INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Superiority (INVICTUS-ASA)

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

This program is a comprehensive evaluation of rheumatic valvular heart disease (RVHD), Atrial fibrillation (AF)/flutter and stroke.

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 Overview

• Status: Withdrawn
• Conditions: Rheumatic Heart Disease
• Intervention / Treatment: Drug: Rivaroxaban (15 mg); Drug: Aspirin

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

   1. 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
   2. In the absence of AF or Flutter, patients would be eligible in the presence of any one of the following:
   1. Left atrial enlargement ≥5.5 cm OR
   2. Left atrial spontaneous echo contrast OR
   3. Left atrial thrombus OR
   4. Frequent ectopic atrial activity (>1000/24 hours) on Holter monitoring

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban (15 mg); Rivaroxaban 15 mg od (n ~ 1000)	Drug: Rivaroxaban (15 mg); Rivaroxaban is superior to aspirin for the prevention of the composite of stroke or systemic embolism in patients with RVHD with AF or flutter who are unsuitable for VKA therapy, or in patients with RVHD without AF or Flutter with at least one of the following: Left atrial enlargement ≥ 5.5 cm, OR; Left atrial spontaneous echo contrast OR; Left atrial thrombus OR; Frequent ectopic atrial activity (>1000/24 hours) on Holter ECG.; Other Names: Xarelto
Active Comparator: Aspirin (ASA); Aspirin 100 mg od (n~1000)	Drug: Aspirin; Rivaroxaban is superior to aspirin for the prevention of the composite of stroke or systemic embolism in patients with RVHD with AF or flutter who are unsuitable for VKA therapy, or in patients with RVHD without AF or Flutter with at least one of the following: Left atrial enlargement ≥ 5.5 cm, OR; Left atrial spontaneous echo contrast OR; Left atrial thrombus OR; Frequent ectopic atrial activity (>1000/24 hours) on Holter ECG.; Other Names: acetylsalicylic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to the first occurrence of Stroke or systemic embolism	Stroke (Ischemic, hemorrhagic or undetermined type)	Approximately 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to the first occurrence of Myocardial Infarction (MI)		Approximately 4 years
Time from randomization to time of vascular death	Vascular death includes death due to stroke, myocardial infarction, heart failure or cardiogenic shock, sudden death or any other death due to cardiovascular causes. In addition, death due to hemorrhage will be included	Approximately 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomization to the first occurrence of a Major bleed	Using the International Society on Thrombosis and Haemostasis (ISTH) major bleeding definition	Approximately 4 years

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: University of Cape Town

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): August 1, 2022

Study Registration Dates

• First Submitted: January 7, 2016
• First Submitted That Met QC Criteria: July 11, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Actual): July 19, 2022
• Last Update Submitted That Met QC Criteria: July 14, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: stroke; atrial fibrillation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Infections; Musculoskeletal Diseases; Connective Tissue Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Rheumatic Fever; Heart Diseases; Rheumatic Diseases; Rheumatic Heart Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Rivaroxaban
• Other Study ID Numbers: INVICTUS - ASA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: cumulative participant data only

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No