Why Does Rivaroxaban Not Work in Severe Mitral Stenosis?

Mitral stenosis is not a rare disease. Rheumatic fever is the principal cause of mitral stenosis. Anulus calcification and congenital heart disease are recognized as other causes of mitral stenosis.[1] In developed countries, the prevalence is approximately 0.6 in 1,000 in the United States, but it is much higher in developing nations: 21 cases per 1,000 in Asia, 15 cases per 1,000 in Africa, and 17 cases per 1,000 in South America.[2] Atrial fibrillation occurs in approximately 32% of symptomatic patients, thus decreasing cardiac output and exercise capacity, and greatly increasing the risk of thromboembolism.[3] Oral anticoagulation is therefore mandatory in these patients. Although direct oral anticoagulants (DOACs) have been found to be noninferior or superior versus vitamin K antagonists (VKAs; e.g., warfarin) in preventing cardioembolism in patients with atrial fibrillation,[4] patients with atrial fibrillation and rheumatic heart disease were not enrolled in earlier trials, thus excluding this pathological condition from approved indications.[5] Since ensuring adequate anticoagulation with laboratory monitoring while using VKAs may be difficult in developing countries, DOACs have the potential to improve the extension of oral anticoagulation without the need of any laboratory control. The commitment to plan a superiority trial (DOAC vs. VKA) came in 2016 from the cardiology community, which aimed to design a superiority trial involving a single-dose DOAC (no laboratory monitoring) versus VKA (with laboratory monitoring), and since the latter showed a poor time in the therapeutic range in countries of Asia, Africa, and Latin America.[6] Thus, a multicenter, randomized, noninferiority trial to evaluate the efficacy and safety of the factor Xa inhibitor, rivaroxaban, in comparison with VKA was planned and recently completed (INVICTUS trial). The trial involved patients with rheumatic heart disease from Africa, Asia, and Latin America,[7] enrolling patients with atrial fibrillation and echocardiographically documented rheumatic heart disease. Eighty-five percent of trial participants had mitral-valve stenosis, which was moderate-to-severe in 82%. These participants had a CHA2DS2VASc score of at least 2, a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast (SEC), or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban (20 mg/day) or dose-adjusted VKA (INR: 2.0–3.0). The mean ± standard deviation (SD) duration of follow-up was 3.1 ± 1.2 years. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. The primary safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH).[8] A total of 4,531 participants were included in the final analysis. Mean age of the patients (72.3% women) was 50.5 years.