Vorapaxar in Patients With Prior Myocardial Infarction Treated With Prasugrel and Ticagrelor (VORA-PRATIC)

Adjunctive Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With New Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-PRATIC): A Prospective, Randomized, Pharmacodynamic Study

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI). However, rates of ischemic recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, continue to be activated. Vorapaxar is a protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease. However, to date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with antiplatelet therapy including prasugrel or ticagrelor, is largely unexplored. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, with withdrawal of aspirin, represents another important area of clinical interest as it has the potential to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction
• Intervention / Treatment: Drug: Prasugrel; Drug: Vorapaxar; Drug: Aspirin; Drug: Ticagrelor

Detailed Description

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI). The novel P2Y12 receptor inhibitors prasugrel and ticagrelor are characterized by more prompt, potent, and predictable antiplatelet effects compared with clopidogrel and are associated with a greater reduction of ischemic events in acute coronary syndrome patients. However, rates of ischemic recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease. A large-scale clinical trial showed that the use of vorapaxar (2.5 mg once/daily) in addition to standard antiplatelet therapy (including aspirin and a P2Y12 receptor inhibitor) was effective in the secondary prevention of recurrent thrombotic events in patients with previous atherothrombosis, in particular in patients with prior MI, at the expense of an increase in major bleeding. However, to date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely unexplored. This may indeed represent a limitation for the uptake of vorapaxar in modern day clinical practice where these agents are being more broadly utilized. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, with withdrawal of aspirin, represents another important area of clinical interest as it has the potential to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin. Pharmacodynamic assessments will be performed at multiple time points and with different assays exploring multiple pathways of platelet aggregation. Exploratory assessments on the safety of such approach will also be evaluated.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients with a prior MI within the previous 2 weeks to 12 months.
2. On DAPT with low-dose aspirin (81mg od) and either prasugrel (10mg od) or ticagrelor (90mg bid) as per standard-of-care for at least 2 weeks.
3. Free from bleeding and ischemic events after the index MI event.
4. Age between 18 and 75 years old.

Exclusion criteria:

1. History of stroke, transient ischemic attack, or intracranial hemorrhage.
2. Active pathological bleeding, history of bleeding events or increased risk of bleeding.
3. Known severe hepatic impairment.
4. Age >75 years.
5. Body weight <60 Kg.
6. Use of strong Cytochrome P450 3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) or inducers (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin).
7. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).
8. On treatment with any antiplatelet agent other than aspirin, prasugrel and ticagrelor in the past 14 days.
9. Creatinine clearance <30 mL/minute.
10. Platelet count <80x106/mL
11. Hemoglobin <10g/dL
12. Hemodynamic instability
13. Pregnant females

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DAPT plus vorapaxar; Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient; Drug: Vorapaxar; Vorapaxar will be administered at the dose of 2.5mg once daily; Other Names: Zontivity; Drug: Aspirin; Aspirin will be administered at the dose of 81mg once daily; Other Names: ASA (acetylsalicylic acid); Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta
Experimental: Prasugrel/ticagrelor plus vorapaxar; Prasugrel or ticagrelor plus vorapaxar 2.5mg od	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient; Drug: Vorapaxar; Vorapaxar will be administered at the dose of 2.5mg once daily; Other Names: Zontivity; Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta
Active Comparator: DAPT; Aspirin in addition to prasugrel or ticagrelor	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient; Drug: Aspirin; Aspirin will be administered at the dose of 81mg once daily; Other Names: ASA (acetylsalicylic acid); Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Platelet Aggregation	The primary end point of our study is the comparison of maximal platelet aggregation measured by light transmittance aggregometry using CAT (collagen-ADP-TRAP) between DAPT and DAPT plus vorapaxar after 30 days of treatment.	30 days

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Publications and helpful links

General Publications

• Franchi F, Rollini F, Faz G, Rivas JR, Rivas A, Agarwal M, Briceno M, Wali M, Nawaz A, Silva G, Shaikh Z, Maaliki N, Fahmi K, Been L, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Baber U, Mehran R, Jennings LK, Bass TA, Angiolillo DJ. Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y12 Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study. J Am Heart Assoc. 2020 Apr 21;9(8):e015865. doi: 10.1161/JAHA.120.015865. Epub 2020 Apr 20.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: September 8, 2015
• First Submitted That Met QC Criteria: September 9, 2015
• First Posted (Estimate): September 10, 2015

Study Record Updates

• Last Update Posted (Actual): September 16, 2020
• Last Update Submitted That Met QC Criteria: September 15, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: prasugrel; ticagrelor; vorapaxar
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor; Prasugrel Hydrochloride; Vorapaxar
• Other Study ID Numbers: IIS 53376

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No