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Trial backs standard of care for rheumatic heart disease and atrial fibrillation

INVICTUS trial presented in a Hot Line Session today at ESC Congress 2022

Cardiovascular Pharmacotherapy

Barcelona, Spain – 28 Aug 2022: The largest trial in patients with rheumatic heart disease has found that in those with atrial fibrillation, vitamin K antagonists reduce cardiovascular events and mortality, without increasing major bleeding, compared to rivaroxaban. The late breaking research is presented in a Hot Line session today at ESC Congress 2022.1

Rheumatic heart disease is a chronic condition resulting from heart valve damage caused by rheumatic fever, an autoimmune inflammatory reaction to infection with streptococcal bacteria. It is estimated that more than 40 million people worldwide have rheumatic heart disease.2 One in five patients with symptomatic valve disease have atrial fibrillation3 and a concomitant risk of stroke and systemic embolism ranging from 0.4% to 4.2% per year.4,5

Professor Ganesan Karthikeyan of the All India Institute of Medical Sciences (AIIMS), New Delhi, India said: “Guidelines recommend vitamin K antagonists (VKA) for stroke prevention in patients with rheumatic heart disease and atrial fibrillation6 but until now there were no randomised controlled trials. Rheumatic heart disease largely occurs in low- and low-middle income countries7 where maintenance of the international normalised ratio, required for the effective use of VKA, is poor.8 Direct oral anticoagulants (DOACs) do not require monitoring and we reasoned that, if safe and effective, they would fulfil a major unmet need in these patients.”

INVICTUS was a randomised, open-label, non-inferiority trial comparing the DOAC rivaroxaban to VKA in patients with echocardiographically documented rheumatic heart disease, atrial fibrillation and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo contrast or thrombus, or CHA2DS2VASc score ≥2).9,10 The trial randomly allocated 4,565 patients from 138 sites in 24 countries in Africa, Asia and South America to rivaroxaban 20 mg once daily or adjusted dose VKA.

The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes. The primary safety outcome was International Society on Thrombosis and Haemostasis (ISTH) major bleeding.

A total of 4,531 patients were included in the final analysis. At a median follow up of 3.1 years, 559 out of 2,275 patients receiving rivaroxaban (8.26% per year) had a primary efficacy outcome event compared to 442 out of 2,258 patients receiving VKA (6.46% per year). The restricted mean survival time (RMST) for the primary outcome was 1,576 days in the rivaroxaban group and 1,652 days in the VKA group (RMST difference -75 days; 95% confidence interval [CI] -117 to -34; p<0.001).

The risk of death was also significantly lower among patients on VKA. The RMST for death was 1,587 days in the rivaroxaban arm and 1,660 days in the VKA arm (RMST difference -73 days, 95% CI -114 to -32).

There was no significant difference between the groups for the primary safety outcome, major bleeding, which occurred in 40 out of 2,266 patients (0.67% per year) in the rivaroxaban group and 56 out of 2,253 patients (0.83% per year) in the VKA group.

Professor Karthikeyan said: “INVICTUS is the first trial to assess anticoagulant therapy for stroke prevention in patients with rheumatic heart disease and atrial fibrillation. The results indicate that adjusted dose vitamin K antagonists should remain the standard of care for this patient population.”



Notes to editor

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This press release accompanies both a presentation and an ESC press conference at ESC Congress 2022. It does not necessarily reflect the opinion of the European Society of Cardiology.


Funding: INVICTUS was an investigator-initiated trial funded by an arm’s length grant from Bayer AG to the Population Health Research Institute.


Disclosures: None.


References and notes

1INVICTUS will be discussed during:

2Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76:2982–3021.

3Zuhlke L, Karthikeyan G, Engel ME, et al. Clinical outcomes in 3343 children and adults with rheumatic heart disease From 14 low- and middle-income countries: Two-year follow-up of the Global Rheumatic Heart Disease Registry (the REMEDY Study). Circulation. 2016;134:1456–1466.

4Karthikeyan G. Stroke risk in rheumatic heart disease. Heart. 2021;107:694–696.

5Karthikeyan G, Connolly SJ, Yusuf S. Overestimation of stroke risk in rheumatic mitral stenosis and the implications for oral anticoagulation. Circulation. 2020;142:1697–1699.

6Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2020;42:373–498.

7Karthikeyan G, Guilherme L. Acute rheumatic fever. Lancet. 2018;392:161–174.

8Zuhlke L, Engel ME, Karthikeyan G, et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur Heart J. 2015;36:1115–1122.

9Karthikeyan G, Connolly SJ, Ntsekhe M, et al. 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;225:69–77.

10CHA2DS2-VASc: Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female).


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