Oral Anticoagulation for Heart Failure in Sinus Rhythm: from Evidence to Clinical Recommendations, or Not?

This editorial refers to ‘Updated meta-analysis on antithrombotic therapy in patients with heart failure and sinus rhythm’, by I. Hopper et al., published in this issue on pages 69–78. The increased risk of thrombotic complications in patients with heart failure (HF) has long been recognized.1 Even in the absence of AF, HF fulfils the three components of ‘Virchow's triad’ for thrombogenesis.2,3 Nonetheless, the potential benefit of oral anticoagulation (OAC) in patients with HF in sinus rhythm still remains controversial.4,5 The latest Guidelines from the European Society of Cardiology (ESC) for the diagnosis and treatment of HF state that ‘other than in patients with atrial fibrillation (AF) (both HF with reduced and preserved ejection fraction), there is no evidence that an oral anticoagulant reduces mortality–morbidity compared with placebo or aspirin’.4 A recent Consensus Document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis, which reviewed the published evidence, summarized ‘best practice’ and put forward consensus statements that may assist management decisions in clinical practice.5 This Consensus Document states ‘Given no overall benefit of warfarin on rates of death and stroke, with an increase in major bleeding—despite the potential for a reduction in ischaemic stroke—there is currently no compelling reason to routinely use warfarin for all HF patients in sinus rhythm’. Thus, whilst there is no doubt about whether HF patients in AF should receive OAC, the routine use of OAC cannot be recommended in those patients in sinus rhythm without any previous AF. In the present issue of the European Journal of Heart Failure, Hopper et al. present an updated meta-analysis on antithrombotic therapy use in patients with HF and sinus rhythm.6 The authors included contemporary prospective randomized trials comparing the effect of antiplatelet drugs (mainly aspirin) with that of warfarin. Four studies met the inclusion criteria—WASH, HELAS, WATCH, and WARCEF—including 4368 patients. The results of the meta-analysis show that OAC compared with aspirin did not reduce mortality, but could reduce the risk of stroke, at the cost of a significant increase in major bleeding.6 The authors conclude that their findings suggest that overall the benefit of warfarin in these patients outweighs the risk. In our opinion, we should perhaps be somewhat cautious with the available evidence. As recognized by Hopper and collaborators, some limitations exist in the included trials.6 All the trials had major recruiting problems and were underpowered. Also, all had heterogeneous HF drug co-administration, and a variable proportion of underlying ischaemic heart disease. The primary outcome in all the trials was a composite endpoint of death, myocardial infarction, and stroke (and, depending on the trial, pulmonary embolism, re-hospitalization, exacerbation of HF, or even intracerebral haemorrhage were included),5 and, thus, this could limit the analysis of particular endpoints. One could also argue that the lack of placebo arm in the WATCH and WARCEF trials may be an important limitation, as we cannot assess the real ‘efficacy’ per se of any antithrombotic therapy. Indeed, aspirin is not recommended in HF in the absence of a specific indication as secondary prevention in ischaemic heart disease.5 The results of the most recently published trial, WARCEF, makes this relevant.7 Although there were no significant differences in mortality, a significant reduction in stroke risk was observed with warfarin, although there was an increase in major bleeds, mainly gastrointestinal complications. New data from large ‘real-world’ cohorts of HF patients may give us valuable information. First, incident HF has been shown to be a major risk factor for stroke and death, especially in the first 30 days following initial diagnosis.8 OAC was associated with a lower incidence of both these endpoints. On the other hand, another study in unselected HF patients found that OAC did not show a favourable effect on mortality and morbidity.9 We may speculate that OAC may be particularly beneficial in some subgroups of HF patients. For example, a subgroup analysis of the WARCEF trial found that warfarin was associated with a 37% reduction in risk of death, ischaemic stroke, or intracranial haemorrhage compared with aspirin in the younger (age <60) subgroup of patients [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.48–0.84; P = 0.001], in contrast to older subjects aged ≥60 (HR 1.09, 95% CI 0.88–1.35; P = 0.442).10 Also, some patients with HF may have undiagnosed AF, or may even develop new-onset AF over time; one study with continuous ECG monitoring in a cohort of patients with stroke risk factors and no known AF at baseline reported that 30% developed newly diagnosed AF over a mean follow-up of 1.1 years.11 Further studies are encouraged to identify prospectively those variables associated with thrombo-embolic complications in HF, in order to determine optimally the subgroups of patients at the highest risk, which may benefit from OAC use.12 Additionally, clinical trials are needed to assess the potential benefit of the new OACs in patients with HF. These new drugs may offer a different risk–benefit profile compared with warfarin and, thus, they could offer a reduction in ischaemic stroke without increasing major bleeding, even compared with aspirin.13,14 For example, apixaban was compared with aspirin in patients with non-valvular AF who were unsuitable for warfarin use in the AVERROES trial, which was prematurely stopped due to a clear superiority of apixaban over aspirin for the prevention of stroke and thrombo-embolism, without significant differences in major bleeding episodes.14 Until more evidence becomes available, clinical decisions to treat patients with HF in sinus rhythm with OAC should be made on an individual basis, balancing the particular risk–benefit ratio. In our opinion, the evidence cannot yet lead to formal clinical recommendations for the routine use of OAC in all patients with HF. Conflict of interest: none declared.