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

Myocardial Infarction Clinical Trial

— VORA-PRATIC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02545933
• Other study ID #: IIS 53376
• Status: Completed
• Phase: Phase 4
• Start date: February 2016
• Est. completion date: January 2020

Study information

• Verified date: September 2020
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: January 2020
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction

Intervention

Drug:
• Prasugrel
Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)
• Vorapaxar
Vorapaxar will be administered at the dose of 2.5mg once daily
• Aspirin
Aspirin will be administered at the dose of 81mg once daily
• Ticagrelor
Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Locations

Country	Name	City	State
United States	University of Florida	Jacksonville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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