Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus

Diabetes Mellitus Clinical Trial

— OPTIMUS-5  

Official title:

Pharmacodynamic Effects of Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus: The Optimizing Anti-Platelet Therapy In Diabetes MellitUS (OPTIMUS)-5 Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02548650
• Other study ID #: IIS 53377
• Status: Completed
• Phase: Phase 4
• Start date: March 25, 2016
• Est. completion date: February 14, 2019

Study information

• Verified date: January 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, more frequently clopidogrel, represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI) or peripheral arterial disease (PAD). However, rates of ischemic recurrences remain high. Vorapaxar is a protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. Patients with diabetes mellitus (DM) are known to be at increased risk of recurrent atherothrombotic events, which translates into worse outcomes, despite the use of standard of care therapy. This is in part due to the hyperreactive platelet phenotype, which characterizes DM patients, and to inadequate response to oral antiplatelet agents, including clopidogrel. Therefore, vorapaxar is an attractive treatment option for DM patients with a prior MI. The pharmacodynamic (PD) effects of vorapaxar in DM patients and how these may differentiate from non-DM patients has not been explored. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen combined with clopidogrel (and stopping aspirin) represents another important area of clinical interest. The proposed prospective, parallel-design study conducted in patients post-MI or with PAD with and without DM will aim the assess the pharmacodynamic effects of vorapaxar in addition to standard DAPT with aspirin and clopidogrel as well as in combination with clopidogrel only following aspirin withdrawal.

Description:

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor, more frequently clopidogrel, represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI) or peripheral arterial disease (PAD). However, rates of ischemic recurrences remain high, 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. Patients with DM are known to be at increased risk of recurrent atherothrombotic events, which translates into worse outcomes, despite the use of standard of care therapy. This is in part due to the hyperreactive platelet phenotype, which characterizes DM patients, and to inadequate response to oral antiplatelet agents, including clopidogrel. Importantly, in DM patients with prior MI included in the TRA 2P trial, vorapaxar reduced the primary composite end point at 3 years by 27% and led to a greater absolute risk reduction compared with those without DM. Therefore, vorapaxar is an attractive treatment option for DM patients with a prior MI. However, to date the PD effects of vorapaxar in DM patients and how these may differentiate from non-DM patients has not been explored. Further, current trends in clinical practice are seeing many patients discontinue aspirin and maintain clopidogrel. Hence, the role of vorapaxar as part of a dual antithrombotic treatment regimen combined with clopidogrel (and stopping aspirin) represents another important area of clinical interest, in order to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, parallel-design study conducted in patients post-MI or with PAD with and without DM will aim the assess the pharmacodynamic effects of vorapaxar in addition to standard DAPT with aspirin and clopidogrel as well as in combination with clopidogrel only following aspirin withdrawal. Pharmacodynamic assessments will be performed at multiple time point, with different assays exploring multiple pathways of platelet aggregation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 66
• Est. completion date: February 14, 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Patients with a prior MI between 2 weeks and 24 months or with PAD.

2. On DAPT with low-dose aspirin (81mg od) and clopidogrel (75mg od) as per standard-of-care for at least 14 days.

3. Age = 18 years old.

Exclusion criteria:

1. History of acute coronary syndrome in the previous 2 weeks.

2. History of stroke, transient ischemic attack, or intracranial hemorrhage.

3. Active pathological bleeding, history of bleeding events or increased risk of bleeding.

4. Known severe hepatic impairment.

5. Use of strong cytochrome P450 3A4 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).

6. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).

7. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days.

8. Creatinine clearance <30 mL/minute.

9. Platelet count <80x106/mL

10. Hemoglobin <10g/dL

11. Hemodynamic instability

12. Pregnant females

Related Conditions & MeSH terms

• Diabetes Mellitus
• Infarction
• Myocardial Infarction
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Intervention

Drug:
• Vorapaxar
Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days
• Clopidogrel
Triple therapy with DAPT plus vorapaxar (vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days
• Aspirin
Triple therapy with DAPT plus vorapaxar(vorapaxar 2.5mg od plus clopidogrel 75 mg od and aspirin 81 mg od) will be administered for 30 days; then patients will stop aspirin and will take dual treatment (vorapaxar 2.5mg od plus clopidogrel 75 mg od ) for other 30 days

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 in DM	Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in diabetic patients	30 days
Secondary	Maximal Platelet Aggregation in Non-DM	Comparison of maximal platelet aggregation (%) measured by light transmittance aggregometry between between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy in non-diabetic patients	30 days