A look back: the quest for thrombosis in heart failure continues after COMMANDER HF

Heart failure (HF) has been associated with an increased incidence of thromboembolic events, while many HF deaths have been thought to be of thrombotic aetiology.1 In terms of pathophysiology, HF bears several prothrombotic features. The deceleration of peripheral and intracardiac blood flow due to peripheral congestion and impaired cardiac contractility, respectively, the prolonged bed rest in severely ill cases, the associated endothelial dysfunction, the increased risk for atrial fibrillation (AF) due to structural and electrical atrial remodelling in the presence of elevated atrial pressures due to left ventricular dysfunction, and the presence of coagulation defects as, for example, in the case of ventricular assist devices are only some of the potential thrombophilic mechanisms in HF.2,3 At the molecular level, endothelial dysfunction with impaired vascular but also platelet response to nitric oxide (NO) has been observed in HF patients with either reduced or preserved ejection fraction, leading to impaired vascular tone and increased platelet aggregation, respectively.4 Impaired NO response seems to result in turn from NO scavenging and reduced activity of soluble guanylate cyclase (sGC), the principal NO sensor.5 In this complex association, HF may be the cause of the prothrombotic state but also the result of common pathogenetic pathways leading to both conditions. In line with the above, the 2016 European Society of Cardiology guidelines for HF recommend the use of anticoagulation with low-molecular weight heparins during hospitalization for acute HF to reduce the risk of venous thromboembolism, which is actually one of the few Class I therapeutic recommendation in these patients.6 In contrast, anticoagulation is not indicated for chronic HF patients, unless they have a history of AF, thromboembolic events, or left ventricular mural thrombus.6 A new episode in the saga of thrombosis in HF is the recently published COMMANDER HF trial, which aimed at challenging the latter guideline recommendation. The study tested the hypothesis that low-dose rivaroxaban, at 2.5 mg twice daily, would reduce the risk of the composite of death, non-fatal myocardial infarction or non-fatal stroke in HF patients with reduced ejection fraction (40% or less), coronary artery disease (CAD) and a recent (3 weeks) history of HF decompensation, but without AF.7 The vast majority of patients (93%) were receiving aspirin and one-third of them (35%) dual-antiplatelet therapy because of the history of CAD. The results of the study rejected its hypothesis: there was no difference in the composite endpoint between patients randomized to rivaroxaban on top of standard therapy and those treated with standard therapy alone.7 Among the components of the primary endpoint of the study, the clearly thrombosis-related ones that might have been benefited by anticoagulation therapy was myocardial infarction and stroke. However, the rate of these events was considerably low compared to all-cause death that accounted for up to 87% of events. The results of COMMANDER AF are in line with those derived by a series of previous trials on antithrombotic therapy comparing warfarin with antiplatelets (aspirin mostly) in HF patients in sinus rhythm, including WASH, HELLAS, WATCH, and WARCEF.8–11 Overall, these studies showed that there was no difference in the incidence of death, stroke, or myocardial infarction between warfarin and single antiplatelet therapy in HF patients in sinus rhythm. Was the population studied in COMMANDER HF a representative cohort of HF patients in the transition phase following HF hospitalization? The outcomes reported by the study, including 22% all-cause mortality, 37% cardiovascular death or HF rehospitalisation, and 28% HF rehospitalization during a median follow-up of 21 months, are roughly in line with the findings of the ESC HF Long-term Registry that reported 1-year mortality and HF hospitalization rates of 26% and 38%, respectively, in a more severely affected cohort of acute HF patients.12 Was the dose of rivaroxaban too low to be effective? COMMANDER HF actually tried to build on the results of two previous trials with low-dose rivaroxaban, ATLAS ACS 2-TIMI 51 and COMPASS.13,14 In these studies, rivaroxaban at 2.5 mg twice daily, added to antiplatelet therapy, was beneficial in reducing the composite of cardiovascular death, myocardial infarction, or stroke in patients with either recent acute coronary syndrome or stable CAD, respectively. As the COMMANDER HF investigators also commended, thrombosis may not constitute a major driver of clinical deterioration in HF without AF or a history of thromboembolic events and this may be true even in the presence of CAD.7 On the other hand, there was no difference in between the two arms of the study in the composite of fatal bleeding or bleeding into a critical space with potential for causing permanent disability (primary safety endpoint), but patients on rivaroxaban suffered more major bleedings as defined by the International Society on Thrombosis and Haemostasis (ISTH). Whether a different anticoagulation regimen with higher dose or a different agent would have been beneficial is not known. Interestingly, in the COMPASS trial in patients with stable CAD, higher-dose rivaroxaban monotherapy (5 mg b.i.d.) was not effective in reducing cardiovascular events in contrast to the combination of rivaroxaban 2.5 mg b.i.d. plus aspirin that was effective.14 Given the prothrombotic properties of HF on one hand and the neutral results of the aforementioned trials on the other, it may be possible that specific subgroups rather than the whole HF population benefit from anticoagulation therapy and these subgroups need to be identified by clinical research.15 Until new evidence challenges the findings of the current and previous trials on anticoagulation in HF without AF or any thromboembolic event, the ESC guideline recommendation to avoid anticoagulants in these patients remains valid. Conflict of interest: G.F. Committee member of trials and registries sponsored by Boehringer Ingelheim, Medtronic, Novartis, Servier and Vifor; Lecture fees from Merck. D.F. Consultation fees, travel grants and/or lecture fees from Abbott, Boehringer Ingelheim, Menarini, Novartis, Pfizer, Roche and Servier. Biography: Prof. Gerasimos Filippatos studied Medicine at the University of Patras, GR, and earned his doctorate Cum Laude from the University of Athens. He subsequently completed his clinical training in Chicago, USA; and Cambridge, UK. He is Professor of Cardiology at the National and Kapodistrian University of Athens and served as Dean of the School of Medicine at the University of Cyprus. Prof Filippatos is past President of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). He has served as Chair of the Clinical Section and the Committee on Acute Heart Failure of the HFA, and as Chair of the ESC’s Working Group on Acute Cardiac Care. He was also member of the ESC Practice Guidelines Committee and American College of Cardiology/American Heart Association HF Guidelines Writing Committee, and International Governor of the American College of Chest Physicians. Dr. Filippatos is Associate Editor of the European Heart Journal and Senior Consulting Editor of JACC-HF. He has published over 450 articles in peer-reviewed journals and authored more than 30 book chapters including the “Acute Heart Failure” chapter in Braunwald’s and Oxford Desc Reference: Cardiology. Moreover, he has (co) edited 5 books including the ESC Textbook of Acute and Intensive Cardiac Care, Highly Commended in the 2011 British Medical Association Medical Book Awards; in 2014 presented the book Heart Failure: The Expert’s Approach and in 2016 the pocket book: Treatment Algorithms in Heart Failure. Prof. Filippatos is in the Thomson Reuters list of Highly Cited Researchers. Honorary Member of many Cardiac Societies: ie French Cardiac Society, Romanian Cardiac Society, Hungarian Cardiac Society. Biography: Prof. Dimitrios Farmakis is an Associate Professor at the University of Cyprus Medical School and a Consultant Cardiologist at Nicosia General Hospital, Cyprus. His focuses his clinical and research activities on heart failure, cardio-oncology and haemoglobinopathy-associated heart disease. He has published 201 papers in PubMed journals (total impact factor, 1397; total citations, 7457; h-index,48). He has authored 67 chapters in medical textbooks, 218 abstracts, and has been invited as a speaker or chairman in more than 150 congresses. He has received research grants and served as primary investigator or steering committee member in European Commission-funded projects. He sits on editorial boards of international medical journals and on several scientific and advisory committees, while he serves as a reviewer for highly-rated journals. He was a member of the European Society of Cardiology (ESC) guideline committee for Cardio-Oncology in 2016 and he is leading the 2019/2020 edition of the Thalassaemia International Federation guidelines. He is the immediate past President of the Working Group for Cardiomyopathies and Basic Research of the Hellenic Society of Cardiology, an ESC fellow, a member of the ESC Heart Failure Association (HFA), a member of the HFA Cardio-Oncology Committee, an ex-officio member of the Board of the ESC Cardio-Oncology Council and a former member of the Board and Treasurer of the Hellenic College of Cardiology. He has received awards and distinctions from Greek and international organizations, such as the University of Athens Medical School, the University of Patras Medical School, the Harvard Medical School and the American Heart Association.