Clinical trial NCT03566303: Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
Official title: Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Prostheses and Implants
Stroke
Valve Heart Disease
Anticoagulants and Bleeding Disorders
Keywords: Valve Heart Disease
Rivaroxaban
Warfarin
Lead sponsor: Hospital Geral Roberto Santos
Sponsor class: OTHER
First posted: 2018-06-25
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization)
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Patients with thromboembolic events: Stroke, transient ischemic attack (TIA), silent brain infarction (SBI) and systemic embolism (SE).
timeFrame: 90 days
measure: major or clinically relevant nonmajor bleeding
timeFrame: 90 days
Secondary outcomes:
measure: Patients with e of stroke/TIA/SBI/SE and/or death from any cause.
timeFrame: 90 days
measure: Cases of myocardial infarction during of follow-up
timeFrame: 90 days
measure: New cases of valve thrombosis with or without symptoms
timeFrame: 90 days
measure: New intracardiac thrombus detected at the end of clinical follow-up by transesophageal echocardiogram
timeFrame: 90 days
Other outcomes:
measure: Cases of minor bleeding
timeFrame: 90 days
Locations:
city: Salvador
country: Brazil
facility: Andre Duraes
state: Bahia
Study officials:
affiliation: Federal University of Bahia
name: Andre Duraes, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.