Clinical trial NCT03718429: Pharmacodynamic Effects of Low-dose Rivaroxaban With Antiplatelet Therapies
Official title: Pharmacodynamic Effects of Low-dose Rivaroxaban in Combination With Antiplatelet Therapies in Patients With Coronary and Peripheral Artery Disease Manifestations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Coronary Artery Disease
Peripheral Arterial Disease
Atrial Fibrillation
Keywords: aspirin
clopidogrel
ticagrelor
rivaroxaban
pharmacodynamic (PD)
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Janssen Scientific Affairs, LLC
First posted: 2018-10-24
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The proposed investigation will be a prospective PD (pharmacodynamic) study conducted in cohorts of patients with CAD, PAD, or atrial fibrillation
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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 \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].

Primary outcomes:
measure: Platelet-Mediated Global Thrombogenicity
timeFrame: 20 days
measure: Platelet Aggregation Measured by VerifyNow PRU
timeFrame: 20 days
measure: Thrombin Generation
timeFrame: 20 days
Secondary outcomes:
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Cardiovascular Research Center,
state: Florida
city: Jacksonville
country: United States
facility: UF Health Jacksonville
state: Florida
Study officials:
affiliation: University of Florida
name: Dominick J Angiolillo, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.