Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis

NCT ID: NCT03566303

Last Updated: 2020-05-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-10
• Study Completion Date: 2020-04-26

Brief Summary

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

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.

Conditions

Prostheses and Implants; Stroke; Valve Heart Disease; Anticoagulants and Bleeding Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Rivaroxaban

Rivaroxaban 15mg BID

Group Type: ACTIVE_COMPARATOR

Rivaroxaban 15 mg

Intervention Type: DRUG

Rivaroxaban 15 mg BID

Warfarin

Warfarin dose adjusted

Group Type: PLACEBO_COMPARATOR

Warfarin

Intervention Type: DRUG

Warfarin

Interventions

Rivaroxaban 15 mg

Rivaroxaban 15 mg BID

Intervention Type: DRUG

Warfarin

Warfarin

Intervention Type: DRUG

Other Intervention Names

Xarelto 15 mg; Rivaroxabana 15 mg; Vitamin K antagonist

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital Geral Roberto Santos

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andre Duraes, PhD

Role: PRINCIPAL_INVESTIGATOR

Federal University of Bahia

Locations

Andre Duraes

Salvador, Estado de Bahia, Brazil

Countries

Brazil

References

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.

Reference Type: DERIVED

PMID: 33150497 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30293126 (View on PubMed)

Other Identifiers

90288318.0.0000.5028

Identifier Type: -

Identifier Source: org_study_id