Editor's Note: This article by Dr. Tricoci is an excellent and comprehensive summary of significant studies supporting the indication for vorapaxar in vascular risk reduction as well as general comments about the protease-activated receptor 1 platelet/thrombin-inhibitor drug class. I believe you will find this an excellent reference source in that regard. George W. Vetrovec, MD, MACC

Introduction

Despite advances in antiplatelet therapy and the use of dual antiplatelet therapies in patients with acute coronary syndromes (ACS) and following coronary stent, the occurrence of recurrent ischemic events remains high. Current antiplatelet therapy is mostly based on aspirin and P2Y₁₂ adenosine diphosphate receptor antagonists.¹ Aspirin is an irreversible COX-1 inhibitor blocking the formation of thromboxane A2 and thus the thromboxane A2-mediated platelet activation.2 P2Y₁₂ antagonist inhibits the effects of adenosine diphosphate on platelet, a key mediator resulting in amplification of platelet activation.² Concomitant inhibition of multiple platelet activation pathways is thought to be effective in reducing atherothrombotic events; therefore, additional targets for platelet inhibitor have been investigated to further reduce cardiovascular (CV) events in addition to standard antiplatelet therapy.

Thrombin is the most potent platelet activator known because it acts at nanomolar concentrations, and the interaction between thrombin and platelet in humans is mediated by the protease activated receptors (PAR)-1 and the PAR-4 receptors.³ PAR-1 is considered the main thrombin receptor because it is activated by low concentration of thrombin.² Vorapaxar, an oral, potent, selective, competitive PAR-1 antagonist with high affinity for the receptor, is the first PAR-1 antagonist approved, both in United States and Europe, for reduction of thrombotic CV events in patients with a history of myocardial infarction (MI) (United States and Europe) and peripheral arterial disease (PAD) (United States) without history of stroke or transient ischemic attack (TIA). Vorapaxar has been shown in pre-clinical studies to inhibit thrombin-mediated platelet activation but have no impact on platelet activation by other agonists, the coagulation cascade, or bleeding time.⁴ The development of vorapaxar relied on the hypothesis that PAR-1 inhibition would reduce ischemic events without significant increase in bleeding. The Phase III clinical trials results confirmed that PAR-1 inhibition is a viable mechanism to reduce ischemic events, but the cost is increased bleeding risk.^5,6

Phase III Trials With Vorapaxar

Vorapaxar was studied in two large Phase III randomized, double blind, placebo-controlled clinical trials. The first, the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial, addressed the use of vorapaxar in non-ST-segment elevation (NSTE) ACS.⁶ The second, TRA 2°P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction), assessed vorapaxar in secondary prevention of atherothrombotic events among patients with recent MI, PAD, or recent stroke.⁵ Notably, in both studies, vorapaxar was assessed as "add-on" therapy on top of standard of care, which largely included aspirin and clopidogrel. Thus, the results reflect a context of triple antiplatelet therapy.

Below is a list of key points from TRA 2°P-TIMI 50:⁵

• A total of 26,499 patients were randomized. They composed 3 different populations: recent MI (2 weeks to 12 months), PAD, or recent stroke (2 weeks to 12 months).
• Patients were randomized to receive vorapaxar 2.5 mg once a day (without loading dose) or placebo in addition to standard of care. Patients were followed for a median of 30 months.
• 78% of post-MI patients were on a thienopyridine, clopidogrel, in nearly all cases.
• Vorapaxar significantly reduced the occurrence of the primary endpoint, CV death, MI, or stroke (9.3% vorapaxar vs. 10.5% placebo at 3 years) (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.80-0.94; p < 0.001).
• Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding occurred at higher rates in the vorapaxar group (4.2%) compared with placebo (2.5%) (HR 1.66; 95% CI, 1.43-1.93; p < 0.001).
• The greatest benefit from vorapaxar was observed in patients who qualified with an MI (17,779 patients) in whom vorapaxar decreased by 20% the risk of the primary endpoint (3-year rates 8.1% vs. 9.7%, HR 0.80, 95% CI, 0.72-0.89; p < 0.0001).⁷
• The trial was terminated early in patients with history of stroke due to the increased risk of intracranial hemorrhage (ICH) (2.4% vorapaxar vs. 0.9% placebo; p < 0.001) and no benefit on the primary endpoint (HR 1.03; 95% CI, 0.85-1.25).⁸

The TRACER trial randomized 12,944 patients with NSTE ACS to receive vorapaxar or placebo.⁶ Key messages from the TRACER trial are listed below:

• Patients with NSTE ACS (>90% with positive cardiac markers) were randomized during the initial presentation, and prior to any revascularization, to receive placebo or vorapaxar 40mg loading dose and 2.5mg daily maintenance dose for the remainder of the trial.
• The primary endpoint was a quintuple composite of death from CV causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization and thus included "softer" unstable angina components.
• Use of concomitant medications was left to the treating physician, and 92% of randomized patients received clopidogrel. Over 20 % received a glycoprotein IIb/IIIa inhibitor during the acute ACS hospitalization. The results of the TRACER trial are thus to be interpreted in the setting of triple or even quadruple antiplatelet therapy.
• The TRACER trial did not meet its primary endpoint because the 8% reduction observed was not statistically significant (HR 0.92; 95%CI, 0.85-1.01; p = 0.07).
• There was a significant reduction of the key secondary endpoint of CV death, MI, or stroke (HR 0.89; 95% CI, 0.81-0.98; p = 0.02).⁶
• Further analysis of the TRACER trial data found that vorapaxar significantly reduced the occurrence of Type 1 MI (spontaneous) by 17% compared with placebo (HR 0.83; 95% CI, 0.73-0.95; p = 0.007).⁹
• Vorapaxar significantly increased serious bleeding (GUSTO moderate and severe bleeding; HR 1.35; 95% CI, 1.16-1.58; p < 0.001) and ICH (1.1% vs. 0.2%, p < 0.001), which lead to the premature termination of the trial after enrollment was completed and during the follow-up phase.⁶

Comment

Based on the results of TRA 2°P-TIMI 50, vorapaxar (2.08 mg tablets of vorapaxar, equivalent to 2.5 mg of vorapaxar sulfate) has been approved by the Food and Drug Administration (FDA) for reduction of thrombotic CV events among patients with a history of MI or PAD and no history of stroke or TIA. The European Medicine Agency has approved vorapaxar for use in patients with prior MI, specifying that the drug should be started at least 2 weeks after the acute MI and preferably within 12 months, based on the TRA 2°P-TIMI 50 design. Unlike the FDA, the European Medicine Agency currently has not approved the PAD indication based on the fact that the manufacturer did not include this indication in its initial submission, as required by the European regulations.

In a secondary analysis of TRA 2°P-TIMI 50, the authors described the efficacy and safety of vorapaxar in the 20,170 patients who met the FDA label indication.¹⁰ They found a 20% reduction in the risk of CV death, MI, or stroke (HR 0.80; 95% CI, 0.73-0.89; p < 0.001) at the expense of increased GUSTO moderate or severe bleeding (HR 1.55; 95% CI, 1.30-1.86; p < 0.001) but no statistically significant increase in ICH (0.6% vs. 0.4%; p = 0.10). For every 1,000 patients treated for 3 years, vorapaxar prevented 16 CV deaths, MIs, or strokes at the expense of 3 GUSTO severe bleeding and 13 GUSTO moderate or severe bleeding outcomes.¹⁰

With the availability of vorapaxar in the antiplatelet armamentarium for chronic treatment of patients with atherosclerosis (aspirin, clopidogrel, prasugrel, ticagrelor, and, in Europe, rivaroxaban), questions arise about the selection of patients for whom vorapaxar may be useful.^1,11 The current FDA indication is quite broad in that that the label, in essence, includes any patients with a history of MI without prior stroke and TIA. Because dual antiplatelet therapy is currently the standard of care in post-MI patients ^1,11 and is used in most patients following MI,¹² a routine and broad application of vorapaxar as a third antiplatelet therapy in addition to aspirin and P2Y₁₂ inhibitor appears potentially hindered by concerns related to costs and increased risk of bleeding associated with triple therapy. In addition, because the TRACER trial did not support the early initiation during acute hospitalization, the decision to start vorapaxar would typically be deferred to post-discharge follow-up. Therefore, in most cases, a physician would need to decide whether to add a third agent in a stable, post-ACS setting. Finally, because vorapaxar was not studied in combination with prasugrel and ticagrelor, no data are available on safety of vorapaxar as a third agent in patients treated with novel, more potent P2Y₁₂ inhibitors.

In our opinion, a more selective approach is needed to identify patients who may be receiving vorapaxar. Patients at high risk of ischemic events, such as those with diabetes,¹³ recurrent spontaneous MI, and prior coronary artery bypass graft surgery (CABG) with recurrent MI, are possible examples of high-risk populations in which a physician may consider adding vorapaxar, provided that the patients do not have history of stroke and TIA and the risk of bleeding is considered acceptable.

A group of patients that has raised interest is that of patients with PAD. There are several aspects that make patients with PAD an interesting group. First, the TRA 2°P-TIMI 50 included a large group of patients with PAD as qualifying diagnosis, which has ultimately lead to FDA approval for this indication.⁵ History of PAD has also been established as an increased ischemic risk indicator in patients with MI. In secondary analysis from TRA 2°P-TIMI 50, patients with PAD who received vorapaxar had decreased hospitalizations for acute limb ischemia (HR 0.58; 95% CI, 0.39-0.86; p = 0.006) and decreased need for peripheral artery revascularization (HR 0.84; 95% CI, 0.73-0.97; p = 0.017).¹⁴ Patients with MI who have concomitant PAD may therefore be another group for which the use of vorapaxar may be considered, with the caveat that the effect on peripheral outcomes needs confirmatory evidence. Because there is a relative paucity of data on antiplatelet therapies in PAD, especially assessing efficacy on limb ischemia, and because the American College of Cardiology, American Heart Association, and American College of Chest Physicians generally recommend monotherapy with aspirin or clopidogrel, there is further opportunity to study vorapaxar in patients with PAD, potentially as monotherapy and with special focus on peripheral outcomes.^15,16

Patients who underwent CABG represent another population of possible interest. In the TRACER trial, 10.1% of patients underwent CABG during the initial NSTE ACS hospitalization.¹⁷ In this population, there was a 45% reduction in the primary endpoint (composite of death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) with vorapaxar (HR 0.55; 95% CI, 0.36-0.83; p = 0.005) and a nonsignificant increase in CABG-related Thrombolysis in Myocardial Infarction major bleeding (9.7% vorapaxar vs. 7.3% placebo; p = 0.12). Patients with prior MI and CABG would fall under the current TRA 2°P-TIMI 50 indication, and, in addition, these promising data with vorapaxar in patients undergoing CABG support the opportunity for further confirmatory clinical trials.

Finally, a possible strategy of vorapaxar is to start the drug, in addition to aspirin, in post-MI patients once they are able to come off P2Y₁₂ inhibitors, thus avoiding triple therapy. One challenge in the application of this approach comes from the fact that P2Y₁₂ inhibitors are currently recommended for 1 year after MIs, and the TRA 2°P-TIMI 50 randomized patients up to 1 year post-MI.¹ Because one can argue that there should not be major differences in patients at 11 or 13 months after MI and because the time cut-off used in trials is often arbitrary, starting vorapaxar after 1 year from the MI may not be unreasonable. But one must be aware that patients in TRA 2°P-TIMI 50 were not included beyond 1 year from the acute MI; thus this scenario was not directly studied in Phase III.

Conclusion

Vorapaxar is a first-in-class PAR-1 antagonist with a positive benefit-risk profile, when added to aspirin and/or clopidogrel, for prevention of atherothrombotic events demonstrated in secondary prevention among patients with prior MI and PAD with no history of stroke or TIA. The Phase III trials with vorapaxar also proved that PAR-1 antagonism is a viable mechanism to reduce recurrent atherothrombotic events, with opportunities to explore further potential clinical applications of the drug. Because of the "crowded" space in chronic antithrombotic treatments, the fact that vorapaxar was studied as "add-on" treatment, and that benefits are demonstrated in stable post-MI patients, the routine use of the drug will predictably be challenging. However, with appropriate patient selection, the drug may still have a role in secondary prevention following MI. Secondary analyses from TRA 2°P-TIMI 50 and the TRACER trial indicated that PAD and CABG patients are potential groups in which further investigation of vorapaxar is warranted. Finally, future studies with different antiplatelet combinations, duration, and doses are needed to clarify if vorapaxar has a role in the treatment of patients with ACS.

References

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2. Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 2009;102:248-57.
3. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258-64.
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7. Scirica BM, Bonaca MP, Braunwald E, et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial. Lancet 2012;380:1317-24.
8. Morrow DA, Alberts MJ, Mohr JP, et al. Efficacy and safety of vorapaxar in patients with prior ischemic stroke. Stroke 2013;44:691-8.
9. Leonardi S, Tricoci P, White HD, et al. Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA·CER) trial. Eur Heart J 2013;34:1723-31.
10. Magnani G, Bonaca MP, Braunwald E, et al. Efficacy and safety of vorapaxar as approved for clinical use in the United States. J Am Heart Assoc 2015;4:e001505.
11. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315.
12. Tricoci P, Lokhnygina Y, Huang Z, et al. Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial. Am Heart J 2014;168:869-77.e1.
13. Cavender MA, Scirica BM, Bonaca MP, et al. Vorapaxar in patients with diabetes mellitus and previous myocardial infarction: findings from the thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events-TIMI 50 trial. Circulation 2015;131:1047-53.
14. Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50. Circulation 2013;127:1522-9.
15. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e669S-90S.
16. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2020-45.
17. Whellan DJ, Tricoci P, Chen E, et al. Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). J Am Coll Cardiol 2014;63:1048-57.

Keywords: Acute Coronary Syndrome, Adenosine, Adenosine Diphosphate, Angina, Unstable, Aspirin, Bleeding Time, Blood Platelets, Confidence Intervals, Coronary Artery Bypass, Coronary Vessels, Diabetes Mellitus, Double-Blind Method, Intracranial Hemorrhages, Ischemic Attack, Transient, Lactones, Myocardial Infarction, Peripheral Arterial Disease, Platelet Activation, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Pyridines, Receptor, PAR-1, Receptors, Thrombin, Risk Reduction Behavior, Secondary Prevention, Stents, Stroke, Sulfates, Thrombin, Thromboxane A2, Ticlopidine, United States Food and Drug Administration

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