DRUG FORECAST
Vorapaxar: Targeting a Novel
Antiplatelet Pathway
Younos Abdulsattar, PharmD, BCPS; Theologia Ternas, PharmD; and Danielle Garcia, PharmD
INTRODUCTION
In the setting of non–ST-segment ele-
vation acute coronary syndromes (NSTE
ACS), optimal management includes
multitiered antithrombotic therapy. Acute
and postcardiac-event antithrombotic
management is focused on the central
role platelets play in thrombosis. Platelets
can be activated by a number of different
agonists, including thromboxane A 2
(TXA2), adenosine diphosphate (ADP),
epinephrine, collagen, and thrombin.1,2
Aspirin irreversibly inhibits cyclo -
oxygenase-1 (COX-1) and impedes the
formation of TXA2, leading to a decrease
in platelet activation and aggregation.1
Clopidogrel irreversibly inhibits the
P2Y12 ADP receptor, also leading to de-
creased platelet activation and aggrega-
tion.3 The concurrent blockade of multi-
ple platelet-aggregating pathways has
been shown to reduce ischemic cardio-
vascular events compared with aspirin
alone in various cardiovascular condi-
tions,2 and yet there is an increase in
bleeding with dual antiplatelet therapy.
At the time of this writing, Dr. Abdulsattar was
Assistant Professor of Pharmacy Practice at
the Arnold & Marie Schwartz College of
Pharmacy, Long Island University, in Brooklyn,
N.Y., and a Drug Information Specialist at
Lenox Hill Hospital in New York, N.Y. Dr. Ter-
nas is Assistant Professor of Pharmacy Prac-
tice at the Arnold & Marie Schwartz College
of Pharmacy and an Internal Medicine/Criti-
cal Care Specialist in the Department of
Pharmacy at Lenox Hill Hospital. Dr. Garcia
is Manager/ Anticoagulation Clinical Phar-
macist in the Department of Pharmacy at
Lenox Hill Hospital. Drug Forecast is a regu-
lar column coordinated by Alan Caspi, PhD,
PharmD, MBA, President of Caspi & Associ-
ates in New York, N.Y.
Disclosure: The authors report no financial
or commercial relationships in regard to this
article.
564 P&T® • September 2011 • Vol. 36 No. 9
Therefore, novel pathways to reduce vorapaxar did not affect the platelet ag-
platelet-mediated thrombosis without gregation induced by ADP, TXA2, or col-
increasing bleeding liability are clinically lagen, nor did it affect prothrombin time
warranted.2,4 or activated partial thromboplastin time.7
Inhibition of thrombin-mediated plate-
let activation may provide an alternate PHARMACOKINETICS AND
pathway for antithrombotic management PHARMACODYNAMICS
with a better safety profile. Thrombin is An orally administered medication, vo-
a potent platelet activator through prote- rapaxar is rapidly and almost completely
olytic activation of cell-surface protease- absorbed via the gastrointestinal tract.
activated receptors (PARs). Four PARs Peak antiplatelet effects are seen within
have been identified: PAR-1, -2, -3, and -4. one to two hours after an oral loading
PAR-1, also known as the thrombin re- dose.2,5,10–12 A clinically insignificant delay
ceptor, is widely expressed in human in absorption and increase in exposure
platelets.2,4–7 were observed with the administration of
The PAR-1 receptor has gained interest food. Moreover, administration of an
since PAR-1 blockade may produce po- antacid yielded a clinically insignificant
tent antiplatelet effects without affecting decrease in exposure and in the maximal
the ability of thrombin to generate fibrin serum concentration. Therefore, vora-
and without inhibiting platelet activation paxar can be administered without con-
by collagen.2,4–6 Theoretically, this alter- sideration of meals or antacid use.2,5,13
nate pathway would block platelet acti- Vorapaxar is metabolized mainly by
vation during clot formation while pre- the cytochrome P450 (CYP) 3A4 en-
ser ving essential vascular repair and zyme. The major route of elimination is
protective hemostatic function.2,4–6 The the feces, with minor renal excretion
PAR-1 receptor is also of interest because (less than 5% of the dose).2 Vorapaxar is
of its role in the vascular repair process in slowly eliminated and has a half-life of
atherosclerotic plaques and in the 159 to 311 hours.2,11 Ethnic differences in
restenosis that often occurs after
percutaneous coronary interven-
tion (PCI).2,6 Currently in phase 3
trials, vorapaxar (SCH 530348,
Schering) may provide an alterna-
tive option in antiplatelet therapy.
PHARMACOLOGY AND
MECHANISM OF ACTION
A synthetic analog of the natural
product himbacine,5,6,8 vorapaxar
(Figure 1) is a novel, orally active,
non-protein, highly selective, com-
petitive PAR-1 inhibitor.2,4,7,9 Vora-
paxar is a thrombin receptor antag-
onist (TRA) that exhibits revers-
ible inhibition (Table 1). It inhibits
thrombin receptor-activating pep-
Figure 1 Chemical structure of vorapaxar.
tide (TRAP)–induced platelet ag-
(From the National Center for Biotechnology
gregation in a dose-dependent
Information, National Institutes of Health.9)
manner.2,5 In preclinical studies,

pharmacokinetics and pharmacodynam-
ics were not observed in Japanese and
Caucasian subjects.14 There is no known
antidote for vorapaxar overdose.5
CLINICAL EFFICACY
Phase 2 Studies
Becker: TRA–PCI Trial15
Becker and colleagues conducted an
international, multicenter, randomized,
double-blind study to assess the safety
and tolerability of vorapaxar in 1,030
patients undergoing non-urgent PCI or
coronary angiography with planned PCI.
The patients were assigned to one of four
loading doses: vorapaxar 10 mg (n = 222),
vorapaxar 20 mg (n = 238), vorapaxar 40
mg (n = 313), or matching placebo (n =
257). Before receiving a loading dose, all
patients were given a dose of aspirin
orally (162–325 mg) or intravenously
(150–500 mg).
Patients were enrolled in the study if
they were 45 years of age or older, had
symptoms of coronary artery disease
(CAD), and were scheduled to undergo
non-urgent PCI or non-urgent coronary
angiography with planned PCI.
Of the 1,030 patients randomly as-
signed to treatment, 573 underwent PCI
and were included in the primary PCI
cohort (n = 129 for vorapaxar 10 mg; n =
120 for vorapaxar 20 mg; n = 173 for vo-
rapaxar 40 mg; and n = 151 for placebo).
All patients in the primary PCI cohort
received unfractionated heparin, low-
molecular-weight heparin, or bivalirudin,
followed by a loading dose of clopidogrel
(300 to 600 mg). A daily maintenance
dose of vorapaxar 0.5 mg (n = 136), vora-
paxar 1.0 mg (n = 139), or vorapaxar 2.5
mg (n = 138) was continued for 60 days
after PCI in the primar y cohort, and
patients were scheduled for return visits
30 days and 60 days after enrollment. A
placebo maintenance dose was given to
patients who had received a placebo load-
ing dose of vorapaxar (n = 149). Eleven
patients in the primary cohort discon-
tinued the study before receiving a main-
tenance dose (reasons unknown). No
maintenance dose was given to patients
who did not undergo PCI (secondary
non-PCI cohort; n = 457); however, these
patients underwent coronary artery by-
pass grafting (CABG) (n = 76) or were
managed medically (n = 381) and were
followed for the remainder of the study.
The primary endpoint was the inci-
DRUG FORECAST
Table 1 Summary of Key Information
Name Vorapaxar (formerly, SCH 530348)
Manufacturer Schering-Plough (now Merck & Co.)
Pharmacologic category Thrombin receptor antagonist
Mechanism of action Inhibits platelet activation via inhibition of PAR-1
Absorption Orally active; absorbed via the GI tract
Metabolism CYP 3A4 enzyme
Elimination Feces (major); renal (< 5%)
Half-life 159 to 311 hours
CYP = cytochrome P450; GI = gastrointestinal; PAR-1 = protease-activated receptor-1.
dence of major or minor bleeding during Platelet aggregation, defined as at least
treatment in the primary PCI cohort, as 80% inhibition of TRAP, was observed in
determined by Thrombolysis in Myo- 42.9% of patients within 120 minutes after
cardial Infarction (TIMI) criteria. Sec- receiving the lowest loading dose of vora-
ondar y endpoints included overt and paxar (10 mg) and in 96.3% of patients
clinically important bleeding not meeting within 120 minutes after receiving the
TIMI criteria for major or minor bleed- highest loading dose (40 mg). At 30 and 60
ing; measures of inhibition of platelet ag- days of maintenance therapy, at least 80%
gregation; and cardiovascular outcomes, of TRAP-induced platelet aggregation was
including death, non-fatal myocardial seen in 90.9% of patients receiving vora-
infarction (MI), and stroke. The primary paxar 0.5 mg daily and in 100% of patients
and secondary endpoints in the second- receiving vorapaxar 1.0 or 2.5 mg daily.
ary non-PCI cohort were TIMI major or In the secondary non-PCI cohort, no
minor bleeding, quantitative chest-tube significant differences in TIMI major or
drainage, the need for transfusion of minor bleeding were noted between
blood products, and the need for surgical placebo and voraxapar (all doses) in both
re-exploration in patients undergoing subgroups: patients undergoing CABG
surgical revascularization. (79% vs. 90%, respectively; absolute dif-
In the primary PCI cohort, the inci- ference in rate: +11.2%; range: –6.9% to
dence of TIMI major or minor bleeding +29.3%) or patients being medically man-
(the primary endpoint) was similar in aged (0% vs. 1%, respectively; absolute
those receiving vorapaxar 10 mg (2/129; difference in rate, +1%; range, –0.2% to
2%), 20 mg (3/120; 3%) or 40 mg (7/173; +2.1%).
4%) compared with patients receiving The authors concluded that treatment
placebo (5/151; 3%) (P = 0.5786). Further, with vorapaxar was well tolerated and
no differences in TIMI major or minor did not result in an increased incidence
bleeding (P = 0.7713) or non-TIMI bleed- of TIMI bleeding among patients with
ing (P = 0.065) were noted when all pla- CAD undergoing PCI and concomitantly
cebo groups and all vorapaxar groups receiving aspirin and clopidogrel.
(loading and maintenance doses) were
compared. The highest dose combination Goto et al.4
tested—a 40-mg loading dose of vora- Goto and associates conducted a multi-
paxar followed by a maintenance dose of center, randomized, double-blind, placebo-
2.5 mg daily—was not linked to TIMI controlled, sequential, parallel-group trial
major bleeding, but TIMI minor bleeding in Japan to assess the safety and efficacy
was observed in two patients (2/58; 3%). of vorapaxar in patients with NSTE ACS
No significant differences were ob- who were receiving standard-of-care
served in death, non-fatal MI, or stroke therapy with planned PCI. The study in-
when placebo was compared with vora- cluded men and women 18 years of age
paxar (all doses) given as either a loading and older with a histor y of ischemic
dose (absolute risk difference, –2.5%; chest discomfort of at least 10 minutes in
range, –7.2% to +2.1%) or a maintenance duration within 24 hours before enroll-
dose (absolute risk difference, –2.8%; ment. Patients were excluded if they
range, –11.5% to +6.0%). were pregnant, had a serious illness, or
Vol. 36 No. 9 • September 2011 • P&T® 565
DRUG FORECAST
used an investigational dr ug within
30 days before study entry. Patients were
also excluded if they had a history of
bleeding diathesis, severe hypertension,
or major surgery within 2 weeks before
study entry; had a platelet count of less
than 100,000/mm3; or had impaired renal
or hepatic function.
A total of 117 patients were randomly
assigned to receive a loading dose of vo-
rapaxar 20 mg, vorapaxar 40 mg, or
placebo not less than one hour before
catheterization. A maintenance dose of
vorapaxar 1.0 mg, vorapaxar 2.5 mg, or
placebo was given for an additional 59
days to patients who initiated PCI (pri-
mary PCI cohort; n = 92). Patients who
did not initiate PCI (n = 25) were classi-
fied as the secondary non-PCI cohort
and were managed medically or under-
went CABG. All patients were receiving
standard-of-care therapy—aspirin, ticlo-
pidine (Ticlid, Roche), and heparin—at
the time of enrollment. The doses of
these medications, however, were not
stated in the published report.
The explorator y efficacy endpoints
included all-cause death and major ad-
verse cardiovascular events (MACE),
which consisted of non-fatal MI, non-fatal
stroke, hospitalization for recurrent is-
chemia, and urgent coronary revascu-
larization. The key safety endpoint was
TIMI major and minor bleeding in the
PCI cohort. TIMI major bleeding was de-
fined as intracranial hemorrhage or clin-
ically significant overt signs of bleeding
associated with a decrease in the hemo-
globin concentration of more than 5 g/dL
(or a decrease in hematocrit of more than
15%). TIMI minor bleeding was defined
as clinically overt signs of bleeding (in-
cluding bleeding detected via imaging)
associated with a decrease in the hemo-
globin concentration of between 3 and
5 g/dL (or a decrease in hematocrit of be-
tween 9% and 15%) that did not other-
wise meet the criteria for major bleeding.
In the primary PCI cohort, the inci-
dence of periprocedural MIs (one com-
ponent of MACE) in patients receiving
vorapaxar plus standard therapy was sig-
nificantly lower compared with that in
patients receiving placebo plus standard
therapy (16.9% vs. 42.9% respectively, P =
0.013). Additional MACE components
(i.e., non-fatal stroke, recurrent ischemia
with hospitalization, or urgent coronary
revascularization) and death did not
566 P&T® • September 2011 • Vol. 36 No. 9
occur in the primary PCI cohort.
TIMI major and minor bleeding oc-
curred in 14% of patients receiving vora-
paxar and in 10% of patients receiving
placebo (point estimate of the difference,
4.6%; 95% confidence interval [CI], –10.4
to +19.5). Clinically important bleeding,
defined as the composite incidence of
intracranial bleeding and bleeding re-
quiring blood transfusion and rehospi-
talization, occurred in five patients (7%)
receiving vorapaxar and in no patients
receiving placebo. Discontinuation re-
sulting from any adverse event (AE) was
observed in 14 of 71 patients (20%) re-
ceiving vorapaxar and in 8 of 21 patients
(38%) receiving placebo.
In the secondary non-PCI cohort, 23 of
25 patients received vorapaxar as a bolus;
three of these patients (13%) experienced
TIMI major bleeding.
The authors concluded that the addi-
tion of vorapaxar to standard therapy was
associated with a significant reduction
in the incidence of periprocedural MI
without an increased risk of bleeding in
Japanese patients with NSTE ACS.
Shinohara et al.16
Shinohara and colleagues conducted a
multicenter, randomized, double-blind,
parallel-group, placebo-controlled study
to evaluate the safety of vorapaxar in
Japanese patients with a history of is-
chemic cerebral infarction receiving
aspirin. A total of 90 subjects received
vorapaxar (1.0 mg or 2.5 mg) or placebo
once daily for a total of 60 days. In addi-
tion to vorapaxar or placebo, all patients
were given daily aspirin at doses ranging
from 75 mg to 150 mg.
The study included patients 18 years of
age or older with stable ischemic stroke
that occurred between 14 days and one
year before randomization with no neu-
rological deficits for at least 24 hours.
Patients were excluded if they had ex-
perienced a cardiogenic cerebral em-
bolism, bleeding diatheses, or an abnor-
mal bleeding episode within 30 days
before study entry; a platelet count of
below 100,000/mm3; or major surgery
within 2 weeks before study entr y.
Patients were also excluded if they had
systolic blood pressure (BP) exceeding
200 mm Hg or diastolic BP exceeding
110 mm Hg; a history of cerebral bleed-
ing or evidence of bleeding on computed
tomography (CT) or magnetic resonance
imaging (MRI); liver enzyme elevations
greater than two times the upper limit of
normal (ULN); or renal dysfunction.
Pregnant women and patients who were
scheduled for carotid or coronary vas-
cular interventions were also excluded
from the study.
The primary endpoint was the overall
incidence of any AE, excluding MACE.
Secondary endpoints included bleeding,
which was categorized as TIMI major
bleeding, TIMI minor bleeding, or clini-
cally important bleeding. Serious AEs
were defined as any AE that caused any
of the following: death; life-threatening,
persistent, or significant disability or
incapacity that required inpatient hospi-
talization or prolonged hospitalization;
congenital anomalies or birth defects; a
reduction in platelet count to less than
50,000/mm3; and other serious events.
The exploratory efficacy endpoints in-
cluded cardiovascular death and MACE.
The overall incidence of any non-
MACE was similar between subjects re-
ceiving vorapaxar and placebo during the
60-day treatment phase (87% [54/62] vs.
79% [22/28], respectively; point estimate
of the difference, 8.5%; 95% CI, –8.8% to
+25.9%). No subjects in the vorapaxar
group experienced TIMI major, TIMI
minor, or clinically important bleeding,
whereas one patient in the placebo group
experienced TIMI minor bleeding (a de-
creased hematocrit level). The incidence
of serious AEs was similar between the
vorapaxar and placebo groups (3% [2/62]
vs. 4% [1/28], respectively). Non-fatal
ischemic stroke occurred in one patient
in the vorapaxar group (1.0 mg) and in
one patient in the placebo group.
The results of this study indicated that
the addition of vorapaxar (1.0 mg or 2.5
mg) once daily to aspirin therapy in
Japanese subjects with a history of is-
chemic stroke was not associated with an
increased risk of bleeding or ischemic
events.
Phase 3 Studies
TRA 2°P–TIMI 50 Trial
(Study Design and Rationale)8,17
The Thrombin-Receptor Antagonist in
the Secondar y Prevention of Athero-
thrombotic Ischemic Events (TRA 2°P)–
TIMI 50 trial is an ongoing phase 3, ran-
domized, mutinational, double-blind,
placebo-controlled, study designed to
evaluate the efficacy and safety of vora-

paxar as long-term therapy in patients
with established atherosclerosis receiv-
ing standard treatment.
Patients were enrolled if they had a
history of atherosclerosis involving the
coronary, cerebral, or peripheral vascu-
lar systems, as evidenced by (1) sponta-
neous (type 1) MI within two weeks to 12
months before enrollment, (2) ischemic
(presumed thrombotic) stroke within
two weeks to 12 months before enroll-
ment, or (3) a history of intermittent clau-
dication in conjunction with an ankle-
brachial index of less than 0.85 or
previous revascularization for limb is-
chemia. Patients with a history of bleed-
ing diathesis, those receiving warfarin,
and those with active hepatobiliary dis-
ease were excluded.
A total of 26,447 patients received
either vorapaxar 2.5 mg or matching
placebo once daily. Randomization was
stratified by the type of disease: CAD,
cerebrovascular disease (CVD), or peri-
pheral vascular disease (PVD). Loading
doses of vorapaxar were not given, be-
cause a rapid onset of effect was not
required in this study’s setting of stable
disease. All other drugs, including anti-
platelet agents, were given at the discre-
tion of the medical staff according to local
treatment guidelines. Follow-up visits
were scheduled at 30 days, 4 months,
8 months, 12 months, and every 6 months
thereafter until completion of the study.
The primary endpoint is a composite
of cardiovascular death, MI, stroke, and
urgent coronary revascularization. The
major secondary endpoint is a composite
of cardiovascular death, MI, and stroke.
The safety of vorapaxar is being deter-
mined by assessing the incidence of
bleeding according to the TIMI, Global
Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded
Coronary Arteries (GUSTO), and Inter-
national Society of Thrombosis and
Hemostasis (ISTH) classification sys-
tems. The study was initiated in Sep-
tember 2007, and a total of 26,447
patients have been enrolled. An interim
analysis of efficacy is planned when ap-
proximately half of the MACE are ac-
counted for.
After reviewing the safety and efficacy
findings, the study’s Data and Safety
Monitoring Board (DSMB) recom-
mended that vorapaxar be immediately
discontinued in patients with history of
stroke or in those who experienced a
stroke during the study period (about
25% of the patients). Therapy with vora-
paxar is being continued in patients who
experienced an MI or PVD. The DSMB’s
recommendation was based on the po-
tential for increased intracranial bleeding
in patients with a history of stroke.
TRA•CER Trial
(Study Design and Rationale)2,17
The Thrombin Receptor Antagonist
for Clinical Event Reduction in Acute
Coronary Syndrome (TRA•CER) trial
was a phase 3, prospective, randomized,
double-blind, multicenter study designed
to examine the role of vorapaxar in addi-
tion to standard care in the management
of patients with high-risk NSTE ACS.
The study planned to enroll and ran-
domly assign 10,000 patients to receive a
40-mg loading dose of vorapaxar or
placebo. A daily maintenance dose of vo-
rapaxar 2.5 mg or placebo was started
the day after randomization and was
planned to continue until the end of the
study or for at least 1 year. Follow-up vis-
its were planned at 30 days, 4 months, 8
months, 12 months, and every 6 months
after the first year for the rest of the study.
The primary efficacy endpoint was a
composite of cardiovascular death, MI,
stroke, recurrent ischemia with rehos-
pitalization, and urgent coronary revas-
cularization. The key secondar y end-
point was a composite of cardiovascular
death, MI, and stroke. Safety was as-
sessed by a composite of moderate and
severe GUSTO bleeding and clinically
significant TIMI bleeding. TRA•CER was
event-driven, and the investigators
planned to continue the trial until 2,334
primary efficacy endpoints and 1,457 key
secondary efficacy endpoints had been
reached. An interim analysis was planned
when approximately half of both the pri-
mary and key secondary efficacy end-
points had been recorded.
As in the TRA 2°P–TIMI 50 trial, the
DSMB reviewed the available safety and
efficacy data and recommended that vo-
rapaxar be immediately discontinued and
the study be terminated. The investiga-
tors stated that they had reached the pre-
defined number of primary and key sec-
ondary efficacy endpoints. However, not
all patients will have received vorapaxar
for the prespecified one-year follow-up
period.
DRUG FORECAST
SAFETY AND TOLERABILITY
Adverse Drug Reactions
Studies of vorapaxar in animals have
shown a range of AEs across the species
studied. In cynomolgus (Macaque) mon-
keys, 1 mg/kg of vorapaxar, alone and in
combination with aspirin 10 mg/kg and
clopidogrel 2 mg/kg, did not increase
postsurgical blood loss.18 Overall, vora-
paxar was generally well tolerated in clin-
ical trials. Adverse drug reactions (ADRs)
seen in a dose-ranging study were mild in
severity; these ADRs included headache,
upper respiratory infection, and fatigue,
none of which were dose-related. No sta-
tistically significant differences in bleed-
ing outcomes were noted when vorapaxar
was compared with placebo.12
In the Becker TRA–PCI study, no in-
crease in TIMI major and minor bleeding
was noted in patients receiving a 40-mg
loading dose of vorapaxar, followed by a
2.5-mg daily maintenance dose, the high-
est dosing regimen studied.15
The TRA 2°P–TIMI 50 trial and the
TRA•CER study were designed to assess
safety outcomes, including bleeding by
GUSTO and TIMI criteria, as well as
ADRs and laboratory abnormalities.2,8 In
press releases from earlier in the year,
Merck announced termination of the
TRA•CER study, with all patients discon-
tinuing the use of vorapaxar. In addition,
at the recommendation of the DSMB,
patients who experienced a stroke before
or after entry into the TRA 2°P–TIMI 50
study were immediately withdrawn from
treatment with vorapaxar. Patients with a
previous MI or PVD (approximately 75%
of enrolled patients) continued to receive
the study drug.17
No other non-bleeding ADRs occurred
more frequently in patients treated with
vorapaxar, even at the highest doses
studied, compared with placebo.
Drug Interactions2,8
Given that vorapaxar is metabolized
primarily by the CYP3A4 enzyme, co-
administration of potent CYP3A4 in -
hibitors (e.g., ketoconazole) may increase
the plasma concentration of vorapaxar. Co-
administration of ketoconazole for 3 weeks
increased vorapaxar exposure by two-
fold. Conversely, potent inducers (e.g.,
rifampin) may reduce plasma concen-
trations of vorapaxar. Coadministration of
vorapaxar and rifampin for 3 weeks re-
duced vorapaxar exposure by 50%.
Vol. 36 No. 9 • September 2011 • P&T® 567
DRUG FORECAST
DOSAGE AND ADMINISTRATION
Phase 1 dose-ranging studies of vora-
paxar examined one-time loading doses
of 5, 10, 20, and 40 mg and maintenance
doses of 0.5, 1.0, and 2.5 mg daily, given
in the morning. Even though both the
20- and 40-mg loading doses of vorapaxar
produced greater than 80% platelet inhi-
bition at one hour, the 40-mg dose did so
in a higher number of patients. Only the
2.5-mg maintenance dose achieved more
than 80% platelet inhibition at day 7.11
Further, the 40-mg loading dose, fol-
lowed by a maintenance dose of 2.5 mg,
was found to effectively inhibit platelets
for up to 28 days.19 These doses were
subsequently used in phase 2 and 3 clin-
ical trials.
Depending on the indication studied,
two dosing regimens of vorapaxar, with
and without a loading dose, have been
evaluated. For NSTE ACS patients with
planned PCI, as well as those with high-
risk features, a 40-mg loading dose, fol-
lowed by a 2.5-mg daily maintenance
dose, has been shown to be safe and ef-
fective.2,15 In patients with established
CAD, vorapaxar 2.5 mg daily without a
loading dose has also been shown to be
safe and effective for secondary preven-
tion of ischemic events.8
COST
The estimated cost of vorapaxar is not
yet available. It is probable, however, that
the price will be additive to that of stan-
dard therapy (i.e., aspirin and clopido-
grel) for the indications studied.
CONCLUSION
Vorapaxar is a competitive and selec-
tive inhibitor of PAR-1. It is metabolized
by the CYP3A4 enzyme, and it interacts
with both CYP3A4 inhibitors (e.g., keto-
conazole) and CYP3A4 inducers (e.g.,
rifampin).
Based on the results of two phase 2
trials, it appears that vorapaxar is well
tolerated when administered orally to
patients undergoing non-urgent PCI,
patients with NSTE ACS who are receiv-
ing standard-of-care antithrombotic ther-
apy and are scheduled for PCI, and
patients with a history of ischemic cere-
bral infarction who are receiving aspirin.
Vorapaxar was not associated with an
increased risk of bleeding when it was
added to standard-of-care therapy.
The efficacy and long-term safety of
568 P&T® • September 2011 • Vol. 36 No. 9
vorapaxar were the focus of two phase 3
studies (TRA 2°P–TIMI 50 and TRA•
CER). Based on recommendations from
the studies’ respective DSMBs, TRA
2°P–TIMI 50 was terminated early in 25%
of the enrolled patients (those who ex-
perienced a stroke before or during the
trial); TRA•CER was terminated in all
patients. The results of the TRA 2°
P–TIMI 50 trial are highly anticipated, as
therapy was continued in patients who
experienced a spontaneous MI or PVD.
It is unclear whether these and future
safety data will delay the FDA’s approval
of vorapaxar, which is expected in 2012.
Additional safety data may be necessary
to ensure appropriate patient selection
before vorapaxar receives final approval.
The health care community eagerly
awaits ongoing updates to the status of
this promising, novel antiplatelet agent.
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1. Anderson JL, Adams CD, Antman EM,
et al. ACC/AHA 2007 guidelines for the
management of patients with unstable
angina/non-ST segment elevation myo-
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50:1–157.
2. The TRA·CER Executive and Steering
Committees. The Thrombin Receptor
Antagonist for Clinical Event Reduction
in Acute Coronary Syndrome (TRA·CER)
trial: Study design and rationale. Am
Heart J 2009;158:327–334.
3. Plavix, package insert. Bridgewater, N.J.:
Bristol Meyers Squibb/Sanofi Pharma-
ceuticals Partnership; February 2011.
4. Goto S, Yamaguchi T, Ikeda Y, et al. Safety
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