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

NCT02832544 | Completed Phase 3 DMC

• 1 other identifier: INVICTUS - VKA
• Study Type: interventional
• Target: 4,565
• Locations: 23 countries
• Sites: 126

Brief Summary

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.

Conditions

Rheumatic Heart Disease

Keywords

atrial fibrillation; stroke

Outcome Measures

Primary Outcomes (1)

• Time from randomization to the first occurrence of vascular death or death of unknown cause, stroke, myocardial infarction or systemic embolism

  Vascular death or death of unknown cause, stroke, myocardial infarction or systemic embolism

  Approximately 4 years

Secondary Outcomes (1)

• Time from randomization to the first occurrence of composite of stroke or systemic embolism

  Approximately 4 years

Other Outcomes (1)

• Time from randomization to the first occurrence of a Major Bleed

  Approximately 4 years

Study Arms (2)

Rivaroxaban (20 mg)

EXPERIMENTAL

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)

Vitamin K antagonists (VKA)

ACTIVE COMPARATOR

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)

Interventions

Rivaroxaban (20 mg) DRUG

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.

Also known as: Xarelto

Rivaroxaban (20 mg)

Vitamin K antagonists (VKA) DRUG

Also known as: Warfarin

Vitamin K antagonists (VKA)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• RVHD diagnosed by echocardiography at any time prior to enrollment
• Age ≥18
• 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
• 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.

You may not qualify if:

• Refusal to give informed consent
• Actively involved in any study that would compromise the protocol of INVICTUS Trial
• Severe co-morbid condition with life expectancy \< 1 year
• 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.
• Likely to have valve replacement surgery within 6 months
• 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.
• Contraindication to the study medication of the trial
• Allergy to rivaroxaban
• Allergy to VKAs ( non-inferiority trial)
• Allergy to aspirin ( superiority trial)
• Severe renal insufficiency with an calculated creatinine clearance (Cockcroft-Gault) \<15 ml/min
• Serious bleeding in the past six months or at high risk for bleeding
• Moderate to severe hepatic impairment
• Ongoing need for dual antiplatelet therapy (patients with on-going aspirin therapy ≤100 mg per day are not excluded)
• Ongoing need for dual strong inhibitors of CYP-3a4 or p-glycoprotein inhibitor.

Sponsors & Collaborators

• Population Health Research Institute: lead
• University of Cape Town: collaborator
• Bayer: collaborator

Study Sites (139)

Princess Marina Hospital

Gaborone, Botswana

Location

Cardresearch - Cardiologia Assistencial e de Pesquisa

Belo Horizonte, Minas Gerais, 30150-240, Brazil

Location

Nucleo de Estudios Clinicos - Universidade Federal do Triângulo Mineiro

Uberaba, Minas Gerais, Brazil

Location

Eurolatino Pesquisas Médicas Ltda

Uberlândia, Minas Gerais, 38411-186, Brazil

Location

Clínica Procardio Ltda.

Blumenau, Santa Catarina, 89010-500, Brazil

Location

Instituto de Pesquisa Clínica de Campinas

Campinas, 13060-080, Brazil

Location

LOEMA - Instituto de Pesquisa Clínica & Consultores Ltda

Campinas, São Paulo, Brazil

Location

Via Médica Centro Clínico Barroso e Sebba Ltda

Goiânia, 74223130, Brazil

Location

Instituto de Cardiologia do Rio Grande do Sul

Porto Alegre, 90620001, Brazil

Location

Fundação Faculdade de Medicina de São José do Rio Preto

São José do Rio Preto, 1509000, Brazil

Location

Instituto do Coração - HCFMUSP

São Paulo, 05403-000, Brazil

Location

Instituto Dante Pazzanese de Cardiologia

São Paulo, 4012909, Brazil

Location

Santa Casa de Misericórdia de Votuporanga

Votuporanga, 15500-003, Brazil

Location

Clinique Coeur Et Vie

Douala, 7562, Cameroon

Location

Douala General Hospital

Douala, Cameroon

Location

St. Elizabeth Catholic General Hospital, Cardiac Centre

Kumbo, Cameroon

Location

Hopital Central Yaounde

Yaoundé, Cameroon

Location

Liangxiang Hospital

Beijing, Beijing Municipality, 102401, China

Location

The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University

Guangzhou, Guangdong, 510062, China

Location

Jixi People's Hospital

Jixi, Heilongjiang, 158100, China

Location

Tieli People's Hospital

Yichun, Heilongjiang, 152500, China

Location

Luoyang Central's Hospital Affiliated to Zhengzhou University

Luoyang, Henan, 471009, China

Location

Dancheng County People's Hospital

Zhoukou, Henan, 477150, China

Location

Suiping Renan Hospital

Zhumadian, Henan, 463100, China

Location

Jianshi County People's Hospital

Enshi, Hubei, 445308, China

Location

Suqian Peaple's Hospital of Nanjing Drum-Tower Hospital Group

Suqian, Jiangsu, 223800, China

Location

Tonghua Central Hospital

Tonghua, Jilin, 134001, China

Location

Affiliated Zhongshan Hospital of Dalian University

Dalian, Liaoning, 116001, China

Location

The First Affiliated Hospital of Dalian Medical University

Dalian, Liaoning, 116011, China

Location

Ningxia Peple's Hospital

Yinchuan, Ningxia, 750021, China

Location

Pi County People's Hospital

Chengdu, Sichuan, 611730, China

Location

Anyue County People's Hospital

Ziyang, Sichuan, 642350, China

Location

Wendeng Central Hospital

Weihai, Wendeng, China

Location

Ninghai People's Hospital

Ningbo, Zhejiang, 315600, China

Location

Beijing Anzhen Hospital

Beijing, 100029, China

Location

Zhongmou County People's Hospital

Henan, 450000, China

Location

Zhengzhou No.7 People's Hospital

Henan, 450016, China

Location

Zhengzhou 9th People's Hospital

Henan, 450053, China

Location

Guangshan County People's Hospital

Henan, China

Location

Fayoum General Hospital

Al Fayyum, 31951, Egypt

Location

Mehallah Rheumatic Heart Center

Al Mansurah, 31951, Egypt

Location

Specialized Medical Hospital - Mansoura

Al Mansurah, 35516, Egypt

Location

Alexandria University Hospital

Alexandria, 21561, Egypt

Location

Assuit General Hospital

Asyut, Egypt

Location

Benha University Cardiology Department

Banhā, Egypt

Location

Beni Suef University Hospital

Banī Suwayf, Egypt

Location

Ain Shams University Hospital

Cairo, 11566, Egypt

Location

Kasr El Einy Hospital (Cairo University)

Cairo, 21561, Egypt

Location

Suez Canal University Hospital

Ismailia, 41522, Egypt

Location

El Minia University Hospital

Minya, 61519, Egypt

Location

Sohag University, Sohag

Sohag, 35516, Egypt

Location

Red Crescent Hospital

Tanta, 31951, Egypt

Location

Zagazig University Hospital

Zagazig, 44519, Egypt

Location

Hawassa University Referral Hospital

Awasa, Snnpr, Ethiopia

Location

College of Health Sciences, Addis Ababa University, Black Lion Hospital

Addis Ababa, 1176, Ethiopia

Location

Jimma University Hospital

Jimma, Ethiopia

Location

Mekelle University

Mek'ele, 1871, Ethiopia

Location

Sri Jayadev Institute of Cardiovascular Sciences and Research

Bangalore, Karnataka, 560069, India

Location

Dr. Ram Manohar Lohia Hospital @ PGIMER

New Delhi, National Capital Territory of Delhi, 110001, India

Location

Govind Ballabh Pant Hospital (GIPMER)

New Delhi, National Capital Territory of Delhi, 110002, India

Location

All India Institute of Medical Sciences

New Delhi, National Capital Territory of Delhi, 110029, India

Location

SMS Medical College

Jaipur, Rajasthan, 302004, India

Location

King George's Medical College

Lucknow, Uttar Pradesh, 226003, India

Location

Sanjay Gandhi Post Graduate Institute of Medical Sciences

Lucknow, Uttar Pradesh, 226014, India

Location

Kazakh National Medical Institute,

Almaty, Kazakhstan

Location

Moi Teaching and Referral Hospital

Eldoret, 30100, Kenya

Location

Karen Hospital

Nairobi, 00200, Kenya

Location

Kenyatta National Hospital / University Of Nairobi

Nairobi, Kenya

Location

Clinical Hospital of administrative department of President and Government of Kyrgyz Republic

Bishkek, 720001, Kyrgyzstan

Location

Queen Elizabeth Central Hospital

Blantyre, 265, Malawi

Location

Kumuzu Central Hospital

Lilongwe, 265, Malawi

Location

Mzuzu Central Hospital

Mzuzu, 265, Malawi

Location

Hospital Angeles León

León, Guanajuato, 37150, Mexico

Location

Hospital Bernardette

Guadalajara, Jalisco, 44200, Mexico

Location

Centro de Estudios Clínicos de Querétaro S.C.

Querétaro City, Querétaro, 76000, Mexico

Location

Centro para el Desarrollo de la Medicina y Asistencia Especializada S.C.

Culiacán, Sinaloa, 80230, Mexico

Location

Instituto de Investigación del Hospital Cardiológica Aguascalientes

Aguascalientes, 20230, Mexico

Location

Hospital General Dr. Jorge Soberon Acevedo.Secretaria de Salud del Estado de Guerrero

Guerrero, 40000, Mexico

Location

Instituto Nacional de Cardiología Ignacio Chavez

México, 14080, Mexico

Location

Maputo Central Hospital

Maputo, 1111, Mozambique

Location

Instituto Nacional de Saude & Universidade Eduardo Mondlane

Maputo, CP 264, Mozambique

Location

College of Medical Sciences

Bharatpur, 44207, Nepal

Location

Chitwan Medical College

Bharatpur, Nepal

Location

Nobel medical college and teaching hospital pvt ltd

Biratnagar, 56613, Nepal

Location

Gautam Buddha Community Heart Hospital

Butwāl, 32907, Nepal

Location

BP Koirala Institute of Health Sciences

Dharān, 56700, Nepal

Location

Manmohan Cardiothoracic Vascular and Trasplant Center, IOM, TU

Kathmandu, 44600, Nepal

Location

Sahid Gangalal Heart Center

Kathmandu, 44600, Nepal

Location

Bheri Zonal Hospital

Nepalgunj, 21900, Nepal

Location

Manipal College of Medical Sciences

Pokhara, 33700, Nepal

Location

Federal Medical Center

Abeokuta, Nigeria

Location

University of Nigeria Teaching Hospital

Enugu, 400201, Nigeria

Location

College of Medicine, University of Ibadan

Ibadan, 200212, Nigeria

Location

Jos University Teaching Hospital

Jos, 930001, Nigeria

Location

Ahmadu Bello University Teaching Hospital

Kaduna, 810001, Nigeria

Location

Aminu Kano University Teaching Hospital

Kano, 700223, Nigeria

Location

Department of Medicine, Lagos University Teaching Hospital

Lagos, 12003, Nigeria

Location

Ladoke Akintola University of Technology Teaching Hospital

Ogbomoso, 4007, Nigeria

Location

Department of Medicine, Delta State University Teaching Hospital

Oghara, Nigeria

Location

Punjab Institute of Cardiology

Lahore, Punjab Province, 54000, Pakistan

Location

Isra University Hospital

Hyderābād, 31300, Pakistan

Location

Nishtar Hospital Multan

Multan, 60000, Pakistan

Location

Lady Reading Hospital

Peshawar, PK 2500, Pakistan

Location

Rawalpindi Institute of Cardiology

Rawalpindi, 46000, Pakistan

Location

Instituto Nacional de Cardiología

Asunción, 1725, Paraguay

Location

Hospital Barrio Obrero

Asunción, 2279, Paraguay

Location

Hospital Regional de Ciudad Del Este

Ciudad del Este, 7000, Paraguay

Location

Hospital Nacional Itaugua

Itauguá, 2740, Paraguay

Location

Clinical Hospital

San Lorenzo, 1863, Paraguay

Location

Palawan Medical City

Puerto Princesa City, Palawan, 5300, Philippines

Location

Philippine General Hospital

Manila, 1000, Philippines

Location

Philippine Heart Center

Quezon City, 1100, Philippines

Location

Quirino Memorial Medical Center

Quezon City, 1109, Philippines

Location

University of Rwanda, Kigali University Teaching Hospital

Kigali, Rwanda

Location

Nelson Mandela Academic Hospital

Mthatha, Eastern Cape, 5099, South Africa

Location

Charlotte Maxeke Academic Hospital

Johannesburg, Parktown, 2193, South Africa

Location

Sefako Makgatho Health Sciences University

Ga-Rankuwa, Pretoria, 0204, South Africa

Location

Cardiology Research Universitas private hospital

Bloemfontein, 9301, South Africa

Location

University of Cape Town

Cape Town, 7925, South Africa

Location

University of Limpopo

Polokwane, 700, South Africa

Location

Port Elizabeth Hospital Complex

Port Elizabeth, 6001, South Africa

Location

Chris Hani Baragwanath Hospital

Soweto, 2013, South Africa

Location

Alobeid Teaching Hospital

Al-Ubayyid, Sudan

Location

Atbara Teaching Hospital

Atbara, Sudan

Location

Ahmed Gasim Hospital

Khartoum, 1111, Sudan

Location

Alshaab Teaching Hospital

Khartoum, 1111, Sudan

Location

Ahmed Gasim Pediatric Hospital

Khartoum, Sudan

Location

Sudan Heart Center

Khartoum, Sudan

Location

Digna Prince Hospital

Port Sudan, Sudan

Location

Medani Heart Centre

Wad Medani, Sudan

Location

Muhimbili University of Health and Allied Sciences

Dar es Salaam, Tanzania

Location

Mbeya Zonal Referral Hospital

Mbeya, 419, Tanzania

Location

Uganda Heart Institute

Kampala, Uganda

Location

Livingstone Central Hospital

Livingstone, 10101, Zambia

Location

University Teaching Hospital (UTH)

Lusaka, Zambia

Location

Ndola Central Hospital

Ndola, 10101, Zambia

Location

Mpilo Hospital, National University Science & Technology

Bulawayo, Zimbabwe

Location

Harare Hospital

Harare, Zimbabwe

Location

Parirenyatwa Hospital

Harare, Zimbabwe

Location

Related Publications (3)

• 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.

  PMID: 36036525 DERIVED

• 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.

  PMID: 33136507 DERIVED

• 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.

  PMID: 32474206 DERIVED

MeSH Terms

Conditions

Rheumatic Heart Disease; Atrial Fibrillation; Stroke

Interventions

Rivaroxaban; acarboxyprothrombin; Warfarin

Condition Hierarchy (Ancestors)

Rheumatic Fever; Streptococcal Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Stuart Connolly, MD

  Population Health Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2015
• First Posted: July 14, 2016
• Study Start: August 22, 2016
• Primary Completion: August 18, 2022
• Study Completion: August 18, 2022
• Last Updated: October 5, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

ET (4); BR (12); TA (2); SU (8); MO (2); ME (7); PA (5); ZI (3); EG (14); BO (1); PH (4); KE (3); MA (3); NE (9); KA (1); CA (4); IN (7); KY (1); ZA (3); NG (9); CN (22); RW (1); UG (1)