Vorapaxar: A novel agent to be considered in the secondary prevention of myocardial infarction.

Patients receiving therapy for the secondary prevention of myocardial infarction (MI) are still at high risk of a major cardiovascular event or death despite the use of currently available treatment strategy. Vorapaxar, an oral protease-activated receptor antagonist, is a novel antiplatelet drug that has been recently approved to provide further risk reduction. The results of two Phase III trials (thrombin receptor antagonists for clinical event reduction and the TRA 2°P-TIMI 50) have showed that vorapaxar, in addition to standard of care therapy, has the potential to provide further risk reduction in patients with prior MI. A search was made on PubMed on articles related to clinical trials and clinical consideration with the use of vorapaxar. This review article summarizes the results of Phase II trials, Phase III trials, subgroup analysis, precautions, and drug interaction with the use of vorapaxar.

The prevalence of cardiovascular (CV) disease has increased significantly over the past decade despite improvement in therapeutic strategies and options. Myocardial infarction (MI) is the leading cause of morbidity and mortality in both developed and developing countries and is associated with huge economic burden.[1] Patients who have survived an initial episode of an MI are still at an increased risk of a subsequent CV event including recurrent MI.[2]

The primary medication used in the prevention of MI is aspirin, which is a thromboxane A2 (TXA2) inhibitor and has provided up to 12% reduction in deaths, 31% reduction in re-infarction, and over 40% reduction in nonfatal stroke.[3] Another medication, clopidogrel, a P2Y12 inhibitor has also been recommended for use in combination with aspirin for up to a year to provide additional risk reduction in patients who have suffered an episode of MI.[4] Despite the wide use of this combination therapy, a relatively high proportion of patients receiving therapy for secondary prevention of MI are still at a high risk of a major CV event or death, and an analysis of a major CV registry (global registry of acute coronary events) has showed a mortality rate of 20% at a median period of 5 years.[5] This finding highlights the need for better strategies for long-term secondary prevention of MI.

In 2014, the Food and Drug Administration (FDA) approved the use of vorapaxar as a first in class inhibitor of thrombin-mediated platelet activation to be used in combination with standard therapy in the secondary prevention of thrombotic CV events in patients with a history of MI or peripheral arterial disease.[6]

This aim of this article is to provide an overview of the clinical trials and clinical consideration with the use of vorapaxar to assist physician make an appropriate prescribing decision.

Methods

A literature search was conducted via PubMed on articles related to vorapaxar published between January 2009 and September 2015 for articles related to Phase II trials, Phase III trials, subgroup analysis, precautions, and drug interaction with the use of vorapaxar.

Search terms used were “antiplatelet,” “antithrombotics,” “cardiovascular event,” “acute coronary syndrome,” “coronary heart disease,” “pharmacology,” “dose,” “adverse effect,” and “drug interaction” in combination with “vorapaxar,” and “PAR-1 receptor antagonist”.

Vorapaxar: First in Class Protease-Activated Receptor Antagonist

Platelet plays a significant role in the formation of pathogenic thrombi, and a number of agonist including adenosine diphosphate (ADP), TXA2, epinephrine, collagen, and thrombin play important roles in platelet activation.[7] Before now, the ADP receptors and TXA2 have been the major targets of antiplatelet used as standard of care and this includes clopidogrel, prasugrel, ticagrelor (ADP receptor antagonist), and aspirin (TXA2 inhibitor).[8] The discovery of the protease-activated receptor-1 (PAR-1) and its novel antagonist, vorapaxar, presents an opportunity for additional option to be considered in the management of MI through the inhibition of thrombin-mediated platelet activation. Vorapaxar (formerly called SCH 530348) is a synthetic tricyclic 3-phenylpyridine structurally similar to himbacine, and it is a selective antagonist of PAR-1 which is the major thrombin receptor found on the surface of human platelets cell. Other PAR receptors that have been identified include the PAR-2, PAR-3, and PAR-4. Vorapaxar has a high bioavailability after oral administration of >90% with a half-life of 126 h–296 h. It binds reversibly to a PAR-1; however, it slowly dissociates making it functionally irreversible.[910]

Flowchart of selection process

Clinical Trial and Significance

Phase II

Three Phase II trials have been conducted to establish the safety, tolerability, and bleeding risk with vorapaxar. All three studies were randomized, placebo-controlled, double-blind study with 60 days treatment follow-up phase. The first trial (TRA-PCI) was a multicenter trial involving 1030 patients with coronary artery disease who were undergoing nonurgent or coronary angiography with planned percutaneous coronary angiography (PCI). In this trial, three different loading doses (10, 20 and 40 mg) of vorapaxar were administered or matching placebo was administered in 3:1 ratio. Subjects in the vorapaxar group who subsequently underwent PCI were placed on a maintenance dose of 0.5, 1, or 2.5 mg/day, and subject in the placebo group continued placebo therapy until the end of the study.[11] The second and third studies were fairly smaller studies conducted in Japanese subject. The second study had a similar design to the TRA-PCI and involves 117 subjects in whom PCI was planned,[12] while the third study involves 90 subjects with a history of ischemic stroke randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily in addition to aspirin therapy.[13] In all the three studies, vorapaxar was not associated with a statistically significant increase in thrombolysis in MI (TIMI) or non-TIMI bleeding.

Phase III

Vorapaxar has been studied in clinical trials in regimen with aspirin and/or clopidogrel. Two Phase III trials have been conducted with vorapaxar in two distinct population. The thrombin receptor antagonists for clinical event reduction (TRACER) trial and the Trial to Assess the Effects of SCH 530348 in preventing heart attack and stroke in patients with atherosclerosis (TRA 2°P–TIMI50).[1415] Both trials were a randomized, multinational, double-blind, placebo-controlled trial [Table 1].

Table 1

Comparison of Phase III clinical trial with vorapaxar (TRACER vs. TRA 2P-TIMI 50)

Thrombin Receptor Antagonists for Clinical Event Reduction

The TRACER study was conducted in moderate to high risk subjects with non-ST elevation acute coronary syndrome (NSTE-ACS) with a composite primary endpoint of death from CV causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization and a median follow-up of 502 days.[15]

The TRACER study did not meet the objective of the study design and was terminated early after a safety review that showed a significant increase in bleeding risk without a significant decrease in the composite endpoint. However, it offered useful information as regards the bleeding risk associated with vorapaxar.

In the TRACER study, there was a nonsignificant reduction in ischemic events (18.5% vs. 19.9% hazard ratio [HR] 0.92; 95% confidence interval [CI]: 0.85–1.01; P = 0.07). However, rate of moderate and severe bleeding was significantly increased, (7.2% vs. 5.2% HR: 1.35; 95% CI: 1.16–1.58; P < 0.001) as well as the rate of intracranial hemorrhage (1.1% vs. 0.2% HR: 3.39; 95% CI: 1.78–6.45; P < 0.001).[15] A second analysis on the result of the TRACER study using the Wei et al.[16] approach, which involves analyzing all CV events rather than focusing on composite endpoints has showed the potential of vorapaxar in significantly reducing the overall occurrences of ischemic events (HR: 0.88; 95% CI: 0.80–0.98; P = 0.02). This is however also accompanied by increase in the occurrence of both moderate and severe global use of strategies to open occluded arteries (GUSTO) bleeding (HR: 1.42; 95% CI: 1.21–1.66; P < 0.001), and TIMI significant bleeding (HR: 1.550; 95% CI: 1.403–1.713; P < 0.001).[17]

A number of post-hoc analyses have been conducted using data from the TRACER study and have offered relevant results. A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition. A total of 1580 MIs was recorded in 1319 patients during a median follow-up of 502 days and vorapaxar was observed to reduce the risk of a first MI of any type by 12% (HR: 0.88; 95% CI: 0.79–0.98; P = 0.021), total number of MIs by 14% (HR: 0.86; 95% CI: 0.77–0.97; P = 0.014), type 1 MI by 17% (HR: 0.83; 95% CI: 0.73–0.95; P = 0.007), and no significant effect on type 4a MI (HR: 0.90; 95% CI: 0.73–1.12; P = 0.35).[18] Although exploratory in nature, these results support the potential benefit of PAR-1 antagonism in the secondary prevention of MI.

Another post-hoc analysis has been conducted in 1312 patients who underwent coronary artery bypass grafting (CABG) during the index hospitalization. In this subgroup, CABG patients on vorapaxar recorded 45% lower rate in the primary endpoint (a composite of death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) compared with CABG patients on placebo therapy (HR: 0.55; 95% CI: 0.36–0.83; P < 0.005), with a positive interaction (P = 0.012).[19] Also, TIMI major bleeding related to CABG was higher with vorapaxar (9.7% vs. 7.3% HR: 1.36; 95% CI: 0.92–2.02; P = 0.12); however, this was not statistically significant. Furthermore, no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%) was recorded. This result suggests that vorapaxar may have the potential to improve outcome in patients with ACS undergoing CABG.[19] However, more clinical trials are required to establish the selective benefit of vorapaxar in this group of patients.

Similarly, an analysis was conducted in 7479 patients from 12,944 patients in the TRACER study who underwent PCI during the index hospitalization. This analysis focused on the implanted stent type (drug-eluting stent [DES] vs. bare metal stent [BMS]) during PCI. The result showed that the efficacy and safety of vorapaxar in PCI patients were consistent with the overall TRACER study result, and the duration of dual antiplatelet therapy was shorter in patients with BMS compared with DES.[20]

In another analysis that assessed the risk-benefit profile of vorapaxar based on ischemic and bleeding risk using a multivariable model, vorapaxar resulted in 1.30% absolute reduction in CV death, MI, and stroke and 0.94% absolute increase in GUSTO severe bleeding (net benefit + 0.34%). Vorapaxar produced a favorable absolute net benefit in patients with high risk of ischemic events but low risk of bleeding. However, a net negative clinical benefit was recorded in patients with an increased risk of blending. This result suggests that NSTE-ACS patients with a high risk of recurrent ischemic event and low risk of bleeding are more likely to benefit from the addition of vorapaxar to the standard of care therapy.[21]

An analysis to assess the impact of the thienopyridines bleeding risk has also been conducted. The majority of the patients in the TRACER trial (87%) were on dual antiplatelet therapy with aspirin and a thienopyridine, mostly clopidogrel and only 13% of patients in the trial were not on a thienopyridine. The result of this analysis showed that patients who were not on a thienopyridine therapy had a lower risk of bleeding, as assessed by all bleeding scales (GUSTO moderate/severe, GUSTO severe, TIMI significant, and TIMI major). Despite the fact that addition of vorapaxar to a thienopyridine regimen increases bleeding risk, more researches are required to justify the use of vorapaxar without a thienopyridine. This is because the TRACER trial was designed to evaluate the effect of the addition of vorapaxar to standard dual antiplatelet therapy often including thienopyridines.[22]

Another analysis that has been conducted from the result of the TRACER trial is on the impact of aspirin dosing. A total of 12,515 (96%) of patients in the TRACER study were on aspirin therapy with a dose range of < 100 mg–>300 mg (<100 mg–>300 mg). High-dose participants were observed to have a higher rates of both ischemic events and bleeding outcomes, and the use of low-dose aspirin with other antiplatelets therapy may be associated with improved outcomes.[23]

In a subgroup analysis to investigate the efficacy and safety of vorapaxar in NSTE-ACS patients with documented peripheral arterial disease (PAD), both ischemic event (25.3% vs. 12.2%, P < 0.001) and GUSTO moderate/severe bleeding (9.1% vs. 5.0%, P = 0.004) were more common in PAD patients compared with non-PAD patients.[24] This suggests that history of PAD may be a risk factor for both ischemic and bleeding events in patients with NSTE-ACS.

An analysis of the subgroup on clopidogrel therapy has observed no interaction between vorapaxar and clopidogrel in the study participants for both efficacy and safety outcomes. In this analysis, vorapaxar was associated with 26% reduction in the composite of CV death, MI, or stroke when used with clopidogrel (HR: 0.74; 95% CI: 0.60–0.91) and 24% reduction when used without clopidogrel (HR: 0.76; 95% CI: 0.56–1.02) (P interaction = 0.89). The hazard of GUSTO bleeding with vorapaxar was not significantly different without clopidogrel (HR: 1.33; 95% CI: 0.81–2.20) or with clopidogrel (HR: 1.09; 95% CI: 0.76–1.56) (interaction; P = 0.53). This suggests a complementary role in the use of vorapaxar with clopidogrel therapy.[25]

In an analysis to evaluate the outcome of medically managed patients (defined as patients who did not undergo any coronary revascularization procedure during the acute hospitalization), a reduction was observed in the primary event rate of patients taking vorapaxar compared with placebo (16.3% vs. 17.0%, HR: 0.99; 95% CI: 0.83–1.17), with no interaction between drug and management strategy (P = 0.75).[26] Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR: 0.89, 95% CI: 0.74-1.07), with no interaction (P = 0.58). As the trend has been in other subgroup analysis, vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR: 1.46, 95% CI: 0.99–2.15) [Table 2].[26]

Table 2

Clinical trials and subgroup analysis with vorapaxar

Trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with atherosclerosis (TRA2°P–TIMI50)

The TRA 2° P–TIMI50 was designed to evaluate the usefulness of vorapaxar in reducing atherothrombotic events in patients with atherosclerosis on standard antiplatelet therapy and to determine if addition of an antiplatelet with a different mode of action is beneficial in secondary prevention of CV event. In this trial, there was a statistically significant decrease in the primary endpoint at 3 years follow-up of 9.3% versus 10.5% (HR: 0.87; 95% CI: 0.80–0.94; P < 0.001) with decrease in cardiac death and no change in all-cause mortality.[14] An absolute and relative risk reduction of 1.2% and 12%, respectively was in the combined endpoint, and this was majorly due to a reduction in the risk of subsequent MI. However, risk of bleeding was significantly increased with a rate of 4.2% versus 2.5% (HR: 1.66; 95% CI: 1.43–1.93; P < 0.001). Also, the rate of intracranial hemorrhage doubled in the vorapaxar arm compared to the placebo arm (1.0%, vs. 0.5% P < 0.001) [Table 1].[14]

A number of subgroup analyses have also been conducted with the result of the TRA 2° P–TIMI50 trial, and this has also provided useful information. An analysis in 4883 patients with prior ischemic stroke in the TRA 2P–TIMI 50 trial showed that vorapaxar was associated with an increased risk of intracranial hemorrhage compared with placebo (2.5% vs. 1.0%, HR: 2.52, 95% CI: 1.46–4.36; P = 0.001).[27] Also, an increased risk for both GUSTO moderate and severe bleeding (4.2% vs. 2.4%, HR: 1.93, 95% CI: 1.33–2.79; P < 0.001) was recorded with vorapaxar compared with placebo. As such, vorapaxar as an add-on therapy has the potential of increasing intracranial hemorrhage in patients with a prior history of ischemic stroke receiving standard antiplatelet therapy.[27]

Furthermore, an analysis has been conducted to determine the incidence of new ischemic stroke in patients with MI or PAD who had no prior stroke or transient ischemic attack. Vorapaxar was observed to reduce first ischemic stroke (HR: 0.57; 95% CI: 0.43–0.75; P < 0.001). The risk of hemorrhagic conversion after stroke (HR: 1.19; 95% CI: 0.49–2.91; P = 0.70) or death (HR: 1.09; 95% CI: 0.57–2.07; P = 0.79) during follow-up was not significantly increased with vorapaxar in patients who had a new ischemic stroke. In spite of the fact that hemorrhagic stroke was increased (HR: 2.79; 95% CI: 1.00–7.73; P = 0.049), overall stroke was significantly reduced (HR: 0.67; 95% CI: 0.52–0.87; P = 0.002).

Subgroup analysis has also been conducted in a cohort of patients with MI. The majority of patients (17,779) in the TRA 2P–TIMI 50 trial have had a prior MI and were assigned to either the vorapaxar or placebo group (8898 vs. 8881) with a median follow-up of 2.5 years. The study result shows a significant decrease in primary endpoint of 8·1% versus 9·7%, (HR: 0·80; 95% CI: 0·72–0·89; P < 0·0001) in vorapaxar compared with placebo. However, GUSTO moderate or severe bleeding was more common in the vorapaxar group compared with the placebo group 3·4% versus 2·1 (HR: 1·61; 95% CI: 1·31–1·97; P < 0·0001). Furthermore, intracranial hemorrhage was recorded in 0·6% of patients in the vorapaxar group compared with 0·4% in the placebo group (P = 0·076).[29]

Further analysis was conducted in the low bleeding risk cohort of the subgroup with prior MI. This analysis was conducted after excluding patients who are at an increased risk of bleeding (patients with prior transient ischemic attack/stroke, body weight <60 kg, and age >75 years). A significant reduction in the primary combined ischemic endpoint (6.8% vs. 8.6%, HR: 0.75; 95% CI: 0.66–0.85; P < 0.0001) was recorded in the vorapaxar group compared with the placebo group with a significant reduction in CV death (1.5% vs. 2.0%, HR: 0.73; 95% CI: 0.56–0.95; P = 0.02). Although GUSTO moderate or severe bleeding still higher with vorapaxar compared with placebo (2.7% vs. 1.8%), this rate was lower in comparison with the rate recorded in the overall trial. This result suggests that vorapaxar may be beneficial as an add-on therapy to standard antiplatelet therapy in patients with prior MI without a significant increase in the risk for intracranial hemorrhage in patients with low bleeding risk.[29]

Another subgroup analysis has been conducted to evaluate the efficacy of vorapaxar in patients with prior MI with and without diabetes mellitus (DM).[30] A total of in 16,896 patients were included in this subgroup analysis after excluding patients with a history of stroke or transient ischemic attack. The primary composite endpoint occurred more frequently in patients with DM compared with patients without DM, and vorapaxar was effective in reducing the incidence of ischemic event irrespective of DM status. In patients with DM, vorapaxar significantly reduced the primary endpoint (11.4% vs. 14.3%, HR: 0.73; 95% CI: 0.60–0.89; P = 0.002), while the incidence of GUSTO moderate/severe bleeding was increased with vorapaxar in this group of patients (4.4% vs. 2.6%, HR: 1.60; 95% CI: 1.07–2.40). Overall, the net clinical outcome was improved with vorapaxar (HR: 0.79; 95% CI: 0.67–0.93), suggesting that the addition of vorapaxar to standard therapy in patients with prior MI and DM significantly reduces the risk of major vascular events.[30]

Another subgroup analysis from the TRA 2P–TIMI 50 trial in patients with peripheral artery disease (n = 3,787) has offered vital information on the use of vorapaxar in PAD. No significant difference was observed in the primary endpoint with vorapaxar in comparison with placebo (11.3% vs. 11.9%; HR: 0.94; 95% CI: 0.78–1.14; P = 0.53). However, a significant decrease was recorded in both the rates of hospitalization for acute limb ischemia (2.3% vs. 3.9%; HR: 0.58; 95% CI: 0.39–0.86; P = 0.006) and peripheral artery revascularization (18.4% vs. 22.2%; HR: 0.84; 95% CI: 0.73–0.97; P = 0.017) in patients taking vorapaxar compared to patients on placebo. Second, bleeding occurred more frequently in the vorapaxar group compared with the placebo group (7.4% vs. 4.5%; HR: 1.62; 95% CI: 1.21–2.18; P = 0.001).[33]

In a subgroup comprising of 14,491 stable patients with a history of coronary stenting, the rate of definite stent thrombosis was evaluated as adjudicated by a central events committee using Academic Research Consortium (ARC) criteria. A total of 152 stent thromboses were recorded, and vorapaxar reduces ARC definite stent thrombosis (1.1% vs. 1.4%; HR: 0.71, 95% CI: 0.51–0.98; P = 0.037).[32]

Another subgroup analysis was conducted in all the patients included in the study to determine the rate of arterial revascularization. Overall, vorapaxar reduces the rate of arterial revascularization (13.6% vs. 15.5%, HR: 0.89; 95% CI: 0.83–0.95; P < 0.001) and this result suggests possible clinical relevance of antagonism of PAR-1 mediated effects on endothelial or smooth muscle cells, as well as platelets.[31]

A subgroup analysis has also been conducted in patients taking thienopyridines and has offered a contrasting result in comparison to the TRACER study. In the TRA 2P–TIMI 50 trial, there was no significant difference in bleeding complications in patients taking thienopyridine (n = 15,356) and patients not taking thienopyridines (n = 11,093), while in the TRACER trial increased hazard of bleeding was observed in patients on a thienopyridine regimen. This contrast may be as a result of differences in both the design and clinical characteristics of patients in the trials.[34]

Another subgroup analysis was conducted to assess the impact of aspirin in 17,779 patients with prior MI with patients baseline aspirin dose categorized as - <100 mg daily, 100–162 mg, and >162 mg. The result of the analysis shows that regardless of baseline ASA dose, vorapaxar reduces the risk of major CV events by approximately 20%, and the relative risk of bleeding was not higher with higher doses of aspirin.[35]

Precaution

Both studies showed that patient with a history of stroke or transient ischemic attack has an increased risk of intracranial hemorrhage.[1415] Vorapaxar increases both the GUSTO and TIMI bleeding criteria. As such, it should be used with caution in patients who are been administered medication with significant bleeding risk and this include anticoagulants and nonsteroidal anti-inflammatory drugs.[17]

Dose

Patient in the TRA 20P-TIMI 50 trial received 2.5 mg of vorapaxar daily in addition to standard care, and this is the dose approved by the FDA. The drug is prepared as vorapaxar sulfate film-coated tablets, 2.5 mg that is equivalent to 2.08 mg of vorapaxar. The medication can be taken with or without food.[3637]

Contraindication

Vorapaxar is contraindicated in patients with history of transient ischemic attack or stroke. Also, it is not recommended in patients with intracranial hemorrhage or any form of active pathologic bleeding.[27]

Renal and hepatic consideration

The metabolism of vorapaxar is via the CYP3A4 and CYP2J2 enzyme and, therefore, concomitant use with strong CYP3A inhibitors or inducer should be avoided.[38] Common CYPA3 inhibitors include the anti-infectives, ketoconazole, posaconazole, itraconazole, nefazodone, clarithromycin saquinavir ritonavir, nelfinavir, and indinavir while CYPA3 inducer includes rifampin, phenytoin, carbamazepine, and St. John's. Wort.[39] Adjustment of the dosage of vorapaxar is not required in patients with renal impairment or in end stage renal disease, and this is because no clinically relevant effect on the pharmacokinetic profile of vorapaxar has been documented in this conditions.[40] Similarly, dosage adjustment is also not necessary in patients with mild to moderate hepatic impairment. However, vorapaxar is not recommended in patients with severe hepatic impairment due to the spontaneous inherent bleeding risk.[41]

Conclusion

The introduction of vorapaxar in CV care presents an opportunity for further reduction in the risk of recurrent MI in patients with prior MI as demonstrated by the result of TRA 2P–TIMI 50 trial. However, vorapaxar is contraindicated in patients with history of transient ischemic attack or stroke due to increased risk of bleeding. The subgroup analysis has highlighted the benefit of vorapaxar in patients with prior MI as an additional therapy to standard of care therapy especially in those with low bleeding risk. In clinical practice, careful consideration should be made in selecting patients with low bleeding risk, and excluding patients with high bleeding risk, especially patients with a history of transient ischemic attack or stroke before recommending vorapaxar.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.