| Protocol No: | ECCT/16/10/01 | Date of Protocol: | 19-10-2015 |
| Study Title: | INVESTIGATION OF RHEUMATIC AF TREATMENT USING VITAMIN K ANTAGONISTS, RIVAROXABAN OR ASPRIN STUDIES |
| Study Objectives: |
1 In patients with rheumatic valvular heart disease (RVHD) and who are in atrial fibrillation or flutter (AF/Flutter) and have other stroke risk factors, rivaroxaban is non-inferior to vitamin K antagonists (VKA) for prevention of stroke or systemic embolism.
2 In patients with RVHD either with AF/Flutter but unsuitable for VKA therapy or with sinus rhythm but with high risk, rivaroxaban is superior to aspirin for prevention of stroke or systemic embolism.
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| Laymans Summary: | INVICTUS study is an international multicenter trial investigating the safety and efficacy of rivaroxaban in prevention of stroke in patients with rheumatic valvular heart disease. Rheumatic valvular heart disease is a condition in which the way through which blood passes into the heart is either narrow or leaks. This normally weakens the heart muscles and can cause abnormal heartbeats known as atrial fibrillation (AF). Atrial fibrillation (AF) can cause blood clots in the heart, which travel to the brain. When blood clot in the heart goes to the brain, it is called stroke, symptoms may be weakness in an arm or leg, or loss of feeling or loss of ability to speak or even death. Drugs to prevent blood coagulation are used to reduce stroke in patients with atrial fibrillation. In rheumatic valvular heart disease, drugs used to prevent blood clots are called vitamin k antagonist, including warfarin or acenocoumarol or phenprocoumon. These antagonists of Vitamin K are effective in reducing stroke but difficult to use because they require regular monitoring. Recently, new drugs to prevent blood clots that are easy to use have shown to be effective in patients with atrial fibrillation but do not have rheumatic valvular heart disease. However, these new drugs have not been tested in patients with rheumatic valvular heart disease and therefore, their use in these patients has not been approved. The purpose of the Invictus study is to test if one of these new drugs, called rivaroxaban is good as a vitamin k antagonist drug for preventing stroke in patients with abnormal heartbeats (AF) and Rheumatic valvular heart disease.
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| Abstract of Study: |
INVICTUS TRIALS: INVESTIGATION OF RHEUMATIC AF TREATMENT USING VITAMIN K ANTAGONISTS, RIVAROXABAN OR ASPRIN STUDIES
BACKGROUND:
Primary Hypotheses
1. In patients with rheumatic valvular heart disease (RVHD) and who are in atrial fibrillation or flutter (AF/flutter) and have other stroke risk factors, rivaroxaban is non-inferior to vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism.
2. In patients with RVHD, either with AF/flutter but unsuitable for VKA therapy, or with sinus rhythm but with high risk, rivaroxaban is superior to aspirin for prevention of stroke or systemic embolism. Study Design
This program is a comprehensive evaluation of RVHD, AF/flutter and stroke. It includes three major components:
1. A multi-centre registry of RVHD
2. A prospective, randomized, parallel group, open-label clinical trial of rivaroxaban versus standard VKA therapy to evaluate non-inferiority of rivaroxaban to VKA, with testing for superiority if non-inferiority is satisfied.
3. A prospective, randomized, open-label superiority trial comparing rivaroxaban to aspirin in high risk patients either with AF and unsuitable for VKA or without AF and with high risk factors.
Study Size
RVHD Registry: 17,000 patients with RVHD (in addition to the existing registry which has already 3300 patients)
Non-Inferiority Trial of rivaroxaban versus VKAs: 4,500 patients
Superiority Trial of rivaroxaban versus aspirin: 2,000 patients
Inclusion Criteria
Registry: Any patient with RVHD diagnosed by echocardiography
Non-Inferiority Trial:
1. RVHD diagnosed by echocardiography at any time prior to enrollment
2. Age ≥18
3. Increased risk of stroke by any of the following
a) CHA2DS2-VASc score ≥ 2 OR
b) Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR
c) Left atrial spontaneous echo contrast OR
d) 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.
Superiority Trial
1. RVHD diagnosed by echocardiography at any time prior to enrollment
2. Age ≥18
3. Increased risk of stroke by any of the following
a) CHA2DS2-VASc score ≥ 2 OR
b) Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR
c) Left atrial spontaneous echo contrast OR
d) Left atrial thrombus
4. Heart Rhythm
a) AF or Flutter and unsuitable for VKA therapy. (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) OR
b) In the absence of AF or Flutter, patients would be eligible in the presence of any one of the following:
a. Left atrial enlargement ≥5.5 cm OR
b. Left atrial spontaneous echo contrast OR
c. Left atrial thrombus OR
d. Frequent ectopic atrial activity (>1000/24 hours) on Holter monitoring Exclusion Criteria
Exclusion Criteria for both non-inferiority and superiority trials:
1. Refusal to 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
a. Allergy to rivaroxaban
b. Allergy to VKAs ( non-inferiority trial)
c. 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.
Treatment Regimen
Non-Inferiority Trial:
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
Superiority Trial:
Patients will be randomized to receive rivaroxaban or aspirin. Treatment will be open-label.
1. Rivaroxaban Arm
- Rivaroxaban 15 mg once daily
- No dose reduction with renal impairment
2. Aspirin Arm
- Aspirin 75 to 100 mg once daily
Registry Outcomes
- All stroke by sub-type
- Systemic embolism
- Myocardial infarction
- Death by cause
- Recurrent rheumatic fever
- Prosthetic valve thrombosis
- Infective endocarditis
- Hospitalization for any cause.
- Valvuloplasty / Surgery
- Infections – Pneumonia, HIV etc. Clinical trial Efficacy Outcomes
Primary Outcome:
- Stroke(ischemic, hemorrhagic or undetermined type)
- Systemic embolism
Secondary Outcomes:
- Myocardial infarction
- Hospitalization
- Vascular death
- Total Death
- Composite of stroke, myocardial infarction, systemic embolism, vascular death
Statistical Considerations
Registry: A sample size of 20,000 (combined REMEDY (3000) and INVICTUS (17,000)) will ensure precise measurement of event rates as infrequent as 0.5/per 100 patient-years, with an absolute precision of 0.1% and 95% confidence.
Non-Inferiority Trial: The sample-size calculations are based on a non-inferiority margin of 1.46 and an expected primary annual event rate of 2% per year in the VKA arm. Study enrolment will occur over two years and all patients will be followed to a common termination at the end of an additional 2 years of follow up or for a total of about four years. Thus, the mean follow-up time will be approximately three years. Assuming 10% non-compliance to rivaroxaban in the first year with additional non-compliance of 5% per year thereafter, enrolment of 4,500 patients will give 86% power to conclude that rivaroxaban is non-inferior to VKAs or the primary outcome. If non-inferiority is established, then testing for superiority of rivaroxaban over VKA will be undertaken without statistical penalty.
Superiority Trial: The sample-size calculations are based on an expected primary annual event rate on aspirin of 3.5%. Study enrolment will occur over two years and all patients will be followed to a common termination at the end of four years. Thus, the mean follow-up time will be approximately three years. We expect a relative risk reduction of 45% Assuming 10% non-compliance to rivaroxaban in the first year with additional non-compliance of 5% per year thereafter, enrolment of 2,000 patients will give 95% power to conclude that rivaroxaban is superior to asprin.
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