Vitamin K antagonist superior to DOAC in RHD with AF – INVICTUS study

Vitamin K antagonist superior to DOAC in RHD with AF – INVICTUS study

The INVICTUS program (INVestIgation of rheumatiC AF Treatment Using VKA) was designed as an open label parallel group trial comparing treatment with vitamin K antagonists or rivaroxaban, in rheumatic heart disease with atrial fibrillation [1]. It was an international multicentre randomized study. A registry of 17,000 patients was also planned to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. RHD is considered as a neglected disease affecting 33 million people, mainly in low and middle income countries.

The study enrolled 4565 patients, of which 4531 were included in the final analysis [2]. Mean age was 50.5 years and 72.3% were women. It is interesting to note that permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. Echocardiographically documented rheumatic heart disease with atrial fibrillation and any of the following risk factors were included in the study:

1. CHA2DS2VASc score of at least 2
2. Mitral valve area of 2 sq. cm or less
3. Left atrial spontaneous echo contrast
4. Left atrial thrombus

The primary outcome assessed in the study was a composite of stroke, systemic embolism, myocardial infarction or death from vascular (cardiac or noncardiac) or unknown causes. The primary safety outcome assessed was major bleeding according to the International Society of Thrombosis and Hemostasis.

560 patients in the rivaroxaban group and 446 patients in the vitamin K antagonist group had a primary outcome event in the intention to treat analysis. There was a higher incidence of death in the rivaroxaban group than in the vitamin K group. Surprisingly, there was no significant difference in the major bleeding between the two groups. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (P<0.001).

A low stroke risk noted in this enriched cohort of RHD AF has prompted a call for risk stratification before oral anticoagulation [3]. It has been mentioned that the perception of very high stroke risk in RHD is reinforced by estimates of stroke burden based on extrapolation from the proportion of stroke admissions who have RHD, rather than the proportion of strokes attributable to RHD in the community. The former rate is 3-8% while the latter rate is only 1-2%.

References

1. Karthikeyan G, Connolly SJ, Ntsekhe M, Benz A, Rangarajan S, Lewis G, Yun Y, Sharma SK, Maklady F, Elghamrawy AE, Kazmi K, Cabral TTJ, Dayi H, Changsheng M, Gitura BM, Avezum A, Zuhlke L, Lwabi P, Haileamlak A, Ogah O, Chillo P, Paniagua M, ElSayed A, Dans A, Gondwe-Chunda L, Molefe-Baikai OJ, Gonzalez-Hermosillo JA, Hakim J, Damasceno A, Kamanzi ER, Musuku J, Davletov K, Connolly K, Mayosi BM, Yusuf S; INVICTUS Investigators. The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation. Am Heart J. 2020 Jul;225:69-77. doi: 10.1016/j.ahj.2020.03.018. Epub 2020 Mar 25. PMID: 32474206.
2. Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, El Sayed A, El Ghamrawy A, Damasceno A, Avezum A, Dans AML, Gitura B, Hu D, Kamanzi ER, Maklady F, Fana G, Gonzalez-Hermosillo JA, Musuku J, Kazmi K, Zühlke L, Gondwe L, Ma C, Paniagua M, Ogah OS, Molefe-Baikai OJ, Lwabi P, Chillo P, Sharma SK, Cabral TTJ, Tarhuni WM, Benz A, van Eikels M, Krol A, Pattath D, Balasubramanian K, Rangarajan S, Ramasundarahettige C, Mayosi B, Yusuf S; INVICTUS Investigators. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation. N Engl J Med. 2022 Aug 28. doi: 10.1056/NEJMoa2209051. Epub ahead of print. PMID: 36036525.
3. Karthikeyan G. Stroke risk in rheumatic heart disease. Heart. 2021 May;107(9):694-696. doi: 10.1136/heartjnl-2020-318756. Epub 2021 Jan 18. PMID: 33462122.