Reviewer: : Dr. Levent Pay

Name of the Study: Rivaroxaban in Rheumatic Heart Disease – Associated Atrial Fibrillation

Link: doi: 10.1056/NEJMoa2209051.

Background:

Patients with atrial fibrillation are at high risk for embolic stroke due to thrombus formation in the left atrium, which embolised the intracerebral circulation. In high-income countries, the development of atrial fibrillation often occurs as a result of hypertension, ischemic heart disease, or advanced age. However, rheumatic heart disease remains an important cause of atrial fibrillation in low- and middle-income countries. Randomized studies have demonstrated the effectiveness of vitamin K antagonists in preventing stroke in patients with atrial fibrillation. In addition to the many dietary and pharmacological interactions, the requirement for regular blood sampling to monitor INR and anticoagulation status is one of the major challenges of vitamin K antagonist therapy. Randomized clinical trials have shown that these non-vitamin K antagonist oral anticoagulants (NOACs) are as effective as vitamin K antagonist therapy in preventing stroke and have a lower risk of intracranial bleeding. However, these large studies investigating NOACs excluded patients with atrial fibrillation associated with rheumatic heart valve disease. This point forms the background of the INVICTUS study. Based on these considerations, a randomized, non-inferior study was conducted to evaluate the efficacy and safety of the factor Xa inhibitor rivaroxaban compared to vitamin K antagonist therapy in patients with atrial fibrillation associated with rheumatic heart disease in Africa, Latin America, and Asia.

Methods:

For this purpose, patients with at least one of the following among patients with atrial fibrillation and rheumatic valve disease detected by echocardiography were included in the study;

1. CHA2DS2VASc score of at least 2,
2. Mitral valve area < 2 cm2,
3. With spontaneous echo contrast,
4. With left atrial thrombus.

Exclusion criteria were the presence of a mechanical heart valve or the possibility of getting a heart valve in the next 6 months, use of dual antiplatelet therapy, severe renal failure, and treatment with potent inhibitors of CYP3A4 and P-glycoprotein. Patients were followed up 1 month after randomization and every 6 months thereafter. The primary endpoint was a combination of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or non-cardiac) or unknown causes. It was assumed that rivaroxaban treatment would be non-inferior to vitamin K antagonist treatment. The primary safety point was determined as major bleeding according to the International Society for Thrombosis and Hemostasis.

Results:

From August 2016 to September 2019, a total of 4565 patients were enrolled from 138 trial centers in 24 countries. While a total of 2292 patients were assigned to the rivaroxaban group, 2273 patients were assigned to the vitamin K antagonist group. While the average patient age was 50.5; 72.3% of the patients are women. Based on the intent-to-treat analysis, the primary outcome event was seen in 560 patients in the rivaroxaban group and 446 patients in the vitamin K antagonist group (proportional hazard ratio, 1.25; 95% confidence interval [CI], 1.10 to 1.41). 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], P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group. There was no significant difference between the groups in the rate of major bleeding.

Conclusion:

The study showed that among patients with atrial fibrillation associated with rheumatic heart disease, vitamin K antagonist treatment resulted in a lower combination of cardiovascular events or death than rivaroxaban treatment, without a higher bleeding rate.

Interpretations:

In patients with atrial fibrillation not associated with rheumatic heart disease, treatment with rivaroxaban or other factor Xa inhibitors has been shown to be no less effective than warfarin therapy for stroke prevention with a large reduction in the risk of hemorrhagic stroke. A randomized trial comparing rivaroxaban with vitamin K antagonist therapy in patients with atrial fibrillation and bioprosthesis mitral valve showed a lower risk of stroke with rivaroxaban at 1-year follow-up and no significant difference in mortality. Therefore, the results of the present trial have been unexpected. Among the possible explanations for these findings, the weak power of this study on stroke can be considered as stroke rates in the two groups were lower than expected. Also, patients in the vitamin K antagonist group had more physician interactions than the rivaroxaban group, as INR control needed to be monitored monthly. This may explain the vitamin K antagonist group resulting in better overall care and fewer strokes and deaths. It is also possible that compliance with rivaroxaban therapy was worse than with vitamin K antagonist therapy, as patients in the rivaroxaban group knew that INR was not monitored.