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

Rheumatic Heart Disease Clinical Trial

— INVICTUS-VKA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02832544
• Other study ID #: INVICTUS - VKA
• Status: Completed
• Phase: Phase 3
• Start date: August 22, 2016
• Est. completion date: August 18, 2022

Study information

• Verified date: July 2022
• Source: Population Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4565
• Est. completion date: August 18, 2022
• Est. primary completion date: August 18, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Diseases
• Rheumatic Diseases
• Rheumatic Heart Disease

Intervention

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.
• Vitamin K antagonists (VKA)

Locations

Country	Name	City	State
Botswana	Princess Marina Hospital	Gaborone
Brazil	Cardresearch - Cardiologia Assistencial e de Pesquisa	Belo Horizonte	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	Goiania
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 Dante Pazzanese de Cardiologia	São Paulo
Brazil	Instituto do Coração - HCFMUSP	São Paulo
Brazil	Nucleo de Estudios Clinicos - Universidade Federal do Triângulo Mineiro	Uberaba	Minas Gerais
Brazil	Eurolatino Pesquisas Médicas Ltda	Uberlândia	Minas Gerais
Brazil	Santa Casa de Misericórdia de Votuporanga	Votuporanga
Cameroon	Clinique Coeur Et Vie	Douala
Cameroon	Douala General Hospital	Douala
Cameroon	St. Elizabeth Catholic General Hospital, Cardiac Centre	Kumbo
Cameroon	Hopital Central Yaounde	Yaounde
China	Beijing Anzhen Hospital	Beijing
China	Liangxiang Hospital	Beijing	Beijing
China	Pi County People's Hospital	Chengdu	Sichuan
China	Affiliated Zhongshan Hospital of Dalian University	Dalian	Liaoning
China	The First Affiliated Hospital of Dalian Medical University	Dalian	Liaoning
China	Jianshi County People's Hospital	Enshi	Hubei
China	The First Affiliated Hospital/School of Clinical Medicine of Guangdong Pharmaceutical University	Guangzhou	Guangdong
China	Guangshan County People's Hospital	Henan
China	Zhengzhou 9th People's Hospital	Henan
China	Zhengzhou No.7 People's Hospital	Henan
China	Zhongmou County People's Hospital	Henan
China	Jixi People's Hospital	Jixi	Heilongjiang
China	Luoyang Central's Hospital Affiliated to Zhengzhou University	Luoyang	Henan
China	Ninghai People's Hospital	Ningbo	Zhejiang
China	Suqian Peaple's Hospital of Nanjing Drum-Tower Hospital Group	Suqian	Jiangsu
China	Tonghua Central Hospital	Tonghua	Jilin
China	Wendeng Central Hospital	Weihai	Wendeng
China	Tieli People's Hospital	Yichun	Heilongjiang
China	Ningxia Peple's Hospital	Yinchuan	Ningxia
China	Dancheng County People's Hospital	Zhoukou	Henan
China	Suiping Renan Hospital	Zhumadian	Henan
China	Anyue County People's Hospital	Ziyang	Sichuan
Egypt	Alexandria University Hospital	Alexandria
Egypt	Assuit General Hospital	Assuit
Egypt	Benha University Cardiology Department	Banha
Egypt	Beni Suef University Hospital	Bani Suwayf
Egypt	Ain Shams University Hospital	Cairo
Egypt	Kasr El Einy Hospital (Cairo University)	Cairo
Egypt	Mehallah Rheumatic Heart Center	El Mansura
Egypt	Specialized Medical Hospital - Mansoura	El Mansura
Egypt	Fayoum General Hospital	Fayoum
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
Ethiopia	College of Health Sciences, Addis Ababa University, Black Lion Hospital	Addis Ababa
Ethiopia	Hawassa University Referral Hospital	Hawassa	Snnpr
Ethiopia	Jimma University Hospital	Jimma
Ethiopia	Mekelle University	Mek'ele
India	Sri Jayadev Institute of Cardiovascular Sciences and Research	Bangalore	Karnataka
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	All India Institute of Medical Sciences	New Delhi	Delhi
India	Dr. Ram Manohar Lohia Hospital @ PGIMER	New Delhi	Delhi
India	Govind Ballabh Pant Hospital (GIPMER)	New Delhi	Delhi
Kazakhstan	Kazakh National Medical Institute,	Almaty
Kenya	Moi Teaching and Referral Hospital	Eldoret
Kenya	Karen Hospital	Nairobi
Kenya	Kenyatta National Hospital / University Of Nairobi	Nairobi
Kyrgyzstan	Clinical Hospital of administrative department of President and Government of Kyrgyz Republic	Bishkek
Malawi	Queen Elizabeth Central Hospital	Blantyre
Malawi	Kumuzu Central Hospital	Lilongwe
Malawi	Mzuzu Central Hospital	Mzuzu
Mexico	Instituto de Investigación del Hospital Cardiológica Aguascalientes	Aguascalientes
Mexico	Centro para el Desarrollo de la Medicina y Asistencia Especializada S.C.	Culiacan	Sinaloa
Mexico	Hospital Bernardette	Guadalajara	Jalisco
Mexico	Hospital General Dr. Jorge Soberon Acevedo.Secretaria de Salud del Estado de Guerrero	Guerrero
Mexico	Hospital Angeles León	León	Guanajuato
Mexico	Instituto Nacional de Cardiología Ignacio Chavez	México
Mexico	Centro de Estudios Clínicos de Querétaro S.C.	Queretaro	Querétaro
Mozambique	Instituto Nacional de Saude & Universidade Eduardo Mondlane	Maputo
Mozambique	Maputo Central Hospital	Maputo
Nepal	Chitwan Medical College	Bharatpur
Nepal	College of Medical Sciences	Bharatpur
Nepal	Nobel medical college and teaching hospital pvt ltd	Biratnagar
Nepal	Gautam Buddha Community Heart Hospital	Butwal
Nepal	BP Koirala Institute of Health Sciences	Dharan Bazar
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
Nigeria	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
Pakistan	Isra University Hospital	Hyderabad
Pakistan	Punjab Institute of Cardiology	Lahore	Punjab
Pakistan	Nishtar Hospital Multan	Multan
Pakistan	Lady Reading Hospital	Peshawar
Pakistan	Rawalpindi Institute of Cardiology	Rawalpindi
Paraguay	Hospital Barrio Obrero	Asunción
Paraguay	Instituto Nacional de Cardiología	Asunción
Paraguay	Hospital Regional de Ciudad Del Este	Ciudad del Este
Paraguay	Hospital Nacional Itaugua	Itaugua
Paraguay	Clinical Hospital	San Lorenzo
Philippines	Philippine General Hospital	Manila
Philippines	Palawan Medical City	Puerto Princesa City	Palawan
Philippines	Philippine Heart Center	Quezon City
Philippines	Quirino Memorial Medical Center	Quezon City
Rwanda	University of Rwanda, Kigali University Teaching Hospital	Kigali
South Africa	Cardiology Research Universitas private hospital	Bloemfontein
South Africa	University of Cape Town	Cape Town
South Africa	Sefako Makgatho Health Sciences University	Ga-Rankuwa,	Pretoria
South Africa	Charlotte Maxeke Academic Hospital	Johannesburg	Parktown
South Africa	Nelson Mandela Academic Hospital	Mthatha	Eastern Cape
South Africa	University of Limpopo	Polokwane
South Africa	Port Elizabeth Hospital Complex	Port Elizabeth
South Africa	Chris Hani Baragwanath Hospital	Soweto
Sudan	Atbara Teaching Hospital	Atbara
Sudan	Alobeid Teaching Hospital	El Obeid
Sudan	Ahmed Gasim Hospital	Khartoum
Sudan	Ahmed Gasim Pediatric Hospital	Khartoum
Sudan	Alshaab Teaching Hospital	Khartoum
Sudan	Sudan Heart Center	Khartoum
Sudan	Digna Prince Hospital	Port Sudan
Sudan	Medani Heart Centre	Wad Medani
Tanzania	Muhimbili University of Health and Allied Sciences	Dar es Salaam
Tanzania	Mbeya Zonal Referral Hospital	Mbeya
Uganda	Uganda Heart Institute	Kampala
Zambia	Livingstone Central Hospital	Livingstone
Zambia	University Teaching Hospital (UTH)	Lusaka
Zambia	Ndola Central Hospital	Ndola
Zimbabwe	Mpilo Hospital, National University Science & Technology	Bulawayo
Zimbabwe	Harare Hospital	Harare
Zimbabwe	Parirenyatwa Hospital	Harare

Sponsors (3)

Lead Sponsor	Collaborator
Population Health Research Institute	Bayer, University of Cape Town

Countries where clinical trial is conducted

Botswana,  Brazil,  Cameroon,  China,  Egypt,  Ethiopia,  India,  Kazakhstan,  Kenya,  Kyrgyzstan,  Malawi,  Mexico,  Mozambique,  Nepal,  Nigeria,  Pakistan,  Paraguay,  Philippines,  Rwanda,  South Africa,  Sudan,  Tanzania,  Uganda,  Zambia,  Zimbabwe, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time from randomization to the first occurrence of a Major Bleed	using the ISTH major bleeding definition	Approximately 4 years
Primary	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	Time from randomization to the first occurrence of composite of stroke or systemic embolism	Composite of stroke or systemic embolism	Approximately 4 years