use of GP IIb/IIIa inhibitors and Kilip class 3–4 were
independent predictors of major bleeding [50].
Anaemia was the most common non-haemorrhagic
adverse event in a total of 19,632 patients treated with
vorapaxar in the TRA 2�P-TIMI 50 and TRACER studies,
occurring in 5.0 % of vorapaxar recipients compared with
4.0 % of the 19,607 placebo-treated patients [9]. Other
adverse events occurring in [2 % of patients treated with
vorapaxar in these trials were depression (2.4 vs. 2.1 % for
placebo) and rashes, eruptions and exanthemas (2.2 vs.
2.0 %). Diplopia and related oculomotor disturbances
occurred in 0.2 % of vorapaxar recipients (30 patients),
compared with 0.06 % of placebo recipients (10 patients)
in these trials.
2.5 Ongoing Clinical Trials
No ongoing clinical trials of vorapaxar are listed in the
clinicaltrials.gov database.
3 Current Status
Vorapaxar received its first global approval on 8 May 2014
for the reduction of thrombotic cardiovascular events in
patients with a history of MI or with PAD in the US. It is
approved for use with aspirin and/or clopidogrel according
to their indications or standard of care.
Disclosure The preparation of this report was not supported by any
external funding. During the peer review process the manufacturer of
the agent under review was offered an opportunity to comment on the
article. Changes resulting from any comments received were made by
the authors on the basis of scientific completeness and accuracy. R.M.
Poole is a contracted employee of Adis, Springer SBM. S. Elkinson is
a salaried employee of Adis, Springer SBM.
References
1. Steg PG, Dorman SH, Amarenco P. Atherothrombosis and the
role of antiplatelet therapy. J Thromb Haemost. 2011;9(Suppl
1):325–32.
2. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF Sec-
ondary Prevention and Risk Reduction Therapy for Patients with
Coronary and other Atherosclerotic Vascular Disease: 2011
update: a guideline from the American Heart Association and
American College of Cardiology Foundation. Circulation. 2011;
124(22):2458–73.
3. Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA
Focused Update Incorporated Into the ACC/AHA 2007 Guide-
lines for the Management of Patients With Unstable Angina/Non-
ST-Elevation Myocardial Infarction: a report of the American
College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation. 2011;123(18):
e426–579.
4. Leonardi S, Tricoci P, Becker RC. Thrombin receptor antagonists
for the treatment of atherothrombosis: therapeutic potential of
vorapaxar and E-5555. Drugs. 2010;70(14):1771–83.
5. Angiolillo DJ. The evolution of antiplatelet therapy in the treat-
ment of acute coronary syndromes: from aspirin to the present
day. Drugs. 2012;72:2087–116.
6. Cho JR, Rollini F, Franchi F, et al. Unmet needs in the man-
agement of acute myocardial infarction: Role of novel protease-
activated receptor-1 antagonist vorapaxar. Vasc Health Risk
Manag. 2014;10:177–88.
Vorapaxar: First Global Approval 1161
7. Gurbel PA, Jeong Y-H, Tantry US. Vorapaxar: a novel protease-
activated receptor-1 inhibitor. Expert Opin Investig Drugs. 2011;
20(10):1445–53.
8. FDA. FDA approves Zontivity to reduce the risk of heart attacks
and stroke in highrisk patients. http://www.fdagov/NewsEvents/
Newsroom/PressAnnouncements/ucm396585htm. 2014.
9. Prescribing information. http://www.merckcom/product/usa/pi_
circulars/z/zontivity/zontivity_pipdf. 2014.
10. Merck. Merck Statement on Changes to Clinical Studies of Vo-
rapaxar. Media Release. 2011.
11. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the
secondary prevention of atherothrombotic events. N Engl J Med.
2012;366(15):1404–13.
12. European Medicines Agency. Applications for new human
medicines under evaluation by the Committee for Medicinal
Products for Human Use, January 2014.
13. Merck. New Merck Begins Operations. Media Release. 2009.
14. Kosoglou T, Reyderman L, Kasserra C, et al. Optimizing dose of
the novel thrombin receptor antagonist SCH 530348 based on
pharmacodynamics and pharmacokinetics in healthy subjects.
Clin Pharmacol Ther. 2008;83(Suppl. 1):55.
15. Kosoglou T, Reyderman L, Tiessen RG, et al. Pharmacodynamics
and pharmacokinetics of the novel PAR-1 antagonist vorapaxar
(formerly SCH 530348) in healthy subjects. Eur J Clin Pharma-
col. 2012;68(3):249–58.
16. Storey RF, Kotha J, Smyth S, et al. Effects of vorapaxar on
platelet reactivity and biomarker expression in non-ST-elevation
acute coronary syndromes. The TRACER Pharmacodynamic
Substudy. Thromb Haemost. 2014;111(5):883–91.
17. Kosoglou T, Hunt TL, Xuan F, et al. Effect of the thrombin
receptor antagonist (PAR-1) vorapaxar on QT/QTc interval in
healthy volunteers: A randomized, placebo- and positive-con-
trolled, parallel group trial. Clin Pharmacol Drug Dev. 2014;3(1):
18–24.
18. Ghosal A, Lu X, Penner N, et al. Identification of human liver
cytochrome P450 enzymes involved in the metabolism of SCH
530348 (Vorapaxar), a potent oral thrombin protease-activated
receptor 1 antagonist. Drug Metab Dispos. 2011;39(1):30–8.
19. Kosoglou T, Reyderman L, Tseng J, et al. Effect of food, antacid,
and age on the pharmacokinetics of the oral thrombin receptor
antagonist vorapaxar (sch 530348) in healthy volunteers. Clin
Pharmacol Drug Dev. 2013;2(3):223–30.
20. Behm MO, Kosoglou T, Miltenburg AMM, et al. The absence of
a clinically significant effect of food on the single dose phar-
macokinetics of Vorapaxar, a PAR-1 antagonist, in healthy adult
subjects. Clin Pharmacol Drug Dev. 2013;2(4):310–5.
21. Kosoglou T, Reyderman L, Kasserra C, et al. No differences in
the pharmacodynamics and pharmacokinetics of the thrombin
receptor antagonist vorapaxar between healthy Japanese and
Caucasian subjects. Eur J Clin Pharmacol. 2012;68(3):291–300.
22. Statkevich P, Kosoglou T, Kumar B, et al. Pharmacokinetics of
vorapaxar and its metabolite sch 2046273 (M20) following oral
administration in healthy chinese and us subjects. Clin Pharmacol
Ther. 2012;91:S54.
23. Statkevich P, Kosoglou T, Preston RA, et al. Pharmacokinetics of
the novel PAR-1 antagonist vorapaxar in patients with hepatic
impairment. Eur J Clin Pharmacol. 2012;68(11):1501–8.
24. Kosoglou T, Kraft WK, Kumar B, et al. Pharmacokinetics and
pharmacodynamics of the novel PAR-1 antagonist vorapaxar in
patients with end-stage renal disease. Eur J Clin Pharmacol.
2012;68(7):1049–56.
25. Kosoglou T, Statkevich P, Kumar B, et al. The effect of multiple
doses of ketoconazole or rifampin on the single- and multiple-
dose pharmacokinetics of vorapaxar. J Clin Pharmacol. 2013;
53(5):540–9.
26. Kosoglou T, Zhu Y, Xuan F, et al. Vorapaxar, an oral PAR-1
receptor antagonist, does not affect the pharmacokinetics and
pharmacodynamics of warfarin. Eur J Clin Pharmacol. 2012;
68(11):1509–16.
27. Kosoglou T, Zhu Y, Statkevich P, et al. The influence of multi-
ple-dose vorapaxar, an oral PAR-1 receptor antagonist, on the
single-dose pharmacokinetics and pharmacodynamics of digoxin.
Clin Pharmacol Drug Dev. 2013;2(1):90–8.
28. Bohula May EA, Bonaca MP, Scirica BM, et al. Rates of arterial
revascularization in patients treated with vorapaxar vs. Placebo in
the TRA 2degreeP-TIMI 50 trial. Circulation. 2012;126(21
SUPPL. 1):A19221.
29. Bonaca MP, Scirica BM, Braunwald E, et al. Efficacy of vora-
paxar is not modified by thienopyridine therapy: Results from
TRA 2degreeP-TIMI 50 trial. Circulation. 2012;126(21 SUPPL.
1):A18595.
30. Scirica BM, Bonaca MP, Braunwald E, et al. Vorapaxar for
secondary prevention of thrombotic events for patients with
previous myocardial infarction: a prespecified subgroup analysis
of the TRA 2degreeP-TIMI 50 trial. Lancet. 2012;380(9850):
1317–24.
31. Scirica BM, Bonaca MP, Braunwal E, et al. Vorapaxar for sec-
ondary prevention after myocardial infarction according to aspirin
dose-insights from the TRA2degreep-timi 50 trial. Circulation.
2012;126(21 SUPPL. 1):A14508.
32. Cavender MA, Scirica B, Bonaca MP, et al. Vorapaxar in patients
with diabetes and prior MI: Findings from the TRA 2p-TIMI 50
trial. [abstract no. 10398]. In: American Heart Association Sci-
entific Sessions; 16–20 Nov 2013; Dallas, TX.
33. Morrow DA, Alberts MJ, Mohr JP, et al. Efficacy and safety of
vorapaxar in patients with prior ischemic stroke. Stroke.
2013;44(3):691–8.
34. Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in
patients with peripheral artery disease: results from TRA2{de-
grees}P-TIMI 50. Circulation. 2013;127(14):1522–9, 9e1–6.
35. Bonaca MP, Scirica BM, Braunwald E, et al. Vorapaxar reduces
coronary stent thrombosis: Results from the TRA2P-TIMI 50
trial. Circulation. 2013;128(22 SUPPL. 1):A18928.
36. Bonaca MP, Scirica BM, Braunwald E, et al. New ischemic stroke
and outcomes with vorapaxar vs. Placebo: Results from TRA
2degreeP-TIMI 50 trial. Circulation. 2012;126(21 SUPPL. 1):
A19144.
37. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist
vorapaxar in acute coronary syndromes. N Engl J Med. 2012;
366(1):20–33.
38. Armaganijan L, Lopes R, Huang Z, et al. Efficacy and safety of
vorapaxar in elderly patients with non-st-segment elevation acute
coronary syndrome: Insights from the tracer trial. Circulation Con-
ference: American Heart Association. 2013;128(22 SUPPL. 1).
39. Jones S, Tricoci P, Huang Z, et al. Vorapaxar in non-ST-segment
elevation acute coronary syndrome patients with peripheral artery
disease: Results from tracer. [abstract no. 17939]. In: American
Heart Association Scientific Sessions; 16–20 Nov 2013; Dallas, TX.
40. Mahaffey KW, Huang Z, Wallentin L, et al. Association of
aspirin dose and vorapaxar safety and efficacy in patients with
non-ST-segment elevation acute coronary syndrome (from the
TRACER Trial). Am J Cardiol. 2014;113(6):936–44.
41. Cornel JH, Tricoci P, Horton J, et al. Effects of glycoprotein IIB/
IIIA inhibitors in combination with vorapaxar, a platelet throm-
bin-receptor antagonist, among patients with non-St-segment
elevation acute coronary syndromes: Insights from the tracer trial.
J Am Coll Cardiol. 2013;(1):E102.
42. Tricoci P, Chen E, Neely ML, et al. CYP2C19 polymorphism and
pon-1 activity in NSTE acs: Vorapaxar effect in relation to
clopidogrel metabolism in the tracer trial. [abstract no. 17658].
1162 R. M. Poole, S. Elkinson
In: American Heart Association Scientific Sessions; 16-20 Nov
2013; Dallas, TX.
43. Leonardi S, Tricoci P, White HD, et al. Effect of vorapaxar on
myocardial infarction in the thrombin receptor antagonist for
clinical event reduction in acute coronary syndrome (TRACER)
trial. Eur Heart J. 2013;34(23):1723–31.
44. Tricoci P, Huang Z, Van De Werf F, et al. Net clinical benefit of
vorapaxar in NSTE ACS: Role of ischemic and bleeding risk
stratification. Circulation. 2012;126(21 SUPPL. 1):A19049.
45. Held C, Tricoci P, Huang Z, et al. Vorapaxar, a platelet thrombin-
receptor antagonist, in medically managed patients with non-st-
segment elevation acute coronary syndrome: Results from the
TRACER Trial. Circulation. 2012;126(21 SUPPL. 1):A9964.
46. Valgimigli M, Tricoci P, Huang Z, et al. Vorapaxar, a platelet
thrombin-receptor antagonist, in patients with non-st-segment
elevation acute coronary syndrome undergoing percutaneous
coronary intervention: Results from the tracer trial. Circulation.
2012;126(21 SUPPL. 1):A18805.
47. Whellan DJ, Tricoci P, Chen E, et al. Vorapaxar in acute coro-
nary syndrome patients undergoing coronary artery bypass graft
surgery: subgroup analysis from the TRACER trial (Thrombin
Receptor Antagonist for Clinical Event Reduction in Acute
Coronary Syndrome). J Am Coll Cardiol. 2014;63(11):1048–57.
48. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and toler-
ability of SCH 530348 in patients undergoing non-urgent per-
cutaneous coronary intervention: a randomised, double-blind,
placebo- controlled phase II study. Lancet. 2009;373:919–28.
49. Goto S, Yamaguchi T, Ikeda Y, et al. Safety and exploratory
efficacy of the novel thrombin receptor (PAR-1) antagonist
SCH530348 for non-ST-segment elevation acute coronary syn-
drome. J Atheroscler Thromb. 2010;17(2):156–64.
50. Tricoci P, Huang Z, White HD, et al. Clinical characteristics
associated with major bleeding in NSTE ACS and the relation-
ship between bleeding risk, ischemic events, and the vorapaxar
effect: analysis from the TRACER trial. Eur Heart J. 2012;
33:322.
Vorapaxar: First Global Approval 1163
