Pharmacodynamic Effects of Low-dose Rivaroxaban With Antiplatelet Therapies

NCT03718429 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: IIS-RIVA0120180155
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 2

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.

Conditions

Coronary Artery Disease; Peripheral Arterial Disease; Atrial Fibrillation

Keywords

aspirin; clopidogrel; ticagrelor; rivaroxaban; pharmacodynamic (PD)

Outcome Measures

Primary Outcomes (3)

• Platelet-Mediated Global Thrombogenicity

  Comparison of platelet-mediated global thrombogenicity measured by light transmittance aggregometry following collagen-related peptide+adenosine diphosphate+ tissue factor (CATF) stimuli between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This was reported as maximal aggregation %. The combination of agonists included in the CATF cocktail leads to activation of multiple platelet pathways including thrombin generation and is therefore a marker of thrombus formation mediated by platelets.

  20 days

• Platelet Aggregation Measured by VerifyNow PRU

  P2Y12 reaction units (PRU) by VerifyNow of dual antiplatelet therapy vs. dual antiplatelet therapy plus rivaroxaban. VerifyNow is a turbidimetric based optical detection system which measures platelet aggregation induced by ADP as an increase in light transmittance.

  20 days

• Thrombin Generation

  Comparison of thrombin generation, reported as peak thrombin level measured by a thrombin generation assay, between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This is reflective of the amount of thrombin that is generated following stimuli with tissue factor. The theombin generation assay will be carried out using Technothrombin® fluorogenic assay kit.

  20 days

Study Arms (4)

aspirin

EXPERIMENTAL

Patients on aspirin 81 mg daily 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 2.5 mg Tablet

aspirin and clopidogrel

EXPERIMENTAL

Patients on aspirin (81 mg daily) plus clopidogrel (75 mg daily) 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 2.5 mg Tablet

aspirin and ticagrelor

EXPERIMENTAL

Patients on aspirin (81 mg daily) and ticagrelor (90 mg bid) 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 2.5 mg Tablet

rivaroxaban

NO INTERVENTION

A control cohort of subjects with atrial fibrillation on full dose rivaroxaban (20 mg daily) as per standard of care will be recruited and will undergo a single PD assessment.

Interventions

Rivaroxaban 2.5 mg Tablet DRUG

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.

Also known as: Xarelto

aspirin; aspirin and clopidogrel; aspirin and ticagrelor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Known CAD (defined as angiographic evidence of \>50% coronary artery stenosis or prior coronary revascularization) or PAD (defined as a positive ankle brachial index (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 creatinine clearance \[CrCl\] \>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.

You may not qualify if:

• Active pathological bleeding, history of clinically significant bleeding events, or deemed at increased risk of bleeding.
• CrCL \<20 mL/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 \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].

Sponsors & Collaborators

• University of Florida: lead
• Janssen Scientific Affairs, LLC: collaborator

Study Sites (2)

Cardiovascular Research Center,

Jacksonville, Florida, 32206, United States

Location

UF Health Jacksonville

Jacksonville, Florida, 32209, United States

Location

Related Publications (1)

• Galli M, Franchi F, Rollini F, Been L, Jaoude PA, Rivas A, Zhou X, Jia S, Maaliki N, Lee CH, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Geisler T, Jennings LK, Bass TA, Angiolillo DJ. Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy. Eur Heart J Cardiovasc Pharmacother. 2022 Sep 29;8(7):728-737. doi: 10.1093/ehjcvp/pvac022.

  PMID: 35353154 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease; Peripheral Arterial Disease; Atrial Fibrillation

Interventions

Rivaroxaban

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Atherosclerosis; Peripheral Vascular Diseases; Arrhythmias, Cardiac; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dominick Angiolillo, MD,PhD
• Organization: University of Florida

dominick.angiolillo@jax.ufl.edu

904-244-3378

Study Officials

• Dominick J Angiolillo, MD,PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The proposed investigation will be a prospective PD (pharmacodynamic) study conducted in cohorts of patients with CAD, PAD, or atrial fibrillation

Study Record Dates

• First Submitted: October 19, 2018
• First Posted: October 24, 2018
• Study Start: January 14, 2019
• Primary Completion: February 13, 2020
• Study Completion: August 30, 2020
• Last Updated: June 27, 2022
• Results First Posted: June 27, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)