Vorapaxar (Zontivity®): A Comprehensive Monograph on a First-in-Class PAR-1 Antagonist

Executive Summary

Vorapaxar, marketed under the brand name Zontivity®, represents a novel therapeutic class as a first-in-class, orally bioavailable protease-activated receptor-1 (PAR-1) antagonist. It is a synthetic organic small molecule derived from the natural product himbacine, designed to inhibit platelet aggregation by targeting a pathway distinct from that of traditional antiplatelet agents such as aspirin and P2Y12 inhibitors. The primary mechanism of action involves the selective and potent antagonism of PAR-1, the main receptor for thrombin on human platelets. By blocking this receptor, Vorapaxar effectively prevents thrombin-mediated platelet activation, a key step in the formation of atherothrombotic clots.

The clinical development of Vorapaxar was defined by the landmark Phase III trial, TRA 2°P-TIMI 50, which evaluated its efficacy and safety in over 26,000 patients with stable atherosclerosis. While the drug demonstrated a statistically significant reduction in the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke in the overall population, this benefit was accompanied by a significant increase in major bleeding, including a doubling of the risk of intracranial hemorrhage (ICH). A critical pre-specified subgroup analysis revealed a stark dichotomy in the drug's risk-benefit profile: in patients with a prior history of stroke or transient ischemic attack (TIA), Vorapaxar conferred net harm, increasing the risk of ICH without providing ischemic benefit. Conversely, in the population of patients with a history of MI or peripheral arterial disease (PAD) and no prior history of cerebrovascular events, Vorapaxar, when added to standard antiplatelet therapy, significantly reduced the risk of major adverse cardiovascular events with an acceptable, though still elevated, bleeding risk.

This pivotal finding led to a highly specific approved indication by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular events exclusively in post-MI or PAD patients without a history of stroke or TIA. The drug carries a Black Box Warning highlighting this contraindication and the general risk of serious, potentially fatal bleeding. Vorapaxar's pharmacokinetic profile is characterized by excellent oral bioavailability, extensive metabolism by CYP3A4 and CYP2J2, and an exceptionally long half-life of approximately 8 days. This prolonged half-life results in a functionally irreversible antiplatelet effect, for which there is no reversal agent, posing a significant challenge in the management of acute bleeding events. The clinical utility of Vorapaxar is therefore contingent upon a rigorous patient selection process, where the primary consideration is the minimization of hemorrhagic risk. The drug's regulatory journey, which saw approval in the United States but a subsequent withdrawal of marketing authorization in the European Union, underscores the global challenges in integrating a potent antithrombotic agent with such a narrow therapeutic index into clinical practice. Vorapaxar remains an important, albeit niche, therapeutic option that exemplifies the critical balance between ischemic benefit and hemorrhagic risk in the long-term management of atherothrombotic disease.

Introduction: A Novel Antiplatelet Agent

The management of atherothrombotic disease relies heavily on antiplatelet therapy to mitigate the risk of ischemic events such as myocardial infarction and stroke. For decades, the therapeutic armamentarium has been dominated by agents that inhibit cyclooxygenase-1 (e.g., aspirin) and the P2Y12 adenosine diphosphate (ADP) receptor (e.g., clopidogrel, prasugrel, ticagrelor).[1] Despite the proven efficacy of these agents, patients with established atherosclerosis remain at a significant residual risk for recurrent thrombotic events, highlighting an unmet clinical need for therapies targeting alternative pathways of platelet activation.[1]

Vorapaxar (Zontivity®) emerged as a direct response to this need, introducing a fundamentally new mechanism to the field of antiplatelet medicine.[2] It is the first-in-class, orally active antagonist of the protease-activated receptor-1 (PAR-1).[4] This mechanism is of particular significance because PAR-1 is the primary receptor for thrombin on the surface of human platelets, and thrombin is widely considered the most potent endogenous activator of platelets.[2] By selectively blocking this pathway, Vorapaxar was designed to offer additional antithrombotic protection on top of standard-of-care therapy, without interfering with the pathways targeted by aspirin or P2Y12 inhibitors.[3]

The chemical origins of Vorapaxar lie in natural product chemistry, a historically rich source of drug discovery. Its structure is a synthetic modification of himbacine, a complex tricyclic alkaloid, representing a successful translation of a natural scaffold into a targeted therapeutic agent.[4] The therapeutic premise was compelling: to specifically inhibit the powerful thrombin-mediated component of platelet aggregation, thereby reducing the incidence of cardiovascular events in high-risk secondary prevention populations.[7]

However, the clinical development journey of Vorapaxar illustrates the profound challenges inherent in developing first-in-class agents that target fundamental physiological pathways. The very novelty and potency that offered the promise of enhanced efficacy also carried an intrinsic and significant liability. Early clinical trials showed promise, but the large-scale Phase III program revealed a substantial increase in the risk of major bleeding, a consequence of inhibiting such a critical component of hemostasis.[14] This duality of potent efficacy and significant risk became the defining characteristic of the drug. The initial vision of a broadly applicable antiplatelet agent was ultimately tempered by the clinical reality of its safety profile, leading to a highly restricted indication for a carefully selected patient population. Vorapaxar's story is thus a compelling case study in the high-stakes nature of pharmaceutical innovation, where a deep understanding of a novel mechanism's role in both pathology and normal physiology is paramount, and where the true balance of risk and benefit is often only fully revealed in large, definitive clinical trials.

Chemical Profile and Physicochemical Properties

The precise identification and characterization of a pharmaceutical agent are foundational to its study and clinical application. Vorapaxar is a well-defined small molecule with a complex structure derived from a natural product scaffold. Its chemical and physical properties have been extensively documented across chemical databases and regulatory filings.

Nomenclature and Identifiers

To ensure unambiguous identification, Vorapaxar is cataloged under a variety of names and codes that reflect its developmental history and chemical structure.

• Generic Name: Vorapaxar [16]
• Brand Name: Zontivity® [4]
• Developmental Codes: The compound was initially developed by Schering-Plough as SCH 530348 and later by Merck & Co. as MK-5348.[4]
• Systematic (IUPAC) Name: The formal chemical name, reflecting its complex stereochemistry and functional groups, is ethyl N-ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f]benzofuran-6-yl]carbamate.[9] Variations in nomenclature exist across databases but describe the same molecule.[9]
• Unique Database Identifiers: Key identifiers used in global databases include:
• DrugBank ID: DB09030 [9]
• CAS Number: 618385-01-6 [9]
• ChEMBL ID: CHEMBL493982 [9]
• PubChem CID: 9869894 [9]
• UNII: ZCE93644N2 [9]

Molecular and Structural Formulae

The molecular composition and three-dimensional arrangement of atoms are defined by its chemical formula and structural representations.

• Chemical Formula: The empirical formula for Vorapaxar is C29​H33​FN2​O4​.[9]
• Molecular Weight: The calculated molecular weight is approximately 492.58 g/mol.[10]
• Structural Representations: For computational and database purposes, the structure is unambiguously represented by:
• SMILES: CCOC(=O)N[C@@H]1CC[C@@H]2[C@@H](C1)C[C@@H]3[C@H]([C@H]2/C=C/C4=NC=C(C=C4)C5=CC(=CC=C5)F)[C@H](OC3=O)C [9]
• InChI: InChI=1S/C29H33FN2O4/c1-3-35-29(34)32-23-10-11-24-20(14-23)15-26-27(17(2)36-28(26)33)25(24)12-9-22-8-7-19(16-31-22)18-5-4-6-21(30)13-18/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34)/b12-9+/t17-,20+,23-,24-,25+,26-,27+/m1/s1 [9]
• InChIKey: ZBGXUVOIWDMMJE-QHNZEKIYSA-N [9]

Physicochemical Properties and Drug Class

Vorapaxar's classification and physical characteristics are critical for understanding its formulation and behavior in vivo.

• Drug Type: Vorapaxar is classified as a Small Molecule drug.
• Chemical Class: It is a synthetic organic compound belonging to multiple chemical classes, including pyridines, carbamate esters, organofluorine compounds, naphthofurans, and lactones, reflecting its complex, polycyclic structure.[9]
• Solubility: It exhibits solubility in organic solvents such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) at concentrations of 30 mg/mL, with limited solubility in aqueous buffers like DMSO:PBS (pH 7.2) at 0.5 mg/mL.[18]
• Calculated Properties: Computational analysis of its structure provides insight into its drug-like properties. It has 1 hydrogen bond donor, 6 hydrogen bond acceptors, and 7 rotatable bonds. Its high calculated lipophilicity (XLogP or AlogP values > 5) results in one violation of Lipinski's Rule-of-Five, a common feature for drugs targeting complex receptor binding pockets.[11]

The following table (Table 1) consolidates the key identifying and chemical properties of Vorapaxar for ease of reference.

Table 1: Summary of Vorapaxar Identification and Chemical Properties

Property	Value	Source(s)
Generic Name	Vorapaxar	16
Brand Name	Zontivity®	4
DrugBank ID	DB09030	9
CAS Number	618385-01-6	9
ATC Code	B01AC26	17
Drug Class	Protease-Activated Receptor-1 (PAR-1) Antagonist	16
Chemical Formula	C29​H33​FN2​O4​	9
Molecular Weight	492.58 g/mol	10
IUPAC Name	ethyl N-ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f]benzofuran-6-yl]carbamate	9
SMILES	CCOC(=O)N[C@@H]1CC[C@@H]2[C@@H](C1)C[C@@H]3[C@H]([C@H]2/C=C/C4=NC=C(C=C4)C5=CC(=CC=C5)F)[C@H](OC3=O)C	9
InChIKey	ZBGXUVOIWDMMJE-QHNZEKIYSA-N	9

Clinical Pharmacology: The Mechanism of PAR-1 Antagonism

The therapeutic effect of Vorapaxar is derived from its unique and highly specific mechanism of action as a competitive antagonist of Protease-Activated Receptor-1 (PAR-1). This mode of action distinguishes it from all other classes of antiplatelet agents and targets a central pathway in thrombosis.

Primary Mechanism of Action

Vorapaxar functions as a selective and potent antagonist of PAR-1, a G-protein-coupled receptor that serves as the primary thrombin receptor on the surface of human platelets.[2] Thrombin is a serine protease that plays a dual role in hemostasis, catalyzing the conversion of fibrinogen to fibrin and acting as the most potent activator of platelets.[2] It activates PAR-1 by cleaving the receptor's extracellular N-terminus, which unmasks a new N-terminal sequence that acts as a "tethered ligand," binding to the receptor to initiate intracellular signaling and subsequent platelet activation and aggregation.[1]

Vorapaxar binds to the PAR-1 receptor with high affinity, indicated by an inhibition constant (Ki​) of 8.1 nM.[10] By occupying the receptor, it physically prevents thrombin from binding and cleaving it, thereby inhibiting the entire downstream signaling cascade. This results in potent inhibition of platelet aggregation induced by both thrombin and thrombin receptor agonist peptide (TRAP), a synthetic peptide that mimics the action of the tethered ligand.[3]

Selectivity of Action

A defining feature of Vorapaxar's pharmacology is its high degree of selectivity. Its inhibitory action is confined to the PAR-1 pathway. Clinical and ex vivo studies have consistently demonstrated that Vorapaxar does not inhibit platelet aggregation induced by other key agonists, including adenosine diphosphate (ADP), collagen, or thromboxane mimetics.[3] This specificity is clinically important because it means Vorapaxar can be added to standard antiplatelet regimens (aspirin and/or P2Y12 inhibitors) to provide an additional, complementary mechanism of platelet inhibition.

Furthermore, Vorapaxar does not directly interfere with the coagulation cascade. It has no effect on standard coagulation parameters such as prothrombin time (PT), activated partial thromboplastin time (aPTT), or bleeding time.[4] This distinguishes it from anticoagulants like warfarin or direct oral anticoagulants, which act on clotting factors. Vorapaxar's effect is purely antiplatelet, targeting the initial phase of thrombus formation.

Functional Irreversibility and Duration of Effect

The clinical behavior of Vorapaxar is dominated by an interplay between its pharmacodynamic and pharmacokinetic properties. At the molecular level, Vorapaxar is a reversible antagonist, meaning it can dissociate from the PAR-1 receptor.[3] However, this molecular characteristic is rendered clinically irrelevant by the drug's exceptionally long pharmacokinetic profile. Vorapaxar has an effective half-life of 3-4 days and a terminal elimination half-life of approximately 8 days.[1]

This slow clearance from the body ensures that even as individual drug molecules dissociate from the receptor, a high plasma concentration is maintained, leading to immediate re-binding and sustained, near-complete receptor blockade. The practical consequence is that the drug's antiplatelet effect is functionally irreversible in a clinical context.[3] This sustained action is demonstrated by the observation that potent inhibition of platelet aggregation (≥80%) is achieved within a week of starting therapy and persists long after the drug is stopped; 50% inhibition of TRAP-induced platelet aggregation is still measurable four weeks after discontinuation.[3] This pharmacokinetic dominance has profound clinical implications: there is no known reversal agent, and temporarily withholding the drug for a few days is ineffective in managing an acute bleeding event because the antiplatelet effect persists for weeks.[4]

Potential Non-Platelet Effects

While the primary therapeutic benefit of Vorapaxar is attributed to its antiplatelet activity, the expression of PAR-1 on other cell types suggests the potential for non-platelet-mediated effects. PAR-1 is also found on vascular endothelial cells, smooth muscle cells, fibroblasts, and cardiac myocytes.[3] On these cells, thrombin-mediated activation of PAR-1 is known to be mitogenic, promoting cell proliferation and potentially contributing to vascular remodeling and the progression of atherosclerosis.[13]

This hypothesis is supported by findings from the TRA 2°P-TIMI 50 trial, where in the cohort of patients with peripheral artery disease (PAD), Vorapaxar significantly reduced the rates of hospitalization for acute limb ischemia and the need for peripheral artery revascularization.[13] While a reduction in acute limb events can be explained by its antiplatelet effect, the reduction in the need for all revascularizations, including non-urgent procedures, suggests a possible long-term effect on the underlying disease process. It is plausible that by antagonizing PAR-1 on vascular cells, Vorapaxar may attenuate the mitogenic signaling of thrombin, thereby reducing vascular remodeling and improving perfusion over time.[13] This remains a compelling area for further research but is not a proven mechanism or an approved indication.

Pharmacokinetics, Metabolism, and Disposition (ADME)

The clinical pharmacology of Vorapaxar is profoundly influenced by its pharmacokinetic profile, particularly its high bioavailability and exceptionally long half-life. Understanding how the body absorbs, distributes, metabolizes, and excretes the drug is essential for its safe and effective use.

Absorption

Vorapaxar is well-absorbed following oral administration, with characteristics that support convenient once-daily dosing.

• Bioavailability: The mean absolute oral bioavailability is approximately 100%, as determined from a micro-dosing study, indicating complete absorption from the gastrointestinal tract.[3]
• Time to Peak Concentration (Tmax​): Absorption is rapid, with peak plasma concentrations (Cmax​) occurring at a median of 1 hour (range: 1 to 2 hours) after oral administration under fasted conditions.[1]
• Food Effect: The administration of Vorapaxar with a high-fat meal does not result in a meaningful change in the overall systemic exposure (Area Under the Curve, AUC). There is a small (21%) decrease in Cmax​ and a 45-minute delay in Tmax​, but these changes are not considered clinically significant. Consequently, Vorapaxar may be administered with or without food.[3]

Distribution

Once absorbed, Vorapaxar distributes extensively throughout the body and is highly bound to plasma proteins.

• Volume of Distribution (Vd​): The mean volume of distribution is large, estimated at approximately 424 to 508 liters. This high value indicates extensive distribution from the plasma into peripheral tissues.[1]
• Plasma Protein Binding: Both Vorapaxar and its major active metabolite, M20, are extensively bound (≥99%) to human plasma proteins, primarily serum albumin. The drug does not preferentially distribute into red blood cells.[1]

Metabolism

Vorapaxar is eliminated almost entirely through hepatic metabolism, a process mediated by the cytochrome P450 (CYP) enzyme system. This metabolic pathway is the primary source of clinically significant drug-drug interactions.

• Primary Pathway and Enzymes: Vorapaxar is metabolized in the liver, principally by CYP3A4 and, to a lesser extent, CYP2J2.[1] The major role of CYP3A4 makes Vorapaxar's plasma concentrations susceptible to alteration by potent inhibitors or inducers of this enzyme.
• Metabolites: The metabolic process yields two key metabolites. The major active circulating metabolite is M20 (a monohydroxy metabolite), which is equipotent to the parent drug. At steady state, M20 accounts for approximately 20% of the total drug-related exposure.[1] The predominant metabolite identified in excreta is M19 (an amine metabolite formed by carbamate cleavage), which is inactive.[1]

Excretion

The metabolites of Vorapaxar are primarily eliminated from the body via the feces.

• Route of Elimination: Following a radiolabeled dose, the primary route of elimination is through the feces, accounting for approximately 58% of the administered radioactivity. A smaller portion (25%) is recovered in the urine. Unchanged Vorapaxar is not detected in the urine, indicating that elimination is dependent on metabolism.[1]
• Half-Life: Vorapaxar exhibits a multi-exponential disposition. Its effective half-life, which correlates with the duration of its pharmacodynamic effect, is 3-4 days. The apparent terminal elimination half-life is significantly longer, averaging 8 days (with a range of 5-13 days).[1] This long terminal half-life is responsible for the prolonged antiplatelet effect observed for weeks after discontinuation.
• Time to Steady State: Due to its long half-life, steady-state plasma concentrations are achieved after approximately 21 days of once-daily dosing, with an accumulation of 5- to 6-fold.[1]

Table 2 provides a summary of the key pharmacokinetic parameters for Vorapaxar.

Table 2: Key Pharmacokinetic Parameters of Vorapaxar

Parameter	Value	Clinical Implication	Source(s)
Absolute Bioavailability	~100%	Complete and reliable absorption after oral dosing.	3
Time to Peak (Tmax​)	~1 hour (fasted)	Rapid onset of exposure.	1
Food Effect	No clinically significant effect on AUC.	Can be taken with or without food, enhancing patient convenience.	3
Volume of Distribution (Vd​)	~424 L	Extensive distribution into tissues.	1
Plasma Protein Binding	≥99%	High binding, low free fraction; potential for displacement interactions is low.	1
Primary Metabolizing Enzymes	CYP3A4, CYP2J2	High potential for drug-drug interactions with strong CYP3A4 inhibitors/inducers.	1
Active Metabolite	M20 (monohydroxy metabolite)	Contributes ~20% of total exposure and is equipotent to parent drug.	1
Route of Elimination	Primarily fecal (as metabolites)	Elimination is dependent on hepatic metabolism.	1
Effective Half-Life	3-4 days	Correlates with the duration of near-maximal platelet inhibition.	3
Terminal Half-Life	~8 days (range 5-13)	Responsible for the prolonged antiplatelet effect lasting weeks after discontinuation; dictates the lack of a short-term reversal strategy.	3

Clinical Efficacy: Analysis of the TRA 2°P-TIMI 50 Trial

The clinical evidence supporting the use of Vorapaxar is derived almost exclusively from a single, large-scale, pivotal clinical trial: the TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50). This trial was not only instrumental in defining the drug's efficacy but also crucial in identifying the specific patient population in whom the benefits outweigh the risks.[13]

Trial Design and Population

TRA 2°P-TIMI 50 was a multinational, randomized, double-blind, placebo-controlled event-driven trial that enrolled 26,449 patients with stable atherosclerotic vascular disease.[13] Patients were eligible if they had a qualifying history of one of the following:

1. Myocardial Infarction (MI): Spontaneous MI within the prior 2 weeks to 12 months.
2. Ischemic Stroke: Ischemic stroke within the prior 2 weeks to 12 months.
3. Peripheral Artery Disease (PAD): Symptomatic PAD with a history of intermittent claudication and an ankle-brachial index <0.85 or a history of prior revascularization for limb ischemia.[13]

Participants were randomly assigned in a 1:1 ratio to receive either vorapaxar sulfate 2.5 mg (equivalent to 2.08 mg of vorapaxar free base) once daily or a matching placebo.[24] The study drug was administered in addition to standard-of-care antiplatelet therapy, which included aspirin and/or a thienopyridine (primarily clopidogrel).[15] The median follow-up duration was 30 months (2.5 years).[7]

Primary Efficacy and Safety Endpoints

The trial was designed to assess the trade-off between reducing ischemic events and increasing bleeding.

• Primary Efficacy Endpoint: The composite of cardiovascular (CV) death, MI, or stroke.[13]
• Principal Safety Endpoint: Moderate or severe bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria.[13]

Results in the Overall Population

In the overall study population of 26,449 patients, Vorapaxar demonstrated a statistically significant reduction in the primary efficacy endpoint. The composite of CV death, MI, or stroke occurred in 9.3% of patients in the vorapaxar group compared to 10.5% in the placebo group (Hazard Ratio 0.87; 95% Confidence Interval [CI] 0.80-0.94; p < 0.001).[15]

However, this ischemic benefit came at the cost of a significant increase in bleeding. GUSTO moderate or severe bleeding occurred in 4.2% of patients receiving vorapaxar versus 2.5% receiving placebo (HR 1.66; p < 0.001). Most concerning was a doubling of the risk of intracranial hemorrhage (ICH), which occurred in 1.0% of the vorapaxar group compared to 0.5% of the placebo group (HR 2.03; p < 0.001).[15] This mixed result, showing modest efficacy with a significant and serious safety signal, clouded the path to approval.

The Critical Subgroup Analysis: Redefining the Drug's Profile

The trajectory of Vorapaxar was fundamentally altered by a pre-specified subgroup analysis based on the patients' qualifying atherosclerotic disease. This analysis revealed that the drug's risk-benefit profile was not uniform across all patient types, a finding that ultimately rescued the drug from potential failure by identifying a population with a favorable net clinical benefit.

• Patients with a History of Stroke: In the 4,883 patients who entered the trial with a qualifying ischemic stroke, Vorapaxar provided no significant reduction in the primary efficacy endpoint. At the same time, it dramatically increased the risk of ICH, with a 3-year rate of 2.5% versus 1.0% for placebo (HR 2.52; 95% CI 1.46-4.36).[4] This clear evidence of net harm led the independent Data and Safety Monitoring Board to recommend the discontinuation of the study drug in this cohort.[30] This finding established the primary contraindication for Vorapaxar use.
• Patients with MI or PAD and No History of Stroke/TIA: This subgroup of 20,170 patients became the basis for the FDA approval. In this population, free from the high baseline risk of ICH associated with prior stroke, the efficacy of Vorapaxar was more pronounced and the safety profile more acceptable.
• Efficacy: Over a 3-year period, the primary endpoint of CV death, MI, or stroke was significantly reduced, occurring in 7.9% of vorapaxar-treated patients versus 9.5% of placebo-treated patients (HR 0.80; 95% CI 0.73-0.89; p < 0.001).[3] A broader composite endpoint including urgent coronary revascularization was also reduced from 11.8% to 10.1% (HR 0.83; p < 0.001).[7]
• Safety: While GUSTO moderate or severe bleeding was still increased (3.7% vs. 2.4%), the absolute increase was modest. Critically, the rate of ICH in this population was not statistically different between the groups (0.6% with vorapaxar vs. 0.4% with placebo).[15] This favorable balance of benefit and risk in this specific, large subgroup provided a clear rationale for regulatory approval.
• Patients with PAD: In the cohort of 3,787 patients with PAD, Vorapaxar did not significantly reduce the primary composite endpoint of CV death, MI, or stroke (11.3% vs. 11.9%; HR 0.94).[13] However, it demonstrated a significant benefit on limb-specific outcomes. Vorapaxar reduced the rate of hospitalization for acute limb ischemia by 42% (2.3% vs. 3.9%; HR 0.58; p=0.006) and the need for peripheral artery revascularization by 16% (18.4% vs. 22.2%; HR 0.84; p=0.017).[13] This finding supported its inclusion in the approved indication alongside post-MI patients.

The TRA 2°P-TIMI 50 trial serves as a landmark example of the power and importance of subgroup analysis in modern clinical drug development. The overall trial results presented a challenging picture of modest benefit overshadowed by serious risk. However, the robust, pre-specified analysis by qualifying disease state was able to dissect this average effect, revealing a clear signal of harm in one population (prior stroke) and a clear signal of benefit in another (post-MI/PAD without prior stroke). This transformed the clinical narrative, allowing for the approval of a novel drug for a well-defined population while simultaneously generating the evidence for a critical, life-saving contraindication. It demonstrates that the concept of "net clinical benefit" is highly dependent on the patient's baseline risk profile and underscores the movement toward more personalized antithrombotic therapy.

Table 3: Key Efficacy and Safety Endpoints from the TRA 2°P-TIMI 50 Trial in the FDA-Approved Population (Post-MI or PAD, No Prior Stroke/TIA)

Endpoint	Vorapaxar (N=10,080)	Placebo (N=10,090)	Hazard Ratio (95% CI)	p-value
Primary Efficacy Endpoint
CV Death, MI, or Stroke (3-year rate)	7.9%	9.5%	0.80 (0.73 - 0.89)	<0.001
Secondary Efficacy Endpoint
CV Death, MI, Stroke, or UCR (3-year rate)	10.1%	11.8%	0.83 (0.76 - 0.90)	<0.001
Principal Safety Endpoints
GUSTO Moderate or Severe Bleeding	3.7%	2.4%	1.55 (1.30 - 1.86)	<0.001
Intracranial Hemorrhage (ICH)	0.6%	0.4%	1.44 (0.93 - 2.24)	0.10
Fatal Bleeding	0.2%	0.2%	1.15 (0.62 - 2.12)	0.66
Data derived from analyses of the TRA 2°P-TIMI 50 trial population that formed the basis of the FDA approval.7

Therapeutic Indications, Dosing, and Administration

The approved use of Vorapaxar is narrowly defined based on the favorable risk-benefit profile observed in a specific subgroup of the TRA 2°P-TIMI 50 trial. Adherence to these indications and dosing instructions is critical for its safe application.

Approved Indication

Vorapaxar, under the brand name Zontivity®, is indicated by the U.S. Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD).[5] The label specifies that in this population, Vorapaxar has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).[16] It is crucial to note that this indication is restricted to patients who do not have a history of stroke or transient ischemic attack (TIA), a major contraindication.[7]

Dosage and Administration

The recommended dosage regimen for Vorapaxar is straightforward, reflecting its long half-life.

• Dose: The recommended dose is one 2.08 mg tablet taken orally once daily.[8] This dose of vorapaxar free base is equivalent to 2.5 mg of vorapaxar sulfate, the salt form used in clinical trials.[28]
• Administration: The tablet can be taken with or without food, as food does not have a clinically meaningful impact on its absorption or overall exposure.[3]

Use with Other Antiplatelet Agents

Vorapaxar is intended as an add-on therapy and not as a standalone antiplatelet agent.

• Adjunctive Therapy: It should be co-administered with aspirin and/or clopidogrel according to their respective indications and the prevailing standard of care.[8] In the pivotal clinical trial, the vast majority of patients were on a background of either single (aspirin) or dual (aspirin plus clopidogrel) antiplatelet therapy.[28]
• Limited Experience with Other Agents: The prescribing information explicitly states that there is limited clinical experience with the concomitant use of Vorapaxar with other antiplatelet drugs, such as prasugrel or ticagrelor, or with its use as the sole antiplatelet agent.[33]

Dosage Adjustments in Special Populations

Dosage adjustments for Vorapaxar are generally not required based on renal function or mild-to-moderate hepatic impairment, but its use is not recommended in severe liver disease.

• Renal Impairment: No dose adjustment is necessary for patients with any degree of renal impairment, including those with end-stage renal disease requiring dialysis.[4] Pharmacokinetic studies have shown that renal function does not substantially alter drug exposure or platelet inhibition.[6]
• Hepatic Impairment: No dose adjustment is required for patients with mild or moderate hepatic impairment.[4] However, Vorapaxar is not recommended for use in patients with severe hepatic impairment. This is not due to altered pharmacokinetics but because these patients have an inherent increased risk of bleeding, which would be exacerbated by a potent antiplatelet agent.[4]

Safety Profile, Contraindications, and Risk Management

The clinical utility of Vorapaxar is inextricably linked to its safety profile, which is dominated by the risk of bleeding. A thorough understanding of its contraindications, adverse effects, and risk factors is paramount for any clinician considering its use. The decision-making process for prescribing Vorapaxar is, in essence, a process of meticulous risk assessment.

FDA Black Box Warning: Bleeding Risk

The U.S. FDA has mandated a Black Box Warning, its strongest cautionary statement, on the prescribing information for Vorapaxar to emphasize the serious risk of bleeding.[33] The warning encapsulates the most critical safety information:

1. Contraindication in Cerebrovascular Disease: Do not use Zontivity in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH).
2. General Bleeding Risk: Antiplatelet agents, including Zontivity, increase the risk of bleeding, including ICH and fatal bleeding.
3. Action on Event: Discontinue Zontivity in patients who experience a stroke, TIA, or ICH.

This warning directly reflects the findings from the TRA 2°P-TIMI 50 trial, where patients with a prior stroke experienced net harm from the drug.[30]

Contraindications

Based on the Black Box Warning and other safety data, the use of Vorapaxar is strictly contraindicated in the following populations:

• History of Cerebrovascular Events: Any history of stroke, TIA, or ICH.[4]
• Active Pathological Bleeding: Patients with any current active bleeding, such as a peptic ulcer or intracranial bleeding.[22]

Adverse Reactions

Bleeding is the most common and most serious adverse reaction associated with Vorapaxar.

• Bleeding Events: In the approved patient population (post-MI or PAD without prior stroke/TIA), Vorapaxar significantly increased the rates of most categories of bleeding compared to placebo. This includes GUSTO moderate or severe bleeding, clinically significant bleeding as defined by the TIMI study group, and gastrointestinal bleeding.[16] While the absolute rates of fatal bleeding and ICH were not statistically different in this specific subgroup, the potential for these events remains the primary safety concern.[28]
• Other Common Adverse Effects: Besides bleeding, other adverse reactions reported more frequently with Vorapaxar (rate ≥2%) in clinical trials include anemia, depression, and various skin reactions (rashes, eruptions, exanthemas).[16] Anemia may be a direct consequence of occult or overt blood loss.
• Symptoms Requiring Medical Attention: Patients must be counseled to seek immediate medical attention if they experience symptoms suggestive of serious bleeding, such as: unexpected or uncontrollable bleeding; pink, red, or brown urine (hematuria); red or black, tarry stools (melena); vomiting blood or material that looks like coffee grounds (hematemesis); coughing up blood (hemoptysis); or neurological symptoms like severe headache, confusion, or slurred speech, which could indicate an ICH.[16]

Risk Management and Patient Selection

The safety profile of Vorapaxar dictates that its indication is effectively defined by the absence of risk factors. The clinical decision to initiate therapy is fundamentally a process of exclusion. A physician must first rigorously screen a patient for contraindications and factors that increase bleeding risk. Only after a patient is deemed to be at a sufficiently low risk of hemorrhage can the potential benefit of reducing thrombotic events be considered.

This approach inverts the typical clinical calculus. For many drugs, the indication is the primary consideration, with side effects being a secondary factor. For Vorapaxar, the safety profile is the primary determinant of its use. General risk factors for bleeding, which are amplified by Vorapaxar, must be carefully evaluated. These include:

• Advanced age [16]
• Low body weight [16]
• History of bleeding disorders [16]
• Impaired renal or hepatic function [16]
• Recent surgery, percutaneous intervention, or other major trauma [16]
• Concomitant use of other medications that increase bleeding risk, such as anticoagulants, chronic NSAIDs, SSRIs, or SNRIs.[6]

Only in patients with a history of MI or PAD who have been carefully vetted and found to be free of these major risk factors can Vorapaxar be considered a viable therapeutic option. This places a significant burden on the clinician to perform a comprehensive risk assessment before prescribing.

Clinically Significant Drug Interactions

Vorapaxar's extensive hepatic metabolism, primarily via the CYP3A4 isoenzyme, makes it highly susceptible to pharmacokinetic drug-drug interactions. Additionally, as a potent antiplatelet agent, it is prone to pharmacodynamic interactions that can potentiate the risk of bleeding. The prescribing information explicitly warns to avoid concomitant use with strong inhibitors or inducers of CYP3A.[8]

Pharmacokinetic Interactions (Metabolism-Based)

These interactions alter the plasma concentration of Vorapaxar, thereby affecting its efficacy and/or safety.

• Strong CYP3A4 Inhibitors: These drugs block the metabolism of Vorapaxar, leading to substantially increased plasma concentrations and a heightened risk of bleeding. Concomitant use should be avoided. Examples include:
• Azole Antifungals: Ketoconazole, itraconazole, posaconazole.[4] Co-administration with ketoconazole has been shown to approximately double the systemic exposure to Vorapaxar.[6]
• Macrolide Antibiotics: Clarithromycin, telithromycin.[4]
• HIV Protease Inhibitors: Ritonavir, saquinavir, nelfinavir, indinavir.[4]
• HCV Protease Inhibitors: Boceprevir, telaprevir.[4]
• Other: Nefazodone, conivaptan.[4]
• Strong CYP3A4 Inducers: These drugs accelerate the metabolism of Vorapaxar, leading to significantly decreased plasma concentrations and a potential loss of therapeutic efficacy. Concomitant use should be avoided. Examples include:
• Anticonvulsants: Carbamazepine, phenytoin.[4]
• Antimycobacterials: Rifampin.[4] Co-administration with rifampin reduces Vorapaxar exposure by approximately 50%.[6]
• Herbal Supplements: St. John's Wort (Hypericum perforatum).[4]

Weak to moderate inhibitors of CYP3A do not appear to cause clinically important interactions, and no dose adjustment is required.[6]

Pharmacodynamic Interactions (Additive Bleeding Risk)

These interactions occur when other drugs with antihemostatic effects are used concurrently, leading to an additive or synergistic increase in the risk of bleeding.

• Anticoagulants: Concomitant use with anticoagulants such as warfarin should be avoided due to the substantially increased risk of hemorrhage.[6]
• Other Antiplatelet Agents: While Vorapaxar is indicated for use with aspirin and/or clopidogrel, the addition of a third antiplatelet agent to a dual antiplatelet therapy regimen (i.e., triple therapy) further increases bleeding risk.[6]
• Fibrinolytics: Concomitant use with fibrinolytic agents is expected to increase the risk of hemorrhage.[6]
• Chronic Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Long-term use of NSAIDs can cause gastrointestinal bleeding and inhibit platelet function, increasing the overall bleeding risk when combined with Vorapaxar.[6]
• Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): These antidepressants are known to increase the risk of bleeding, and caution is advised when they are used concomitantly with Vorapaxar.[6]

Drug-Food Interactions

There are no clinically significant interactions between Vorapaxar and food.[8] However, given its reliance on CYP3A4 for metabolism, it is prudent for patients to avoid grapefruit and grapefruit juice, which are potent inhibitors of intestinal CYP3A4.[26]

Table 4 summarizes the most critical drug interactions and provides clear management recommendations.

Table 4: Major Drug Interactions and Management Recommendations

Interacting Drug Class	Examples	Effect of Interaction	Management Recommendation	Source(s)
Pharmacokinetic Interactions
Strong CYP3A4 Inhibitors	Ketoconazole, Itraconazole, Clarithromycin, Ritonavir	Increases Vorapaxar plasma concentration and risk of bleeding.	Avoid Concomitant Use	4
Strong CYP3A4 Inducers	Rifampin, Carbamazepine, Phenytoin, St. John's Wort	Decreases Vorapaxar plasma concentration and potential for reduced efficacy.	Avoid Concomitant Use	4
Pharmacodynamic Interactions
Anticoagulants	Warfarin	Additive antithrombotic effect, substantially increasing bleeding risk.	Avoid Concomitant Use	6
Chronic NSAIDs	Ibuprofen, Naproxen	Increased risk of gastrointestinal and other bleeding.	Use with caution; monitor for bleeding.	6
SSRIs / SNRIs	Fluoxetine, Sertraline, Venlafaxine	Increased risk of bleeding.	Use with caution; monitor for bleeding.	6

Regulatory History and Global Status

The regulatory journey of Vorapaxar was complex, marked by intense scrutiny of its risk-benefit profile. The outcomes in the world's two largest pharmaceutical markets, the United States and the European Union, ultimately diverged, reflecting different interpretations of the same clinical trial data and highlighting varying regulatory philosophies on acceptable risk.

United States (Food and Drug Administration - FDA)

Merck submitted a New Drug Application (NDA) for Vorapaxar to the FDA, which was formally accepted for review in July 2013.[5] The application was supported by the extensive data from the TRA 2°P-TIMI 50 trial. In January 2014, the FDA's Cardiovascular and Renal Drugs Advisory Committee convened to review the data. Despite the concerns over bleeding, the committee voted 10-to-1 in favor of approving the drug for the specific population of post-MI and PAD patients without a history of stroke or TIA, recognizing the net clinical benefit in this subgroup.[5]

Following the advisory committee's recommendation, the FDA granted its first approval for Vorapaxar (Zontivity) on May 8, 2014.[5] The approval was for the narrow indication of reducing thrombotic cardiovascular events in patients with a history of MI or PAD.[7] The FDA's approval was contingent on several risk management measures, including the prominent Black Box Warning detailing the bleeding risk and the contraindication in patients with prior cerebrovascular events, as well as a requirement for a patient Medication Guide to be dispensed with every prescription to ensure patients were aware of the risks.[14]

European Union (European Medicines Agency - EMA)

Following the FDA's decision, Vorapaxar was also reviewed by the European Medicines Agency. The EMA granted a marketing authorization for Zontivity on January 19, 2015.[42] The initial indication was for the reduction of atherothrombotic events in adult patients with a history of MI, co-administered with standard antiplatelet therapy. This indication was later extended to include patients with symptomatic PAD.[37] The European approval also carried strong warnings regarding the risk of bleeding and contraindications similar to those mandated by the FDA.[37]

However, the drug's tenure on the European market was short-lived. On June 23, 2017, the European Commission, at the request of the marketing authorization holder, withdrew the marketing authorization for Zontivity in the European Union.[37] As a result, Vorapaxar is listed by the EMA as a "Medicinal product no longer authorised" and is not available for clinical use in the EU.[37]

The divergent long-term outcomes for Vorapaxar in the US and EU, based on the same pivotal trial data, offer a compelling case study in regulatory science. Both agencies recognized the efficacy in the non-stroke subgroup and the significant bleeding risk. The FDA's approach was to manage the risk through stringent labeling and a narrow indication, allowing the drug to remain available for a carefully selected population. The subsequent withdrawal in the EU suggests that either the commercial viability was deemed insufficient by the manufacturer to support its continued marketing, or that the real-world challenges of safely integrating a drug with such a narrow therapeutic window into diverse European healthcare systems were considered too great. This divergence underscores that regulatory approval is not a monolithic global process but is subject to regional differences in clinical practice, risk tolerance, and the complex interplay between regulatory assessment and market dynamics.

Medicinal Chemistry and Synthesis Overview

The development of Vorapaxar is a notable achievement in medicinal chemistry, showcasing the successful transformation of a complex natural product scaffold into a potent, selective, and orally bioavailable therapeutic agent.

Scaffold Origin from Himbacine

Vorapaxar's chemical architecture is not a product of de novo design but is based on the natural product himbacine.[4] Himbacine is a complex tricyclic alkaloid isolated from the bark of Australian magnolia trees (

Galbulimima belgraveana). Natural products have long served as a rich source of inspiration for drug discovery due to their inherent biological activity and structural complexity, which often provides a privileged starting point for interacting with biological targets. The himbacine scaffold provided the core three-dimensional structure that medicinal chemists at Schering-Plough systematically modified to develop a potent antagonist for the PAR-1 receptor.[12]

Structure-Activity Relationship (SAR) Studies

The journey from the himbacine hit to the clinical candidate Vorapaxar involved extensive structure-activity relationship (SAR) studies. This iterative process involves synthesizing numerous chemical analogues of a lead compound and testing them to understand how specific structural modifications affect biological activity, selectivity, and pharmacokinetic properties.

Research publications detail the systematic optimization of the himbacine scaffold. Chemists explored modifications at various positions of the tricyclic core to enhance potency and fine-tune the drug's properties.[12] For instance, studies describe the synthesis and evaluation of analogues with different amino substituents at the C-7 position, the introduction of a hydroxyl group at the C-9a position, and the creation of C-7 spirocyclic structures.[12] This work was aimed at improving the binding affinity for the PAR-1 receptor, altering the metabolic profile (as the C7-carbamate side-chain of Vorapaxar is a known site of metabolism), and optimizing the overall pharmacokinetic profile for once-daily oral dosing.[12] The discovery of Vorapaxar was the culmination of these efforts, identifying a compound with an optimal balance of high potency, selectivity, and oral bioavailability.[12]

Synthesis Overview

While the full, multi-step industrial synthesis of Vorapaxar is proprietary, the scientific literature provides insights into the key chemical strategies used to construct Vorapaxar and its analogues. The synthetic routes typically begin with known ketone intermediates that contain the core himbacine-like ring system.[12]

Standard organic chemistry reactions are then employed in a modular fashion to build the final molecule. These include:

• Wittig Olefination: Used to introduce carbon-carbon double bonds, such as the vinyl ether precursor to the side chain.[12]
• Functional Group Manipulations: Standard reactions such as reductions, mesylations, and azide displacements are used to install the key amine functionality at the C-7 position.[12]
• Cross-Coupling Reactions: Suzuki-type cross-coupling reactions are used to attach the 5-(3-fluorophenyl)pyridine moiety to the core structure. This is a powerful method for creating the biaryl system that is crucial for the drug's activity.[23]

This modular approach allows chemists to readily synthesize a wide variety of analogues by simply changing the coupling partners or the reagents used to modify the core functional groups, facilitating the rapid exploration of the SAR that ultimately led to the identification of Vorapaxar as the optimal clinical candidate.

Conclusion: Balancing Efficacy and Hemorrhagic Risk

Vorapaxar (Zontivity®) stands as a significant, if highly specialized, innovation in antithrombotic therapy. As the first and only approved antagonist of the protease-activated receptor-1 (PAR-1), it offers a unique mechanism for reducing the risk of ischemic events in patients with established atherosclerosis. Its development and clinical application provide a powerful lesson in the delicate balance between thrombotic prevention and hemostatic integrity.

The central theme of the Vorapaxar story is the critical trade-off between its demonstrated efficacy and its inherent, significant risk of bleeding. The pivotal TRA 2°P-TIMI 50 trial unequivocally established that Vorapaxar, when added to standard antiplatelet therapy, reduces major adverse cardiovascular events in patients with a prior myocardial infarction or peripheral artery disease. However, the same trial also issued a stark warning, revealing a prohibitive risk of intracranial hemorrhage in patients with a history of stroke or TIA, leading to a finding of net harm in that population.

This dichotomy has shaped every aspect of Vorapaxar's clinical identity. Its therapeutic indication is not defined by who might benefit, but rather by who can safely tolerate its potent effects. The clinical use of Vorapaxar is therefore predicated on an exceptionally rigorous process of patient selection—a process of exclusion based on a comprehensive assessment of hemorrhagic risk. The drug's Black Box Warning and contraindications are not mere precautions; they are the primary guideposts for its application.

Furthermore, the drug's unique pharmacology, particularly its functionally irreversible effect due to a long pharmacokinetic half-life, presents ongoing management challenges. The absence of a reversal agent means that the clinical consequences of a bleeding event can be severe and prolonged, demanding that the decision to initiate therapy be made with the utmost caution.

In conclusion, Vorapaxar represents a potent but demanding therapeutic tool. It provides a mechanistically distinct option for reducing the burden of recurrent ischemic events in a carefully selected, high-risk secondary prevention population. However, its successful integration into clinical practice depends entirely on a clinician's ability to navigate the narrow therapeutic window between benefit and harm. The legacy of Vorapaxar is that of a powerful lesson in personalized medicine: in the realm of potent antithrombotic therapy, a deep understanding of the individual patient's unique balance of thrombotic and hemorrhagic risk is paramount to achieving a positive clinical outcome.

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