The Search for Therapeutic Advances in Reducing Thromboembolic Events in HFrEF

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. 

References:

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3.     Stratton JR, Nemanich JW, Johannessen KA, et al. Fate of left ventricular thrombi in patients with remote myocardial infarction or idiopathic cardiomyopathy. Circulation 1988;78:1388-93.

4.     Dunkman WB, Johnson GR, Carson PE, et al. Incidence of thromboembolic events in congestive heart failure: the V-HeFT VA Cooperative Studies Group. Circulation. 1993;87 6 Suppl:VI94–101.

5.      Cioffi G, Pozzoli M, Forni G, et al. Systemic thromboembolism in chronic heart failure: a prospective study in 406 patients. Eur Heart J. 1996;17:1381–9.

6.     Baker DW, Wright RF. Management of heart failure, IV: anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA. 1994;272:1614–8.

7.     Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997;336:251–7.

8.     Al-Khadra AS, Salem DN, Rand WM, et al. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 1998;31:749–53.

9.     Dries DL, Domanski MJ, Waclawiw MA, et al. Effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. Am J Cardiol. 1997;79:909

10.  Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation. 2009;119:1616–24.

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.