VORA-PRATIC: Vorapaxar in Patients With Prior Myocardial Infarction Treated With Prasugrel and Ticagrelor

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT02545933
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 130
• Location: 1
• Arms: 3
• Actual Duration (Months): 47
• Patients Per Site Per Month: 2.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Infarction	Drug: Prasugrel; Drug: Vorapaxar; Drug: Aspirin; Drug: Ticagrelor	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: May 1, 2019
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DAPT plus vorapaxar Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient ; Drug: Vorapaxar; Vorapaxar will be administered at the dose of 2.5mg once daily; Other Names: Zontivity ; Drug: Aspirin; Aspirin will be administered at the dose of 81mg once daily; Other Names: ASA (acetylsalicylic acid) ; Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta
Experimental: Prasugrel/ticagrelor plus vorapaxar Prasugrel or ticagrelor plus vorapaxar 2.5mg od	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient ; Drug: Vorapaxar; Vorapaxar will be administered at the dose of 2.5mg once daily; Other Names: Zontivity ; Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta
Active Comparator: DAPT Aspirin in addition to prasugrel or ticagrelor	Drug: Prasugrel; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Effient ; Drug: Aspirin; Aspirin will be administered at the dose of 81mg once daily; Other Names: ASA (acetylsalicylic acid) ; Drug: Ticagrelor; Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily); Other Names: Brilinta

Outcome Measures

Primary Outcome Measures

1. Maximal Platelet Aggregation [30 days]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209

Sponsors and Collaborators

• University of Florida
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Dominick J Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 30, 2018
• Informed Consent Form - Jul 5, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT02545933
• Other Study ID Numbers: IIS 53376
• First Posted: Sep 10, 2015
• Last Update Posted: Sep 16, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Florida: prasugrel; ticagrelor; vorapaxar
• Additional relevant MeSH terms: Myocardial Infarction; Infarction; Aspirin; Ticagrelor; Prasugrel Hydrochloride; Vorapaxar

Study Results

Participant Flow

Arm/Group Title	DAPT Plus Vorapaxar	Prasugrel/Ticagrelor Plus Vorapaxar	DAPT
Arm/Group Description	Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od 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)	Prasugrel or ticagrelor plus vorapaxar 2.5mg od 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 Ticagrelor: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)	Aspirin in addition to prasugrel or ticagrelor Prasugrel: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/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)
Period Title: Overall Study
STARTED	44	43	43
COMPLETED	38	40	39
NOT COMPLETED	6	3	4

Baseline Characteristics

Arm/Group Title	DAPT Plus Vorapaxar	Prasugrel/Ticagrelor Plus Vorapaxar	DAPT	Total
Arm/Group Description	Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od 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)	Prasugrel or ticagrelor plus vorapaxar 2.5mg od 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 Ticagrelor: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)	Aspirin in addition to prasugrel or ticagrelor Prasugrel: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/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)	Total of all reporting groups
Overall Participants	44	43	43	130
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (9)	56 (9)	56 (10)	56 (10)
Sex: Female, Male (Count of Participants)
Female	14 31.8%	11 25.6%	14 32.6%	39 30%
Male	30 68.2%	32 74.4%	29 67.4%	91 70%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	17 38.6%	14 32.6%	13 30.2%	44 33.8%
White	24 54.5%	26 60.5%	29 67.4%	79 60.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 6.8%	3 7%	1 2.3%	7 5.4%
Region of Enrollment (Count of Participants)
United States	44 100%	43 100%	43 100%	130 100%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	11 25%	12 27.9%	10 23.3%	33 25.4%

Outcome Measures

1. Primary Outcome

Title	Maximal Platelet Aggregation
Description	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.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

130 patients were randomized and exposed to at least one dose of study medication (triple therapy, n=44; dual therapy, n= 43; DAPT, n=43). Of these, 115 patients (triple therapy, n=37; dual therapy, n= 39; DAPT, n=39) had valid primary endpoint data

Arm/Group Title	DAPT Plus Vorapaxar	Prasugrel/Ticagrelor Plus Vorapaxar	DAPT
Arm/Group Description	Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od 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)	Prasugrel or ticagrelor plus vorapaxar 2.5mg od 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 Ticagrelor: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)	Aspirin in addition to prasugrel or ticagrelor Prasugrel: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/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)
Measure Participants	37	39	39
Mean (Standard Deviation) [percent aggregation]	52 (21)	64 (20)	74 (10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DAPT Plus Vorapaxar, Prasugrel/Ticagrelor Plus Vorapaxar, DAPT
	Comments	We hypothesized that adjunctive vorapaxar would result in a significant reduction of CAT-induced platelet aggregation. Assuming a 10% absolute reduction in CAT-induced maximal platelet aggregation with a common standard deviation of 13%, 37 patients per group with valid primary endpoint data were required to detect a significant difference with a 90% power and 2-sided alpha=0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	least square mean difference
	Estimated Value	27
	Confidence Interval	(2-Sided) 95%; 19 to 34
	Parameter Dispersion	Type: Value:
	Estimation Comments	DAPT group vs DAPT plus vorapaxar group

Adverse Events

Time Frame	Duration of the study (30 days)
Arm/Group Title	DAPT Plus Vorapaxar		Prasugrel/Ticagrelor Plus Vorapaxar		DAPT
Arm/Group Description	Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od 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)		Prasugrel or ticagrelor plus vorapaxar 2.5mg od 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 Ticagrelor: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)		Aspirin in addition to prasugrel or ticagrelor Prasugrel: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/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)
All Cause Mortality
	DAPT Plus Vorapaxar		Prasugrel/Ticagrelor Plus Vorapaxar		DAPT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/43 (0%)		0/43 (0%)
Serious Adverse Events
	DAPT Plus Vorapaxar		Prasugrel/Ticagrelor Plus Vorapaxar		DAPT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/43 (0%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	DAPT Plus Vorapaxar		Prasugrel/Ticagrelor Plus Vorapaxar		DAPT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/44 (20.5%)		6/43 (14%)		4/43 (9.3%)
Blood and lymphatic system disorders
BARC 1 bleeding	6/44 (13.6%)	6	1/43 (2.3%)	1	0/43 (0%)	0
Cardiac disorders
chest pain	0/44 (0%)		0/43 (0%)		4/43 (9.3%)
Gastrointestinal disorders
diarrhea	1/44 (2.3%)		2/43 (4.7%)		0/43 (0%)
General disorders
dizziness	1/44 (2.3%)		2/43 (4.7%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
dyspnea	1/44 (2.3%)		1/43 (2.3%)		0/43 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.