Clinical trial NCT02832544: INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority
Official title: INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatic Heart Disease
Keywords: atrial fibrillation
stroke
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: University of Cape Town
name: Bayer
First posted: 2016-07-14
Enrollment: 4565
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Time from randomization to the first occurrence of vascular death or death of unknown cause, stroke, myocardial infarction or systemic embolism
timeFrame: Approximately 4 years
Secondary outcomes:
measure: Time from randomization to the first occurrence of composite of stroke or systemic embolism
timeFrame: Approximately 4 years
Other outcomes:
measure: Time from randomization to the first occurrence of a Major Bleed
timeFrame: Approximately 4 years
Locations:
city: Gaborone
country: Botswana
facility: Princess Marina Hospital
city: Belo Horizonte
country: Brazil
facility: Cardresearch - Cardiologia Assistencial e de Pesquisa
state: Minas Gerais
city: Uberaba
country: Brazil
facility: Nucleo de Estudios Clinicos - Universidade Federal do Triângulo Mineiro
state: Minas Gerais
city: Uberlândia
country: Brazil
facility: Eurolatino Pesquisas Médicas Ltda
state: Minas Gerais
city: Blumenau
country: Brazil
facility: Clínica Procardio Ltda.
state: Santa Catarina
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clínica de Campinas
city: Campinas
country: Brazil
facility: LOEMA - Instituto de Pesquisa Clínica & Consultores Ltda
city: Goiania
country: Brazil
facility: Via Médica Centro Clínico Barroso e Sebba Ltda
city: Porto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
city: São José do Rio Preto
country: Brazil
facility: Fundação Faculdade de Medicina de São José do Rio Preto
city: São Paulo
country: Brazil
facility: Instituto do Coração - HCFMUSP
city: São Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
city: Votuporanga
country: Brazil
facility: Santa Casa de Misericórdia de Votuporanga
city: Douala
country: Cameroon
facility: Clinique Coeur Et Vie
city: Douala
country: Cameroon
facility: Douala General Hospital
city: Kumbo
country: Cameroon
facility: St. Elizabeth Catholic General Hospital, Cardiac Centre
city: Yaounde
country: Cameroon
facility: Hopital Central Yaounde
city: Beijing
country: China
facility: Liangxiang Hospital
state: Beijing
city: Guangzhou
country: China
facility: The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University
state: Guangdong
city: Jixi
country: China
facility: Jixi People's Hospital
state: Heilongjiang
city: Yichun
country: China
facility: Tieli People's Hospital
state: Heilongjiang
city: Luoyang
country: China
facility: Luoyang Central's Hospital Affiliated to Zhengzhou University
state: Henan
city: Zhoukou
country: China
facility: Dancheng County People's Hospital
state: Henan
city: Zhumadian
country: China
facility: Suiping Renan Hospital
state: Henan
city: Enshi
country: China
facility: Jianshi County People's Hospital
state: Hubei
city: Suqian
country: China
facility: Suqian Peaple's Hospital of Nanjing Drum-Tower Hospital Group
state: Jiangsu
city: Tonghua
country: China
facility: Tonghua Central Hospital
state: Jilin
city: Dalian
country: China
facility: Affiliated Zhongshan Hospital of Dalian University
state: Liaoning
city: Dalian
country: China
facility: The First Affiliated Hospital of Dalian Medical University
state: Liaoning
city: Yinchuan
country: China
facility: Ningxia Peple's Hospital
state: Ningxia
city: Chengdu
country: China
facility: Pi County People's Hospital
state: Sichuan
city: Ziyang
country: China
facility: Anyue County People's Hospital
state: Sichuan
city: Weihai
country: China
facility: Wendeng Central Hospital
state: Wendeng
city: Ningbo
country: China
facility: Ninghai People's Hospital
state: Zhejiang
city: Beijing
country: China
facility: Beijing Anzhen Hospital
city: Henan
country: China
facility: Zhongmou County People's Hospital
city: Henan
country: China
facility: Zhengzhou No.7 People's Hospital
city: Henan
country: China
facility: Zhengzhou 9th People's Hospital
city: Henan
country: China
facility: Guangshan County People's Hospital
city: Alexandria
country: Egypt
facility: Alexandria University Hospital
city: Assuit
country: Egypt
facility: Assuit General Hospital
city: Banha
country: Egypt
facility: Benha University Cardiology Department
city: Banī Suwayf
country: Egypt
facility: Beni Suef University Hospital
city: Cairo
country: Egypt
facility: Ain Shams University Hospital
city: Cairo
country: Egypt
facility: Kasr El Einy Hospital (Cairo University)
city: El Mansura
country: Egypt
facility: Mehallah Rheumatic Heart Center
city: El Mansura
country: Egypt
facility: Specialized Medical Hospital - Mansoura
city: Fayoum
country: Egypt
facility: Fayoum General Hospital
city: Ismailia
country: Egypt
facility: Suez Canal University Hospital
city: Minya
country: Egypt
facility: El Minia University Hospital
city: Sohag
country: Egypt
facility: Sohag University, Sohag
city: Tanta
country: Egypt
facility: Red Crescent Hospital
city: Zagazig
country: Egypt
facility: Zagazig University Hospital
city: Hawassa
country: Ethiopia
facility: Hawassa University Referral Hospital
state: Snnpr
city: Addis Ababa
country: Ethiopia
facility: College of Health Sciences, Addis Ababa University, Black Lion Hospital
city: Jimma
country: Ethiopia
facility: Jimma University Hospital
city: Mek'ele
country: Ethiopia
facility: Mekelle University
city: New Delhi
country: India
facility: Dr. Ram Manohar Lohia Hospital @ PGIMER
state: Delhi
city: New Delhi
country: India
facility: Govind Ballabh Pant Hospital (GIPMER)
state: Delhi
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
state: Delhi
city: Bangalore
country: India
facility: Sri Jayadev Institute of Cardiovascular Sciences and Research
state: Karnataka
city: Jaipur
country: India
facility: SMS Medical College
state: Rajasthan
city: Lucknow
country: India
facility: King George's Medical College
state: Uttar Pradesh
city: Lucknow
country: India
facility: Sanjay Gandhi Post Graduate Institute of Medical Sciences
state: Uttar Pradesh
city: Almaty
country: Kazakhstan
facility: Kazakh National Medical Institute,
city: Eldoret
country: Kenya
facility: Moi Teaching and Referral Hospital
city: Nairobi
country: Kenya
facility: Karen Hospital
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital / University Of Nairobi
city: Bishkek
country: Kyrgyzstan
facility: Clinical Hospital of administrative department of President and Government of Kyrgyz Republic
city: Blantyre
country: Malawi
facility: Queen Elizabeth Central Hospital
city: Lilongwe
country: Malawi
facility: Kumuzu Central Hospital
city: Mzuzu
country: Malawi
facility: Mzuzu Central Hospital
city: León
country: Mexico
facility: Hospital Angeles León
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Hospital Bernardette
state: Jalisco
city: Queretaro
country: Mexico
facility: Centro de Estudios Clínicos de Querétaro S.C.
state: Querétaro
city: Culiacan
country: Mexico
facility: Centro para el Desarrollo de la Medicina y Asistencia Especializada S.C.
state: Sinaloa
city: Aguascalientes
country: Mexico
facility: Instituto de Investigación del Hospital Cardiológica Aguascalientes
city: Guerrero
country: Mexico
facility: Hospital General Dr. Jorge Soberon Acevedo.Secretaria de Salud del Estado de Guerrero
city: México
country: Mexico
facility: Instituto Nacional de Cardiología Ignacio Chavez
city: Maputo
country: Mozambique
facility: Maputo Central Hospital
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saude & Universidade Eduardo Mondlane
city: Bharatpur
country: Nepal
facility: College of Medical Sciences
city: Bharatpur
country: Nepal
facility: Chitwan Medical College
city: Biratnagar
country: Nepal
facility: Nobel medical college and teaching hospital pvt ltd
city: Butwal
country: Nepal
facility: Gautam Buddha Community Heart Hospital
city: Dharān Bāzār
country: Nepal
facility: BP Koirala Institute of Health Sciences
city: Kathmandu
country: Nepal
facility: Manmohan Cardiothoracic Vascular and Trasplant Center, IOM, TU
city: Kathmandu
country: Nepal
facility: Sahid Gangalal Heart Center
city: Nepalgunj
country: Nepal
facility: Bheri Zonal Hospital
city: Pokhara
country: Nepal
facility: Manipal College of Medical Sciences
city: Abeokuta
country: Nigeria
facility: Federal Medical Center
city: Enugu
country: Nigeria
facility: University of Nigeria Teaching Hospital
city: Ibadan
country: Nigeria
facility: College of Medicine, University of Ibadan
city: Jos
country: Nigeria
facility: Jos University Teaching Hospital
city: Kaduna
country: Nigeria
facility: Ahmadu Bello University Teaching Hospital
city: Kano
country: Nigeria
facility: Aminu Kano University Teaching Hospital
city: Lagos
country: Nigeria
facility: Department of Medicine, Lagos University Teaching Hospital
city: Ogbomoso
country: Nigeria
facility: Ladoke Akintola University of Technology Teaching Hospital
city: Oghara
country: Nigeria
facility: Department of Medicine, Delta State University Teaching Hospital
city: Lahore
country: Pakistan
facility: Punjab Institute of Cardiology
state: Punjab
city: Hyderabad
country: Pakistan
facility: Isra University Hospital
city: Multan
country: Pakistan
facility: Nishtar Hospital Multan
city: Peshawar
country: Pakistan
facility: Lady Reading Hospital
city: Rawalpindi
country: Pakistan
facility: Rawalpindi Institute of Cardiology
city: Asunción
country: Paraguay
facility: Instituto Nacional de Cardiología
city: Asunción
country: Paraguay
facility: Hospital Barrio Obrero
city: Ciudad del Este
country: Paraguay
facility: Hospital Regional de Ciudad Del Este
city: Itaugua
country: Paraguay
facility: Hospital Nacional Itaugua
city: San Lorenzo
country: Paraguay
facility: Clinical Hospital
city: Puerto Princesa City
country: Philippines
facility: Palawan Medical City
state: Palawan
city: Manila
country: Philippines
facility: Philippine General Hospital
city: Quezon City
country: Philippines
facility: Philippine Heart Center
city: Quezon City
country: Philippines
facility: Quirino Memorial Medical Center
city: Kigali
country: Rwanda
facility: University of Rwanda, Kigali University Teaching Hospital
city: Mthatha
country: South Africa
facility: Nelson Mandela Academic Hospital
state: Eastern Cape
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Academic Hospital
state: Parktown
city: Ga-Rankuwa,
country: South Africa
facility: Sefako Makgatho Health Sciences University
state: Pretoria
city: Bloemfontein
country: South Africa
facility: Cardiology Research Universitas private hospital
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Polokwane
country: South Africa
facility: University of Limpopo
city: Port Elizabeth
country: South Africa
facility: Port Elizabeth Hospital Complex
city: Soweto
country: South Africa
facility: Chris Hani Baragwanath Hospital
city: Atbara
country: Sudan
facility: Atbara Teaching Hospital
city: El Obeid
country: Sudan
facility: Alobeid Teaching Hospital
city: Khartoum
country: Sudan
facility: Ahmed Gasim Hospital
city: Khartoum
country: Sudan
facility: Alshaab Teaching Hospital
city: Khartoum
country: Sudan
facility: Ahmed Gasim Pediatric Hospital
city: Khartoum
country: Sudan
facility: Sudan Heart Center
city: Port Sudan
country: Sudan
facility: Digna Prince Hospital
city: Wad Medani
country: Sudan
facility: Medani Heart Centre
city: Dar es Salaam
country: Tanzania
facility: Muhimbili University of Health and Allied Sciences
city: Mbeya
country: Tanzania
facility: Mbeya Zonal Referral Hospital
city: Kampala
country: Uganda
facility: Uganda Heart Institute
city: Livingstone
country: Zambia
facility: Livingstone Central Hospital
city: Lusaka
country: Zambia
facility: University Teaching Hospital (UTH)
city: Ndola
country: Zambia
facility: Ndola Central Hospital
city: Bulawayo
country: Zimbabwe
facility: Mpilo Hospital, National University Science & Technology
city: Harare
country: Zimbabwe
facility: Harare Hospital
city: Harare
country: Zimbabwe
facility: Parirenyatwa Hospital
Study officials:
affiliation: Population Health Research Institute
name: Stuart Connolly, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.