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

October 3, 2022 updated by: Population Health Research Institute

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, 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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

Study Type

Interventional

Enrollment (Actual)

4565

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Botswana
      • Gaborone, Botswana
        • Princess Marina Hospital
  • Brazil
      • Campinas, Brazil, 13060-080
        • Instituto de Pesquisa Clínica de Campinas
      • Campinas, Brazil, São Paulo
        • LOEMA - Instituto de Pesquisa Clínica & Consultores Ltda
      • Goiania, Brazil, 74223130
        • Via Médica Centro Clínico Barroso e Sebba Ltda
      • Porto Alegre, Brazil, 90620001
        • Instituto de Cardiologia do Rio Grande do Sul
      • São José do Rio Preto, Brazil, 1509000
        • Fundação Faculdade de Medicina de São José do Rio Preto
      • São Paulo, Brazil, 05403-000
        • Instituto do Coração - HCFMUSP
      • São Paulo, Brazil, 4012909
        • Instituto Dante Pazzanese de Cardiologia
      • Votuporanga, Brazil, 15500-003
        • Santa Casa de Misericórdia de Votuporanga
    • Minas Gerais
      • Belo Horizonte, Minas Gerais, Brazil, 30150-240
        • CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
      • Uberaba, Minas Gerais, Brazil
        • Nucleo de Estudios Clinicos - Universidade Federal do Triângulo Mineiro
      • Uberlândia, Minas Gerais, Brazil, 38411-186
        • Eurolatino Pesquisas Medicas Ltda
    • Santa Catarina
      • Blumenau, Santa Catarina, Brazil, 89010-500
        • Clínica Procardio Ltda.
  • Cameroon
      • Douala, Cameroon
        • Douala General Hospital
      • Douala, Cameroon, 7562
        • Clinique Coeur Et Vie
      • Kumbo, Cameroon
        • St. Elizabeth Catholic General Hospital, Cardiac Centre
      • Yaounde, Cameroon
        • Hopital Central Yaoundé
  • China
      • Beijing, China, 100029
        • Beijing Anzhen Hospital
      • Henan, China, 450000
        • Zhongmou County People's Hospital
      • Henan, China, 450016
        • zhengzhou No.7 people's Hospital
      • Henan, China, 450053
        • Zhengzhou 9th People's Hospital
      • Henan, China
        • Guangshan County People's Hospital
    • Beijing
      • Beijing, Beijing, China, 102401
        • Liangxiang Hospital
    • Guangdong
      • Guangzhou, Guangdong, China, 510062
        • The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University
    • Heilongjiang
      • Jixi, Heilongjiang, China, 158100
        • Jixi People's Hospital
      • Yichun, Heilongjiang, China, 152500
        • Tieli People's Hospital
    • Henan
      • Luoyang, Henan, China, 471009
        • Luoyang Central's Hospital Affiliated to Zhengzhou University
      • Zhoukou, Henan, China, 477150
        • Dancheng County People's Hospital
      • Zhumadian, Henan, China, 463100
        • Suiping Renan Hospital
    • Hubei
      • Enshi, Hubei, China, 445308
        • Jianshi County People's Hospital
    • Jiangsu
      • Suqian, Jiangsu, China, 223800
        • Suqian Peaple's Hospital of Nanjing Drum-Tower Hospital Group
    • Jilin
      • Tonghua, Jilin, China, 134001
        • Tonghua Central Hospital
    • Liaoning
      • Dalian, Liaoning, China, 116001
        • Affiliated Zhongshan hospital of Dalian university
      • Dalian, Liaoning, China, 116011
        • The First Affiliated Hospital of Dalian Medical University
    • Ningxia
      • Yinchuan, Ningxia, China, 750021
        • Ningxia Peple'S Hospital
    • Sichuan
      • Chengdu, Sichuan, China, 611730
        • Pi County People's Hospital
      • Ziyang, Sichuan, China, 642350
        • Anyue County People's Hospital
    • Wendeng
      • Weihai, Wendeng, China
        • Wendeng Central Hospital
    • Zhejiang
      • Ningbo, Zhejiang, China, 315600
        • Ninghai People's Hospital
  • Egypt
      • Alexandria, Egypt, 21561
        • Alexandria University Hospital
      • Assuit, Egypt
        • Assuit General Hospital
      • Banha, Egypt
        • Benha University Cardiology Department
      • Banī Suwayf, Egypt
        • Beni Suef University Hospital
      • Cairo, Egypt, 11566
        • Ain Shams University Hospital
      • Cairo, Egypt, 21561
        • Kasr El Einy Hospital (Cairo University)
      • El Mansura, Egypt, 31951
        • Mehallah Rheumatic Heart Center
      • El Mansura, Egypt, 35516
        • Specialized Medical Hospital - Mansoura
      • Fayoum, Egypt, 31951
        • Fayoum General Hospital
      • Ismailia, Egypt, 41522
        • Suez Canal University Hospital
      • Minya, Egypt, 61519
        • El Minia University Hospital
      • Sohag, Egypt, 35516
        • Sohag University, Sohag
      • Tanta, Egypt, 31951
        • Red Crescent Hospital
      • Zagazig, Egypt, 44519
        • Zagazig University Hospital
  • Ethiopia
      • Addis Ababa, Ethiopia, 1176
        • College of Health Sciences, Addis Ababa University, Black Lion Hospital
      • Jimma, Ethiopia
        • Jimma University Hospital
      • Mek'ele, Ethiopia, 1871
        • Mekelle University
    • Snnpr
      • Hawassa, Snnpr, Ethiopia
        • Hawassa University Referral Hospital
  • India
    • Delhi
      • New Delhi, Delhi, India, 110029
        • All India Institute of Medical Sciences
      • New Delhi, Delhi, India, 110001
        • Dr. Ram Manohar Lohia Hospital @ PGIMER
      • New Delhi, Delhi, India, 110002
        • Govind Ballabh Pant Hospital (GIPMER)
    • Karnataka
      • Bangalore, Karnataka, India, 560069
        • Sri Jayadev Institute of Cardiovascular Sciences and Research
    • Rajasthan
      • Jaipur, Rajasthan, India, 302004
        • SMS Medical College
    • Uttar Pradesh
      • Lucknow, Uttar Pradesh, India, 226003
        • King George's Medical College
      • Lucknow, Uttar Pradesh, India, 226014
        • Sanjay Gandhi Post Graduate Institute of Medical Sciences
  • Kazakhstan
      • Almaty, Kazakhstan
        • Kazakh National Medical Institute,
  • Kenya
      • Eldoret, Kenya, 30100
        • Moi Teaching and Referral Hospital
      • Nairobi, Kenya, 00200
        • Karen Hospital
      • Nairobi, Kenya
        • Kenyatta National Hospital / University Of Nairobi
  • Kyrgyzstan
      • Bishkek, Kyrgyzstan, 720001
        • Clinical Hospital of administrative department of President and Government of Kyrgyz Republic
  • Malawi
      • Blantyre, Malawi, 265
        • Queen Elizabeth Central Hospital
      • Lilongwe, Malawi, 265
        • Kumuzu Central Hospital
      • Mzuzu, Malawi, 265
        • Mzuzu Central Hospital
  • Mexico
      • Aguascalientes, Mexico, 20230
        • Instituto de Investigación del Hospital Cardiológica Aguascalientes
      • Guerrero, Mexico, 40000
        • Hospital General Dr. Jorge Soberon Acevedo.Secretaria de Salud del Estado de Guerrero
      • México, Mexico, 14080
        • Instituto Nacional de Cardiologia Ignacio Chavez
    • Guanajuato
      • León, Guanajuato, Mexico, 37150
        • Hospital Angeles Leon
    • Jalisco
      • Guadalajara, Jalisco, Mexico, 44200
        • Hospital Bernardette
    • Querétaro
      • Queretaro, Querétaro, Mexico, 76000
        • Centro de Estudios Clínicos de Querétaro S.C.
    • Sinaloa
      • Culiacan, Sinaloa, Mexico, 80230
        • Centro para el Desarrollo de la Medicina y Asistencia Especializada S.C.
  • Mozambique
      • Maputo, Mozambique, 1111
        • Maputo Central Hospital
      • Maputo, Mozambique, CP 264
        • Instituto Nacional de Saude & Universidade Eduardo Mondlane
  • Nepal
      • Bharatpur, Nepal, 44207
        • College of Medical Sciences
      • Bharatpur, Nepal
        • Chitwan Medical College
      • Biratnagar, Nepal, 56613
        • Nobel medical college and teaching hospital pvt ltd
      • Butwal, Nepal, 32907
        • Gautam Buddha Community Heart Hospital
      • Dharān Bāzār, Nepal, 56700
        • BP Koirala Institute of Health Sciences
      • Kathmandu, Nepal, 44600
        • Manmohan Cardiothoracic Vascular and Trasplant Center, IOM, TU
      • Kathmandu, Nepal, 44600
        • Sahid Gangalal Heart Center
      • Nepalgunj, Nepal, 21900
        • Bheri Zonal Hospital
      • Pokhara, Nepal, 33700
        • Manipal College of Medical Sciences
  • Nigeria
      • Abeokuta, Nigeria
        • Federal Medical Center
      • Enugu, Nigeria, 400201
        • University of Nigeria Teaching Hospital
      • Ibadan, Nigeria, 200212
        • College of Medicine, University of Ibadan
      • Jos, Nigeria, 930001
        • Jos University Teaching Hospital
      • Kaduna, Nigeria, 810001
        • Ahmadu Bello University Teaching Hospital
      • Kano, Nigeria, 700223
        • Aminu Kano University Teaching Hospital
      • Lagos, Nigeria, 12003
        • Department of Medicine, Lagos University Teaching Hospital
      • Ogbomoso, Nigeria, 4007
        • Ladoke Akintola University of Technology Teaching Hospital
      • Oghara, Nigeria
        • Department of Medicine, Delta State University Teaching Hospital
  • Pakistan
      • Hyderabad, Pakistan, 31300
        • Isra University hospital
      • Multan, Pakistan, 60000
        • Nishtar Hospital Multan
      • Peshawar, Pakistan, PK 2500
        • Lady Reading hospital
      • Rawalpindi, Pakistan, 46000
        • Rawalpindi Institute of Cardiology
    • Punjab
      • Lahore, Punjab, Pakistan, 54000
        • Punjab Institute of Cardiology
  • Paraguay
      • Asunción, Paraguay, 1725
        • Instituto Nacional de Cardiologia
      • Asunción, Paraguay, 2279
        • Hospital Barrio Obrero
      • Ciudad del Este, Paraguay, 7000
        • Hospital Regional de Ciudad Del Este
      • Itaugua, Paraguay, 2740
        • Hospital Nacional Itaugua
      • San Lorenzo, Paraguay, 1863
        • Clinical Hospital
  • Philippines
      • Manila, Philippines, 1000
        • Philippine General Hospital
      • Quezon City, Philippines, 1109
        • Quirino Memorial Medical Center
      • Quezon City, Philippines, 1100
        • Philippine Heart Center
    • Palawan
      • Puerto Princesa City, Palawan, Philippines, 5300
        • Palawan Medical City
  • Rwanda
      • Kigali, Rwanda
        • University of Rwanda, Kigali University Teaching Hospital
  • South Africa
      • Bloemfontein, South Africa, 9301
        • Cardiology Research Universitas private hospital
      • Cape Town, South Africa, 7925
        • University of Cape Town
      • Polokwane, South Africa, 700
        • University of Limpopo
      • Port Elizabeth, South Africa, 6001
        • Port Elizabeth Hospital Complex
      • Soweto, South Africa, 2013
        • Chris Hani Baragwanath Hospital
    • Eastern Cape
      • Mthatha, Eastern Cape, South Africa, 5099
        • Nelson Mandela Academic Hospital
    • Parktown
      • Johannesburg, Parktown, South Africa, 2193
        • Charlotte Maxeke Academic Hospital
    • Pretoria
      • Ga-Rankuwa,, Pretoria, South Africa, 0204
        • Sefako Makgatho Health Sciences University
  • Sudan
      • Atbara, Sudan
        • Atbara Teaching Hospital
      • El Obeid, Sudan
        • Alobeid Teaching Hospital
      • Khartoum, Sudan, 1111
        • Ahmed Gasim Hospital
      • Khartoum, Sudan, 1111
        • AlShaab Teaching Hospital
      • Khartoum, Sudan
        • Ahmed Gasim Pediatric Hospital
      • Khartoum, Sudan
        • Sudan Heart Center
      • Port Sudan, Sudan
        • Digna Prince Hospital
      • Wad Medani, Sudan
        • Medani Heart Centre
  • Tanzania
      • Dar es Salaam, Tanzania
        • Muhimbili University of Health and Allied Sciences
      • Mbeya, Tanzania, 419
        • Mbeya Zonal Referral Hospital
  • Uganda
      • Kampala, Uganda
        • Uganda Heart Institute
  • Zambia
      • Livingstone, Zambia, 10101
        • Livingstone Central Hospital
      • Lusaka, Zambia
        • University Teaching Hospital (UTH)
      • Ndola, Zambia, 10101
        • Ndola Central Hospital
  • Zimbabwe
      • Bulawayo, Zimbabwe
        • Mpilo Hospital, National University Science & Technology
      • Harare, Zimbabwe
        • Parirenyatwa Hospital
      • Harare, Zimbabwe
        • Harare Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

    • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Rivaroxaban (20 mg)
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)
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.
Other Names:
  • Xarelto
Active Comparator: Vitamin K antagonists (VKA)
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)
Other Names:
  • Warfarin

What is the study measuring?

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
Time Frame: Approximately 4 years
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
Time Frame: Approximately 4 years
Composite of stroke or systemic embolism
Approximately 4 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time from randomization to the first occurrence of a Major Bleed
Time Frame: Approximately 4 years
using the ISTH major bleeding definition
Approximately 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Population Health Research Institute

Collaborators

Bayer
University of Cape Town

Investigators

  • Principal Investigator: Stuart Connolly, MD, Population Health Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 22, 2016

Primary Completion (Actual)

August 18, 2022

Study Completion (Actual)

August 18, 2022

Study Registration Dates

First Submitted

December 10, 2015

First Submitted That Met QC Criteria

July 11, 2016

First Posted (Estimate)

July 14, 2016

Study Record Updates

Last Update Posted (Actual)

October 5, 2022

Last Update Submitted That Met QC Criteria

October 3, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INVICTUS - VKA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

cumulative participant data only

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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