Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis (RIWA)
Primary Purpose
Prostheses and Implants, Stroke, Valve Heart Disease
Status
Terminated
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
Rivaroxaban 15 mg
Warfarin
Sponsored by
About this trial
This is an interventional treatment trial for Prostheses and Implants focused on measuring Valve Heart Disease, Rivaroxaban, Warfarin
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
Sites / Locations
- Andre Duraes
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Rivaroxaban
Warfarin
Arm Description
Rivaroxaban 15mg BID
Warfarin dose adjusted
Outcomes
Primary Outcome Measures
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
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)
Secondary Outcome Measures
Patients with e of stroke/TIA/SBI/SE and/or death from any cause.
Combined outcome
Cases of myocardial infarction during of follow-up
Myocardial infarction in the course of treatment
New cases of valve thrombosis with or without symptoms
Clinical or asymptomatic valve thrombosis
New intracardiac thrombus detected at the end of clinical follow-up by transesophageal echocardiogram
Emergence of intracardiac thrombus seen on transesophageal echocardiogram
Full Information
NCT ID
NCT03566303
First Posted
June 8, 2018
Last Updated
May 13, 2020
Sponsor
Hospital Geral Roberto Santos
1. Study Identification
Unique Protocol Identification Number
NCT03566303
Brief Title
Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
Acronym
RIWA
Official Title
Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
Study Type
Interventional
2. Study Status
Record Verification Date
May 2020
Overall Recruitment Status
Terminated
Why Stopped
Coronavirus Pandemic
Study Start Date
July 10, 2018 (Actual)
Primary Completion Date
April 26, 2020 (Actual)
Study Completion Date
April 26, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital Geral Roberto Santos
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostheses and Implants, Stroke, Valve Heart Disease, Anticoagulants and Bleeding Disorders
Keywords
Valve Heart Disease, Rivaroxaban, Warfarin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization)
Masking
Investigator
Allocation
Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rivaroxaban
Arm Type
Active Comparator
Arm Description
Rivaroxaban 15mg BID
Arm Title
Warfarin
Arm Type
Placebo Comparator
Arm Description
Warfarin dose adjusted
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban 15 mg
Other Intervention Name(s)
Xarelto 15 mg, Rivaroxabana 15 mg
Intervention Description
Rivaroxaban 15 mg BID
Intervention Type
Drug
Intervention Name(s)
Warfarin
Other Intervention Name(s)
Vitamin K antagonist
Intervention Description
Warfarin
Primary Outcome Measure Information:
Title
Patients with thromboembolic events: Stroke, transient ischemic attack (TIA), silent brain infarction (SBI) and systemic embolism (SE).
Description
The primary endpoint was defined as stroke, TIA, SBI and systemic embolism
Time Frame
90 days
Title
major or clinically relevant nonmajor bleeding
Description
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)
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Patients with e of stroke/TIA/SBI/SE and/or death from any cause.
Description
Combined outcome
Time Frame
90 days
Title
Cases of myocardial infarction during of follow-up
Description
Myocardial infarction in the course of treatment
Time Frame
90 days
Title
New cases of valve thrombosis with or without symptoms
Description
Clinical or asymptomatic valve thrombosis
Time Frame
90 days
Title
New intracardiac thrombus detected at the end of clinical follow-up by transesophageal echocardiogram
Description
Emergence of intracardiac thrombus seen on transesophageal echocardiogram
Time Frame
90 days
Other Pre-specified Outcome Measures:
Title
Cases of minor bleeding
Description
Any minor bleeding
Time Frame
90 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andre Duraes, PhD
Organizational Affiliation
Federal University of Bahia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Andre Duraes
City
Salvador
State/Province
Bahia
ZIP/Postal Code
41815000
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33150497
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.
Results Reference
derived
PubMed Identifier
30293126
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.
Results Reference
derived
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Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
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