Vitamin K Antagonist Prevails Over Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation

By Liane Arcinas, MD - Last Updated: October 21, 2022

Direct oral anticoagulants (DOAC) have been shown in randomized trials to be effective in stroke prevention in patients with nonvalvular atrial fibrillation (AF)1. Importantly, these trials excluded patients who have AF in the setting of rheumatic heart disease (RHD).  The INVICTUS trial, presented at European Society of Cardiology (ESC) Congress 2022 and published at the New England Journal of Medicine (NEJM), is the largest randomized clinical trial conducted in patients with rheumatic heart disease, and the first to compare vitamin K antagonist therapy to rivaroxaban (a factor Xa inhibitor) in RHD-related AF. It showed that in these patients, VKA therapy led to a lower rate of cardiovascular events or death than rivaroxaban, without a higher rate of bleeding2.

The INVICTUS trial was a randomized, open-label, non-inferiority trial that compared rivaroxaban to VKA in patients with rheumatic heart disease, AF and elevated stroke risk (CHA2DS2VASc > 2, mitral valve area <2cm2, left atrial echo contrast or left atrial thrombus). The trial enrolled 4,565 patients from 24 countries in Africa, Asia, and South America. Participants were randomly allocated to 20mg once daily rivaroxaban or to dose-adjusted Vitamin K antagonist (predominantly warfarin) with an INR goal of 2-3. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes.

Dr. Alexander Benz, International Fellow at the Population Health Research Institute in Hamilton, Canada and one of the co-authors of INVICTUS, adds, “Rheumatic heart disease affects more than 30 million individuals globally. Patients with rheumatic heart disease-associated atrial fibrillation differ from other patients with atrial fibrillation; they are typically younger, predominantly female, and often have advanced valvular disease. The burden of traditional cardiovascular risk factors like hypertension or diabetes in this population is low, but heart failure is common.”

After a mean follow-up of 3.1 years, significantly more patients in the rivaroxaban group (event rate 8.21%/year) experienced the primary composite outcome compared to those assigned to vitamin K antagonist therapy (event rate 6.49%/year) (proportional HR = 1.25; 95% CI, 1.1-1.41, p < 0.001). Rates of major bleeding (0.67%/year vs 0.83%/year, p = 0.18) did not differ significantly between the treatment groups.

“Moderate-to-severe mitral stenosis was present in >80% of patients participating in INVICTUS. Although mitral stenosis is widely believed to represent a strong risk factor for stroke, the rates of stroke in this trial were relatively low at approximately 1-1.5%/year. In contrast, the rates of mortality were markedly higher,” says Dr. Benz.

The results of this trial support current guidelines which recommend vitamin K antagonist therapy for stroke and systemic embolism prevention for patients with AF in the setting of rheumatic heart disease.


  1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10. PMID: 21830957.
  2. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019 Jul 9;140(2):e125-e151. doi: 10.1161/CIR.0000000000000665. Epub 2019 Jan 28. Erratum in: Circulation. 2019 Aug 6;140(6):e285. PMID: 30686041.
  3. Connolly SJ, Karthikeyan G, Ntsekhe MI et al. 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.
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