Epidemiology and treatment of acute and chronic heart failure

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Issue contains three Viewpoint contributions from our ‘Year in Cardiovascular Medicine 2022’ series: ‘The year in cardiovascular medicine 2022: the top 10 papers in heart failure and cardiomyopathies’ authored by Johann Bauersachs and Rudolf de Boer;1 ‘The year in cardiovascular medicine 2022: the top 10 papers in arrhythmias’ authored by Harry J.G.M. Crijns, Pier Lambiase, and Prash Sanders;2 and ‘The year in cardiovascular medicine 2022: the top 10 papers in cardio-oncology’ authored by Joerg Herrmann, Teresa Lopez-Fernandez, and Alexander Lyon.3 I am sure that the readers will find this series extremely useful. Indeed, in each contribution, the authors, who are Editors of the European Heart Journal, summarize and comment on the ten 10 game-changing original manuscripts published in 2022 in a specific field of cardiovascular medicine. The issue continues with a focus on heart failure (HF) and cardiomyopathies. The choice of myocardial revascularization in stable patients remains controversial.4–10 In a Fast Track clinical research article entitled ‘Surgical or percutaneous coronary revascularization for heart failure: an in silico model using routinely collected health data to emulate a clinical trial’, Suraj Pathak from the University of Leicester in the UK, and colleagues note that the choice of revascularization with coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in people with ischaemic left ventricular dysfunction is not guided by high-quality evidence.11 A trial of CABG vs. PCI in people with HF was modelled in silico using routinely collected healthcare data. The in silico trial cohort was selected by matching the target trial cohort, identified from Hospital Episode Statistics in England, with individual patient data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial. The primary outcome was 5-year all-cause mortality or cardiovascular hospitalization. Instrumental variable analysis (IVA) was used for the primary analysis. Results were expressed as average treatment effects (ATEs) with 95% confidence intervals (CIs). The target population included 13 519 HF patients undergoing CABG or complex PCI between April 2009 and March 2015. After matching, the emulated trial cohort included 2046 patients. The unadjusted primary outcome rate was 51% in the CABG group and 70% in the PCI group. IVA of the emulated cohort showed that CABG was associated with a significantly lower risk of the primary outcome (ATE −16.2%), with comparable estimates in the unmatched target population (ATE −15.5%). Pathak et al conclude that in people with HF, in silico modelling suggests that CABG is associated with fewer deaths or cardiovascular hospitalizations at 5 years vs. complex PCI. A pragmatic clinical trial is needed to test this hypothesis and this trial would be feasible. The contribution is accompanied by an Editorial by Bernard J. Gersh from the Mayo Clinic College of Medicine in Rochester, MN, USA and David De Mets from the University of Wisconsin-Madison, WI, USA.12 The authors conclude that the results of such trials will not be available for several years. In the interim, the totality of evidence supports the role of CABG as the preferred treatment in patients with ischaemic cardiomyopathy, but with the caveat that this only applies to patients who are ‘good’ surgical candidates as defined by age, comorbidities including frailty, and—after informed joint discussion—patient preference. In patients judged to be poor surgical candidates, PCI is a good alternative for the relief of anginal symptoms that limit the quality of life, but current data would not support the recommendation for PCI in the expectation that this will improve survival. Albuminuria is common in patients with HF and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in HF is still incompletely understood. In a Clinical Research article entitled ‘Albuminuria as a marker of systemic congestion in patients with heart failure’, Eva Boorsma from the University of Groningen in the Netherlands, and colleagues evaluated the association of clinical characteristics and biomarker profile with albuminuria in patients with HF with both reduced and preserved ejection fractions.13 A total of 2315 patients included in the index cohort of BIOSTAT-CHF were evaluated, and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as a urinary albumin–creatinine ratio (UACR) >30 mg/gCr and >300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35% and 10%, respectively. Patients with albuminuria had more severe HF, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal probrain natriuretic peptide (NT-proBNP) (all P < 0.001). The presence of albuminuria was associated with increased risk of mortality and HF (re)hospitalization in both cohorts (Figure 1). The strongest independent association with log UACR was found for log NT-proBNP (P < 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings. Survival analyses, proportion free from mortality or heart failure hospitalization in the validation cohort.13 Boorsma et al. conclude that in patients with new-onset or worsening HF, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion. The contribution is accompanied by an Editorial by Nicola Riccardo Pugliese, Stefano Taddei, and Stefano Masi from the University of Pisa in Italy.14 The authors conclude that there is convincing evidence that albuminuria is a solid risk marker in HF, but we need more data to better appreciate its role, especially in HF with preserved ejection fraction. We must also look for causality before considering albuminuria a therapeutic target in HF. HF is typically highly prevalent in the elderly, while its prevalence in the young is less investigated.14–17 In a Clinical Research article entitled ‘Epidemiology of heart failure in young adults: a French nationwide cohort study’, Emmanuel Lecoeur from the Hôpital Européen Georges-Pompidou in Paris, France, and colleagues note that HF in young adults is uncommon, and changes in its incidence and prognosis in recent years are poorly described.18 The incidence and prognosis of HF in young adults (18–50 years) were characterized using nationwide medico-administrative data from the French National Hospitalization Database (period 2013–2018). A total of 1 486 877 patients hospitalized for incident HF were identified, including 70 075 (4.7%) patients aged 18–50 years (estimated incidence of 0.44‰ for this age group). During the study period, the overall incidence of HF tended to decrease in the total population but significantly increased by ∼0.041‰ in young adults (P < 0.001). This increase was notably observed among young men (from 0.51‰ to 0.59‰, P < 0.001), particularly those aged 36–50 years. In these young men, ischaemic heart disease (IHD) was the most frequently reported cause of HF, whereas non-ischaemic HF was mainly observed in patients ≤35 years old. In contrast to non-ischaemic HF, the incidence of IHD increased over the study period, which suggests that IHD-related HF is progressively affecting younger patients. Concordantly, young HF patients presented with high rates of traditional IHD risk factors, including obesity, smoking, hypertension, dyslipidaemia, or diabetes. Lastly, the rates of re-hospitalization (for HF or for any cause) within 2 years after the first HF event and in-hospital mortality were high in all groups, indicating a population with a poor prognosis. Lecoeur et al. conclude that strategies for the prevention of IHD risk factors should be strongly considered for patients under 50 years old. This manuscript is accompanied by an Editorial by Maria Schaufelberger and Carmen Basic from the University of Gothenburg in Sweden.19 The authors conclude that everything must be done to stop the increase of HF in young adults. To do this, it is important to make both the profession and society aware of the ongoing HF epidemic in young adults. It is well recognized that sodium–glucose co-transporter-2 (SGLT-2) inhibitors improve the outcomes of HF.20–26 In a Clinical Research article entitled ‘Empagliflozin, irrespective of blood pressure, improves outcomes in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial’, Michael Böhm from the Saarland University in Germany, and colleagues sought to evaluate if systolic blood pressure (SBP) modulates these effects.27 The association of SBP and the treatment effects of empagliflozin in EMPEROR-Preserved (empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) were evaluated. Randomized patients (n = 5988) were grouped according to SBP at baseline (<110 mmHg, n = 455; 110–130 mmHg, n = 2415; >130 mmHg, n = 3118). The effect of empagliflozin on blood pressure, cardiovascular death, or HF hospitalization (primary outcome), total HF hospitalizations, and rate of decline in estimated glomerular filtration rate (eGFR) was studied. Over a median of 26.2 months, the placebo-corrected decline was small and not significantly different across baseline SBP. On placebo, the risk of cardiovascular death or hospitalization for HF was 8.58 events per 100 patient-years at >130 mmHg, 8.26 at 110–130 mmHg, and 11.59 at <110 mmHg (P = 0.12 vs. >130 mmHg, P = 0.08 vs. 110–130 mmHg). There was no evidence for baseline SBP moderating the effect of empagliflozin on risk of HF events (primary endpoint interaction P = 0.69, recurrent HF hospitalizations interaction P = 0.55). When comparing empagliflozin with placebo, SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure. The authors conclude that in EMPEROR-Preserved, empagliflozin is effective and safe without SBP meaningfully moderating empagliflozin's treatment effects. This analysis of EMPEROR-Preserved shows that empagliflozin can be used safely and effectively without blood pressure being a meaningful moderator of the drug benefit. The contribution is accompanied by an Editorial by Kieran Docherty and Pardeep Jhund from the University of Glasgow in the UK.28 Docherty and Jhund conclude that the analysis by EMPEROR-Preserved investigators adds further detail to the picture of SGLT2 inhibitors and blood pressure in HF. In this case, the authors welcome the ‘failure’ of the gliflozins to influence blood pressure. As seen in this analysis, and others, it is clear that in patients with HF, the SGLT2 inhibitors have no significant clinical effect on blood pressure. It is hoped that this finding will help reassure clinicians about the remarkable safety profile of these drugs and ultimately lead to more patients receiving these prognosis-improving drugs. In a Clinical Research article entitled ‘Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial’, Joan Carles Trullàs from the Hospital d’Olot i comarcal de la Garrotxa in Spain, and colleagues evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute HF (AHF).29 This was a prospective, double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The co-primary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48% women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo (−2.3 vs. −1.5 kg; P = 0.002), but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P = 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P = 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P < 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (decrease in eGFR >50%: 46.5 vs. 17.2%; P < 0.001), while hypokalaemia and hypokalaemia were similar between groups (Figure 2). There were no differences in mortality or rehospitalizations. Graphical summary of the design and main findings of the CLOROTIC trial.29 The authors conclude that the addition of HCTZ to loop diuretic therapy improves diuretic response in patients with AHF. The manuscript is accompanied by an Editorial by Rosita Zakeri from King's College London, UK, Selma Mohammed from Creighton University, Omaha, USA, and David Wilson from Worcestershire Acute Hospitals NHS Trust, UK.30 The authors conclude that CLOROTIC is a welcome addition to a limited evidence base for combination diuretic management of AHF. It shows that HCTZ, an inexpensive thiazide diuretic, is a safe and modestly effective addition to loop diuretic therapy in patients with AHF and volume overload. The HF community now finally has randomized data to support loop–thiazide efficacy in AHF. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Left atrial volume and left ventricular mass for pulmonary capillary wedge pressure assessment with cardiovascular magnetic resonance: accurate enough for clinical use?’, Davide Genovese from the University of Padova in Italy, and colleagues comment on the recent publication ‘Cardiac magnetic resonance identifies raised left ventricular filling pressure: prognostic implications’ by Pankaj Garg from the University of Sheffield in the UK, and colleagues.31,32 Garg et al. respond in a separate comment.33 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.