INVICTUS - Rivaroxaban versus VKA for rheumatic atrial fibrillation

Presented at the ESC congress 2022 by: Prof. Ganesan Karthikeyan, MD - New Delhi, India

Introduction and methods

Rheumatic heart disease (RHD) affects over 40 million people worldwide, mainly young people living in low- and low-middle income countries. About 20% of symptomatic RHD patients have AF and an elevated stroke risk. No RCTs on anticoagulation in RHD-AF have been performed so far. Less than 50% of RHD-AF patients are prescribed a vitamin K antagonist (VKA), and only one-third achieve the therapeutic international normalized ratio (INR). An anticoagulant that does not need monitoring would therefore be of great benefit.

INVICTUS was a global, randomized, open-label, non-inferiority trial with blinded outcome assessment in which RHD-AF patients with an elevated stroke risk (f.e., mitral stenosis (valve area ≤2 cm2) or CHA2DS2-VASc score ≥2) were randomized to rivaroxaban 20 mg or 15 mg in case of low creatinine clearance (n=2275) or locally approved VKA with target INR of 2–3 (n=2256).

Originally, the primary efficacy outcome was a composite of stroke and systemic embolism, but because of low stroke and high mortality rates, this was later expanded to include MI and death from vascular or unknown cause. The primary safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis. The mean follow-up duration was 3.1 years.

Main results

• Compared with previous AF trials, RHD-AF patients in this study were younger and predominantly female and 85% had mitral valve stenosis.
• The primary efficacy outcome rate was 8.2% per year in rivaroxaban-treated patients and 6.5% per year in VKA-treated patients (hazard ratio (HR): 1.25; 95%CI: 1.10–1.41).
• The mortality rate was 8.0%/year in the rivaroxaban group and 6.4%/year in the VKA group (HR: 1.23; 95%CI: 1.09–1.40). The risk of ischemic stroke was 1.1%/year and 0.7%/year, respectively (HR: 1.53; 95%CI: 1.06–2.20).
• The primary safety outcome rate was 0.7%/year in the rivaroxaban group and 0.8%/year in the VKA group (HR: 0.76; 95%CI: 0.51–1.15). There was a slight increase in the risk of fatal bleeding in the VKA group compared with the rivaroxaban group (0.2%/year vs. 0.1%/year), but the numbers were too small to draw any meaningful conclusions.
• The unanticipated difference in mortality risk could not be explained by a difference in stroke rate (VKAs prevented 26 ischemic strokes vs. 110 deaths) but was driven entirely by the occurrence of HF and sudden death. Of note, the mortality benefit of VKAs did not become apparent until after 3 years and coincided with the time the INR was in the therapeutic range in the VKA arm.
• The permanent study medication discontinuation rate was 23% for rivaroxaban—which, according to Professor Karthikeyan, is not unusual—and only 6% for VKAs.

Conclusion

In RHD-AF patients, VKAs reduced the frequency of ischemic stroke and mortality without increasing the risk of major bleeding, compared with rivaroxaban. Professor Karthikeyan concluded his presentation by emphasizing that VKAs should remain the standard of care for RHD-AF and that the mortality benefit of VKA in RHD patients requires further study.

• Our reporting is based on the information provided at the ESC Congress -

The results of this study were simultaneously published in N Engl J Med.