Rivaroxaban, the direct oral, factor Xa inhibitor, does not reduce the risk of a composite end point of survival, myocardial infarction (MI) and stroke after an episode of worsening heart failure in patients with heart failure, sinus rhythm, and coronary artery disease.
This was the key finding from COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) presented in a Hot Line Session and also published in The New England Journal of Medicine (DOI: 10.1056/NEJMoa1808848).
Patients with worsening heart failure experience high rates of hospital readmission, and death. Previous studies have suggested that the enzyme thrombin may contribute to these poor outcomes by inducing inflammation, endothelial dysfunction, and vascular thrombosis.
The COMMANDER HF trial tested whether, compared to placebo, rivaroxaban 2.5 mg twice daily could lower rates of death and cardiovascular events in patients with recent worsening of chronic heart failure, who had reduced ejection fraction (EF) of ≤ 40% (median EF 34%), coronary artery disease and no atrial fibrillation.
Study author Professor Faiez Zannad, (University of Lorraine, Nancy, France), said: “COMMANDER HF is not just another trial of oral anticoagulation in heart failure. The aim is to interfere with disease processes that rely on thrombin using a targeted antithrombin drug”.
The trial enrolled 5,022 patients, median age 66, from 28 countries, who were randomly assigned rivaroxaban 2.5 mg, twice daily, or matching placebo in combination with antiplatelet therapy and standard therapy for heart failure. Patients were followed-up for the primary efficacy outcome of all-cause mortality, MI, or stroke. The primary safety outcome was the composite of fatal bleeding or bleeding into a critical space with a potential for permanent disability.
During a median follow-up of 21.1 months, the primary efficacy outcome occurred in 626 (25.0%) of 2,507 patients assigned to rivaroxaban compared to 658 (26.2%) of 2,515 on placebo (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.84–1.05, p=0.27). There were no differences between groups in all-cause mortality (HR 0.98, 95% CI 0.87–1.10, p=0.74) or nonfatal MI (HR 0.83, 95% CI 0.63–1.08, p=0.17) but there was a significantly lower rate of nonfatal stroke in the rivaroxaban group, compared to placebo (HR 0.66, 95% CI 0.47–0.95, p=0.023).
The principal safety outcome occurred in 18 (0.7%) patients assigned to rivaroxaban and 23 (0.9%) assigned to placebo (HR 0.80, 95% CI 0.43–1.49, p=0.48). Patients taking rivaroxaban had a significantly higher risk of major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) compared to those on placebo (HR 1.68, 95% CI 1.18–2.39, p=0.003). Serious adverse events were reported in 479 (19.2%) patients taking rivaroxaban and 451 (18.0%) on placebo. The percentage of patients who permanently discontinued study medication due to an adverse event was 7.1% in the rivaroxaban group and 5.8% in the placebo group.
Professor Zannad said: “The most likely reason rivaroxaban failed to improve the primary efficacy outcome is that thrombin-mediated events are not the major driver of cardiovascular events in patients with recent heart failure hospitalisation. Whether a higher dose of rivaroxaban could have led to a more favourable result is unknown.”