Vitamin K antagonists remain the INVICTUS standard of care for patients with rheumatic heart disease and atrial fibrillation

Comment on the article ‘Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation’, presented at the 53rd European Society of Cardiology Congress in August 2022 and simultaneously published in The New England Journal of Medicine, DOI: 10.1056/NEJMoa2209051. The Investigation of Rheumatic Atrial Fibrillation Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies (INVICTUS) was an investigator-initiated, randomized, open-label, non-inferiority trial comparing the direct oral anticoagulant (DOAC) rivaroxaban with a vitamin K antagonist (VKA) in patients with documented rheumatic heart disease (RHD), atrial fibrillation (AF), and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo contrast or thrombus, or CHA2DS2VASc score ≥2).1 The trial was funded by an unrestricted grant from Bayer AG. The trial randomly allocated 4565 patients (mean age 51 years; 72% women) from 138 sites in 24 countries in Africa, Asia, and South America to rivaroxaban 20 mg once daily (or 15 mg according to renal function) or a dose-adjusted VKA [international normalized ratio (INR) range 2.0–3.0]. Warfarin was the most used VKA (in 79%–85% of the patients, varying between visits). Moderate-to-severe mitral valve stenosis (valve area ≤ 2.0 cm2) was present in 82% of the patients and a CHA2DS2VASc score ≥2 in 56% of the patients. VKA therapy was being used before enrolment in 53% of the patients. 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 4531 patients were included in the final analysis. At a median follow-up of 3.1 years, 559 of 2275 patients receiving rivaroxaban (8.3% per year) had a primary efficacy outcome event compared to 442 of 2258 patients receiving VKA (6.5% per year) [proportional hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.10–1.41]. Event curves appeared to diverge after 18 months of follow-up. The restricted mean survival time (RMST) for the primary outcome was 1599 days in the rivaroxaban group and 1675 days in the VKA group (difference, −76 days; 95% CI, −121 to −31 days; P < 0.001 for superiority). More patients in the rivaroxaban group had a stroke (90 vs. 65; proportional HR = 1.37; 95% CI, 1–1.89), primarily ischaemic stroke. Incidence of death was higher in the rivaroxaban group than in the VKA group (552 vs. 442 patients died; RMST: 1608 vs. 1680 days; difference, −72 days; 95% CI, −117 to −28). The difference in mortality was primarily due to higher rates of sudden cardiac death and death due to mechanical pump failure in the rivaroxaban group. There was no statistically significant difference between the groups for the primary safety outcome, ISTH major bleeding, which occurred in 40 patients (0.67% per year) in the rivaroxaban group and 56 patients (0.83% per year) in the VKA group (proportional HR = 0.76; 95% CI, 0.51–1.15; P = 0.18). However, the rate of fatal bleeding was lower in the rivaroxaban group than the VKA group (4 vs. 15 patients; proportional HR = 0.29; 95% CI, 0.1–0.88). Mean adherence to rivaroxaban therapy was 84% ± 17%. The INR was in the therapeutic range in 56% of the VKA patients at 6 months, in 59% at 1 year, in 65% at 2 years, and in 65% at 3 years. Permanent discontinuation of the study drug was more common in the rivaroxaban group (23%) than in the VKA group (6%), with the most common reasons being hospitalization for valve surgery and patient decision. RHD, a chronic condition resulting from heart valve damage caused by an autoimmune inflammatory reaction to infection with streptococcal bacteria, affects more than 40 million people worldwide.2 One in five patients with symptomatic valve disease has AF3 and a concomitant high risk of stroke and systemic embolism ranging from 0.4% to 4.2% per year.4,5 These patients have high mortality and morbidity despite being young; those from low- and lower-middle–income countries have a poorer prognosis associated with advanced disease and low education.3 Early trials of anticoagulant therapy in AF conducted in North America and Europe excluded patients with RHD due to their prohibitive risk of stroke and the unethical nature of randomization in this setting. RHD patients were also excluded from contemporary randomized stroke prevention trials of DOACs. Nevertheless, the guidelines recommend VKAs for stroke prevention in these patients.6 Notably, RHD occurs mainly in low- and middle-income countries where maintenance of an optimal INR, required for effective use of VKAs, is hard to be achieved.7 Indeed, less than half of these patients are treated with VKAs. For those who are treated, only one-third maintain an INR in the therapeutic range. DOACs that do not require monitoring would fulfil an important unmet need in these patients. INVICTUS is the first randomized trial to evaluate anticoagulant therapy for stroke prevention in patients with RHD-associated AF.1 After 3 years of follow-up, patients who received rivaroxaban had a 25% increased risk of experiencing an outcome of the primary endpoint. In terms of individual components of the primary endpoint, rivaroxaban increased the risk of death by 23% and the risk of stroke by 37%.1 The results of the present trial were unexpected. Indeed, in patients with non-valvular AF, treatment with rivaroxaban or other factor Xa inhibitors has been shown to be non-inferior to warfarin therapy for stroke prevention, with a 10% reduction in mortality mainly due to a large reduction in the risk of haemorrhagic stroke8 and with consistent effects in patients with non-rheumatic valvular heart disease and those with non-valvular AF.9 In patients with bioprosthetic mitral valves, a lower risk of stroke and no significant difference in mortality were observed with rivaroxaban vs. VKA at 1 year of follow-up.10 Patients with RHD-associated AF enrolled in the INVICTUS trial differed from those with non-valvular AF enrolled in previous trials in that they were younger and more often female, and a lower percentage had hypertension. However, most of them had advanced mitral valve stenosis (82%).1 Therefore, similar or even greater risk of stroke was expected in this population. Surprisingly, stroke rates in the two groups were lower than the expected, and the difference in stroke rate could be due to chance. The difference in mortality was large and was therefore unlikely to be due to chance. Treatment with rivaroxaban resulted in a higher rate of both sudden cardiac death and death from mechanical pump failure that is not easily explained by effects on stroke, bleeding, or valve deterioration. The authors hypothesized that the VKA-treated patients had more frequent interactions with physicians because of the need for monthly INR monitoring, which could have resulted in better overall care and fewer strokes and deaths. However, untoward effects of rivaroxaban in this unexplored clinical setting cannot be excluded. Rheumatic AF patients represent a different subset of patients always considered at higher risk. Mechanistic data show elevated markers of coagulation even when patients have a normal sinus rhythm.2 The clinical implication is that RHD-related AF patients have a variety of disorders including congestive heart failure and poor functional class at presentation, and although stroke prevention is one of the pillars of their care, other events (such as advanced congestive heart failure, infective endocarditis, and pneumonia) are more common despite anticoagulation. The INVICTUS trial is highly relevant for countries with a high prevalence of RHD-associated AF, and its results clearly indicate that VKA therapy should remain the standard of care for these patients.