From Pages to Practice

By Angela Chen, MBBS, MPH

Published January 5, 2022


Eric knew another hospital admission for his heart failure was inevitable, but it had only been one month since his last hospitalization. However, his breathlessness and ankle swelling had become worse in the last week. Dreading another week of hospital food (all mashed potatoes are not created equal), Eric asks his primary care physician, “Is there anything else I can take, anything at all? I’m so sick of the needles and the food in the hospital.”

In patients with chronic heart failure, acute exacerbations are associated with increased risk of hospital readmission and death. Mechanistically, acute exacerbations activate procoagulant pathways and increase thrombin formation, leading to enhanced inflammation, endothelial dysfunction, and thrombosis. Rivaroxaban is an oral direct factor Xa inhibitor that reduces thrombin production, is widely used as an anticoagulant, and has been shown to reduce the risk of stroke in patients with atrial fibrillation. Low-dose rivaroxaban in combination with antiplatelet medication has also been shown to reduce the risk of death in patients with coronary artery disease.

In the COMMANDER HF study, investigators examined whether adding a low dose of rivaroxaban to antiplatelet therapy reduced mortality and cardiovascular events in patients with heart failure, sinus rhythm, and coronary artery disease. In this double-blinded, randomized, placebo-controlled trial, 5022 patients with chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation received low-dose rivaroxaban (2.5 mg twice daily) or placebo in addition to standard antiplatelet medications following an exacerbation of heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, and stroke. As the intervention involved use of an anticoagulant, the primary safety outcome was bleeding that was fatal or led to permanent disability. Could rivaroxaban be Eric’s “anything else”?

Unfortunately, the addition of rivaroxaban was not associated with improvement in the primary outcome. At a median of 21 months of follow-up, the primary efficacy outcome did not differ significantly between the two groups (25.0% and 26.2% of rivaroxaban and placebo recipients, respectively; hazard ratio, 0.98; 95% CI, 0.84–1.05; P=0.27), and safety outcomes were similar (18 and 23 events, respectively; HR, 0.80; 95% CI, 0.43–1.49; P=0.48). With respect to Eric’s specific concern about being hospitalized again, the rate of rehospitalization for heart failure also did not differ between the two groups.

In an accompanying editorial, cardiologists Marc A. Pfeffer and Jean-Claude Tardif discuss the importance of considering whether the neutral study findings were a result of the trial design rather than to an ineffective therapy. They conclude that “the lack of effect of rivaroxaban on the primary end point … is consistent with results from previous randomized trials with warfarin,” and further explain that “the most likely explanation for the neutral findings is that the majority of clinical events … were deaths from any cause and hospitalizations for heart failure, and most likely such events would not have been related to thrombin generation.”

Although the COMMANDER HF trial evaluated an interesting mechanistic hypothesis, low-dose rivaroxaban in patients with chronic heart failure, sinus rhythm, and coronary artery disease did not improve cardiovascular and mortality outcomes.

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Angela is a 2018-2019 NEJM editorial fellow. She is an endocrine fellow who trained at Flinders Medical Centre and the Royal Adelaide Hospital. Angela recieved her medical degree from the University of Adelaide, and masters of public health from the University of Sydney. Her clinical and research interests are in the areas of glucocorticoid and cardiovascular endocrinology and diabetes medicine.