Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis

Study Overview
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Brief Summary
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Mechanical heart valves (MHV) demand lifelong anticoagulation with vitamin K antagonists (VKA) due to the high thrombogenicity of the prosthesis. Rivaroxaban has previously been tested in experimental and animal models with encouraging results. The investigators recently sent for publication an experiment with 7 patients who used rivaroxaban in metallic prosthesis with encouraging results. In this way it was decided to do a randomized non-inferiority clinical trial comparing rivaroxaban with warfarin in patients with metallic prosthesis.

Detailed Description
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For patients with severe and symptomatic valvular heart disease, valve replacement surgery improves morbidity and mortality outcomes. It is estimated that four million valve replacement procedures have been performed over the last 50 years and it remains the only definitive treatment for most patients with advanced heart valve disease.1 Patients who received mechanical heart valves (MHV) had a significantly lower mortality, higher cumulative incidence of bleeding and, in some age groups, stroke than did recipients of a biologic prosthesis. In addition, MHV demands lifelong anticoagulation with vitamin K antagonists (VKA), most commonly warfarin, due to the high thrombogenicity of the prosthesis. Even with the appropriate use of therapy, there is a high incidence of thromboembolic events: 1% to 4% per year. Furthermore, bleeding risk is significant, ranging from 2% to 9% per year.4 Indeed, variability in the international normalized ratio (INR) is a major independent predictor of reduced survival in patients with MHV.5 Due to the narrow therapeutic index, interactions, genetic variants, and need for blood monitoring of patients taking VKAs, alternatives to warfarin have now been made available: specifically, inhibitors that directly target Factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban).6 RE-ALIGN was a prospective, randomized, phase 2, open-label trial that randomized 252 patients within a 2:1 unblinded fashion to either dabigatran or warfarin, with patients stratified according to interval since replacement (within three to seven days in population A; >three months in population B). Unfortunately, the trial was terminated prematurely because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. The negative results of this study can be explained by the selection of 50 ng/mL as the target dabigatran trough level, the possibility of this drug inducing downstream effects on the coagulation cascade that impair its ability to blunt the postoperative hypercoagulable state relative to warfarin and the inclusion of early postoperative patients (population A) since it is a phase of high incidence of thromboembolic events. On the other hand, rivaroxaban has already been tested in experimental9 and animal models10 with encouraging results. According to these findings, the investigators hypothesized that a direct Factor Xa inhibitor could be evaluated in patients with MHV for prevention of thromboembolic events.

Official Title
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Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis

Conditions
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Valve Heart Disease, Prostheses and Implants, Stroke, Anticoagulants and Bleeding Disorders

Intervention / Treatment
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* Drug: Rivaroxaban 15 mg
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Mechanical prosthetic valve replacement after at least 3 months postoperative Exclusion Criteria: Previous hemorrhagic stroke Ischemic stroke in the last 3 months Severe renal impairment (CrCl rates < 30 ml/min) Active liver disease (any etiology) Concomitant use of any antiplatelet (aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, etc.) Increased risk of bleeding (congenital or acquired) Uncontrolled SAH Gastrointestinal hemorrhage within the past year Anemia (Hb level < 10 g/dl) or thrombocytopenia (platelet count < 100 × 109/l) Active infective endocarditis Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rivaroxaban<br>Rivaroxaban 15mg BID | Drug: Rivaroxaban 15 mg<br>* Rivaroxaban 15 mg BID<br>* Other names: Rivaroxabana 15 mg;|
| Placebo Comparator: Warfarin<br>Warfarin dose adjusted | Drug: Warfarin<br>* Warfarin<br>* Other names: Vitamin K antagonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients with thromboembolic events: Stroke, transient ischemic attack (TIA), silent brain infarction (SBI) and systemic embolism (SE). | The primary endpoint was defined as stroke, TIA, SBI and systemic embolism | 90 days | 
| major or clinically relevant nonmajor bleeding | The primary safety outcome was major or clinically relevant nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and Bleeding Academic Research Consortium (BARC) | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients with e of stroke/TIA/SBI/SE and/or death from any cause. | Combined outcome | 90 days | 
| Cases of myocardial infarction during of follow-up | Myocardial infarction in the course of treatment | 90 days | 
| New cases of valve thrombosis with or without symptoms | Clinical or asymptomatic valve thrombosis | 90 days | 
| New intracardiac thrombus detected at the end of clinical follow-up by transesophageal echocardiogram | Emergence of intracardiac thrombus seen on transesophageal echocardiogram | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Warfarin, Valve Heart Disease, Rivaroxaban