More cardiovascular events and deaths occurred among rivaroxaban users than in VKA users during a 3-year follow-up.

Factor Xa inhibitors are commonly used to reduce stroke risk in patients with atrial fibrillation. However, because clinical trials of these medications excluded people with rheumatic heart disease, guidelines do not recommend these oral anticoagulants for atrial fibrillation in those patients. In the industry-funded INVICTUS trial (NCT02832544), investigators assessed the efficacy and safety of the factor Xa inhibitor rivaroxaban, as compared with vitamin K antagonists (VKAs), in patients with rheumatic heart disease- associated atrial fibrillation. Rivaroxaban is not approved for this indication in these patients.

The randomised, noninferiority trial enrolled 4565 patients from 138 sites in 24 countries in Africa, Asia and South America. Their average age was 51 years, and 72% were women. About one-third had a history of heart failure and 11% of stroke. The mean CHA2DS2VASc score was 1.4. Moderate-to-severe mitral stenosis was present in 82%. For the VKA recipients, the international normalised ratio was in the therapeutic range in 56% at six months and 64% at four years.

The trial was terminated early because the study question was considered answered. During a mean follow up of three years, the primary outcome – a composite of stroke, systemic embolism, myocardial infarction and death from a vascular or unknown cause – occurred more commonly in the rivaroxaban group (proportional-hazards ratio, 1.25). A composite outcome of stroke and systemic embolism was not different between groups. However, death occurred in 8.0% per year in the rivaroxaban group compared with 6.4% per year in the VKA group (proportional-hazards ratio, 1.23), driven by more deaths from sudden cardiac and mechanical/pump failure with rivaroxaban. Major bleeding was not significantly different.

Comment: This study shows that rivaroxaban should not be used in place of vitamin K antagonists for patients with rheumatic disease-associated atrial fibrillation, including those with moderate-to-severe mitral stenosis. These findings emphasise the importance of conducting trials on specific populations and the wisdom of the current guidelines in not assuming that factor Xa inhibitors would be equivalent to or even preferred for stroke prevention in patients with rheumatic heart disease and atrial fibrillation. The trial does have some puzzling features as the outcomes driving the differences were unexpected and hard to explain, but the differences were large enough for the trial to be ended prematurely.
HARLAN M. KRUMHOLZ, MD, SM
Harold H. Hines, Jr. Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, USA.

Connolly SJ, et al. Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N Engl J Med 2022 Aug 28; e-pub (https://doi.org/10.1056/NEJMoa2209051).

This summary is taken from the following Journal Watch title: Cardiology.