Myocardial Infarction, Diabetes Mellitus, Peripheral Arterial Disease
Conditions
Keywords
myocardial infarction, diabetes mellitus, vorapaxar, peripheral arterial disease
Brief 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.
Detailed 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.
Interventions
DRUGVorapaxar
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
DRUGClopidogrel
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
DRUGAspirin
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
Sponsors
Merck Sharp & Dohme LLC
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Platelet Aggregation in DM | 30 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Platelet Aggregation in Non-DM | 30 days | 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 |
Countries
United States
Participant flow
Pre-assignment details
Between March 2016 and October 2018, 71 patients agreed to participate in the study; 5 patients were not eligible for randomization due to the presence of an exclusion criteria. 66 patients (DM, n=30; non-DM, n=36) were exposed to at least one dose of study medication, representing the safety population.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Diabetes Triple therapy (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. | 30 |
| Patients Without Diabetes Triple therapy (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. | 34 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Therapy | Adverse Event | 1 | 1 |
| Double Therapy | Withdrawal by Subject | 0 | 1 |
| Triple Therapy | Adverse Event | 1 | 0 |
| Triple Therapy | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Patients With Diabetes | Patients Without Diabetes | Total |
|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 8 | 56 years STANDARD_DEVIATION 9 | 58 years STANDARD_DEVIATION 10 |
| chronic kidney disease | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 11 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 15 Participants | 22 Participants | 37 Participants |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 23 Participants | 23 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 36 |
| other Total, other adverse events | 2 / 30 | 2 / 36 |
| serious Total, serious adverse events | 0 / 30 | 0 / 36 |
Outcome results
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
Time frame: 30 days
Population: The PD population included all patients with PD data and without a major protocol deviation thought to affect the PD effects of vorapaxar, aspirin and clopidogrel. Two patients were not compliant with medications and therefore excluded from the PD analysis. Some patients did not have primary end point data but were considered for other analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy | Maximal Platelet Aggregation in DM | 65 percentage of aggregation | Standard Deviation 20 |
| Dual Therapy | Maximal Platelet Aggregation in DM | 78 percentage of aggregation | Standard Deviation 20 |
Comparison: The primary end point of our study was the comparison of CAT-induced MPA measured by LTA between triple (vorapaxar plus DAPT) and dual (vorapaxar plus clopidogrel) therapy. We hypothesized that dual therapy would be non-inferior to triple therapy after 30±5 days of treatmentp-value: >0.0595% CI: [3, 21]ANOVA
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
Time frame: 30 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy | Maximal Platelet Aggregation in Non-DM | 60 percentage of aggregation | Standard Deviation 15 |
| Dual Therapy | Maximal Platelet Aggregation in Non-DM | 70 percentage of aggregation | Standard Deviation 20 |