RIvaroxaban for Valvular Heart diseasE and atRial Fibrillation Trial -RIVER Trial

Study Overview
=================
Brief Summary
-----------------
RIvaroxaban for Valvular heart diseasE and atRial fibrillation trial (RIVER trial).

Detailed Description
-----------------
A Phase 2, Randomized, Open label, Non-Inferiority Clinical Trial to Explore the Safety and Efficacy of Rivaroxaban compared with vitamin K antagonism in Patients with Atrial Fibrillation with Bioprosthetic Mitral valves - RIVER. Main analysis for the primary endpoint are based on the Restricted Mean Survival Time (RMST) method.

Official Title
-----------------
A Phase 2, Randomized, Open Label, Non-Inferiority Clinical Trial to Explore the Safety and Efficacy of Rivaroxaban Compared With Vitamin K Antagonism in Patients With Atrial Fibrillation With Bioprosthetic Mitral Valves - RIVER

Conditions
-----------------
Valvular Heart Disease

Intervention / Treatment
-----------------
* Drug: Rivaroxaban
* Drug: Warfarin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients aged >18 years at time of inclusion Patients with Persistent or paroxysmal Atrial Fibrillation or flutter with bioprosthetic mitral valves. The patient must be able to give informed consent Exclusion Criteria: Cardiovascular-related conditions as known presence of cardiac thrombus or tumor Active endocarditis Uncontrolled hypertension Hemorrhage risk-related criteria Active internal bleeding History of, or condition associated with, increased bleeding risk Concomitant conditions and therapies History of previous thromboembolism with high risk of bleeding: Severe, disabling stroke (modified Rankin score of 4-5, inclusive) within 3 months Acute thromboembolic events or thrombosis (venous/arterial) within the last 14 days prior to randomization Acute MI within the last 14 days prior to randomization Treatment with: Chronic aspirin therapy > 100 mg daily or dual antiplatelet therapy; Intravenous antiplatelets; Fibrinolytics; Anticipated need for long-term treatment with a nonsteroidal antiinflammatory drug; Systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors; Treatment with a strong inducer of cytochrome P450 3A4, such as rifampicin, phenytoin, phenobarbital, or carbamazepine. Anemia Pregnancy or breastfeeding or women of reproductive age not using effective contraceptive methods Calculated creatinine clearance bellow 30 mL/min Known significant liver disease or alanine aminotransferase N3× the upper limit of normal Previous participation in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rivaroxaban 20mg<br>Oral Rivaroxaban, 20 mg od. Patients with a calculated creatinine clearance of 30 to 49 mL/min per 1.73 m2 received a reduced dose of rivaroxaban of 15 mg od. | Drug: Rivaroxaban<br>* Patients assigned to rivaroxaban will receive oral rivaroxaban, 20 mg od. Patients with a calculated creatinine clearance of 30 to 49 mL/min per 1.73 m2 received a reduced dose of rivaroxaban of 15 mg od.<br>Drug: Warfarin<br>* Patients will take the warfarin once daily (q.d.). The individual doses will be titrated as needed to maintain a target INR of 2.0-3.0. Patients with 65 > years old, should take warfarin (2,5mg/day) and all others patients should take 5mg/day.<br>|
| Active Comparator: Warfarin<br>Warfarin Warfarin once daily (q.d.). The individual doses will be titrated as needed to maintain a target INR of 2.0-3.0. | Drug: Rivaroxaban<br>* Patients assigned to rivaroxaban will receive oral rivaroxaban, 20 mg od. Patients with a calculated creatinine clearance of 30 to 49 mL/min per 1.73 m2 received a reduced dose of rivaroxaban of 15 mg od.<br>Drug: Warfarin<br>* Patients will take the warfarin once daily (q.d.). The individual doses will be titrated as needed to maintain a target INR of 2.0-3.0. Patients with 65 > years old, should take warfarin (2,5mg/day) and all others patients should take 5mg/day.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Clinical Events | Combined Endpoint of major clinical events as defined by strokes (CVA), transient ischemic attack (TIA), major bleeding, all-cause death, valve thrombosis and non-CNS systemic embolism, hospitalization due to cardiac failure. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major bleeding | Clinically overt bleeding associated with: fatal outcome, involving a critical site, or clinically overt bleeding associated with a fall in hemoglobin concentration of ≥2 g/dL, or leading to transfusion of ≥2 units of packed red blood cells or whole blood. | 12 months | 
| Combined endpoint of nonfatal stroke (CVA), transient ischemic attack (TIA), systemic embolism, valve thrombosis, venous thromboembolism and vascular causes death.thrombosis, and vascular death | Stroke: sudden, focal neurologic deficit from a presumed cerebrovascular cause, not reversible within 24 hours and not due to na identifiable cause. Non-CNS systemic embolism: abrupt vascular insufficiency associated with clinical or radiologic evidence of arterial occlusion. Valve thrombosis: any thrombus attached to or near an implanted valve that occludes part of the blood flow, interferes with function or warrant treatment. Mortality: Deaths any cause. Venous thromboembolism: verification by definitive diagnostic evaluation. Deep Vein Thrombosis: abnormal compression ultrasound or intraluminal filling defect on venography or autopsy. Pulmonary embolism: at least one: 1) intraluminal filling defect on CT scan; 2) intraluminal filling defect on pulmonary angiogram; 3) high- probability on v/p lung scan; 4)inconclusive spiral CT, pulmonary image with demonstration of DVT in the lower extremities; 5) autopsy | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bioprosthetic mitral valve, valvular heart disease, anticoagulant agents, NOACs, rivaroxaban, warfarin