Acute and chronic heart failure: exciting therapeutic perspectives

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure (HF) and cardiomyopathies contains the State of the Art Review article entitled ‘Iron deficiency and cardiovascular disease’ by Gianluigi Savarese from the Karolinska Institutet in Stockholm, Sweden.1 The authors indicate that iron deficiency (ID) is common in patients with cardiovascular disease.2–4 Up to 60% of patients with coronary artery disease, and an even higher proportion of those with HF or pulmonary hypertension, have ID; the evidence for cerebrovascular disease, aortic stenosis, and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction, and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to antithrombotic therapy or gastrointestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer an independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that i.v. ferric carboxymaltose improved symptoms, health-related quality of life, and exercise capacity, and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials. In a second State of the Art Review article entitled ‘Valvular heart disease: shifting the focus to the myocardium’, Nina Ajmone Marsan from Leiden University Medical Center in the Netherlands, and colleagues note that adverse cardiac remodelling is the main determinant of patient prognosis in degenerative valvular heart disease (VHD).5 However, to give an indication for valvular intervention, current guidelines include parameters of cardiac chamber dilatation or function which are subject to variability, do not directly reflect myocardial structural changes, and, more importantly, seem to be not sensitive enough in depicting early signs of myocardial dysfunction before irreversible myocardial damage has occurred.6–8 To avoid irreversible myocardial dysfunction, novel biomarkers are advocated to help in refining indications for intervention and risk stratification. Advanced echocardiographic modalities, including strain analysis, and magnetic resonance imaging have been shown to be promising in providing new tools to depict the important switch from adaptive to maladaptive myocardial changes in response to severe VHD. This review, therefore, summarizes the current available evidence on the role of these new imaging biomarkers in degenerative VHD, aiming at shifting the clinical perspective from a valve-centred to a myocardium-focused approach for patient management and therapeutic decision-making. Sodium–glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their efficacy in acute HF (AHF) is still unknown.9–16 Empagliflozin in acute heart failure: the EMPULSE Trial. CI, confidence interval. Data shown for the treatment effect graphs are adjusted mean change from baseline, with error bars representing standard error. *The units of weight changes per mean daily loop diuretic dose are presented in kg/40 mg of intravenous furosemide (or 80 mg of oral furosemide) or equivalent. The equivalent to 40 mg of furosemide was defined as 20 mg of torasemide or 1 mg of bumetanide. †Measured as changes in haematocrit (%). ‡Calculated as a sum of the points allocated for dyspnoea, orthopnoea, and fatigue. For each variable, a 0- to 3-point scale has been used, where points were allocated for: absence (0 points), seldom (1 point), frequent (2 points), and continuous (3 points) based on the frequency of the clinical sign. §The hierarchy and the components of the primary outcome measured by the win ratio: (1) time to all-cause death; (2) number of heart failure (HF) events (including hospitalizations for HFs, urgent HF visits, and unplanned outpatient visits); (3) time to first HF event; (4) ≥ 5 point difference in change from baseline in KCCQ total symptom score (KCCQ-TSS) after 90 days of treatment.17 In a Clinical Research article entitled ‘Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial’, Jan Biegus from the Wroclaw Medical University in Poland, and colleagues indicate that effective and safe decongestion remains a major goal for optimal management of patients with AHF.17 The effects of the SGLT2 inhibitor empagliflozin on decongestion-related endpoints were evaluated in the EMPULSE trial (NCT0415775). A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL) and WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal probrain natriuretic peptide levels, haemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time points: adjusted mean differences at Days 15, 30, and 90 were: for WL −1.97, −1.74, −1.53 kg; for WL-adjusted: −2.31, −2.79, −3.18 kg/40 mg furosemide i.v. or equivalent; (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90, with a win ratio of 1.75; P < 0.0001) (Figure 1). The authors conclude that initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective, and sustained decongestion which is associated with clinical benefit at Day 90. The contribution is accompanied by an Editorial by Alexandre Mebazaa and Alain Cohen Solal from the Université Paris Cité in France, and Paolo Colombo from Columbia University Irving Medical Center in New York, USA.18 The authors conclude that recent positive trials on AHF demonstrated that acetazolamide and gliflozins, on top of furosemide, are effective in reducing congestion in AHF. However, the same trials also showed that many patients remain congested at discharge, or later, despite these new therapies. Further research is needed, possibly using the congestion endpoints already validated in EMPULSE and ADVOR. Graphical Abstract.24 Management of congenital heart disease is a challenge of growing complexity.19–23 In particular, the long-term survival of patients with isolated congenital ventricular septal defect (VSD) is not well described. In a Clinical Research article entitled ‘Survival of patients with congenital ventricular septal defect’, Filip Eckerström from the Copenhagen University Hospital in Denmark, and colleagues sought to describe the survival of a national cohort of patients with VSD compared with the general population.24 Using Danish nationwide medical registries, all patients diagnosed with congenital VSD (n = 9136) in the period 1977–2018 were included. Patients with chromosomal abnormalities and concomitant congenital cardiac malformations other than atrial septal defect were excluded. Each patient was matched by birth year and sex with 10 controls from the general Danish population. Median follow-up was 22 years. VSD patients displayed lower survival (P < 0.001) yielding a hazard ratio (HR) for mortality of 2.7 [95% confidence interval (CI) 2.4–3.0] compared with matched controls. The adjusted HR for mortality among patients with unrepaired VSD was 2.7 and 2.8 for patients with surgically closed VSD. Stratified by era of VSD diagnosis, the HR for mortality was 3.2 for unrepaired patients diagnosed before 1990 and 2.4 for patients diagnosed later. Cardiac-related death was the most common cause of death among unrepaired (30%) and surgically closed (65%) patients (Figure 2). Eckerström and colleagues conclude that patients with VSD have lower survival compared with the general population. This manuscript is accompanied by an Editorial by Anne Marie Valente and Michael Freed from Harvard Medical School in Boston, MA, USA.25 The authors conclude by pointing out that in 1968, Dr Julien Hoffman published a report of the natural history of congenital heart disease regarding problems in its assessment with special reference to VSDs. His conclusion reads ‘At present, we have to make decisions about prognosis and treatment on insufficient evidence, and it will take another 50 years of careful follow-up of each variety of congenital heart disease, with anatomic and physiological variations distinguished, before giving definite answers to some of the questions which are now being asked.’ Now, 54 years later, we continue to search for those answers. In a Viewpoint article entitled ‘Fit for the future: empowering clinical trials with digital technology’, Dipak Kotecha from the University of Birmingham Institute of Cardiovascular Sciences in the UK, and colleagues remind us that digital innovation and the increasing ability for easier application are transforming our daily lives.26 This transformation is being driven by rapid changes in technology but also consumerism. Whilst there is a clear opportunity to apply these innovations to clinical research, advances here have been much slower.27–31 There is a need for relevant stakeholders to embrace digital innovation and to balance it with research governance, security of patient information, trustworthiness, and a social licence to use these techniques in health research. Changes are required to rapidly accelerate advancements in cardiovascular diseases (and reverse withdrawal of industry investment), based on more efficient cardiovascular outcome trials which remain the bedrock of our discipline. In this Viewpoint, the authors highlight the need for a paradigm change to reinitialize large-scale pragmatic cardiovascular trials. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘More costs than benefits from screening for cardiovascular disease with computed tomography in the DANCAVAS study’, Niels Holmark Andersen from Aalborg University Hospital in Denmark and colleagues comment on the recent publication ‘Cost effectiveness of population screening vs. no screening for cardiovascular disease: the Danish Cardiovascular Screening trial (DANCAVAS)’ by Rikke Søgaard from the University of Southern Denmark, and colleagues.32,33 Søgaard et al. respond in a separate comment.34 Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.