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 Table of Contents  
Year : 2017  |  Volume : 8  |  Issue : 4  |  Page : 127-134

Clinical use of vorapaxar as an emerging antithrombin agent: A literature review of current evidence

Department of Hematology Division, Internal Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia

Date of Web Publication12-Jan-2018

Correspondence Address:
Dr. Farjah H Algahtani
King Saud University, Riyadh
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_41_17

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In response to the high prevalence of atherothrombotic diseases and the residual risks left by the current antiplatelet therapies, the Food and Drug Administration approved the use of vorapaxar as a secondary prevention of cardiovascular events. Vorapaxar is a novel oral antiplatelet agent that antagonizes protease-activated receptor-1 and inhibits platelet activation without influencing coagulation parameters. In this review, we summarized findings of the main studies and the subanalyses from two pivotal phase III clinical trials of vorapaxar, as well as the results of the available observational studies to assist treatment decision-making of vorapaxar for clinicians. Evidence shows that vorapaxar treatment brings favorable results to patients with myocardial infraction history, peripheral arterial diseases, and acute coronary syndrome and those who underwent coronary artery bypass grafting surgery. Studies supported the efficacy of vorapaxar in treating incident coronary stent thrombosis, acute limb ischemia, and peripheral revascularization which outweighed the safety concern of bleeding. However, vorapaxar should not be administered to patients with prior stroke or transient ischemic attack due to excessive risks of bleeding. Future studies should focus on examining the long-term risks and benefits of vorapaxar on single cardiovascular outcomes and the optimal dosage of vorapaxar for different patient populations.

Keywords: Bleeding, protease-activated-receptor 1 inhibitor, thrombosis, vorapaxar

How to cite this article:
Algahtani FH. Clinical use of vorapaxar as an emerging antithrombin agent: A literature review of current evidence. J Appl Hematol 2017;8:127-34

How to cite this URL:
Algahtani FH. Clinical use of vorapaxar as an emerging antithrombin agent: A literature review of current evidence. J Appl Hematol [serial online] 2017 [cited 2020 Feb 29];8:127-34. Available from: http://www.jahjournal.org/text.asp?2017/8/4/127/223175

  Introduction Top

Atherothrombotic disease is the leading cause of morbidity and mortality in the United States and worldwide.[1] In Saudi Arabia, the overall prevalence of coronary artery disease (CAD) is 5.5% and the overall prevalence of peripheral artery disease (PAD) is 11.7% among people 45 years of age or older.[2],[3] Despite the prevention and treatment advances, there are significant residual atherosclerotic risks left that calls for new antiplatelet therapies.[4],[5] In May 2014, the US Food and Drug Administration approved vorapaxar (Zontivity, SCH 530348; Merck), the first of its kind oral antiplatelet agent, as a therapeutic option in the secondary prevention of thrombotic cardiovascular events, in addition to the standard antiplatelet drugs of aspirin and P2Y12 inhibitors.[6] In January 2015, the European Medicines Agency approved vorapaxar for treating atherothrombotic events in patients with myocardial infarction (MI) history and symptomatic peripheral arterial disease (PAD).[7] The pharmacodynamics of varapaxar lies in antagonizing the protease-activated-receptor 1 (PAR-1), an important thrombin receptor expressed on human platelets, which results in inhibiting thrombin-induced platelet aggregation.[8],[9] Vorapaxar is recommended for patients with a history of MI or PAD but not recommended for patients with a history of stroke or transient ischemic attack.[6],[10],[11],[12]

The approval of vorapaxar was mainly based on two large-scale phase III clinical trials that included nearly 39,400 participants worldwide – the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER)[10] and the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Events (TRA2P)–Thrombolysis in Myocardial Infarction (TIMI) 50 trial.[11] However, the clinical trial evidence had also shown a significant increased risk of bleeding introduced by vorapaxar despite the risk reduction in the composite outcome of cardiovascular death, MI, and stroke. Mixed results[10],[11] reported in the trials and post hoc subgroup analyses have raised the questions about balancing risk and benefits of vorapaxar in different patient population and its adaptability with other treatment/therapy in the clinical practice. In this narrative review, we will summarize the cumulative and recent evidence to assess the safety and efficacy of vorapaxar in treating atherothrombotic disease under different clinical settings.

  Summary Top

Overview of the landmark trials

TRACER and TRA2P-TIMI50 are the two landmark phase III trials of vorapaxar.[10],[11] The TRACER trial enrolled 12,944 patients with non-ST elevation acute coronary syndrome (NSTE-ACS). Eligible participants had hospitalization within 24 h of ischemic symptoms with elevated cardiac markers or electrocardiographic changes and one or more of the following risk factors: (1) age over 55 years; (2) previous MI, percutaneous intervention, or coronary artery bypass graft (CABG); (3) diabetes; or (4) PAD. TRACER failed to find significant reduction in primary composite outcome (death from cardiovascular causes, MI, stroke, recurrent ischemia with hospitalization, or urgent coronary revascularization) and reported higher risks of intracranial hemorrhage in the vorapaxar arm (1.1%) compared to the placebo arm (0.2%). However, this trial showed a benefit trend indicating that vorapaxar could lower the risks of secondary composite endpoint (death from cardiovascular causes, MI, or stroke) by 11% (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.81–0.98). Using expanded endpoint, White et al.[13] reported that in the TRACER trial, vorapaxar reduced the overall occurrences of ischemic events, including both first and subsequent, by 12% with number needed to treat (NNT) equal to 51 (HR = 0.88, 95% CI 0.80–0.98).

The TRA2P-TIMI50 enrolled 26,449 patients with stable atherosclerotic vascular disease within 2 weeks to 12 months before the enrollment, or PAD with ankle-brachial index of <0.85, or previous limb ischemia. TRA2P-TIMI50 demonstrated that vorapaxar significantly reduce the risk of primary composite endpoint (death from cardiovascular causes, MI, or stroke) by 13% (HR = 0.87, 95% CI: 0.80–0.94). This trial also showed 12% risk reduction (HR = 0.88, 95% CI: 0.82–0.95) in the secondary endpoint, defined as the primary endpoint additionally composite with urgent coronary revascularization. Similar to the TRACER trial, the achieved antithrombotic benefit was at the cost of increased risks of bleeding outcomes: vorapaxar arm had 4.2% (vs. 2.5% in placebo arm) Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding rate, 15.8% (vs. 11.1%) TIMI bleeding event, and 1.0% (vs. 0.5%) intracranial hemorrhage rate. Bohula et al.[14] stratified the atherothrombotic risks of the TRA2P-TIMI50 participants based on the number of risks indicators (age, diabetes mellitus [DM], hypertension, smoking, PAD, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction) possessed by each individual. Vorapaxar reduced the absolute risks of primary endpoint by 3.2% in high-risk population (patients with 3 or more risk indicators) and by 2.1% in intermediate-risk population (patients with 1–2 risk indicators). There was also a trend of increased risks of bleeding across groups (P for trend < 0.01). This study supported quantifying baseline risks when balancing the efficacy and safety of vorapaxar in different patient population.

Pharmacodynamics and pharmacokinetics

The early studies showed that vorapaxar (SCH 530348) is rapidly absorbed and distributed in human body and reaches its peak plasma level within 60–90 min.[15],[16] The effective half-life of vorapaxar is 3–4 days and its terminal elimination half-life is 8 days. The clinical used dose of vorapaxar sulfate for achieving the antiplatelet effect that prevents MI or PAD is 2.5 mg/day without the loading dose.[15],[16],[17],[18]

Results from two randomized,[8] placebo-controlled studies of vorapaxar pharmacodynamics and pharmacokinetics revealed that single vorapaxar dose (20 mg and 40 mg) created over 80% reduction of platelet aggregation at 1 h, which lasted for about 72 h. In a substudy of TRACER trial,[9] platelet aggregation was assessed among 44 subjects of vorapaxar arm and 41 subjects of placebo arm. The study found that the PAR-1 number in the vorapaxar group at 1 month was significantly lower than at baseline, compared to the placebo group, along with significant difference in biomarker level between the two groups. Randomized open-label trials based on healthy subjects revealed that concomitant food increases the vorapaxar exposure and decreases the absorption rate without affect the drug's efficacy.[19],[20] Kosoglou et al.[21] conducted a randomized parallel group study to examine the effect of single-dose vorapaxar on QT/corrected QT interval among healthy participants. With vorapaxar arm (120 mg) and placebo arm as Group 1 and moxifloxacin (400 mg) and placebo as Group 2, they found that vorapaxar had no significant effect on the length of QT/corrected QT interval.

Statkevich et al.[22] reported in an open-label study that hepatic impairment status was not likely to change the pharmacokinetics of vorapaxar and no dosage adjustment was required for patients with mild-to-moderate hepatic impairment. Kosoglou et al.[8] compared the pharmacokinetics of vorapaxar between patients with end-stage renal disease (ESRD) and healthy subjects. They found that ESRD did not alter the pharmacokinetics or the platelet aggregation profile of vorapaxar.

Vorapaxar's impact on blood test results

In an animal model, the mechanism of inhibition of PAR-1 has been shown to reduce arterial thrombosis by reducing thrombin-induced platelet aggregation without prolonging bleeding times or influencing coagulation parameters. The use of PAR-1 antagonist to inhibit PAR-1 did not inhibit ADP-induced or collagen-induced platelet aggregation, suggesting that PAR-1 antagonism does not affect other platelet-dependent pathways.[23] 1 Other study using animal model had also shown that the use of PAR-1 antagonist or antibodies to PAR-1 reduced thrombosis induced by vascular injury without harming the platelet-dependent coagulation functions, such as activated clotting time, activated partial thromboplastin time, and prothrombin times.[24] Rosser et al.[25] conducted the point-of-care global thrombosis test that employed nonanticoagulated blood to assess thrombotic and thrombolytic status on 57 patients randomized to either vorapaxar or placebo. They measured the time required to form a shear-induced thrombus under physical conditions (occlusion time [OT]) and the time to achieve endogenous lysis of the thrombus (lysis time [LT]). They found that patients on vorapaxar had longer OT and shorter LT versus when they were off the treatment; while patients who took placebo did not experience differences in OT or LT on versus off the treatment. This study supported that in addition to its antiplatelet effect, vorapaxar could enhance endogenous thrombolysis, which is frequently impaired among patients with coronary heart disease.


Patients with myocardial infarctions history

The substudies of TRACER and TRA2P-TIMI50 trials conducted among defined population revealed insights of vorapaxar in secondary cardiovascular disease prevention. Among 17,779 patients with a history of MI in TRA2P-TIMI50 trial, vorapaxar was associated with 20% decreased risks of cardiovascular death, MI, or stroke compared to placebo (HR = 0.80, 95% CI 1.31–1.97; P < 0.0001) during 2–3 years of follow-up. Even though moderate-to-severe bleeding was significantly higher among vorapaxar group (3.4%) than the placebo group (2.1%), there is no significant difference in the occurrence of intracranial hemorrhage (P = 0.076).[26] Whalen et al.[27] estimated the long-term health benefits and risks of vorapaxar in combination with standard care antiplatelet therapy (lifetime aspirin and up to 12 months of clopidogrel) among patients from TRA2P-TIMI50 trial who had MI history and without stroke. They found that increased life expectancy was associated with adding vorapaxar on standard care therapy with 8.27 discounted quality-adjusted life-years (QALYs) versus 7.96 discounted QALYs in the standard care only group.

Patients with recurrent versus incident ischemic stroke

A total of 4883 patients from the TRA2P-TIMI50 trial with prior ischemic stroke were assessed separately for the efficacy and safety of vorapaxar. In this stroke cohort, vorapaxar treatment did not reduce the risks of cardiovascular death, MI, or stroke (HR = 1.03, 95% CI 0.85–1.25) over 3 years of follow-up. However, intracranial hemorrhage was significantly increased in the vorapaxar treatment arm compared to the placebo arm (HR = 2.52, 95% CI 1.46–4.36).[28] This subgroup analysis provided critical evidence of nonapplicability of vorapaxar among patients with ischemic stroke history. However, among 20,170 patients with MI/PAD and no history of stroke or transient ischemic attack in the TRA2P-TIMI50 trial, vorapaxar treatment significantly reduced the risks of first ischemic stroke by 43% (HR = 0.57, 95% CI 0.43–0.75) but increased risks of hemorrhagic stroke (HR = 2.27, 95% CI 1.00–7.73). There was no significant increase in the risks of hemorrhagic conversion after stroke (P = 0.70) or death (P = 0.79). This evidence supported the use of vorapaxar in the secondary prevention of incident ischemic stroke.[29] The contradicting effect of vorapaxar on recurrent versus incident ischemia stroke patients require extra cautious in clinical practice. We anticipated that the antiplatelet pathway through PAR is likely to play a more weighted role among patients with incident ischemia stroke versus recurrent ischemia episode(s). Patients who were naïve to thrombosis process (patients without ischemia stroke history) could be more sensitive and responsive to PAR inhibitors, which allows for a favorable risk/benefit profile seen in this population.

Patients with acute coronary syndromes

In the subpopulation of 1712 TRA2P-TIMI50 participants who experienced new ACS events during the trial, there was no significant difference in the rate of GUSTO severe bleeding (HR = 0.99, 95%CI 0.33–2.94) or the rate of GUSTO moderate/severe bleeding (HR = 1.59, 95% CI 0.78–3.24) through 7 days after ACS incidence. The favorable efficacy of vorapaxar was consistent with the overall population.[30] This study indicated that vorapaxar is promising among patients with new ACS in preventing cardiovascular death, MI, and stroke. However, further evidence is needed to evaluate the long-term safety of using vorapaxar in this patient population.

Patients with peripheral artery disease history

Among 936 patients who had history of PAD from the TRACER trial, compared to placebo, vorapaxar was associated lower but nonsignificant risks of peripheral revascularization procedures (P = 0.16) and extremity amputation (P = 0.11). The increased hazard of GUSTO moderate/server bleeding was similar between patients with and without PAD (P for interaction = 0.92).[31] Among the 3787 patients with history of PAD in the TRA2P-TIMI50 trial, vorapaxar did not significantly reduce the risks of the primary composite endpoint of cardiovascular death, MI, or stroke (HR = 0.94, 95% CI 0.78–1.14) but significantly increased the hazard of bleeding (HR = 1.62, 95% CI 1.21–2.18). However, the vorapaxar treatment group had significantly lower hospitalization rate for acute limb ischemia (ALI) (HR = 0.58, 95% CI 0.39–0.86) and peripheral artery revascularization (HR = 0.84, 95% CI 0.73–0.97).[32]

Patients undergoing coronary artery bypass graft surgery

Among the 1312 patients from the TRACER trial who had CABG surgery, vorapaxar was associated with 45% decreased risks of the primary composite endpoint (HR = 0.55, 95% CI 0.36, 0.83) compared to placebo, without significantly increase in CABG-related major bleeding, fatal bleeding, or need for reoperation.[33] Consistent conclusion was confirmed in the TRA2P-TIMI50 trial. Among patients with prior CABG surgery, vorapaxar significantly reduced 29% hazard of the primary endpoint (HR = 0.71, 95% CI 0.58–0.88, NNT = 27). There was no significant difference in the rate of TIMI CABG major bleeding between the vorapaxar and the placebo arms (HR = 1.39, 95% CI 0.58–4.01).[34] The evidence collected from the two trials suggested that patients underwent CABG surgery is a population favoring vorapaxar therapy.

Patients undergoing noncardiac surgery

A study based on the patients from TRACER trial who had ACS and underwent noncardiac surgery (NCS) found no difference in the primary ischemic endpoint (P = 0.41) or NCS bleeding (P = 0.17) between the vorapaxar arm and the placebo arm.[35]

Medically managed patients

Held et al.[36] conducted subanalysis among 4194 medically managed patients in the TRACER trial, including 1120 patients with no significant stenosis or prior CAD, 464 patients with no significant stenosis but prior CAD, 1473 patients with significant stenosis, and 1137 patients who did not undergo coronary angiography. They found that among the medically managed subcohort, there was no interaction between vorapaxar treatment and management strategy (P = 0.75), and they confirmed the findings regarding the efficacy and safety of vorapaxar consistent with the overall population.

Patients with diabetes mellitus and myocardial infarctions

Among 3623 patients with DM and no prior stroke from the TRA2P-TIMI50 trial, vorapaxar reduced the hazard of the primary endpoint by 27% (HR = 0.73, 95% CI 0.60–0.89, NNT = 29), which was greater than the overall trial. Even though the risk of moderate/severe bleeding was higher for DM patients who received vorapaxar (HR = 1.60, 95% CI 1.07–2.40), while the net clinical outcome favoring vorapaxar treatment (HR = 0.79, 95% CI 0.67–0.93).[37]

Individual cardiovascular disease outcomes

Myocardial infarctions

In the exploratory analysis of TRACER trial, 1319 among 12,944 patients had MIs during follow-up time, including 64.9% spontaneous MI (type 1), followed by 22.3% percutaneous coronary intervention-related MI (type 4a). Vorapaxar treatment was associated with 12% decreased hazard of first MI regardless of the type (HR = 0.88, 95% CI 0.78–0.97) and 14% decrease in total number of MIs (HR = 0.86, 95% CI 0.77–0.97) over time. Breaking down to subtypes of MIs, vorapaxar significantly reduced the hazard of type 1 MI (HR = 0.83, 95% CI 0.73–0.95) but not type 4a MI (HR = 0.90, 95% CI 0.73–1.12).[38]

Coronary stent thrombosis

Among TRA2P-TIMI50 trial participants who had coronary stent implantation before randomization (14,042) and during the trial (449), vorapaxar treatment was associated with risk reduction of the Academic Research Consortium defined coronary stent thrombosis (ST) by 29% (HR = 0.71, 95% CI 0.51–0.98). The risk reduction was consistent across study follow-up time, diabetes status, and medication use. However, the ST benefit was also associated with significantly increased risks of GUSTO moderate/severe bleeding (HR = 1.57, 95% CI 1.26–1.94).[39]

Acute limb ischemia

A subanalysis of the TRA2P-TIMI50 trial included 3787 symptomatic PAD patients and among whom 108 had at least one ALI event. This study found that compared to placebo, vorapaxar treatment reduced the 41% risks of first ALI event (HR = 0.58, 95% CI 0.39–0.86) and 41% risks of total ALI event (HR = 0.59, 95% CI 0.38–0.93). Vorapaxar had consistent efficacy over different types of ALI.[40]

Peripheral revascularization

Among 5845 patients with a history of PAD in the TRA2P-TIMI50 trial, 934 individuals experienced at least one peripheral revascularization over 2.5 years (median) of follow-up. Compared to placebo, vorapaxar treatment significantly reduced the hazard of peripheral revascularization by 18% (HR = 0.82, 95% CI 0.72–0.93). The efficacy of vorapaxar was consistent between first and overall peripheral revascularization, as well as across different indications.[41]

Comparison with other antiplatelet agents

Different antiplatelet drugs are developed in response to the different pathways following platelet activations: (1) vorapaxar functions against thrombin generation and activation of its PAR-1 and PAR-4 receptors that are supported by change in surface membrane; (2) aspirin suppresses cyclooxygenase-1 and thromboxane 2 formation, which are followed by the activation of phospholipases and release of arachidonic acid; (3) thienopyridines (ticlopidine, clopidogrel, and prasugrel) and ticagrelor adenosine inhibit diphosphate (ADP) secretion and its binding to P2Y1 and P2Y12 receptors, which interfere with the normal process of intraplatelet calcium increase and cAMP concentrations reduction; and (5) GPIIb/IIIa inhibitors inactivate fibrinogen binding and platelet aggregation. The antiplatelet agents and multiple pathways have been graphically summarized in previous studies.[42],[43],[44]

A systematic review and network meta-analysis,[45] based on 49 RCTs and 34,518 patients, compared the efficacy and safety of different antiplatelet drugs of aspirin, ticlopidine, clopidogrel, ticagrelor, cilostazol, picotamide and vorapaxar as monotherapies or in combination with aspirin in PAD patients. The study found that aspirin, cilostazol, vorapaxar, and picotamide were ineffective in reducing major adverse cardiovascular events (MACE), including vascular deaths, nonfatal MI, and nonfatal stroke. Ticagrelor plus aspirin was associated with 33% MACE risk decrease (risk ratio [RR]: 0.67; 95% chronic renal insufficiency [CrI]: 0.46–0.96, NNT = 66), clopidogrel was associated with 28% MACE risk decrease (RR: 0.72; 95% CrI: 0.58–0.91, NNT = 80), ticlopidine was associated with 25% MACE risk decrease (RR: 0.75; 95% CrI: 0.58–0.96, NNT = 87), and clopidogrel plus aspirin combination was associated 22% MACE risk decrease (RR: 0.78; 95% CrI: 0.61–0.99, NNT = 98). Severe bleeding was significantly higher with prescription of ticlopidine (RR: 5.03; 95% CrI: 1.23–39.6, NNH = 25), vorapaxar (RR: 1.80; 95% CrI: 1.22–2.69, NNH = 130), and clopidogrel plus aspirin (RR: 1.48; 95% CrI: 1.05–2.10, NNH = 215). Overall, the study found that clopidogrel monotherapy showed the most favorable benefit-harm profile compared to other antiplatelet monotherapy or combination therapy. There is a lack of evidence supporting triple therapy with vorapaxar in addition to aspirin and the more potent platelet antagonists, prasugrel and ticagrelor, given the elevated bleeding risk introduced by vorapaxar. Mechanically, it is still unclear that whether PAR-1 antagonism will have additional benefit if ADP receptor inhibition has already been approached. Ongoing trial of vorapaxar in patients with prior MI treated with prasugrel and ticagrelor (VORA-PRATIC) will provide insight to this evidence gap.[46]

Interaction with other drugs and therapy

In clinical practice, vorapaxar is usually used in combination with other drugs and therapies. For patients with ACS, vorapaxar is used in combination with dual-antiplatelet therapy consisting of aspirin and clopidogrel or single-antiplatelet therapy.[10] Previous studies reported the absence of clinical significant drug interaction between vorapaxar and warfarin or other CYP2C9/CYP2C19 substrates,[47] clopidogrel,[48] thienopyridine,[49],[50] digoxin,[51] or rosiglitazone.[52] Kosoglou et al.[51] found that ketoconazole and rifampin could moderately increase or decrease the vorapaxar exposure (AUC and C(max)) and thus are not recommended for concomitant use with vorapaxar. Even though the study found nonsignificant drug interaction of vorapaxar and glycoprotein IIb/IIIa receptor inhibitors either up to 7 days (P for interaction = 0.89) or 30 days (P for interaction = 0.74), the combination of the two drugs was associated with increased bleeding risks.[53] A recent study carried out by Anderson et al.[54] found that among healthy population, there was no drug–drug interaction between vorapaxar and prasugrel, a platelet inhibitor that acts as a P2Y12 receptor antagonist, which indicated that the coadministration of the two drugs is well tolerated. However, it is unknown whether they interact in the same way among different patient populations.

Cai et al.[55] explored the potential of introducing platelet transfusion to vorapaxar monotherapy and its combination with aspirin and/or clopidogrel in controlling bleeding. They found that transfusion of fresh human platelet plasma reversed the increased bleeding time in the situation when vorapaxar (1 mg/kg, per orally [PO]), aspirin (5 mg/kg, intravenous), and clopidogrel (1 mg/kg, PO) were used in combination. This study provided clinically insightful solution for the safety concern of vorapaxar when using the triple-antiplatelet therapy.

Vorapaxar and population demographics


With the population of median age of the TRACER trail equaled to 64, Armaganijan et al. examine the age-specific efficacy and safety of varapaxar and the interaction of age groups with treatment assignment (vorapaxar versus placebo). Compared to the placebo arm, the hazards of primary endpoint associated with vorapaxar in four age groups were ≤54 years of age: 1.12 (95% CI, 0.88–1.43), 44–64 years of age: 0.88 (95% CI: 0.76–1.02), 65–74 years of age: 0.89 (95% CI, 0.76, 1.04), and ≥75 years of age 0.88 (95% CI, 0.74–1.06). The hazards of moderate/severe GUSTO bleeding in the above four age groups were as follows: 1.73 (95% CI 0.89–3.34), 1.39 (95% CI 1.04–1.86), 1.10 (95% CI 0.85–1.42), and 1.73 (95% CI 1.29–2.33). No interaction was found between treatment assignment with primary endpoint (P = 0.44) or bleeding outcome (P = 0.57).[56] Furthermore, risks of bleeding associated with vorapaxar increased with older age.[57]


Early study conducted among healthy Japanese and Caucasian individuals did not find significant racial difference in the pharmacodynamics and pharmacokinetics of vorapaxar.[58] Another open-label study comparing the pharmacokinetics of vorapaxar between Chinese and American subjects also reported the absence of racial/ethnic differences.[59]

Body weight

Currently, a fixed dosage of vorapaxar is prescribed regardless of patients' body weight. The secondary analysis on the subpopulation of low body weight (<60 kg) from both the TRACER trial (n = 1046) and the TRA2P-TIMI50 trial (n = 1825) reported decreased risk of bleeding in the heaviest weight quintile and increased risk in patients in two lowest weight quintiles when comparing the vorapaxar arm to the placebo arm.[60] This study indicated the need for further evaluation of dose adjustment based on patients' body weight.

  Conclusion Top

Vorapaxar has been proved to be a promising oral antiplatelet agent in the secondary prevention of cardiovascular events, such as recurrent MI, new ischemia stroke, coronary ST, ALI, and peripheral revascularization. Patients with prior MI and comorbidity of DM and PADs and those who underwent CABG surgery are the population who will benefit from using vorapaxar. Vorapaxar is not recommended for patients with prior stroke or transient ischemic attack due to the excessive risks of bleeding. Future studies should examine the long-term risks and benefits of vorapaxar focusing on individual cardiovascular outcomes and seek for dose adjustment for patients with different age, body weight, and disease conditions.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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