INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority

Study Overview
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Brief Summary
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This program is a comprehensive evaluation of rheumatic valvular heart disease (RVHD), Atrial fibrillation (AF)/flutter and stroke. A prospective, randomized, parallel group, open-label clinical trial of rivaroxaban versus standard vitamin K antagonists (VKA) therapy to evaluate non-inferiority of rivaroxaban to VKA, with testing for superiority if non-inferiority is satisfied.

Detailed Description
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Non-Inferiority Trial of rivaroxaban versus VKAs: 4,500 patients Inclusion Criteria: RVHD diagnosed by echocardiography at any time prior to enrollment Age ≥18 Increased risk of stroke by any of the following CHA2DS2-VASc score ≥ 2 OR Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR Left atrial spontaneous echo contrast OR Left atrial thrombus Heart Rhythm a) AF or Flutter should be documented on baseline 12-lead ECG, or on a previous 12-lead ECG, Holter monitor, in-hospital ECG rhythm strip or Pacemaker or ICD electrogram. Treatment: Patients will be randomized either to receive rivaroxaban or any approved VKA. Treatment will be open-label. Rivaroxaban Arm Rivaroxaban 20 mg once daily Rivaroxaban 15 mg once daily (for patients with an creatinine clearance ≥15 and <50 ml/min) VKA Arm Any VKA approved for use in the participating country VKA titrated to achieve an INR of 2.0-3.0

Official Title
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INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies

Conditions
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Rheumatic Heart Disease

Intervention / Treatment
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* Drug: Rivaroxaban (20 mg)
* Drug: Vitamin K antagonists (VKA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RVHD diagnosed by echocardiography at any time prior to enrollment Age ≥18 Increased risk of stroke by any of the following CHA2DS2-VASc score ≥ 2 OR Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR Left atrial spontaneous echo contrast OR Left atrial thrombus Heart Rhythm *AF or Flutter should be documented on baseline 12-lead ECG, or on a previous 12-lead ECG, Holter monitor, in-hospital ECG rhythm strip or Pacemaker or ICD electrogram. Exclusion Criteria: Refusal to give informed consent Actively involved in any study that would compromise the protocol of INVICTUS Trial Severe co-morbid condition with life expectancy < 1 year Other serious condition(s) or logistic factors likely to interfere with study participation or with the ability to complete the trial, as appropriate to country or region. Likely to have valve replacement surgery within 6 months Mechanical valve prosthesis or other condition requiring treatment with VKAs. Patients with deep vein thrombosis or recent pulmonary embolism can be enrolled where both VKAs and rivaroxaban are approved. Contraindication to the study medication of the trial Allergy to rivaroxaban Allergy to VKAs ( non-inferiority trial) Allergy to aspirin ( superiority trial) Severe renal insufficiency with an calculated creatinine clearance (Cockcroft-Gault) <15 ml/min Serious bleeding in the past six months or at high risk for bleeding Moderate to severe hepatic impairment Ongoing need for dual antiplatelet therapy (patients with on-going aspirin therapy ≤100 mg per day are not excluded) Ongoing need for dual strong inhibitors of CYP-3a4 or p-glycoprotein inhibitor. Received an investigational drug in the past 30 days Patients considered unsuitable for trial inclusion because of unwillingness to attend follow up visits Women who are pregnant and/or breastfeeding Women of child bearing age who do not use an effective form of birth control.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban (20 mg)<br>Rivaroxaban 20 mg od (n   2250); 15 mg od (once daily) in patients with creatinine clearance (CrCl) 15-49 ml/min | Drug: Rivaroxaban (20 mg)<br>* Rivaroxaban is non-inferior to VKAs for the prevention of stroke or systemic embolism in patients with AF/flutter and RVHD and potentially superior to VKAs.<br>* Other names: Xarelto;|
| Active Comparator: Vitamin K antagonists (VKA)<br>Any approved VKA in the participating country (n   2250); VKA titrated to achieve an INR of 2.0-3.0 | Drug: Vitamin K antagonists (VKA)<br> <br> * Other names: Warfarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to the first occurrence of vascular death or death of unknown cause, stroke, myocardial infarction or systemic embolism | Vascular death or death of unknown cause, stroke, myocardial infarction or systemic embolism | Approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to the first occurrence of composite of stroke or systemic embolism | Composite of stroke or systemic embolism | Approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atrial fibrillation, stroke