Vorapaxar in Patients With Prior Myocardial Infarction Treated With Prasugrel and Ticagrelor
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 3/17/2019 |
| Start Date: | February 2016 |
| End Date: | September 2019 |
| Contact: | Dominick J Angiolillo, MD, PhD |
| Email: | dominick.angiolillo@jax.ufl.edu |
| Phone: | +1-904-244-3378 |
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.
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.
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.
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.
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 CYP3A 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
We found this trial at
1
site
Jacksonville, Florida 32209
Principal Investigator: Dominick J Angiolillo, MD, PhD
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