New Oral Anticoagulants in Heart Failure (2013)

This editorial refers to ‘Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial’, by J. Ferreira et al., published in this issue on pages 1053–1061. Heart failure (HF) is one of the epidemics in cardiovascular disease of the 21st century.1 Hypertension, myocardial infarction, valvular heart disease, diabetes, and atrial fibrillation (AF) are the most frequent risk factors. Although survival has improved over the years, the prognosis of HF remains awful, as ∼ 35% of the patients with HF will die within 5 years.2,3 Stroke and thrombo-embolism contribute to morbidity and mortality in these patients. About 14–20% of patients with stroke have some form of HF or impaired LV function.4 The incidence of ischaemic stroke has been reported to be 18 per 1000 patients during the first year following HF diagnosis, increasing to 47 per 1000 patients at 5 years follow-up.5 The risk of stroke is highest early after the diagnosis of HF.6 The reduction in risk after a longer duration of HF may relate to treatment of the disease and initiation of oral anticoagulation. If patients suffer from atrial fibrillation (AF), the risk increases by two- to three-fold. While HF thus increases the risk of stroke, there remains debate over the benefit of antithrombotic therapy in HF. Clearly patients with AF in association with HF with either a reduced (HF-REF) or preserved ejection fraction (HF-PEF) have an indication for antithrombotic therapy. However, in HF patients who are in sinus rhythm, there is no evidence that oral anticoagulants reduce the occurrence of mortality and morbidity.1 Stroke is a heterogeneous disease and relates to Virchow's triad for thrombogenesis including (i) abnormal blood flow; (ii) abnormalities in the vessel wall; and (iii) abnormalities in blood constituents, all contributing to a prothrombotic or hypercoagulable state (Figure 1).1,4 In HF, the first component, abnormal blood flow, could be the major component of Virchow's triad due to LV dysfunction, aneurysms and areas with dyskinesis, and AF being present in up to 40% of the patients. Abnormalities of the endocardial and endothelial vessel wall are also evident, being reflected by the presence of endothelial damage/dysfunction.7 Endothelial dysfunction may contribute to increased peripheral vasoconstriction but also promotes monocyte and platelet adhesion to the endothelium, setting the stage for stroke. Whether this component of Virchow's triad just reflects the underlying co-morbidities, i.e. atherosclerosis, and thus is more relevant in patients having ischaemic as compared with non-ischaemic HF remains to be elucidated. Abnormalities in blood constituents include increased coagulation,7–10 impaired fibrinolysis,9,11 and increased platelet aggregation, and all thus have been detected in HF.7,9,10,12 Activation of the renin–angiotensin–aldosterone and sympathetic nervous systems may contribute to rheological changes including increased aggregation of platelets and an imbalance between coagulation and fibrinolysis. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, reduction of activation of the renin–angiotensin–aldosterone system by losartan significantly reduced the occurrence of stroke in patients with a history of AF and hypertension, with associated LV hypertrophy as compared with those patients randomized to atenolol.13 Angiotensin converting enzyme inhibitors also reduce the hypercoagulable state by beneficial changes in fibrinolytic activity and endothelial cell activation.14,15 In addition, iron deficiency occurring at early stages of HF is related to reactive thrombocytosis and other changes leading to an anaemia-related hypercoagulable state and increased risk of thrombo-embolic complications.16,17 Finally, digoxin use has been associated with increased levels of endothelial and platelet activation.18 Thus, many factors in patients with HF may contribute to the hypercoagulable state and the increased risk of stroke. The exact mechanisms and the precise contribution of the separate parameters involved in hypercoagulability may vary depending on the underlying associated disease, severity of HF, the presence of HF-PEF or HF-REF, concomitant medications, and the presence of (silent) AF. Studies investigating the underlying mechanisms involved in stroke amongst patients with HF are sparse. Recently Vemmos et al.19 showed that of 2904 patients with acute stroke, 283 (9.7%) suffered from HF. Although stroke severity was comparable between patients with and without HF, there were major differences in aetiology. Indeed, hypoperfusion and cardio-embolism were more often observed in HF patients, and, in patients with HF and stroke, 51% had concomitant AF. If AF was present, cardio-embolism was the major cause of stroke. In those without documented AF, the mechanism of stroke was dependent upon the underlying disease. In patients with hypertension or coronary artery disease, strokes were predominantly of atherosclerotic aetiology or lacunar as compared with cardio-embolism in HF patients with dilated cardiomyopathy or valvular diseases. Lacunar strokes and intracerebral haemorrhages occurred more frequently in patients without HF. Given the associated prothrombotic state in HF, one may expect that patients with HF would benefit from oral anticoagulant therapy.20 In the last 10 years, four randomized controlled trials assessed the efficacy of warfarin in patients with HF and sinus rhythm (Table 1).21–24 However, none of these trials was able to show a reduction of the combined endpoint of cardiovascular morbidity and mortality when compared with placebo or aspirin. In the largest and most recent trial, the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study, a significant reduced risk of ischaemic stroke was observed with warfarin [0.72 vs. 1.36 events/100 patient-year; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.33–0.82, P = 0.005)]. A comparable albeit not statistically significant reduction in stroke by warfarin vs. aspirin was observed in the WATCH study (HR 0.58, 95% CI 0.25–1.3). However, the beneficial effect of reduction of stroke in the WARCEF study was offset by an increased risk of major haemorrhage (1.78 vs. 0.87 events per 100 patient-years; adjusted rate ratio 2.05, 95% CI 1.36–3.12). Importantly, the primary endpoint was predominantly death, which occurred at similar rates (6.5 per 100 patient-years) in the randomized groups. Although one may argue that incorporating death into the primary endpoint in this group of patients may simply dilute the beneficial effect of warfarin on the prevention of stroke; this endpoint seems justified since death dictates the outcome in these patients. The lack of a beneficial effect of warfarin in patients with HF suggests that mortality in these patients is perhaps not related to thrombo-embolic events but instead to progression of HF or ventricular arrhythmias. Interestingly, a recent subanalysis of the WARCEF study 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 group.25 As discussed above, beneficial effects of warfarin in HF patients may vary depending on the underlying disease, severity of HF, additional presence of AF, age, and other unrecognized parameters. Interestingly, the presence of subclinical atrial tachycardias lasting for 6 min or more was recently shown to be associated with an increase by 2.5-fold in ischaemic stroke in elderly patients with hypertension, i.e. often being patients with HF-PEF.26 This suggests the need for careful monitoring of the rhythm in these patients. Thus, although anticoagulation in AF significantly contributes to improved prognosis by a reduction of thrombo-embolic complications, it is still uncertain whether this also applies for patients with HF in sinus rhythm. While there seems no doubt that the prevalence of stroke is significantly reduced, all trials used a combined primary endpoint often including bleeding and mortality next to stroke. Until fairly recently, the vitamin K antagonists and aspirin were the only drugs available for reduction of hypercoagulability. Recently, new oral anticoagulants (NOACs) have become available as alternatives to warfarin.27 These new agents include the oral direct thrombin inhibitor (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban).28–30 Recent subanalyses of these landmark Phase III clinical trials have been performed in patients with HF (Tables 2 and 3).31–33 In this issue of the European Journal of Heart Failure. Ferreira et al.31 report on the outcome of dabigatran vs. warfarin in the subgroup of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial with symptomatic HF. A total of 4904 of 18 113 (27%) patients with AF were defined to have HF at baseline. For the purpose of this analysis, HF was defined as both being in the functional class II or higher for HF within 6 months before screening and at least one previous hospitalization for HF. Patients with HF were younger (68.3 ± 10.2 vs. 72.7 ± 7.7 years) and more often male (66.9% vs. 62.3%). The LV function was assessed in 49.1% of the population. A reduced LVEF (≤ 40%) was present in 43.5% of the HF patients vs. only 11.2% in those without HF (P < 0.001). The mean CHADS2 score (2.6 ± 1.1 vs. 2.0 ± 1.1, P < 0.001) and plasma NT-proBNP levels (1552 ± 2006 μg/mL vs. 963 ± 964 μg/mL, P < 0.001) were significantly higher in the HF group. In the warfarin group, the median time in the therapeutic range was 64% for patients with HF as compared with 69% for those without HF (P < 0.001). During the median follow-up of 2 years, the beneficial effect of dabigatran was similar in the patients with HF to that in those without HF (Table 3), although no significant beneficial effect of the higher dosage could be observed. The latter may have been caused by the low number of patients included in this analysis. Intracranial bleeding and total bleeding occurred significantly less frequently, whereas major bleeding occurred at equal rates in all three groups. Recently, post-hoc analyses of the Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation trial (ARISTOTLE) HF groups were also published.32,33 Definitions of HF differed between these three trials (Table 2). In the ROCKET-AF trial, 64% of all patients who were included had the HF criterion, which was defined as either having a history of HF or LVEF <40%.33 In the HF post-hoc analysis of ARISTOTLE, Mc Murray et al. reported on 14 671 of 18 201 (81%) patients for whom information was available on the presence of symptomatic HF, <3 months of inclusion, and presence of LV dysfunction, defined as an EF <40%, who were included.33 Patients in this analysis were divided into three groups: (i) patients with HF-REF with or without symptoms; (ii) patients with HF-PEF; and (iii) patients with no HF symptoms and a normal LV function. Patients in ROCKET-AF were older, and had more co-morbidities and a higher CHADS2 score. The baseline characteristics of the subgroup of patients with HF-REF included in ARISTOTLE were comparable with the HF subgroup included in RE-LY. In these post-hoc analyses, outcomes were comparable with those of the main trials. Rivaroxaban was not significantly different from warfarin either for efficacy or for safety outcomes in HF patients. Apixaban was superior to warfarin for the prevention of stroke and emboli in patients with HF-REF, whilst major bleeding, total bleeding, and intracranial bleeding occurred at a lower rate (Table 3). Furthermore, while vascular death and hospitalizations occurred significantly more often in the HF groups of all three trials, stroke and systemic emboli still occurred at similar rates despite higher CHADS2 scores in the HF patients (Table 3). A meta-analysis of these three trials comparing warfarin with NOACs demonstrated that for patients without HF, the new drugs are superior to warfarin [odds ratio (OR) 0.76, 95% CI 0.67–0.87, P < 0.001], while being not significantly different from warfarin among patients with HF (OR 0.91, 95% CI: 0.78–1.06 P = 0.22, Figure 2).34 These data are the first showing outcomes of treatment with NOACs in patients with HF and AF. Data on NOACs in patients with HF in sinus rhythm are, however, not yet available, and many questions remain unanswered. For example, the pathophysiological mechanisms involved in the occurrence of a hypercoagulable state in HF are still incompletely known. Interestingly, however, recent post-hoc analyses of both RE-LY and ARISTOTLE showed that plasma levels of NT-proBNP were independently related to increased risks of stroke and mortality (Figure 3).35,36 Indeed, NT-proBNP, which is a well established risk marker for prognosis in HF patients with both HF-REF and HF-PEF,37 may become a valuable marker to predict risk of stroke. New oral anticoagulants appear to be as safe and effective in patients with AF with and without HF, albeit in underpowered post-hoc analyses and for the type of patients who have been included in these trials. More than half of the patients included had AF in the setting of HF-PEF, implying that the present data should not be extrapolated to all patients with HF. Secondly, patients with severe renal insufficiency were excluded from the trials. In the European Society of Cardiology guidelines for AF, NOACs are contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min), and dose reductions are recommended for moderate renal insufficiency. Thus, one of the limitations of prescription of NOACs is that they cannot be prescribed in patients with renal insufficiency. Indeed, patients with HF would require creatinine clearance assessments at regular intervals.38 We should, however, remember that both stroke and bleeding occur more frequently in patients with renal impairment.39,40 What do the HF subgroup analyses from the recent trials tell us about patients with renal impairment? Patients with moderate renal impairment (creatinine clearance 30–49 mL/min) included in ROCKET-AF were older and had more co-morbidities as compared with those with creatinine clearances in the higher range.41 Also, patients responded favourably to the reduced and recommended dose of 15 mg once daily compared with warfarin and comparably to the response of patients with a preserved renal function to 20 mg once daily. A comparable increased risk for stroke and bleeding in patients with renal insufficiency was observed in ARISTOTLE.42 However, apixaban reduced the rate of both stroke and major bleeding as compared with warfarin in these patients, although it is presumed that many patients with more severe renal insufficiency would have received apixaban 2.5 mg b.i.d. which is the recommended dose for patients with two of three criteria: age >80 years, weight <60 kg, and serum creatinine >1.5 mL/dL. Thus, apixaban may be particularly suited to address the unmet need for a more effective and safe stroke prevention in patients with AF and renal dysfunction, which is often the case in patients with HF. Thirdly, the mean time in the therapeutic range in the warfarin group was significantly lower in patients with HF as compared with no HF (in RE-LY, 64% vs. 69%, P < 0.001; in ROCKET-AF, 53% vs. 59%). HF is one of the risk features within the new SAMe-TT2R2 [Sex female, Age less than 60, Medical history, Treatment strategy (rhythm control), Tobacco use (doubled), Race non Caucasian (doubled)] score, which is a score to identify those patients who could potentially do well on warfarin, with a high percentage time in the therapeutic range. If the SAMe-TT2R2 score is 0–1, these patients are likely to do well on warfarin, whilst those with a SAMe-TT2R2 score ≥ 2 are likely to have poor anticoagulation control if warfarin is used, and an NOAC could be a better option.43 Fourthly, although routine monitoring is not necessary with NOACs, plasma levels of NOACs may fluctuate, especially with associated instabilities in renal function in patients with HF, where changes in (dosages of) various drugs can occur on a regular basis, and renal function should be assessed on a regular basis.38 In conclusion, the NOACs represent an important step forward in our management of AF. They would work best if used correctly, and in the appropriate patients. Patients with HF and AF require some precautions, but in these patients NOACs will most proabably also gain a place. What the place of NOACs in HF patients with sinus rhythm will be is at present not known, but studies in this field are being developed (COMMANDER HF NCT 01977915). Conflict of interest: none declared.