Optimizing heart failure management: anticoagulation, diuretic withdrawal, iron substitution, and novel inotropes

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Heart failure with reduced ejection fraction or HFrEF is associated with enlarged ventricles and atria where blood flow may be low or stasis may even be present in some areas,1 particularly when remodelling due to high blood pressure2 or ventricular aneurysms after an infarction develop.3 At such sites, thrombi may form and embolize. Indeed, before the advent of primary percutaneous coronary intervention (PCI), ventricular thrombi were quite common after an acute myocardial infarction, and certain patients experienced a stroke after infarction.4 Whether anticoagulation would be protective in patients with ischaemic HFrEF in sinus rhythm was investigated in the COMMANDER trial randomizing 5022 patients to rivaroxaban 2.5 mg b.i.d. or placebo.5 Although the trial missed its primary endpoint of first occurrence of death, stroke, or myocardial infarction, Mandeep Mehra and colleagues from the Brigham and Women’s Hospital in Boston, Massachusetts, USA further analysed this data set in their FAST TRACK contribution entitled ‘A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial’.6 The authors examine the incidence, timing, type, severity, and predictors of a stroke or a transient ischaemic attack, and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban. Over a median follow-up of close to 2 years, 150 all-cause strokes or transient ischaemic attacks occurred, of which 82% were of ischaemic and 11% of haemorrhagic origin (Figure 1). Overall, around half of all first-time strokes were disabling or fatal. Prior stroke, geographic region, and the CHA2DS2-VASc score were independent predictors. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or transient ischaemic attack compared with placebo by 32%. The principal safety endpoint of fatal bleeding or bleeding into a critical space occurred at a similar rate in both groups. Thus, patients with ischaemic HFrEF and in sinus rhythm are at risk for stroke or transient ischaemic attack following an episode of worsening heart failure. Although COMMANDER missed its combined endpoint of death, stroke, or myocardial infarction, rivaroxaban at a dose of 2.5 mg did markedly reduce rates of stroke or transient ischaemic attack compared with placebo. These clinically important findings are further discussed in a balanced Editorial by Aldo P. Maggioni from the Fondazione per il Tuo Cuore in Florence, Italy.7 Time to first occurrence of stroke or transient ischaemic attack. Cox proportional hazards models were adjusted for all covariates presented in Table 2. Analyses were performed in the intention-to-treat cohort including all randomized unique subjects who have a signed valid informed consent. CI, confidence interval; HR, hazard ratio; TIA, transient ischaemic attack (from Mehra MR, Vaduganathan M, Fu M, Ferreira JP, Anker SD, Cleland JGF, Lam CSP, van Veldhuisen DJ, Byra WM, Spiro TE, Deng H, Zannad F, Greenberg B, on behalf of the COMMANDER HF Investigators. A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial. See pages 3593–3601). Besides the renin–angiotensin system8 and beta-blockers,9 as well as mineralocorticoid receptor antagonists,10–12 diuretics are a mainstay of the management of HFrEF. However, diuretics lower potassium and may increase arrythmia and mortality risk,13,14 and they have an unfavourable metabolic profile. Thus, although their use is not disputed during episodes of decompensation, it is heavily discussed for stable HFrEF. This is addressed in a second FAST TRACK ‘Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial’ by Luis Rohde and colleagues from the Hospital de Clinicas de Porto Alegre in Porto Alegre, RS Brazil.15 In a prospective, randomized and double-blind protocol, they tested the safety and tolerability of withdrawing low-dose furosemide in 188 stable HFrEF patients. There was no significant difference in dyspnoea. However, three-quarters in the withdrawal group and 84% in the maintenance group were free of furosemide re-use during follow-up, with a hazard ratio of 0.59 (Figure 2). Heart failure hospitalizations, emergency room visits, and deaths were infrequent and similar between groups. Thus, in stable heart failure outpatients, diuretic withdrawal did not result in increased self-perception of dyspnoea or increased need of furosemide re-use. Diuretic discontinuation seems to be a safe strategy that deserves consideration in the outpatient setting, a conclusion that is critically discussed in a thought-provoking Editorial by G. Michael Felker from the Duke Clinical Research Institute in Durham, North Carolina (USA).16 Proportion of patients free from (No) and in need of (Yes) additional furosemide use during the 90-days study period. 95% confidence intervals are described in parenthesis. NT-proBNP, N-terminal pro-brain natriuretic peptide levels and is expressed in pg/mL; OR, odds ratio for additional furosemide use in the withdrawal group (from Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simões MV, Silvestre OM, Ribeiro ALP, Zytynski Moura L, Beck-da-Silva L, Prado D, Sant’ Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A. Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. See pages 3605–3612). Iron deficiency is common in heart failure patients17and negatively impacts symptoms and prognosis. Indeed, in cardiomyocytes, it impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts18 and improves symptoms in patients with HFrEF.19 However, the aetiology of iron deficiency in HFrEF is largely unknown. In their article entitled ‘Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use’, Peter van der Meer and colleagues from the University Medical Center Groningen in The Netherlands studied determinants and the biomarker profile of iron deficiency in 2357 worsening heart failure patients.20 Iron deficiency was present in two-thirds of the patients, with the highest prevalence in females. Independent determinants of iron deficiency were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein, and lower serum albumin levels, as well as P2Y12 inhibitor use. Iron deficiency was associated with pro-inflammatory markers such as paraoxonase 3 and tartrate-resistant acid phosphatase type 5 (TR-AP). In multivariable analyses, iron deficiency was also associated with worse outcome, independently of predictors of iron deficiency. Thus, the aetiology of iron deficiency in worsening heart failure is complex, multifactorial, and seems to consist of a combination of reduced iron uptake due to malnutrition and fluid overload, impaired iron storage due to inflammation, chronic kidney disease, and iron loss due to the use of antiplatelet drugs. Pacemakers are commonly used in heart failure patients. However, most of them, with the exception of biventricular pacing,21,22 have only one lead in the right ventricle providing unphysiological stimulation of the heart. Bhupendar Tayal and colleagues from the Aalborg Universitetshospital in Denmark assess in their article ‘Incidence of heart failure after pacemaker implantation: a nationwide Danish Registry-based follow-up study’23 the risk of heart failure with right ventricular pacing in 27 704 patients of the Danish nationwide registries. An age- and gender-matched control cohort of 138 520 individuals without pacemaker and heart failure was identified to compare the risk. Outcome was the cumulative incidence of heart failure. The incidence of fatal and non-fatal heart failure was 10.6% in pacemaker patients. The risks for three time intervals were: <30 days hazard ratio 5.98, 30–180 days hazard ratio 1.84, and >80 days hazard ratio 1.11. Among those with a pacemaker, factors associated with increased risk of heart failure were: male sex with a hazard ratio of 1.33, presence of chronic kidney disease with a hazard ratio of 1.64, and prior myocardial infarction with a hazard ratio 1.77. Thus, right ventricular pacing is strongly associated with risk of heart failure specifically within the first 6 months. Patients with antecedent history of myocardial infarction and chronic kidney disease had substantially increased risk, clinically relevant findings that are put into context in an Editorial by Faisal M. Merchant from the Emory University School of Medicine in Atlanta, Georgia, USA.24 In patients with severe and particularly acute HFrEF, or cardiogenic shock of various causes,25 inotropic agents often have to be used to stabilize haemodynamics.26 In their Special Article ‘Treatments targeting inotropy’ Christoph Maack from the Julius-Maximilians-Universitat Wurzburg in Germany and colleagues27 remind us that positive inotropic agents, such as catecholamines or phosphodiesterase inhibitors, are associated with increased mortality. Newer drugs, such as levosimendan28 or omecamtiv mecarbil,29 target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this. For omecamtiv mecarbil, phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic heart failure, and a phase III morbidity/mortality trial has recently begun. The pathophysiological basis of systolic dysfunction in patients with heart failure and the mechanisms through which different inotropic agents improve cardiac function differ importantly. Since ATP production in mitochondria is intimately linked to the processes of excitation–contraction coupling, inotropic agents also impact on mitochondrial bioenergetics and redox regulation. This position paper should identify novel therapeutic targets that potentially also improve myocardial structure and function over a longer term. This issue is also complemented by various Discussion Forum contributions. In a contribution entitled ‘Conversion to and maintenance of sinus rhythm do not yield a significant increase in stroke-volume in HFREF patients, whose heart works on the flat branch of Frank–Starling curve, thereby making the retrieval of the atrial mechanical contribution in this subset a substantially futile choice’, Renato De Vecchis and colleagues from the Elena d’Aosta Intermediate Infirmary in Naples, Italy comment on a recently published article entitled ‘Atrial fibrillation ablation in heart failure’ by Sergio Richter and colleagues from the Heart Center – University of Leipzig in Germany.30,31 Richter et al. respond to De Vecchis et al. in a separate comment.32 In another Discussion Forum contribution, Franz Messerli and colleagues from the Inselspital Universitätsspital Bern in Switzerland comment on a recent publication entitled ‘Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood’ by Jawahar L. Mehta from the University of Arkansas for Medical Sciences in Little Rock, USA and colleagues.33,34 Mehta et al. respond in a separate contribution.35 The editors hope that readers of this issue of the European Heart Journal will find of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.