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Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis (RIWA)

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ClinicalTrials.gov Identifier: NCT03566303
Recruitment Status : Terminated (Coronavirus Pandemic)
First Posted : June 25, 2018
Last Update Posted : May 15, 2020
Sponsor:
Information provided by (Responsible Party):
Hospital Geral Roberto Santos

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.

Condition or disease Intervention/treatment Phase
Prostheses and Implants Stroke Valve Heart Disease Anticoagulants and Bleeding Disorders Drug: Rivaroxaban 15 mg Drug: Warfarin Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization)
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis
Actual Study Start Date : July 10, 2018
Actual Primary Completion Date : April 26, 2020
Actual Study Completion Date : April 26, 2020

Resource links provided by the National Library of Medicine


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 Name: Vitamin K antagonist




Primary Outcome Measures :
  1. Patients with thromboembolic events: Stroke, transient ischemic attack (TIA), silent brain infarction (SBI) and systemic embolism (SE). [ Time Frame: 90 days ]
    The primary endpoint was defined as stroke, TIA, SBI and systemic embolism

  2. major or clinically relevant nonmajor bleeding [ Time Frame: 90 days ]
    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 :
  1. Patients with e of stroke/TIA/SBI/SE and/or death from any cause. [ Time Frame: 90 days ]
    Combined outcome

  2. Cases of myocardial infarction during of follow-up [ Time Frame: 90 days ]
    Myocardial infarction in the course of treatment

  3. New cases of valve thrombosis with or without symptoms [ Time Frame: 90 days ]
    Clinical or asymptomatic valve thrombosis

  4. New intracardiac thrombus detected at the end of clinical follow-up by transesophageal echocardiogram [ Time Frame: 90 days ]
    Emergence of intracardiac thrombus seen on transesophageal echocardiogram


Other Outcome Measures:
  1. Cases of minor bleeding [ Time Frame: 90 days ]
    Any minor bleeding



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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03566303


Locations
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Brazil
Andre Duraes
Salvador, Bahia, Brazil, 41815000
Sponsors and Collaborators
Hospital Geral Roberto Santos
Investigators
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Principal Investigator: Andre Duraes, PhD Federal University of Bahia
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hospital Geral Roberto Santos
ClinicalTrials.gov Identifier: NCT03566303    
Other Study ID Numbers: 90288318.0.0000.5028
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospital Geral Roberto Santos:
Valve Heart Disease
Rivaroxaban
Warfarin
Additional relevant MeSH terms:
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Heart Diseases
Hemostatic Disorders
Heart Valve Diseases
Blood Coagulation Disorders
Cardiovascular Diseases
Hematologic Diseases
Vascular Diseases
Hemorrhagic Disorders
Vitamin K
Warfarin
Rivaroxaban
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifibrinolytic Agents
Fibrin Modulating Agents
Hemostatics
Coagulants