An Answer at Last with INVICTUS: Patients with Rheumatic Heart Disease and Mitral Stenosis Should Remain on Warfarin, as Rivaroxaban Has a Higher Mortality Risk.

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By Enrico G. Ferro, MD on

Key Points

  • While DOACs have revolutionized the field of atrial fibrillation for patients with non-valvular disease, the equally important population of patients with valvular atrial fibrillation has traditionally been excluded from randomized trials and represent a fundamental unmet need at the global level, since rheumatic heart disease affects 40 million people around the world, primarily concentrated in low- and middle-income countries (LMIC).
  • The INVICTUS trial finally provided randomized evidence that VKA like warfarin should remain the standard of care for patients with valvular atrial fibrillation in the setting of mitral stenosis. In this study, rivaroxaban was found to have a significantly higher rate of the primary outcome of stroke, systemic embolism, myocardial infarction or death, compared to VKA (8.26% vs 6.46% per year), with cross-over of the Kaplan-Meier curves at about 18 months, and a resulting mean survival time (RMST) of difference-75 days in favor of VKA (95% CI -117 to -34; p<0.001). The mortality benefit of VKA became most apparent starting around 3 years of observation time.

Since the early 2010s, DOACs have revolutionized the field of atrial fibrillation by providing a safer and more effective anticoagulation option compared to vitamin K antagonists (VKA) like warfarin, as shown in several trials of patients with non-valvular atrial fibrillation. (1) However, a special population remains understudied in the field of DOAC, namely patients with valvular atrial fibrillation, defined as patients with mitral stenosis or artificial heart valves.

In November 2020, the RIVER trial was conducted among patients with atrial fibrillation and a bioprosthetic mitral valve, where the DOAC rivaroxaban was found to be noninferior to VKA with regard to the composite outcome of death, major cardiovascular events, or major bleeding at 12 months (2). While this was an important advance in the field of oral anticoagulation, the equally important population of patients with mitral stenosis from rheumatic heart disease (RHD) continues to be excluded from atrial fibrillation trial, leaving a fundamental gap in the scientific literature as well as a global unmet need – since RHD affects 40 million people around the world, primarily concentrated in low- and middle-income countries (LMIC).  About 20% of these patients have atrial fibrillation with elevated stroke risk, and have traditionally remained on VKA due to the lack of applicable evidence with regards to DOAC use. VKA use in this population, as in any other population, comes with the associated challenges of reaching therapeutic INR, which is usually achieved in only 30% of patients on therapy. Thus, the potential to transition this population from VKA to DOAC remains a potential yet unstudied possibility.

This dilemma finally found its answer during the 2022 European Society of Cardiology Conference in Barcelona, where Dr. presented the results of the INVICTUS trial (NCT02832544). This multicenter, prospective, randomized, non-inferiority trial with open-label design but blinded outcome assessment enrolled 4,531 patients with documented at least moderate mitral stenosis (valve area ≤2 cm2), presence of left atrial clots or spontaneous echo contrast, with a CHAD2DS2VAsc score ≥2.  These patients were randomized to either rivaroxaban 20 mg (n=2,275, including dose-reduced rivaroxaban 15 mg in patients with documented impaired renal function) or VKA with goal INR 2-3 (n=2,256). Compared to prior atrial fibrillation trials, patients were younger (mean age of 50 years), predominantly female (~70%), with about 45% of patients with a CHAD2DS2VAsc score of 0-1, and about 10-12% patients with a prior stroke. Importantly, there was high representation of LMIC in this trial, with most patients recruited in Africa, South Asia and Latin America.

Drug compliance was rather high in the VKA arm compared to prior trials, with only 6% of patients discontinuing VKA and a remarkably high % of patients at target INR goal, up to 65% at 4 years. The compliance rate was lower in the rivaroxaban arm with 23% of patients discontinuing the study drug, though this pattern may have been driven by transition to mechanical mitral valve replacement and thus transition to post-operative VKA therapy.

The primary outcome of the study was originally designed to be the composite of stroke or systemic embolism, which however was expanded to include myocardial infarction and death, given lower than expected rates of stroke and higher than expected death rates – nonetheless, a composite outcome that has been established in prior similar trials in the field. At a median follow up of 3.1 years, rivaroxaban was found to have a significantly higher rate of the primary outcome, compared to VKA (8.26% vs 6.46% per year), with cross-over of the Kaplan-Meier curves at about 18 months, which a resulting mean survival time (RMST) of 1,576 days in the rivaroxaban arm and 1,652 days in the VKA arm (RMST difference -75 days; 95% CI -117 to -34; p<0.001). This difference was driven primarily by a higher mortality rates among patients in the rivaroxaban arm, which became most apparent starting around 3 years of observation time. In terms of safety, both drugs were found to be safe over the study period, with low and similar rates of major bleeding, including intracranial bleeding.

The reduction in deaths observed in the VKA arm was particularly surprising, especially as it did not seem to be explained directly by a reduction in ischemic strokes per se, but rather by a reduction in heart failure and sudden deaths. While this may be at least partly due to more frequent healthcare contact among patients in the VKA arm for INR measurements, the reasons behind this important signal warrant more definitive investigation. In conclusion, the INVICTUS trial finally provided randomized evidence that VKA should remain the standard of care for patients with valvular atrial fibrillation in the setting of mitral stenosis, as it leads to a significant reduction in their mortality rate.

  1. Ferro EG, Kazi DS, Zimetbaum PJ. Informing the Choice of Direct Oral Anticoagulant Therapy in Patients With Atrial Fibrillation. JAMA. 2021 Dec 21;326(23):2372-2374. PMID: 34932097.
  2. https://www.nejm.org/doi/full/10.1056/NEJMoa2029603