INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority
NCT ID: NCT02832544
Last Updated: 2022-10-05
Study Results
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Basic Information
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COMPLETED
PHASE3
4565 participants
INTERVENTIONAL
2016-08-22
2022-08-18
Brief Summary
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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.
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Detailed Description
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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
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
NONE
Study Groups
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Rivaroxaban (20 mg)
Rivaroxaban 20 mg od (n \~ 2250); 15 mg od (once daily) in patients with creatinine clearance (CrCl) 15-49 ml/min
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.
Vitamin K antagonists (VKA)
Any approved VKA in the participating country (n \~ 2250); VKA titrated to achieve an INR of 2.0-3.0
Vitamin K antagonists (VKA)
Interventions
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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.
Vitamin K antagonists (VKA)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
ALL
No
Sponsors
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University of Cape Town
OTHER
Bayer
INDUSTRY
Population Health Research Institute
OTHER
Responsible Party
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Principal Investigators
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Stuart Connolly, MD
Role: PRINCIPAL_INVESTIGATOR
Population Health Research Institute
Locations
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Princess Marina Hospital
Gaborone, , Botswana
Cardresearch - Cardiologia Assistencial e de Pesquisa
Belo Horizonte, Minas Gerais, Brazil
Nucleo de Estudios Clinicos - Universidade Federal do Triângulo Mineiro
Uberaba, Minas Gerais, Brazil
Eurolatino Pesquisas Médicas Ltda
Uberlândia, Minas Gerais, Brazil
Clínica Procardio Ltda.
Blumenau, Santa Catarina, Brazil
Instituto de Pesquisa Clínica de Campinas
Campinas, , Brazil
LOEMA - Instituto de Pesquisa Clínica & Consultores Ltda
Campinas, , Brazil
Via Médica Centro Clínico Barroso e Sebba Ltda
Goiânia, , Brazil
Instituto de Cardiologia do Rio Grande do Sul
Porto Alegre, , Brazil
Fundação Faculdade de Medicina de São José do Rio Preto
São José do Rio Preto, , Brazil
Instituto do Coração - HCFMUSP
São Paulo, , Brazil
Instituto Dante Pazzanese de Cardiologia
São Paulo, , Brazil
Santa Casa de Misericórdia de Votuporanga
Votuporanga, , Brazil
Clinique Coeur Et Vie
Douala, , Cameroon
Douala General Hospital
Douala, , Cameroon
St. Elizabeth Catholic General Hospital, Cardiac Centre
Kumbo, , Cameroon
Hopital Central Yaounde
Yaoundé, , Cameroon
Liangxiang Hospital
Beijing, Beijing Municipality, China
The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University
Guangzhou, Guangdong, China
Jixi People's Hospital
Jixi, Heilongjiang, China
Tieli People's Hospital
Yichun, Heilongjiang, China
Luoyang Central's Hospital Affiliated to Zhengzhou University
Luoyang, Henan, China
Dancheng County People's Hospital
Zhoukou, Henan, China
Suiping Renan Hospital
Zhumadian, Henan, China
Jianshi County People's Hospital
Enshi, Hubei, China
Suqian Peaple's Hospital of Nanjing Drum-Tower Hospital Group
Suqian, Jiangsu, China
Tonghua Central Hospital
Tonghua, Jilin, China
Affiliated Zhongshan Hospital of Dalian University
Dalian, Liaoning, China
The First Affiliated Hospital of Dalian Medical University
Dalian, Liaoning, China
Ningxia Peple's Hospital
Yinchuan, Ningxia, China
Pi County People's Hospital
Chengdu, Sichuan, China
Anyue County People's Hospital
Ziyang, Sichuan, China
Wendeng Central Hospital
Weihai, Wendeng, China
Ninghai People's Hospital
Ningbo, Zhejiang, China
Beijing Anzhen Hospital
Beijing, , China
Zhongmou County People's Hospital
Henan, , China
Zhengzhou No.7 People's Hospital
Henan, , China
Zhengzhou 9th People's Hospital
Henan, , China
Guangshan County People's Hospital
Henan, , China
Fayoum General Hospital
Al Fayyum, , Egypt
Mehallah Rheumatic Heart Center
Al Mansurah, , Egypt
Specialized Medical Hospital - Mansoura
Al Mansurah, , Egypt
Alexandria University Hospital
Alexandria, , Egypt
Assuit General Hospital
Asyut, , Egypt
Benha University Cardiology Department
Banhā, , Egypt
Beni Suef University Hospital
Banī Suwayf, , Egypt
Ain Shams University Hospital
Cairo, , Egypt
Kasr El Einy Hospital (Cairo University)
Cairo, , Egypt
Suez Canal University Hospital
Ismailia, , Egypt
El Minia University Hospital
Minya, , Egypt
Sohag University, Sohag
Sohag, , Egypt
Red Crescent Hospital
Tanta, , Egypt
Zagazig University Hospital
Zagazig, , Egypt
Hawassa University Referral Hospital
Awasa, Snnpr, Ethiopia
College of Health Sciences, Addis Ababa University, Black Lion Hospital
Addis Ababa, , Ethiopia
Jimma University Hospital
Jimma, , Ethiopia
Mekelle University
Mek'ele, , Ethiopia
Sri Jayadev Institute of Cardiovascular Sciences and Research
Bangalore, Karnataka, India
Dr. Ram Manohar Lohia Hospital @ PGIMER
New Delhi, National Capital Territory of Delhi, India
Govind Ballabh Pant Hospital (GIPMER)
New Delhi, National Capital Territory of Delhi, India
All India Institute of Medical Sciences
New Delhi, National Capital Territory of Delhi, India
SMS Medical College
Jaipur, Rajasthan, India
King George's Medical College
Lucknow, Uttar Pradesh, India
Sanjay Gandhi Post Graduate Institute of Medical Sciences
Lucknow, Uttar Pradesh, India
Kazakh National Medical Institute,
Almaty, , Kazakhstan
Moi Teaching and Referral Hospital
Eldoret, , Kenya
Karen Hospital
Nairobi, , Kenya
Kenyatta National Hospital / University Of Nairobi
Nairobi, , Kenya
Clinical Hospital of administrative department of President and Government of Kyrgyz Republic
Bishkek, , Kyrgyzstan
Queen Elizabeth Central Hospital
Blantyre, , Malawi
Kumuzu Central Hospital
Lilongwe, , Malawi
Mzuzu Central Hospital
Mzuzu, , Malawi
Hospital Angeles León
León, Guanajuato, Mexico
Hospital Bernardette
Guadalajara, Jalisco, Mexico
Centro de Estudios Clínicos de Querétaro S.C.
Querétaro City, Querétaro, Mexico
Centro para el Desarrollo de la Medicina y Asistencia Especializada S.C.
Culiacán, Sinaloa, Mexico
Instituto de Investigación del Hospital Cardiológica Aguascalientes
Aguascalientes, , Mexico
Hospital General Dr. Jorge Soberon Acevedo.Secretaria de Salud del Estado de Guerrero
Guerrero, , Mexico
Instituto Nacional de Cardiología Ignacio Chavez
México, , Mexico
Maputo Central Hospital
Maputo, , Mozambique
Instituto Nacional de Saude & Universidade Eduardo Mondlane
Maputo, , Mozambique
College of Medical Sciences
Bharatpur, , Nepal
Chitwan Medical College
Bharatpur, , Nepal
Nobel medical college and teaching hospital pvt ltd
Biratnagar, , Nepal
Gautam Buddha Community Heart Hospital
Butwāl, , Nepal
BP Koirala Institute of Health Sciences
Dharān, , Nepal
Manmohan Cardiothoracic Vascular and Trasplant Center, IOM, TU
Kathmandu, , Nepal
Sahid Gangalal Heart Center
Kathmandu, , Nepal
Bheri Zonal Hospital
Nepalgunj, , Nepal
Manipal College of Medical Sciences
Pokhara, , Nepal
Federal Medical Center
Abeokuta, , Nigeria
University of Nigeria Teaching Hospital
Enugu, , Nigeria
College of Medicine, University of Ibadan
Ibadan, , Nigeria
Jos University Teaching Hospital
Jos, , Nigeria
Ahmadu Bello University Teaching Hospital
Kaduna, , Nigeria
Aminu Kano University Teaching Hospital
Kano, , Nigeria
Department of Medicine, Lagos University Teaching Hospital
Lagos, , Nigeria
Ladoke Akintola University of Technology Teaching Hospital
Ogbomoso, , Nigeria
Department of Medicine, Delta State University Teaching Hospital
Oghara, , Nigeria
Punjab Institute of Cardiology
Lahore, Punjab Province, Pakistan
Isra University Hospital
Hyderābād, , Pakistan
Nishtar Hospital Multan
Multan, , Pakistan
Lady Reading Hospital
Peshawar, , Pakistan
Rawalpindi Institute of Cardiology
Rawalpindi, , Pakistan
Instituto Nacional de Cardiología
Asunción, , Paraguay
Hospital Barrio Obrero
Asunción, , Paraguay
Hospital Regional de Ciudad Del Este
Ciudad del Este, , Paraguay
Hospital Nacional Itaugua
Itauguá, , Paraguay
Clinical Hospital
San Lorenzo, , Paraguay
Palawan Medical City
Puerto Princesa City, Palawan, Philippines
Philippine General Hospital
Manila, , Philippines
Philippine Heart Center
Quezon City, , Philippines
Quirino Memorial Medical Center
Quezon City, , Philippines
University of Rwanda, Kigali University Teaching Hospital
Kigali, , Rwanda
Nelson Mandela Academic Hospital
Mthatha, Eastern Cape, South Africa
Charlotte Maxeke Academic Hospital
Johannesburg, Parktown, South Africa
Sefako Makgatho Health Sciences University
Ga-Rankuwa, Pretoria, South Africa
Cardiology Research Universitas private hospital
Bloemfontein, , South Africa
University of Cape Town
Cape Town, , South Africa
University of Limpopo
Polokwane, , South Africa
Port Elizabeth Hospital Complex
Port Elizabeth, , South Africa
Chris Hani Baragwanath Hospital
Soweto, , South Africa
Alobeid Teaching Hospital
Al-Ubayyid, , Sudan
Atbara Teaching Hospital
Atbara, , Sudan
Ahmed Gasim Hospital
Khartoum, , Sudan
Alshaab Teaching Hospital
Khartoum, , Sudan
Ahmed Gasim Pediatric Hospital
Khartoum, , Sudan
Sudan Heart Center
Khartoum, , Sudan
Digna Prince Hospital
Port Sudan, , Sudan
Medani Heart Centre
Wad Medani, , Sudan
Muhimbili University of Health and Allied Sciences
Dar es Salaam, , Tanzania
Mbeya Zonal Referral Hospital
Mbeya, , Tanzania
Uganda Heart Institute
Kampala, , Uganda
Livingstone Central Hospital
Livingstone, , Zambia
University Teaching Hospital (UTH)
Lusaka, , Zambia
Ndola Central Hospital
Ndola, , Zambia
Mpilo Hospital, National University Science & Technology
Bulawayo, , Zimbabwe
Harare Hospital
Harare, , Zimbabwe
Parirenyatwa Hospital
Harare, , Zimbabwe
Countries
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References
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Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, El Sayed A, El Ghamrawy A, Damasceno A, Avezum A, Dans AML, Gitura B, Hu D, Kamanzi ER, Maklady F, Fana G, Gonzalez-Hermosillo JA, Musuku J, Kazmi K, Zuhlke L, Gondwe L, Ma C, Paniagua M, Ogah OS, Molefe-Baikai OJ, Lwabi P, Chillo P, Sharma SK, Cabral TTJ, Tarhuni WM, Benz A, van Eikels M, Krol A, Pattath D, Balasubramanian K, Rangarajan S, Ramasundarahettige C, Mayosi B, Yusuf S; INVICTUS Investigators. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation. N Engl J Med. 2022 Sep 15;387(11):978-988. doi: 10.1056/NEJMoa2209051. Epub 2022 Aug 28.
Karthikeyan G, Connolly SJ, Yusuf S. Overestimation of Stroke Risk in Rheumatic Mitral Stenosis and the Implications for Oral Anticoagulation. Circulation. 2020 Nov 3;142(18):1697-1699. doi: 10.1161/CIRCULATIONAHA.120.050347. Epub 2020 Nov 2. No abstract available.
Karthikeyan G, Connolly SJ, Ntsekhe M, Benz A, Rangarajan S, Lewis G, Yun Y, Sharma SK, Maklady F, Elghamrawy AE, Kazmi K, Cabral TTJ, Dayi H, Changsheng M, Gitura BM, Avezum A, Zuhlke L, Lwabi P, Haileamlak A, Ogah O, Chillo P, Paniagua M, ElSayed A, Dans A, Gondwe-Chunda L, Molefe-Baikai OJ, Gonzalez-Hermosillo JA, Hakim J, Damasceno A, Kamanzi ER, Musuku J, Davletov K, Connolly K, Mayosi BM, Yusuf S; INVICTUS Investigators. The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation. Am Heart J. 2020 Jul;225:69-77. doi: 10.1016/j.ahj.2020.03.018. Epub 2020 Mar 25.
Other Identifiers
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INVICTUS - VKA
Identifier Type: -
Identifier Source: org_study_id
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