Vorapaxar in Patients With Prior Myocardial Infarction Treated With Prasugrel and Ticagrelor

NCT ID: NCT02545933

Last Updated: 2020-09-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 130 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-29
• Study Completion Date: 2020-01-31

Brief Summary

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.

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.

Conditions

Myocardial Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DAPT plus vorapaxar

Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od

Group Type: EXPERIMENTAL

Prasugrel

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Vorapaxar

Intervention Type: DRUG

Vorapaxar will be administered at the dose of 2.5mg once daily

Aspirin

Intervention Type: DRUG

Aspirin will be administered at the dose of 81mg once daily

Ticagrelor

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Prasugrel/ticagrelor plus vorapaxar

Prasugrel or ticagrelor plus vorapaxar 2.5mg od

Group Type: EXPERIMENTAL

Prasugrel

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Vorapaxar

Intervention Type: DRUG

Vorapaxar will be administered at the dose of 2.5mg once daily

Ticagrelor

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

DAPT

Aspirin in addition to prasugrel or ticagrelor

Group Type: ACTIVE_COMPARATOR

Prasugrel

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Aspirin

Intervention Type: DRUG

Aspirin will be administered at the dose of 81mg once daily

Ticagrelor

Intervention Type: DRUG

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Interventions

Prasugrel

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Intervention Type: DRUG

Vorapaxar

Vorapaxar will be administered at the dose of 2.5mg once daily

Intervention Type: DRUG

Aspirin

Aspirin will be administered at the dose of 81mg once daily

Intervention Type: DRUG

Ticagrelor

Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Intervention Type: DRUG

Other Intervention Names

Effient; Zontivity; ASA (acetylsalicylic acid); Brilinta

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dominick J Angiolillo, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida College of Medicine-Jacksonville

Locations

University of Florida

Jacksonville, Florida, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32306797 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

IIS 53376

Identifier Type: -

Identifier Source: org_study_id