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Original ArticleFree Preview

Rivaroxaban in Rheumatic Heart Disease–Associated Atrial Fibrillation

List of authors.
  • Stuart J. Connolly, M.D.,
  • Ganesan Karthikeyan, M.D., D.M.,
  • Mpiko Ntsekhe, M.D., Ph.D.,
  • Abraham Haileamlak, M.D.,
  • Ahmed El Sayed, M.D.,
  • Alaa El Ghamrawy, M.D.,
  • Albertino Damasceno, M.D., Ph.D.,
  • Alvaro Avezum, M.D., Ph.D.,
  • Antonio M.L. Dans, M.D.,
  • Bernard Gitura, M.Med.,
  • Dayi Hu, M.D.,
  • Emmanuel R. Kamanzi, M.Med.,
  • Fathi Maklady, M.D.,
  • Golden Fana, M.Med.,
  • J. Antonio Gonzalez-Hermosillo, M.D.,
  • John Musuku, M.Med.,
  • Khawar Kazmi, M.D.,
  • Liesl Zühlke, M.D., Ph.D.,
  • Lillian Gondwe, M.B., B.S.,
  • Changsheng Ma, M.D.,
  • Maria Paniagua, M.D.,
  • Okechukwu S. Ogah, M.B., B.S., Ph.D.,
  • Onkabetse J. Molefe-Baikai, M.Med.,
  • Peter Lwabi, M.Med.,
  • Pilly Chillo, M.D.,
  • Sanjib K. Sharma, M.D., D.M.,
  • Tantchou T.J. Cabral, M.D., Ph.D.,
  • Wadea M. Tarhuni, M.D.,
  • Alexander Benz, M.D.,
  • Martin van Eikels, M.D.,
  • Amy Krol, B.Sc.,
  • Divya Pattath, M.Sc.,
  • Kumar Balasubramanian, M.Sc.,
  • Sumathy Rangarajan, M.Sc.,
  • Chinthanie Ramasundarahettige, M.Sc.,
  • Bongani Mayosi, M.D., D.Phil.,
  • and Salim Yusuf, D.Phil.
  • for the INVICTUS Investigators



Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease–associated atrial fibrillation has been limited.


We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis.


Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, −76 days; 95% confidence interval [CI], −121 to −31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, −72 days; 95% CI, −117 to −28). No significant between-group difference in the rate of major bleeding was noted.


Among patients with rheumatic heart disease–associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS number, NCT02832544.)

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Funding and Disclosures

Supported by a nonrestricted grant from Bayer to the Population Health Research Institute.

Disclosure forms provided by the authors are available with the full text of this article at

This article was published on August 28, 2022, at

A data sharing statement provided by the authors is available with the full text of this article at

This article is dedicated to the memory of Dr. Bongani Mayosi, of the University of Cape Town, who was the initial principal investigator of the INVICTUS trial, for which he played a pivotal role in the design and initiation. We were saddened by his untimely death on July 27, 2018.

Author Affiliations

From the Population Health Research Institute, McMaster University, Hamilton, ON, Canada (S.J.C., A.B., A.K., D.P., K.B., S.R., C.R., S.Y.); the All India Institute of Medical Sciences, New Delhi (G.K.); the Division of Cardiology, Faculty of Health Sciences, University of Cape Town (M.N., B.M.), and the South African Medical Research Council (L.Z.) — both in Cape Town, South Africa; Jimma University Medical Center, Jimma, Ethiopia (A.H.); the University of Gazira, Wad Madani, Sudan (A.E.S.); Mahalla Heart Center, El Mahalla El Kubra (A.E.G.), and Suez Canal University Hospital, Ismailia (F.M.) — both in Egypt; the Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique (A.D.); the International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo (A.A.); the College of Medicine, University of the Philippines, Manila (A.M.L.D.); Kenyatta National Hospital, Nairobi (B.G.); the People’s Hospital of Peking University (D.H.) and the Beijing Anzhen Hospital (C.M.) — both in Beijing; the University Teaching Hospital of Kigali, Kigali, Rwanda (E.R.K.); the University of Zimbabwe, College of Health Sciences, Harare (G.F.); Instituto Nacional de Cardiología Ignacio Chávez, Mexico City (J.A.G.-H.); the University Teaching Hospital, Lusaka, Zambia (J.M.); the National Institute of Cardiovascular Diseases, Karachi, Pakistan (K.K.); Kamuzu Central Hospital, Lilongwe, Malawi (L.G.); Barrio Obrero Hospital, Asuncion, Paraguay (M.P.); the Department of Medicine, University of Ibadan–College Hospital, Ibadan, Nigeria (O.S.O.); Princess Marina Hospital, University of Botswana, Gaborone (O.J.M.-B.); Uganda Heart Institute, Kampala (P.L.); Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania (P.C.); the B.P. Koirala Institute of Health Sciences, Dharan, Nepal (S.K.S.); St. Elizabeth Catholic General Hospital, Kumbo, Cameroon (T.T.J.C.); the Department of Medicine, University of Saskatchewan, Saskatoon, the Department of Medicine, Western University, London, ON, and the Windsor Cardiac Centre, Windsor, ON — all in Canada (W.M.T.); the Department of Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg University, Mainz (A.B.), and Bayer, Berlin (M.E.) — both in Germany.

Dr. Connolly can be contacted at or at the Population Health Research Institute, 30 Birge St., Hamilton, ON L8L 0A6, Canada.

Bongani Mayosi, M.D., D.Phil., is deceased.

A complete list of the INVICTUS investigators is provided in the Supplementary Appendix, available at