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

Population Health Research Institute (PHRI)

Status and phase: Completed; Phase 3

Conditions: Rheumatic Heart Disease

Treatments: Drug: Rivaroxaban (20 mg); Drug: Vitamin K antagonists (VKA)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02832544

INVICTUS - VKA

Details and patient eligibility

About

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.

Full description

Non-Inferiority Trial of rivaroxaban versus VKAs: 4,500 patients

Inclusion Criteria:

1. RVHD diagnosed by echocardiography at any time prior to enrollment

2. Age ≥18

3. Increased risk of stroke by any of the following

   1. CHA2DS2-VASc score ≥ 2 OR
   2. Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR
   3. Left atrial spontaneous echo contrast OR
   4. Left atrial thrombus

4. 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.

1. Rivaroxaban Arm

   • Rivaroxaban 20 mg once daily
   • Rivaroxaban 15 mg once daily (for patients with an creatinine clearance ≥15 and <50 ml/min)

2. VKA Arm

   • Any VKA approved for use in the participating country
   • VKA titrated to achieve an INR of 2.0-3.0

Enrollment: 4,565 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. RVHD diagnosed by echocardiography at any time prior to enrollment

2. Age ≥18

3. 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

4. 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

1. Refusal to give informed consent

2. Actively involved in any study that would compromise the protocol of INVICTUS Trial

3. Severe co-morbid condition with life expectancy < 1 year

4. 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.

5. Likely to have valve replacement surgery within 6 months

6. 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.

7. Contraindication to the study medication of the trial

   • Allergy to rivaroxaban
   • Allergy to VKAs ( non-inferiority trial)
   • Allergy to aspirin ( superiority trial)

8. Severe renal insufficiency with an calculated creatinine clearance (Cockcroft-Gault) <15 ml/min

9. Serious bleeding in the past six months or at high risk for bleeding

10. Moderate to severe hepatic impairment

11. Ongoing need for dual antiplatelet therapy (patients with on-going aspirin therapy ≤100 mg per day are not excluded)

12. Ongoing need for dual strong inhibitors of CYP-3a4 or p-glycoprotein inhibitor.

13. Received an investigational drug in the past 30 days

14. Patients considered unsuitable for trial inclusion because of unwillingness to attend follow up visits

15. Women who are pregnant and/or breastfeeding

16. Women of child bearing age who do not use an effective form of birth control.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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4,565 participants in 2 patient groups

Rivaroxaban (20 mg)

Experimental group

Description:

Rivaroxaban 20 mg od (n \~ 2250); 15 mg od (once daily) in patients with creatinine clearance (CrCl) 15-49 ml/min

Treatment:

Drug: Rivaroxaban (20 mg)

Vitamin K antagonists (VKA)

Active Comparator group

Description:

Any approved VKA in the participating country (n \~ 2250); VKA titrated to achieve an INR of 2.0-3.0

Treatment:

Drug: Vitamin K antagonists (VKA)