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

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

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.