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Pharmacodynamic Effects of Low-dose Rivaroxaban With Antiplatelet Therapies

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ClinicalTrials.gov Identifier: NCT03718429
Recruitment Status : Recruiting
First Posted : October 24, 2018
Last Update Posted : February 6, 2019
Sponsor:
Collaborator:
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
University of Florida

Brief Summary:

Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations.

To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Peripheral Arterial Disease Atrial Fibrillation Drug: Rivaroxaban 2.5Mg Tablet Phase 4

Detailed Description:

Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations.

However, although the introduction of newer antithrombotic strategies has been associated with a reduction in ischemic recurrences in high-risk patients, these have been consistently associated with an increase in bleeding complications. These have been observed particularly with the combination of an oral anticoagulant agent, including low-dose rivaroxaban, with standard DAPT, also known as "triple therapy". Observations from laboratory and clinical studies suggest that in the presence of effective blockade of other pathways triggering thrombotic complications aspirin may not offer added antithrombotic effects but contribute to the increased bleeding. These observations have set the basis for a large number of clinical outcomes studies evaluating whether dropping aspirin in the presence of more potent and effective blockade of other pathways triggering thrombosis has a better safety profile without a tradeoff in efficacy. Amongst these strategies, the use of low-dose rivaroxaban in adjunct to a P2Y12 inhibitor, also known as dual therapy, has been proposed. This approach may be of potential benefit to reduce atherothrombotic complications in high-risk patients following an acute coronary event. On the other hand, regimens with more modest antithrombotic effects compared with a combination of low-dose rivaroxaban and a P2Y12 receptor inhibitor such as low-dose rivaroxaban alone or in combination with aspirin may be more suitable in more stabilized patients.

To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The proposed investigation will be a prospective PD (pharmacodynamic) study conducted in cohorts of patients with CAD, PAD, or atrial fibrillation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacodynamic Effects of Low-dose Rivaroxaban in Combination With Antiplatelet Therapies in Patients With Coronary and Peripheral Artery Disease Manifestations
Actual Study Start Date : January 14, 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Rivaroxaban

Arm Intervention/treatment
Experimental: aspirin
Patients will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days.
Drug: Rivaroxaban 2.5Mg Tablet
PD assessments will be conducted at 3 time points: i) baseline (while on standard of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, and iii) 7-10 days after dropping aspirin.
Other Name: Xarelto

Experimental: aspirin and clopidogrel
Patients will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days.
Drug: Rivaroxaban 2.5Mg Tablet
PD assessments will be conducted at 3 time points: i) baseline (while on standard of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, and iii) 7-10 days after dropping aspirin.
Other Name: Xarelto

Experimental: aspirin and ticagrelor
Patients will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days.
Drug: Rivaroxaban 2.5Mg Tablet
PD assessments will be conducted at 3 time points: i) baseline (while on standard of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, and iii) 7-10 days after dropping aspirin.
Other Name: Xarelto

No Intervention: rivaroxaban
A control cohort of subjects with atrial fibrillation on full dose rivaroxaban (20 mg/qd) as per standard of care will be recruited and will undergo a single PD assessment.



Primary Outcome Measures :
  1. Platelet aggregation measured by VerifyNow PRU [ Time Frame: 20 days ]
    P2Y12 reaction units (PRU) by VerifyNow with or without low-dose rivaroxaban in addition to each regimen of antiplatelet therapy

  2. Thrombin generation [ Time Frame: 20 days ]
    Comparison of clot kinetic assessed as thrombin generation measured by Technothrombin fluorogenic assay kit with or without low-dose rivaroxaban in addition to each regimen of antiplatelet therapy


Secondary Outcome Measures :
  1. Platelet aggregation measured by VASP PRI [ Time Frame: 20 days ]
    Platelet reactivity index (PRI) by VASP with or without low-dose rivaroxaban in addition to each regimen of antiplatelet therapy

  2. Clot strength [ Time Frame: 20 days ]
    Comparison of thrombus formation assessed as clot strength measured by thromboelastography with or without low-dose rivaroxaban in addition to each regimen of antiplatelet therapy



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Known CAD (defined as angiographic evidence of >50% coronary artery stenosis or prior coronary revascularization) or PAD (defined as a positive ABI or prior revascularization)
  • on treatment with either aspirin (81mg/qd), aspirin (81mg/qd) plus clopidogrel (75mg/qd), or aspirin (81mg/qd) plus ticagrelor (90mg/bid) for at least 3 months per standard of care OR
  • Atrial fibrillation (paroxysmal, persistent or permanent) on treatment with rivaroxaban 20 mg qd (if CrCl >50 mL/min) or 15 mg qd (if CrCl 15 - 50 mL/min) per standard of care. Patients with concomitant CAD or PAD who are also taking antiplatelet medications are not eligible. However, if these are only on oral anticoagulation with rivaroxaban (and no antiplatelet therapy) the person will be eligible.

Exclusion criteria:

  • Active pathological bleeding, history of clinically significant bleeding events, or deemed at increased risk of bleeding.
  • CrCL <20mL/min
  • Any clinical indication to be on triple antithrombotic therapy (DAPT plus an oral anticoagulant)
  • An acute coronary event in the past 90 days
  • Prior hemorrhagic stroke or intracranial hemorrhage
  • Ischemic stroke/transient ischemic attack in the past 6 months
  • Chronic use of nonsteroidal anti-inflammatory drugs
  • On treatment with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) or inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).
  • Known moderate or severe hepatic impairment (Child-Pugh B and C)
  • Prior hypersensitivity reaction to rivaroxaban
  • On treatment with prasugrel in the past 10 days.
  • Platelet count <80x106/mL
  • Hemoglobin <10g/dL
  • Hemodynamic instability
  • Pregnant females [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study].

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03718429


Contacts
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Contact: Dominick J Angiolillo, MD,PhD 904-244-3378 dominick.angiolillo@jax.ufl.edu
Contact: Andrea Goosen 904-244-5617 Andrea.Goosen@jax.ufl.edu

Locations
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United States, Florida
Cardiovascular Research Center, Recruiting
Jacksonville, Florida, United States, 32206
Contact: Dominick J Angiolillo, MD, PhD       dominick.angiolillo@jax.ufl.edu   
UF Health Jacksonville Recruiting
Jacksonville, Florida, United States, 32209
Contact: Dominick J Angiolillo, MD, PhD       dominick.angiolillo@jax.ufl.edu   
Principal Investigator: Dominick J Angiolillo, MD, PhD         
Sponsors and Collaborators
University of Florida
Janssen Scientific Affairs, LLC
Investigators
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Principal Investigator: Dominick J Angiolillo, MD,PhD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03718429     History of Changes
Other Study ID Numbers: IIS-RIVA01
First Posted: October 24, 2018    Key Record Dates
Last Update Posted: February 6, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No sharing is planned

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Florida:
aspirin
clopidogrel
ticagrelor
rivaroxaban
pharmacodynamic (PD)

Additional relevant MeSH terms:
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Atrial Fibrillation
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Peripheral Arterial Disease
Peripheral Vascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Atherosclerosis
Aspirin
Clopidogrel
Ticagrelor
Rivaroxaban
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors