December 10, 2019
Chronic heart failure with reduced ejection fraction (HFrEF) is associated with high risk of thromboembolic events. Potential mechanisms for increased thrombosis include, but are not limited to, activation of thrombin-related pathways1 and blood stasis in dilated hypokinetic cardiac chambers, and peripheral blood vessels.2-3 Despite these mechanisms, the risk of thromboembolism is clinically stable patients is low at 1-3% per year.4-10 To date, oral anti-platelet or anticoagulants have not significantly lowered the risk of thromboembolic events. Despite the negative results, the search for improving outcomes in HFrEF using newer anti-coagulants continues.
To this end, the COMMANDER HF Study (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), was a double-blind, placebo-controlled, trial conducted to test the hypothesis that rivaroxaban 2.5mg, a direct factor Xa inhibitor, added to standard therapy would improve outcomes in patients with worsening heart failure and underlying coronary artery disease, but without atrial fibrillation.11 This mega-trial of 5022 patients was not associated with a significant lower rate of death, myocardial infarction, or stroke versus placebo over a median follow-up of 21 months. The rate of major bleeds was 1.3% higher in rivaroxaban assigned patients versus placebo, the majority of which received aspirin. Limitations of the study may be the dose of 2.5mg of rivaroxaban and potentially patient selection who may be more likely to have higher rates of thromboembolic events. This study follows negative outcomes of earlier prospective and retrospective studies of inhibitors of thromboembolic pathology.
The take home message here is that in heart failure without atrial fibrillation clinical events are not related to thrombin generation, therefore direct acting factor Xa inhibitors would not be expected to be of benefit. However, in heart failure with atrial fibrillation, the reduction of strokes remains important and direct acting factor Xa inhibitors could be prescribed.
Mark A. Munger, PharmD, FCCP, FACC, is a professor of pharmacotherapy and adjunct professor of internal medicine, at the University of Utah, where he also serves as the associate dean of Academic Affairs for the College of Pharmacy.
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- Zannad F, Anker SD, Byra WM, et al. for the COMMANDER HF Investigators. Rivaroxaban in patients in heart failure, sinus rhythm, and coronary disease. N Engl J Med 2018;569:1332-42.