Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis (RIWA)

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.

Study Overview

• Status: Terminated
• Conditions: Stroke; Valve Heart Disease; Anticoagulants and Bleeding Disorders; Prostheses and Implants
• Intervention / Treatment: Drug: Warfarin; Drug: Rivaroxaban 15 mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Bahia
    • Salvador, Bahia, Brazil, 41815000
      • Andre Duraes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rivaroxaban; Rivaroxaban 15mg BID	Drug: Rivaroxaban 15 mg; Rivaroxaban 15 mg BID; Other Names: Xarelto 15 mg; Rivaroxabana 15 mg
Placebo Comparator: Warfarin; Warfarin dose adjusted	Drug: Warfarin; Warfarin; Other Names: Vitamin K antagonist

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cases of minor bleeding	Any minor bleeding	90 days

Collaborators and Investigators

• Sponsor: Hospital Geral Roberto Santos
• Investigators: Principal Investigator: Andre Duraes, PhD, Federal University of Bahia

Publications and helpful links

General Publications

• Duraes AR, de Souza Lima Bitar Y, Schonhofen IS, Travassos KSO, Pereira LV, Filho JAL, Neto MG, Junior RA, Roever L. Rivaroxaban Versus Warfarin in Patients with Mechanical Heart Valves: Open-Label, Proof-of-Concept trial-The RIWA study. Am J Cardiovasc Drugs. 2021 May;21(3):363-371. doi: 10.1007/s40256-020-00449-3. Epub 2020 Nov 5.
• Duraes AR, de Souza Lima Bitar Y, Filho JAL, Schonhofen IS, Camara EJN, Roever L, Cardoso HEDP, Akrami KM. Rivaroxaban versus Warfarin in Patients with Mechanical Heart Valve: Rationale and Design of the RIWA Study. Drugs R D. 2018 Dec;18(4):303-308. doi: 10.1007/s40268-018-0249-5.

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2018
• Primary Completion (Actual): April 26, 2020
• Study Completion (Actual): April 26, 2020

Study Registration Dates

• First Submitted: June 8, 2018
• First Submitted That Met QC Criteria: June 21, 2018
• First Posted (Actual): June 25, 2018

Study Record Updates

• Last Update Posted (Actual): May 15, 2020
• Last Update Submitted That Met QC Criteria: May 13, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Rivaroxaban; Warfarin; Valve Heart Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Heart Diseases; Hemostatic Disorders; Blood Coagulation Disorders; Heart Valve Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrin Modulating Agents; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Rivaroxaban; Warfarin
• Other Study ID Numbers: 90288318.0.0000.5028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No