Vorapaxar

(1)
General Information
Zontivity (vorapaxar) is a protease-activated receptor-1 (PAR-1) antagonist.
Zontivity is specifically indicated for the reduction of thrombotic cardiovascular events in
patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).
Zontivity is supplied as a tablet for oral administration. The recommended dose is one tablet
(2.08 mg) orally once daily, with or without food.

Clinical Results
FDA Approval
The FDA approval of Zontivity was based on TRA 2°P - TIMI 50. TRA 2°P was a
multicenter, randomized, double-blind, placebo-controlled study conducted in patients who
had evidence or a history of atherosclerosis involving the coronary, cerebral (ischemic
stroke), or peripheral vascular systems. Subjects were randomized to receive daily treatment
with Zontivity (n=13,225) or placebo (n=13,224) in addition to standard of care. The study’s
primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary
revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed
as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years). The findings
in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M
event rate of 11.2% in the Zontivity group compared to 12.4% in the placebo group
(p=0.001). The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier
(K-M) event rate of 9.3% in the Zontivity group compared to 10.5% in placebo group
(p<0.001).

Side Effects
Adverse effects associated with the use of Zontivity may include, but are not limited to, the
following:

 bleeding, including life-threatening and fatal bleeding

Mechanism of Action
Zontivity (varapaxar) is a reversible antagonist of the protease-activated receptor-1 (PAR-1)
expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar
inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet
aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by
adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect
coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell
types, including endothelial cells, neurons, and smooth muscle cells, but the
pharmacodynamic effects of vorapaxar in these cell types have not been assessed.
(2)
Abstract: This article reviews the pharmacology, clinical efficacy, and safety of vorapaxar in
reducing cardiovascular risk. Vorapaxar is a tricyclic himbacine-derived reversible inhibitor
of platelet surface protease activator receptor-1, which prevents thrombin from activating
platelets. Two Phase III clinical trials and multiple subanalyses from the two trials with
vorapaxar have been published. In patients with recent acute coronary syndrome, vorapaxar,
when added to standard therapy, did not reduce the composite cardiovascular end point. In
contrary, in a study of secondary prevention for patients with cardiovascular diseases,
vorapaxar reduced the risk of cardiovascular death or ischemic events (myocardial infarction,
stroke) in patients with stable atherosclerosis who were receiving standard therapy. Vorapaxar
is approved in the US for use with aspirin and/or clopidogrel in the secondary prevention of
thrombogenic cardiovascular events in stable patients with peripheral arterial disease or a
history of myocardial infarction. Vorapaxar increases risk of bleeding and is contraindicated
in patients with previous cerebrovascular events. It is essential to balance individual patient’s
bleeding risk to any further cardiovascular benefits that they may get. Future investigation is
also needed to evaluate use of vorapaxar with newer antiplatelet agents such as ticagrelor and
cangrelor, as well as its role as monotherapy.
Introduction
Cardiovascular diseases, including coronary artery disease (CAD), cerebrovascular disease,
peripheral arterial disease (PAD), are leading causes of morbidity and mortality
worldwide. Atherosclerosis leading to thrombotic occlusion of arteries is the main
pathophysiologic mechanism of these events. Platelets produce vasoactive and prothrombotic
mediators in response to vascular injury, which leads to thrombus formation.
Antiplatelet drug therapies play an important role in cardiovascular disease management.
Aspirin (cyclooxygenase inhibitor) has been well established for primary and secondary
prevention of cardiovascular diseases. Dual antiplatelet therapy (DAPT) with aspirin and
P2Y12 receptor antagonists, such as clopidogrel, prasugrel, and ticagrelor, has been evaluated
to benefit patients with acute coronary syndrome (ACS) and/or those undergoing
percutaneous coronary intervention (PCI). More recently, the first intravenous
P2Y12 inhibitor, cangrelor, has also become available for use in patients undergoing PCI.
Cangrelor provides quick onset of antiplatelet effects and has been demonstrated to
significantly reduce the rate of ischemic events, including stent thrombosis, when used during
PCI. Intravenous glycoprotein IIb/IIIa inhibitors have also been established to be used in
certain high-risk patients undergoing PCI. The development of newer antiplatelet agents
continues because despite all the pharmacotherapeutic advances, the risk of recurrent
ischemic complications among patients with CAD continues to be high. Vorapaxar is among
one of the new classes of antiplatelet agent introduced. Vorapaxar is a protease activator
receptor-1 (PAR-1) antagonist. It is the first in its class. Thrombin interacts with PAR-1 to
generate fibrin formation and subsequently induces platelet aggregation. Vorapaxar was
approved by the US Food and Drug Administration in May 2014 and was launched in the US
for reduction in the risk of recurrent cardiovascular events and cardiovascular death and the
need for revascularization in patients with previous myocardial infarction (MI) or PAD. At
the time of publication, vorapaxar has not yet been launched for use in other countries
(although approved in the European Union). This article reviews the role of vorapaxar in
reducing cardiovascular risk.
Pharmacology
Vorapaxar is a tricyclic himbacine-derived reversible inhibitor of platelet surface PAR-
1. Thrombin is one of the many agonists of platelet activation. Thrombin binds to PAR-1,
cleaves the receptor, and allows it to bind to neighboring thrombin receptor, which
subsequently leads to more platelet activation and aggregation. It is the first drug in its class to
become available in the market. Although vorapaxar binds to PAR-1 reversibly, its long half-
life (terminal half-life ~8 days) makes its effect essentially irreversible.
Vorapaxar is rapidly and completely absorbed after oral administration. The peak plasma
concentration occurs within 1–2 hours. Food has no effect on its oral bioavailability. The
mean volume of distribution of vorapaxar is ~424 L. Vorapaxar is primarily metabolized by
CYP3A4 and CYP2J2 to an inactive metabolite (M19) and an equally potent active metabolite
M20. Vorapaxar and M20 are extensively bound (≥99%) to albumin. Metabolites of
vorapaxar are eliminated by the kidney. There is no unchanged vorapaxar detected in urine.
Vorapaxar exhibits multicompartment pharmacokinetic profile, with an effective half-life of
3–4 days and an apparent terminal elimination half-life of 8 days. Steady-state vorapaxar
serum concentration is achieved by 21 days following once-daily dosing. Because of the
metabolism by CYP3A4, the use of vorapaxar with strong CYP3A inhibitors (eg,
ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, to name a
few) and strong CYP3A inducers (eg, rifampin) should be avoided. A multiple-dose drug
interaction study demonstrated a doubling of steady-state AUC0–24 h and Cmax of vorapaxar
when administered with 400 mg of ketoconazole daily, while rifampin 600 mg daily halved
AUC0–24 h and Cmax of vorapaxar. Factors such as age, race, sex, body weight (<60 kg vs
≥60 kg), moderate renal impairment (creatinine clearance 30–59 mL/min), and moderate
hepatic impairment (Child-Pugh Class B) do not affect pharmacokinetics of vorapaxar. Since
vorapaxar pharmacokinetics has not been defined in patients with severe hepatic impairment,
due to the potential increased risk of bleeding in these patients, the manufacturer does not
recommend its use in this patient population.
Vorapaxar concentrations of 5 mg/mL are necessary to achieve at least 80% blockage of
thrombin receptors. Platelet function recovers after ~28 days of discontinuation of -
vorapaxar. Platelet transfusion or hemodialysis cannot reverse the antiplatelet effect of
vorapaxar. Vorapaxar does not affect measurement of laboratory coagulation parameters.

Clinical trials
Two pivotal clinical trials with vorapaxar have been published to date that help to support the
approval of the drug by the US Food and Drug Administration. Thrombin Receptor
Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) was
designed to evaluate the use of vorapaxar in ACS, and Thrombin Receptor Antagonist in
Secondary Prevention of Atherothrombotic Ischemic Events – Thrombolysis in Myocardial
Infarction 50 (TRA 2P-TIMI 50) was designed to evaluate the role of vorapaxar in secondary
prevention of atherothrombotic events. Table 1summarizes pertinent information on study
design and results.
Table 1 Clinical trials of vorapaxar used in patients with cardiovascular diseases

Notes: P-values calculated using Cox proportional-hazards model.

Abbreviations: TRACER, Thrombin Receptor Antagonist for Clinical Event Reduction in Acute
Coronary Syndrome; TRA 2P-TIMI 50, Thrombin Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events – Thrombolysis in Myocardial Infarction 50; NSTE-ACS, Non-ST-
segment elevation acute coronary syndrome; MI, myocardial infarction; PAD, peripheral arterial disease;
HR, hazard ratio; CI, confidence interval; GUSTO, Global Use of Strategies to Open Occluded Arteries;
TIMI, thrombolysis in myocardial infarction; ICH, intracranial hemorrhage.

TRACER was a randomized, double-blinded, placebo-controlled, multicenter trial evaluating

whether vorapaxar, when added to standard therapy for ACS, would improve cardiovascular
end points. A total of 12,944 patients who presented within 24 hours of non-ST-segment
elevation ACS and who received standard treatment, including aspirin, P2Y12 receptor
antagonist, anticoagulant, and beta-blocker, were included. Patients were randomized to
receiving vorapaxar (40 mg loading dose followed by 2.5 mg daily) or placebo for at least
1 year. The primary efficacy end point was the composite incidence of cardiovascular death,
MI, stroke, recurrent ischemia with hospitalization, and urgent coronary revascularization.
The safety end points for bleeding were assessed using the Global Use of Strategies to Open
Occluded Arteries (GUSTO) and Thrombolysis in Myocardial Infarction (TIMI) classification
systems.
For the primary end point, composite events occurred in 18.5% of patients receiving
vorapaxar versus 19.9% of patients receiving placebo (P=0.07). Rates of the major safety end
point, GUSTO moderate or severe bleeding, were increased by 35% compared to placebo, and
clinically significant TIMI bleeding was increased by 43%. Intracranial hemorrhage (ICH)
occurred in 1.1% of patients with vorapaxar compared to 0.2% with placebo (P<0.001). This
significant increase in ICH led to early termination of the trial. Subgroup analysis showed
higher rates of GUSTO moderate or severe bleeding in patients with lower body weight
(P=0.03).
In a subanalysis of 4,194 patients managed medically (including those who underwent
angiography but without interventions), event rates for primary outcomes were 16.3% with
vorapaxar and 17.0% with placebo (hazard ratio [HR] 0.99, 95% confidence interval [CI]
0.83–1.17). Vorapaxar increased GUSTO moderate or severe bleeding numerically in
medically managed patients (adjusted HR 1.46, 95% CI 0.99–2.15). This is consistent with
the whole population. Similarly, in another subanalysis of patients who underwent PCI, the
efficacy and bleeding are consistent with the overall population. Whether glycoprotein IIb/IIIa
receptor inhibitors were used during PCI did not affect the outcome. In contrary, in another
subanalysis evaluating 1,312 patients with non-ST-segment elevation ACS undergoing
coronary arterial bypass graft (CABG) surgery, vorapaxar was associated with a significant
reduction in ischemic events (45% lower) and no significant increase in major CABG
surgery-related bleeding. Because the number of patients undergoing CABG surgery is small,
randomized trials are needed to confirm the observation. In another subanalysis of 936 (7.2%)
patients who had a history of PAD, the rates of primary end points were similar between
vorapaxar and placebo (21.7% vs 24.8%, P interaction =0.787).
A separate analysis examined the impact of DAPT on vorapaxar bleeding risk. Approximately
87% (11,307) of patients in TRACER were receiving DAPT, with the vast majority receiving
aspirin plus clopidogrel. The use of DAPT was associated with increased bleeding risk when
vorapaxar was added. The impact of aspirin dose was also evaluated. Whether the patients
were receiving ≤100 mg or ≥300 mg aspirin had no impact on the risk of bleeding (adjusted
HR for GUSTO severe bleeding: 1.88 vs 1.63, P=0.954).
The TRA 2P-TIMI 50 is a Phase III clinical trial designed to evaluate the use of vorapaxar for
secondary prevention of atherothrombosis. Patients with a previous history of MI or ischemic
stroke within the previous 2 weeks–12 months or PAD were randomized to receive vorapaxar
2.5 mg daily or placebo. The primary efficacy end point was the composite of cardiovascular
death, MI, and stroke.
After a median follow-up of 24 months, the protocol was amended to exclude patients with a
history of stroke due to an increased risk of ICH in these patients, by 2.5-fold (vorapaxar
2.5% vs placebo 1%, P<0.001). For the primary end point, composite events occurred in 9.3%
patients receiving vorapaxar versus 10.5% patients receiving placebo (P<0.001). Safety in
TRA 2P-TIMI 50 was also evaluated using GUSTO moderate or severe bleeding criteria and
TIMI bleeding criteria. In the whole population, there was significantly more bleeding in
those receiving vorapaxar (4.2% of patients who received vorapaxar vs 2.5% of those who
received placebo; HR 1.66, 95% CI 1.43–1.93, P<0.001). There was an increase in the rate of
ICH in the vorapaxar group (1.0% vs 0.5% in the placebo group, P<0.001). A composite
primary efficacy and GUSTO moderate or severe bleeding safety end points (net clinical
benefit) showed no significant difference between placebo and vorapaxar. The additional
clinical benefit provided by vorapaxar appeared to have been offset by the bleeding risk. The
net clinical outcome was 11.7% in the vorapaxar group and 12.1% in the placebo group
(P=0.40).
A subanalysis was done for the 3,787 patients with a history of PAD. One-third of them were
on a thienopyridine, 11% on cilostazol, and 88% on aspirin for PAD management. Similar to
the rest of the cohort, vorapaxar did not reduce incidence of primary end point (vorapaxar
11.3% vs placebo 11.9%, P=0.53). Vorapaxar, however, significantly reduced ischemic
events in the limbs (vorapaxar 2.3% vs placebo 3.9%, P=0.006) and the need for peripheral
artery revascularization (vorapaxar 18.4% vs placebo 22.2%, P=0.017).
Another prespecified subgroup analysis examined 17,779 patients who were enrolled due to
past history of MI. In all, 98% of patients received aspirin and 78% received thienopyridine at
enrollment. Vorapaxar significantly reduced primary end points as compared to placebo
(vorapaxar 8.1% vs placebo 9.7%, P<0.0001). Specifically examining those patients who had
a previous MI and also diabetes (n=3,623), vorapaxar significantly reduced the primary end
point (vorapaxar 11.4% vs placebo 14.3%, HR 0.73, 95% CI 0.60–0.89, P=0.002). In all these
patient subgroups, bleeding increased with vorapaxar use as compared to placebo, similar to
the rest of the cohort.
In the overall TRA 2P-TIMI 50 trial, ~58% (15,356) of patients were also concurrently on
thienopyridine and 94% (24,734) received aspirin. The use of thienopyridine had no impact
on the risk of GUSTO moderate or severe bleeding. A substudy that evaluated the impact of
aspirin dose also reported no differences in moderate or severe bleeding in those receiving
low (<100 mg), moderate (100–162 mg), or high aspirin doses (>162 mg). The number of
patients receiving high-dose aspirin was small (16%); thus, a firm conclusion cannot be made.

Adverse events
Besides bleeding, based on combined results from TRACER and TRA 2P-TIMI 50, anemia,
depression, and exanthems are some of the most commonly reported side effects, which
occurred in 5%, 2.4%, and 2.2% of patients, respectively.
Patients being considered for vorapaxar should be carefully assessed for overall bleeding risk
versus cardiovascular benefits. Risk factors that can increase bleeding include older age, low
body weight, reduced renal or hepatic function, history of bleeding disorders, and use of
certain concomitant medications (eg, anticoagulants, fibrinolytics, nonsteroidal anti-
inflammatory drugs). Vorapaxar is contraindicated in patients with a history of stroke,
transient ischemic attack, or ICH. Currently, there is no antidote for vorapaxar. Although the
current data suggest that vorapaxar may be safely used perioperatively in patients undergoing
PCI or CABG surgery, the number of patients in the vorapaxar studies undergoing these
procedures is small and further risk evaluation is necessary.
Dosage and administration
Vorapaxar has been approved for use in patients with a history of MI and PAD in the US to
reduce cardiovascular events. The drug is available as 2.5 mg vorapaxar sulfate film-coated
tablets (contains 2.08 mg of vorapaxar). The recommended dose is one tablet daily.
Vorapaxar can be used with aspirin and/or clopidogrel based on standards of care. There is a
lack of clinical data in use of vorapaxar with other antiplatelet drugs or as monotherapy.
Renal impairment or mild-to-moderate hepatic impairment (Child-Pugh Class A or B) does
not require dosage adjustment when using vorapaxar. In patients with severe hepatic
impairment (Child-Pugh Class C), vorapaxar use should be avoided. Vorapaxar is
contraindicated in patients with a history of stroke, transient ischemic attack, ICH, or active
bleeding.
Therapeutic role
Because the risk of recurrent ischemic complications among patients with established CAD
continues to be high, newer antithrombotic agents continue to be developed with an aim to
further optimize the risk. Vorapaxar, when used in patients with cardiovascular diseases who
were receiving standard therapy, reduced the risk of cardiovascular events. However, such
benefits came with increased risk of bleeding, which appeared to offset the benefits. The use
of vorapaxar has not been incorporated into any treatment guidelines to date. The decision in
using vorapaxar should be based on careful balance of individual patients’ bleeding risk and
the further cardiovascular benefits that they may get. If patients experienced recurrent
ischemic events despite optimal standard of therapy, then vorapaxar should be considered
with close monitoring of bleeding complications.
Conclusion
Vorapaxar is a selective and competitive PAR-1 antagonist that inhibits thrombin-induced
platelet aggregation. In patients with recent ACS, vorapaxar, when added to standard therapy,
did not reduce the composite cardiovascular end point. In contrary, in a study of secondary
prevention for patients with cardiovascular diseases, vorapaxar reduced the risk of
cardiovascular death or ischemic events (MI, stroke) in patients with stable atherosclerosis
who were receiving standard therapy. Vorapaxar is approved in the US for use with aspirin
and/or clopidogrel in the secondary prevention of thrombogenic cardiovascular events in
stable patients with PAD or a history of MI. Vorapaxar increases risk of bleeding. The
manufacturer and the US Food and Drug Administration both indicated that the use in
individuals who have an increase in bleeding risk, including elderly patients and patients with
low body weight, requires caution. It is essential to balance individual patient’s bleeding risk
to any further cardiovascular benefits that they may get. Future investigation is also needed to
evaluate the use of vorapaxar with newer antiplatelet agents such as ticagrelor or cangrelor, as
well as its role as monotherapy.

(3)

DRUG TRIALS SUMMARY

What is the drug for?

ZONTIVITY is used to treat people who have had a heart attack or reduced blood flow in
their legs (peripheral arterial disease, PAD). ZONTIVITY is used with aspirin and/or
clopidogrel to lower the patient’s chance of having another serious problem with their heart or
blood vessels, such as heart attack, stroke, or death. It must not be used in people with a prior
stroke, transient ischemic attack (TIA) or intracranial hemorrhage, because ZONTIVITY
increases the risk of bleeding in the brain in these patients.

How do I use this drug?

ZONTIVITY is a pill taken once a day along with aspirin and/or clopidogrel.

What are the benefits of this drug?

Studies showed that ZONTIVITY reduced the rate of heart attack, stroke and cardiovascular
death when compared to a placebo pill. It also reduced the need for emergency procedures in
order to improve blood flow to the heart.

Were there any differences in how well the drug worked in clinical trials among sex,
race and age?
Subgroup analyses were conducted for sex, race and age.
 Sex: ZONTIVITY is similarly effective in men and women.
 Race: Subgroup analyses were conducted, but the number of patients in the non-
Caucasian subgroups was limited. Therefore, differences in response to ZONTIVITY by
race could not be determined.
 Age: ZONTIVITY is similarly effective across all age groups studied.
What are the possible side effects?
The most common side effect of Zontivity during clinical trials was bleeding, which was
observed in 25% of subjects taking ZONTIVITY compared to 17.6% of subjects who were
given a placebo pill (see Table 5). More severe bleeding - bleeding requiring a transfusion -
was reported in 3% of patients taking ZONTIVITY and 2% of patients taking placebo. Less
common side effects included anemia, depression, and rash.
ZONTIVITY increases the risk of bleeding. Therefore, do not take ZONTIVITY if you have
had a stroke or “mini stroke” (also known as transient ischemic attack, or TIA), have had
bleeding in your brain, or currently have unusual bleeding, such as bleeding in your head,
stomach or intestines (an ulcer.)

Were there any differences in side effects among sex, race and age?
Subgroup analyses were conducted for sex, race and age.
 Sex:  The risk of bleeding is higher among women taking ZONTIVITY than men.
 Race: There were too few non-Caucasian patients to make a reliable assessment of
bleeding risk by race.
 Age:  ZONTIVITY increases the risk of bleeding in all age groups. Because older
patients have a higher risk of bleeding in general, there is more bleeding in older patients
taking ZONTIVITY.

WHO WAS IN THE STUDY?

Who participated in the clinical trial?  

The FDA approved ZONTIVITY based on evidence from a clinical trial study of 26,449
patients with a history of heart or blood vessel conditions. The studies were conducted in
North America, Europe, Latin America, Asia/Pacific/Australia/New Zealand, South Africa,
and Israel.

Figure 1 summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

Source: Adapted from FDA Medical Review, Table 24

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial.

Figure 2. Baseline Demographics by Race

Source: Adapted from FDA Medical Review, Table 24

Table 1. Baseline Demographics by Race for the Intent to Treat (ITT) Population

Race Number of Patients Percentage

White 23086 87.3%

Black/African American 689 2.6%

Asian 1194 4.5%

American Indian / Alaska Native 49 0.2%

Multiracial 1390 5.3%

 Native Hawaiian/Pacific Islander 29 0.1%

Missing Data 12 0.05%

Source: Adapted from FDA Medical Review, Table 24

How was the study designed?

ZONTIVITY was approved by the FDA based on a clinical study (TRA 2○ P - TIMI 50,
Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic
Events) of 26,449 patients with a history of myocardial infarction (MI), ischemic stroke, or
peripheral arterial disease (PAD).  Half the patients were randomly assigned to ZONTIVITY
and half were assigned to placebo. Neither the patients nor the health care professionals knew
which patients were taking ZONTIVITY and which ones were taking the placebo until after
the drug trial was complete. Along with the ZONTIVITY or placebo, all patients were to take
aspirin, clopidogrel, or both drugs, and about three-fourths of patients took both. Patients were
followed for up to four years. The primary endpoint of the study was the time to first heart
attack, stroke, cardiovascular death, or urgent procedure to improve blood flow to the heart
(coronary revascularization). An interim analysis revealed that patients who had experienced
an ischemic stroke or TIA prior to entry into the study had an unacceptably increased rate of
intracranial hemorrhage, so a decision was made to discontinue these patients from the study.
Analyses were carried out on all patients randomized, (26,449) but also on the subset of
patients with MI and PAD who had not experienced a stroke or TIA prior to study entry
(20,170).

What are the results of the efficacy study?

ZONTIVITY, taken with aspirin and/or clopidogrel, reduced the rate of heart attack, stroke,
cardiovascular death, and urgent procedures to improve blood flow to the heart (coronary
revascularization) when compared to placebo.

What are the results of the safety study?

Patients taking ZONTIVITY experienced increased moderate or severe bleeding events by
55%.

GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer
specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new
ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is
compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described
in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the
same way as, an active drug or treatment being tested. The effects of the active drug or
 treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets
include sex, race, and age groups.

(4)

ST PAUL, MN — The US Food and Drug Administration has approved vorapaxar (Zontivity,

Merck Sharpe & Dohme), a novel protease-activated receptor 1 (PAR-1) inhibitor, to reduce
the risk of MI, stroke, cardiovascular death, and need for revascularization procedures in
patients with a previous MI or peripheral artery disease[1].
This is a first-in-class approval for this antiplatelet medication.
The approval comes after a January meeting of the Cardiovascular and Renal Drugs Advisory
Committee voted 10 to 1 in favor of approving vorapaxar in this setting. The drug will be
packaged with a boxed warning alerting physicians to the risk of bleeding and is
contraindicated in people who have had a stroke, transient ischemic attack (TIA), or
intracranial hemorrhage because of the increased bleeding risk.
The basis for approval is from the TRA 2°P TIMI-50 clinical trial. Reported
by heartwire when it was presented in 2012 at the American College of Cardiology Scientific
Sessions , the 26 499-patient study showed that time to cardiovascular death, MI, stroke, or
urgent coronary revascularization was reduced by 13% in patients taking 2.5 mg of vorapaxar.
When coronary revascularization was excluded, the secondary end point of cardiovascular
death, MI, or stroke was also significantly reduced.
On the downside, moderate or severe bleeding occurred in 4.2% of patients treated with
vorapaxar compared with 2.5% in the placebo-treated patients, a statistically significant 66%
increase.

(5)

Abstract

Introduction

Despite the current standard of care, patients with cardiovascular disease remain at a high
risk for recurrent events. Inhibition of thrombin-mediated platelet activation through
protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease
beyond those achievable with the current standard of care.
Objective

Our primary objective is to evaluate the clinical literature regarding the role of vorapaxar
(Zontivity™) in the reduction of cardiovascular events in patients with a history of
myocardial infarction and peripheral artery disease. In particular, we focus on the potential
future directions for protease-activating receptor antagonists in the treatment of a broad
range of atherosclerotic diseases.

Data Sources

A literature search of PubMed and EBSCO was conducted to identify randomized clinical
trials from August 2005 to June 2016 using the search terms: ‘vorapaxar’, ‘SCH 530348’,
‘protease-activated receptor-1 antagonist’, and ‘Zontivity™’. Bibliographies were searched
and additional resources were obtained.

Results

Vorapaxar is a first-in-class, protease-activated receptor-1 antagonist. The Thrombin

Receptor Antagonist for Clinical Event Reduction (TRACER) trial did not demonstrate a
significant reduction in a broad primary composite endpoint. However, the Thrombin-
Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA
2°P-TIMI 50) trial examined a more traditional composite endpoint and found a significant
benefit with vorapaxar. Vorapaxar significantly increased bleeding compared with standard
care. Ongoing trials will help define the role of vorapaxar in patients with peripheral arterial
disease, patients with diabetes mellitus, and other important subgroups. The use of
multivariate modeling may enable the identification of subgroups with maximal benefit and
minimal harm from vorapaxar.

Conclusion

Vorapaxar provides clinicians with a novel mechanism of action to further reduce the
burden of ischemic heart disease. Identification of patients with a high ischemic risk and
low bleeding risk would enable clinicians to maximize the utility of this unique agent.

1 Introduction

Cardiovascular diseases (CVDs) represent a significant global public health problem.

According to the World Health Organization, CVDs are the world’s leading cause of death
and disability. Currently, 17 million deaths are attributable to cardiovascular events (CVEs)
annually [1]. Of those, over 75% have atherothrombosis as an underlying pathophysiology:
7.3 million due to ischemic heart disease and 6.2 million due to strokes. Even with early
revascularization and potent dual antiplatelet therapy, residual mortality remains high [ 2].
As a result, assessment of new antiplatelet agents is an expanding research area.

Platelets play a major role in primary hemostasis, vascular repair, and formation of
pathogenic thrombi. Inhibition of platelet activation by aspirin and adenosine diphosphate
(ADP) receptor antagonists decreases platelet aggregation and thus decreases CVEs (Online
Fig. 1) [3]. These agents show long-term benefits in secondary prevention but are associated
with increased bleeding, and the rate of recurrent ischemic events remains high. Targeting
the protease-activated receptor-1 (PAR-1) found on human platelets provides a promising
new mechanism to block platelet activation and decrease the residual risk of CVEs.

Vorapaxar, a first in its class, is an orally available PAR-1 antagonist approved for the
reduction of CVEs in patients with a history of myocardial infarction (MI) or with
peripheral arterial disease (PAD). Vorapaxar reduced the rate of the combined endpoint of
cardiovascular death, stroke, and MI in one of two phase III trials [4, 5]. However, coupled
to this reduction in the primary endpoint is the increased risk of bleeding. This article
outlines the effects of vorapaxar on ischemic and bleeding outcomes as well as its
potentially novel roles in the treatment of atherosclerotic disease.

2 Data Sources

A literature search of PubMed, IPA, OneSearch, and MEDLINE was conducted from June
2008 to June 2016. The search terms ‘vorapaxar’, ‘SCH 530348’, ‘protease-activated
receptor-1 antagonist’, and ‘Zontivity™’ were used. Studies published in English evaluating
vorapaxar were reviewed with an emphasis on randomized controlled trials. Citations from
available articles were retrieved for additional references.

3 Pharmacology

Thrombin, a serine protease, facilitates hemostasis via multiple actions including platelet
activation, protein C activation, and conversion of fibrinogen to fibrin. Thrombin is the most
potent circulating activator of platelets and mediates these effects primarily through activation
of the G-protein-coupled PAR-1 on the platelet surface [6, 7, 8]. Platelet activation through
PAR-1 signaling results in extracellular ADP release, which then acts in an autocrine fashion
to activate platelet ADP receptors, sustaining long-term effects [9].

Vorapaxar (SCH50348) is a potent, oral, reversible thrombin receptor antagonist, which

selectively antagonizes the PAR-1 to prevent thrombin-mediated platelet activation (Online
Fig. 1). Selective PAR-1 blockade by vorapaxar results in inhibition of thrombin-induced
platelet aggregation but does not appear to impact primary hemostatic functions, including the
formation of fibrin to stabilize the platelet plug [10, 11].

4 Pharmacokinetics

In patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS),

vorapaxar rapidly achieves ≥80% inhibition of thrombin receptor-activating, peptide-induced
platelet aggregation by 2 h [12, 13]. Owing to its long half-life of 173–269 h, steady-state
concentrations of vorapaxar are reached approximately 21 days after initial dosing and
platelet inhibition is sustained for >4 months.

Vorapaxar pharmacokinetic parameters are unaffected by food consumption [14, 15]. No

dosage adjustment is needed for patients with end-stage renal failure [16]. While no dosage
adjustment is recommended for mild to moderate hepatic impairment, vorapaxar is not
recommended in patients with severe hepatic failure owing to the increased inherent risk of
bleeding in these patients [17, 18]. Vorapaxar is hepatically metabolized by cytochrome P450
(CYP)3A4 and CYP2J2 enzymes, resulting in the formation of an active metabolite with
equal potency to the parent compound [19]. Vorapaxar is a weak inhibitor of intestinal p-
glycoprotein [20, 21]. Table 1 shows additional pharmacokinetic parameters.
Table 1
Pharmacokinetic parametersa

  Fasted Fedb

Absorption [13]

 Mean C max 23.7 ng/mL 19.4 ng/mL

 Mean AUC0–72 h 323 ng·h/mL 313 ng·h/mL

 Median T max 1.25 h 2.00 h

Distribution [15, 19]

 Mean V d/F 508 L  

 Plasma protein binding ≥99%  

Metabolism [18, 19]

 Primary metabolites

  Metabolites produced: M19 ≫ M20

  M19: inactive amine metabolite formed by carbamate cleavage

  M20: hydroxylated metabolite equipotent with vorapaxar

 Hepatic isoenzymes

  CYP3A4

   Major CYP enzyme responsible for M19 formation

   Primary metabolite of vorapaxar is the M19 metabolite (≈80% of exposure)

  CYP2J2 and CYP3A4

   Responsible for the metabolism of vorapaxar to M20

   Only becomes detectable after long-term administration of vorapaxar

 Elimination

  Metabolites eliminated primarily in feces and, to a much smaller extent, urine

  No unchanged vorapaxar detectable in urine

   Fasted Fedb

Excretion

 Mean CL/F [15] 1.66 L/h  

 Mean half-life [12] 173–269 h  

AUC 0–-72 h area under the plasma concentration–time curve from time 0 to
72 h, CL/Fapparent total body clearance, C max maximum plasma
concentration, CYP cytochrome P450, T max time to maximum plasma
concentration, V d /F apparent volume of distribution
a
Values based on 2.08-mg tablet (equivalent to vorapaxar sulfate 2.50 mg)
b
Fed state after a high-fat meal

5 Drug Interactions

Pharmacokinetic drug interaction studies are few with vorapaxar; however, because vorapaxar
is metabolized by CYP3A4 (alongside CYP2J2), drugs that are inducers or inhibitors of
CYP3A4 will potentially impact the elimination of vorapaxar. Co-administration of
ketoconazole for 3 weeks increased vorapaxar exposure by twofold while co-administration
with rifampin reduced vorapaxar exposure by 50% [22]. Thus, strong inducers or inhibitors of
CYP3A4 should be avoided. Additionally, dose adjustments appear to be unnecessary for
patients on CYP2C9/2C19 substrates [18]. It was determined that vorapaxar is only a weak
inhibitor of p-glycoprotein as evidenced by the fact that vorapaxar had no impact on serum
digoxin concentrations. Thus, no dose adjustment of digoxin is necessary [21]. Concomitant
use of vorapaxar and platelet glycoprotein IIb–IIIa inhibitors should be limited because of the
potential for a pharmacodynamic drug interaction, resulting in a heightened predisposition to
bleeding [23].

6 Current Use of Vorapaxar

Vorapaxar is approved for the reduction of thrombotic CVEs in patients with a history of MI
or with PAD. The current clinical use of vorapaxar is based on two large, randomized clinical
trials conducted in patients with a broad range of vascular diseases. At present, vorapaxar has
limited clinical utility. Multivariate analyses will be required to identify features of patients
with a high ischemic risk and low bleeding risk in whom vorapaxar presents a net clinical
benefit.

7 Clinical Trials Overview

The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial was a
randomized, double-blind, multinational trial comparing vorapaxar (40-mg loading dose
followed by 2.08 mg daily) with placebo, on a background of standard antiplatelet therapy,
in 12,944 patients with NSTE-ACS (Table 2) [4, 24].
Table 2
Phase III vorapaxar clinical trials
  TRACER trial [4, 24]
Population NSTE-ACE
Number of 12,994
patients
Key At least 18 years old
inclusion
criteria Acute symptoms of coronary ischemia
within 24 h prior to hospitalization with at
least one of the following: troponin I or T
level >ULN, creatine kinase MB level
>ULN, new ST-segment depression
>0.1 mV, or transient ST-segment
elevation (<30 min) >0.1 mV in ≥2
contiguous leads. In addition, ≥1 of the
following: >55 years old, previous MI,
PCI, CABG, DM, or PAD
Key Concurrent or anticipated treatment with
exclusion antithrombotics including warfarin, factor
criteria Xa inhibitor, or direct thrombin inhibitor;
concurrent or anticipated treatment with a
potent inducer or inhibitor of CYP3A4
enzymes; active bleeding within the past
30 days; any history of intracranial
hemorrhage; active hepatobiliary disease;
sustained severe hypertension
(SBP ≥200 mm Hg or DBP >100 mm Hg)
within the previous 10 days; serious co-
morbidity
Primary Combination of death from CV causes,
efficacy non-fatal MI, non-fatal stroke, recurrent
endpoint ischemia with rehospitalization, urgent
coronary revascularization
Secondary Combination of death from CV causes,
TRA 2P°-TIMI 50 trial [5, 25]
History of atherosclerosis (MI, ischemic
stroke) or PAD
26,449
At least 18 years old
History of atherosclerosis involving the
coronary, cerebral, or peripheral vascular
systems: CAD—presumed spontaneous
MI ≥2 weeks but ≤12 months prior OR
Cerebrovascular disease—ischemic
(presumed thrombotic) ≥2 weeks
but ≤12 months prior OR
PAD with a history of intermittent
claudication with either ankle-brachial index
of <0.85 or previous revascularization for
limb ischemia
Clinically unstable at time of enrollment;
planned coronary revascularization
procedure; active bleeding within the past
30 days; concurrent or anticipated treatment
with antithrombotics including warfarin,
factor Xa inhibitor, or direct thrombin
inhibitor; concurrent or anticipated
treatment with a potent inducer or inhibitor
of CYP3A4 enzymes; any history of
intracranial hemorrhage; or active
hepatobiliary disease; sustained severe
hypertension (SBP ≥200 mm Hg or
DBP >100 mm Hg) within the previous
10 days; serious co-morbidity
Combination of death from CV causes, non-
fatal MI, non-fatal stroke
Combination of death from CV causes, non-
   TRACER trial [4, 24] TRA 2P°-TIMI 50 trial [5, 25]

efficacy non-fatal MI, non-fatal stroke fatal MI, non-fatal stroke, recurrent
endpoint ischemia with rehospitalization, urgent
coronary revascularization
CABG coronary artery bypass grafting, CAD coronary artery disease, creatine kinase
MBcardiac isozyme of creatine kinase, CV cardiovascular, CYP cytochrome
P450, DBP diastolic blood pressure, DM diabetes mellitus, Hg mercury, MI myocardial
infarction, NSTE-ACEnon-ST-segment elevation acute coronary syndrome, PAD peripheral
artery disease, PCIpercutaneous coronary intervention, SBP systolic blood
pressure, TRACER Thrombin Receptor Antagonist for Clinical Event Reduction, TRA 2°P-
TIMI 50 Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic
Ischemic Events, UNL upper limit of normal

The primary efficacy endpoint of death from cardiovascular causes, MI, stroke, recurrent
ischemia with hospitalization, or urgent coronary revascularization occurred in 1031 of
6473 (18.5%) patients taking vorapaxar and in 1102 of 6371 (19.9%) patients receiving
placebo (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.85–1.01; p = 0.07).
Vorapaxar did reduce the composite endpoint of death from cardiovascular causes, MI, or
stroke compared with placebo (16.4 vs. 14.7%; HR 0.89; 95% CI 0.81–0.98; p = 0.02).
However, cautious interpretation of this secondary endpoint is warranted in light of the non-
significant difference in the primary endpoint.

Vorapaxar, in comparison with placebo, was associated with a significantly increased risk of
bleeding when added to aspirin and a P2Y 12 inhibitor (GUSTO combined moderate and
severe bleeding: 7.2% vorapaxar and 5.2% placebo, p < 0.001; TIMI clinically significant
bleeding: 20.2 vs. 11.7%, p < 0.001). Importantly, intracranial bleeding was increased
fivefold in vorapaxar-treated patients compared with placebo (1.1 vs. 0.2%, p < 0.001). As a
result of this increased risk of intracranial bleeding, an interim safety review in 2011
recommended discontinuation of the trial 6 months prior to the originally planned end date.

The Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic

Events (TRA 2°P-TIMI 50) trial was a phase III, randomized, double-blind, placebo-
controlled, multinational clinical trial created to evaluate the safety and efficacy of
vorapaxar in secondary prevention (Table 2) [5, 25]. There are several important differences
between TRACER and TRA 2°P-TIMI 50. While TRACER enrolled patients during the
acute phase, TRA 2°P-TIMI 50 enrolled 26,449 patients receiving standard care for a broad
range of CVDs, including coronary, cerebrovascular, and peripheral disease. Another
notable difference between these two large phase III trials is the study treatment dosing, as
the loading dose used in TRACER was omitted in TRA 2°P-TIMI 50. Last, the primary
endpoint in TRA 2°P-TIMI 50 was truncated to the composite of cardiovascular death,
nonfatal MI, or nonfatal stroke and did not include recurrent ischemia with re-
hospitalization or urgent coronary revascularization. Once the increased risk of intracranial
bleeding became apparent in the TRACER trial, study treatment was discontinued in all
TRA 2°P-TIMI 50 patients with a prior stroke or transient ischemic attack.

Like TRACER, TRA 2°P-TIMI 50 found a significant reduction in the composite of

cardiovascular death, nonfatal MI, or nonfatal stroke with vorapaxar treatment (9.3 vs.
10.5%; HR 0.87; 95% CI 0.80–0.94; p < 0.001) [5, 25]. However, this risk reduction was
accompanied by an increased risk of GUSTO moderate or severe bleeding (4.2 vs. 2.5%),
TIMI clinically significant bleeding (15.8 vs. 11.1%), and intracranial hemorrhage (1.0 vs.
0.5%) in the vorapaxar group (p < 0.001 for all three assessments).

Together, TRACER and TRA 2°P-TIMI 50 demonstrate that vorapaxar, in addition to

standard antiplatelet therapy, provides an incremental risk reduction by targeting a novel
platelet activation pathway. These two trials also demonstrate that triple antiplatelet therapy
is accompanied by a significant increase in the risk of bleeding. While the goals of
TRACER and TRA 2°P-TIMI 50 were to demonstrate the benefits of PAR-1 antagonism in
a wide range of patients, a net clinical benefit is unlikely to be achieved in the majority of
patients owing to the significant bleeding risk of vorapaxar. However, subsequent re-
analysis of well curated data from these robust clinical trials has provided insight into
subgroups of patients whose risk of atherosclerotic disease justifies the risk of bleeding
(diabetes mellitus) or who lack effective treatment options without vorapaxar (PAD).
Interestingly, vorapaxar was studied in the NSTE-ACS population, which is more
heterogeneous and at an overall lower risk than the STE-ACS population. Furthermore,
head-to-head comparisons between vorapaxar and more potent P2Y 12 antagonists would be
of considerable interest.

8 Future Directions: Potential Clinical Use of Vorapaxar

Although the development of another PAR-1 antagonist, atopaxar, has been discontinued, the
TRACER and TRA 2°P-TIMI 50 studies support a role for vorapaxar in a select group of
patients. Preliminary data suggest that multivariable modeling can be used to identify patients
at a high ischemic risk and low bleeding risk [26]. A meta-analysis which combined phase II
and III clinical trials investigated the overall clinical effects of vorapaxar [27]. Overall,
reductions in MI were offset by a doubling in the risk of intracranial hemorrhage. There was
no significant difference in TIMI major bleeding or cardiovascular mortality.

However, several questions remain to be answered. There is limited evidence on triple therapy
with vorapaxar in addition to aspirin and the more potent platelet antagonists, prasugrel and
ticagrelor. Because of the significant potential for bleeding, this combination therapy should
be avoided with few exceptions. Similarly, whether PAR-1 antagonism provides benefit in
addition to extremely potent ADP receptor inhibition is unknown. An ongoing
pharmacodynamic trial of 126 patients will provide initial data on this combination of platelet
antagonists [28].

Although TRA 2°P-TIMI 50 demonstrated a significant benefit in the reduction of recurrent

ischemic events, the risk of bleeding necessitates careful identification of candidates for this
very potent platelet inhibitor. The inclusion of a heterogeneous cohort of coronary,
cerebrovascular, and PADs necessitates “teasing out”, which subgroups derive the most
benefit and least harm with vorapaxar treatment. In this section, we review the TRACER and
TRA 2°P-TIMI 50 to search for answers to these important questions.

8.1 Peripheral Artery Disease

Patients with PAD are not only at an increased risk for acute limb-threatening events, but also
for systemic manifestations of atherosclerotic disease, such as cardiovascular death, MI, and
ischemic stroke [29, 30]. In the TRA 2°P-TIMI 50 trial, 3787 patients were diagnosed with
PAD, defined as a history of claudication and an ankle-brachial index of <0.85 or prior
revascularization for limb ischemia. Although the primary composite endpoint (which
included coronary, cerebrovascular, and peripheral components) was not significantly reduced
in patients with PAD taking vorapaxar, hospitalization as a result of acute limb ischemia and
peripheral artery revascularization was significantly reduced by vorapaxar (2.3% vorapaxar
vs. 3.9% placebo; p = 0.006 and 18.4% vorapaxar vs. 22.2% placebo; p = 0.017, respectively).
This benefit was offset by a significant increase in the risk of bleeding with vorapaxar (7.4%
vorapaxar vs. 4.5% placebo; p = 0.001) [30].

The TRACER trial did not purposefully target patients with PAD and only 936 (7.2%) such
patients were randomized. While the event rates between vorapaxar and placebo were not
significantly different owing to the small sample size, the overall profile of vorapaxar was
similar to that found in TRA 2°P-TIMI 50: reduced peripheral revascularization procedures
and a lower extremity amputation rate (8.1 vs. 9.0%; p = 0.158 and 0.9 vs. 1.5%; p = 0.107,
respectively). Similarly, GUSTO moderate/severe bleeding was increased with vorapaxar use
in patients with PAD (HR 1.47, 95% CI 0.89–2.45) but not to a greater extent than patients
without PAD (p-interaction = 0.921) [31]. These results indicate that vorapaxar may have a
role in the treatment of PAD, given the lack of effective therapies available. Although a small
phase IV trial is underway to evaluate vorapaxar in this setting, a prospective study is likely
required for vorapaxar to gain an indication specifically for the prevention of acute limb
ischemia or peripheral revascularization [32].

8.2 Diabetes Mellitus

Patients with diabetes, owing to their increased risk of CVEs, may benefit from additional
platelet inhibition with vorapaxar to a greater extent than non-diabetic patients. In diabetic
patients (n = 3623) in TRA 2°P-TIMI 50, the primary endpoint of cardiovascular death, MI,
or cerebrovascular accident occurred more frequently than in non-diabetic patients
(n = 16,896) regardless of randomization (14.1 vs. 7.4%; p < 0.001) [33, 34]. However,
diabetic patients significantly benefited from additional antiplatelet therapy with vorapaxar
with respect to the primary composite endpoint (12.6 vs. 15.7%; p = 0.004). GUSTO
moderate to severe bleeding was increased in diabetic patients with vorapaxar vs. placebo (4.7
vs. 2.8%, HR 1.59, 95% CI 1.09–2.32; p = 0.02). The risk of GUSTO moderate to severe
bleeding was not different with vorapaxar in diabetic and non-diabetic patients (p-
interaction = 0.95). An ongoing phase IV trial is designed to assess the effects of vorapaxar in
addition to dual antiplatelet therapy with aspirin and clopidogrel compared with just dual
antiplatelet therapy alone in diabetic patients [35].

8.3 Coronary Artery Bypass Grafting

The increased risk of thrombotic complications following coronary artery bypass grafting
(CABG) can be attributed to increased thrombin generation, which occurs both during the
procedure and continues after the procedure [36]. Whellan et al. proposed that PAR-1
antagonism could reduce both graft occlusion and native coronary thrombosis after CABG
[37]. Among 1312 patients undergoing CABG during the TRACER trial (vorapaxar, n = 639
and placebo, n = 673), vorapaxar significantly reduced ischemic events compared with
placebo (HR 0.55, 95% CI 0.36–0.83; p = 0.005). Bleeding related to CABG during
hospitalization did not differ significantly between vorapaxar and placebo (GUSTO moderate
to severe bleeding: odds ratio 1.25, 95% CI 0.93–1.68; p = 0.13; TIMI major bleeding: odds
ratio 1.36, 95% CI 0.92–2.02; p = 0.12) [4, 37]. Hence, in patients with NSTE-ACS
undergoing CABG, vorapaxar was associated with a significant decrease in ischemic events.
Notably, clopidogrel was used in only 18% of patients undergoing CABG vs. 85% in non-
CABG. It is possible that the increase in bleeding events was not seen in this subgroup owing
to the infrequent use of clopidogrel.

8.4 Stroke

Vorapaxar is strictly contraindicated in patients with a history of stroke or transient ischemic

attack because of a significant increase in the risk of intracranial bleeding. Among TRA 2°P-
TIMI 50 patients with prior stroke, recurrent stroke was not reduced by vorapaxar (10.1%
vorapaxar vs. 7.5% placebo, HR 1.13, 95% CI 0.90–1.40; p = 0.30), and GUSTO moderate or
severe bleeding was higher in the vorapaxar group (4.2% vorapaxar vs. 2.4% placebo, HR
1.93, 95% CI 1.33–2.79; p < 0.001) [5, 38]. Importantly, intracranial bleeding was
significantly increased in the vorapaxar group, including subdural or epidural bleeding (2.5%
vorapaxar vs. 1.0% placebo; p < 0.001). Fatal bleeding was numerically higher for vorapaxar
vs. placebo but not statistically significant (8 vs. 4; p = 0.26). However, a more recent study
demonstrates that vorapaxar may provide effective stroke prevention in patients without a
history of prior stroke [39].

8.5 Background Antiplatelet Therapy

Vorapaxar may have greater efficacy in patients treated with aspirin alone compared with
aspirin plus a P2Y12 inhibitor [4]. In TRACER patients treated with clopidogrel (91.8% of all
patients), the risk of GUSTO moderate or severe bleeding was increased significantly
compared with those treated with aspirin alone (HR 0.95, 95% CI 0.65–1.40 with no
thienopyridine and HR 1.45, 95% CI 1.23–1.71 with thienopyridine; p-interaction = 0.04)
[40, 41].

In TRA 2°P-TIMI 50, dual antiplatelet therapy was less common than in TRACER (58% of
all patients) [42]. Thienopyridines were intentionally used in 15,256 patients (58%) overall.
There was no significant difference in the reduction of the primary endpoint between
vorapaxar with thienopyridine and vorapaxar with no thienopyridine (p-interaction = 0.64).
Compared with TRACER, GUSTO moderate to severe bleeding was increased with
vorapaxar in TRA 2°P-TIMI 50, but there was no significant interaction based on current (p-
interaction = 0.29) or prior (p-interaction = 0.99) thienopyridine use. Vorapaxar decreased the
risk of CVD, MI, or stroke in stable patients with a history of CVD with or without
thienopyridines [42, 43]. In both TRACER and TRA 2°P-TIMI 50, few patients were
receiving more potent P2Y12 inhibition with prasugrel or ticagrelor. The interaction between
aspirin dose and the efficacy and safety profile of vorapaxar was investigated in both
TRACER and TRA 2°P-TIMI 50. Aspirin dose did not modify the efficacy or safety profile
significantly in either study [4, 5].

Because vorapaxar has been documented to increase bleeding risks, healthcare professionals
must be cognizant of a patient’s general underlying bleeding risk. General risk factors for
bleeding include older age, low body weight, reduced renal or hepatic function, history of
bleeding disorders, and use of other drugs that impact the coagulation pathways. Vorapaxar
should be used cautiously or not at all in these patients. The patients who have a high
ischemic risk coupled with a low bleeding risk will benefit most from the addition of
vorapaxar to standard care [26].
9 Conclusion

The residual risk of atherosclerotic events in patients with coronary, cerebrovascular, and
PAD remains unacceptably high, even after revascularization and treatment with potent
platelet ADP receptor antagonists. Vorapaxar, the only available PAR-1 antagonist, may
provide clinicians with an effective treatment for patients with strong risk factors, such as
diabetes. Similarly, vorapaxar may represent a novel approach to the treatment of PAD. The
major limitation to vorapaxar therapy is bleeding, as expected with antiplatelet therapy.
However, vorapaxar may meet the requirements of patients who need additional therapy to
reduce the risk for CVEs.