Pharmacodynamic Effects of Low-dose Rivaroxaban With Antiplatelet Therapies

Pharmacodynamic Effects of Low-dose Rivaroxaban in Combination With Antiplatelet Therapies in Patients With Coronary and Peripheral Artery Disease Manifestations

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Peripheral Arterial Disease; Atrial Fibrillation
• Intervention / Treatment: Drug: Rivaroxaban 2.5 mg Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • UF Health Jacksonville
    • Jacksonville, Florida, United States, 32206
      • Cardiovascular Research Center,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• 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.

Exclusion criteria:

• 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].

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: aspirin; 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; 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 Names: Xarelto
EXPERIMENTAL: aspirin and clopidogrel; 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; 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 Names: Xarelto
EXPERIMENTAL: aspirin and ticagrelor; 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; 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 Names: Xarelto
NO_INTERVENTION: rivaroxaban; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Janssen Scientific Affairs, LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 14, 2019
• Primary Completion (ACTUAL): February 13, 2020
• Study Completion (ACTUAL): August 30, 2020

Study Registration Dates

• First Submitted: October 19, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (ACTUAL): October 24, 2018

Study Record Updates

• Last Update Posted (ACTUAL): June 27, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: ticagrelor; clopidogrel; aspirin; rivaroxaban; pharmacodynamic (PD)
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Arrhythmias, Cardiac; Coronary Disease; Coronary Artery Disease; Peripheral Arterial Disease; Peripheral Vascular Diseases; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: IIS-RIVA01; 20180155 (OTHER: WIRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No sharing is planned

Drug and device information, study documents

• 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