Focus on heart failure and cardiomyopathies: new ESC Guidelines and key meta-analyses

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies contains the ‘2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC)’ from authors of the ESC Scientific Document Group.1 This is a new guideline, not an update of existing guidelines, with the exception of the section on hypertrophic cardiomyopathy, in which the authors have provided a focused update to the 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy.2 As such, most of the recommendations in this guidelines are new. It is beyond the scope of this guidelines to provide detailed descriptions and recommendations for each individual cardiomyopathy phenotype; instead, the aim is to provide a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations. The issue also contains the ‘2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC’.3 Since the publication of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (HF)4, there have been several randomized controlled trials that should change patient management ahead of the next scheduled full guidelines. This 2023 Focused Update addresses changes in recommendations for the treatment of HF because of this new evidence. New evidence was considered until 31 March 2023. All major randomised controlled clinical trials and meta-analyses were presented, discussed, and then voted upon for inclusion. Members with declared interests in specific topics were asked to abstain from voting on those topics. The trials were presented and discussed in detail before a consensus was reached about any possible classes of recommendations and levels of evidence to be assigned. For decades, HF with preserved ejection fraction (HFpEF) proved an elusive entity to treat. In a State of the Art Review article entitled ‘Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction’, Arjun Pandey from McMaster University in Hamilton, Ontario, Canada, and colleagues note that sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of HF hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials.5 While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux and to alter iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions of inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF. In a Viewpoint article entitled ‘REVIV(E)ing the ischaemic paradigm in heart failure: STICHes are needed’, Luis Rohde from the Universidade Federal do Rio Grande do Sul in Porto Alegre, Brazil and John McMurray from the University of Glasgow in the UK remind us that over recent decades, HF with reduced EF (HFrEF) has been transformed from a highly lethal disorder with a short life expectancy to a more chronic condition with much-improved quality and quantity of life.6 Most of these successful therapies modulate homeostatic systems that are deleteriously activated after an index insult to the heart. Despite unquestionable benefits, our therapeutic actions are primarily restricted to ameliorating the secondary consequences of reduced cardiac contractility. However, therapeutic strategies aimed at preventing recurrent direct myocardial injury, e.g. due to further coronary artery progression should also be a priority. Moreover, in patients with severe obstructive coronary artery disease (CAD), chronic myocardial hypoperfusion may cause or exacerbate left ventricular systolic dysfunction (hibernating myocardium), and this might be reversible with restoration of coronary blood flow. The logical extension of this conceptual framework, if correct, is that diagnosis and treatment of CAD should be central to the management of patients with HFrEF. Surprisingly, however, few randomized clinical trials have evaluated the efficacy and safety of coronary revascularization in patients with HFrEF. A third of patients with hypertrophic cardiomyopathy (HCM) have non-obstructive HCM (nHCM) without left ventricular outflow tract obstruction at rest or with provocation. In another Viewpoint article entitled ‘Beta-blockers in non-obstructive hypertrophic cardiomyopathy: time to ease the heart rate restriction?’, Adaya Weissler-Snir from the University of Connecticut Farmington in Connecticut, USA, and colleagues note that despite a paucity of evidence, beta-blockers are recommended in nHCM.7 In this contribution, the authors discuss emerging data that suggest that this guidance may lack a convincing rationale and may well be disadvantageous. Pulmonary hypertension is a complex disease.8–11 Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for HF (HHF). In a Fast Track Clinical Research article entitled ‘Efficacy of pulmonary artery pressure monitoring in patients with chronic heart failure: a meta-analysis of three randomized controlled trials’, Pascal Clephas from the Erasmus MC University Medical Centre in Rotterdam, Netherlands, and colleagues conducted a meta-analysis of large randomized trials investigating this question.12 A systematic literature search was performed for randomized clinical trials with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HHF. Treatment effects are expressed as hazard ratios (HR), and pooled effect estimates were obtained applying random effects meta-analyses. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II–IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean follow-up was 14.7 months, 68% of the patients were men, and 66% had an EF ≤ 40%. Compared with patients in the control group, the HR for total HHF in those randomized to PA pressure monitoring was 0.70 (0.58–0.86) (P = .0005). The corresponding HR for the composite of total HHF, urgent visits, and all-cause mortality was 0.75 and for all-cause mortality 0.92 (Figure 1). Subgroup analyses, including EF phenotype, revealed no evidence of heterogeneity in the treatment effect. The upper part of the figure shows the characteristics of the included RCTs at the sides, and the pulmonary artery sensor, patient electronics system, and the pulmonary artery pressure database in the middle. In the lower part of the figure, the x-axis presents the risk ratio, the y-axis presents the data points of clinical endpoints as addressed, the dot is the point estimate of the hazard ratio pooled estimate, and the bars correspond to the 95% confidence interval. CI, confidence interval; EF, ejection fraction; HR, hazard ratio; HF, heart failure; HFH, heart failure hospitalization; M, months; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PA, pulmonary artery.12 The authors conclude that the use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations. The contribution is accompanied by an Editorial by Christiane Angermann and Georg Ertl from the University and University Hospital Würzburg in Germany.13 The authors note that in contrast to previous meta-analyses on haemodynamic monitoring, in this meta-analysis only controlled randomized trials evaluating the CardioMEMSTM pulmonary arterial pressure (PAP) remote monitoring system were included. This commercially available technology uses a wireless implantable sensor powered externally by radiofrequency energy placed in a branch of the left pulmonary artery to transmit daily snapshot estimates of PAP to health-care providers, thus facilitating close remote patient management without the need for in-person visits, and timely dynamic adjustments of HF treatments as required. The authors of this Editorial also identify some limitations. No individual patient data were available from CHAMPION and GUIDE-HF, thus limiting the ability to assess interaction between variables. Even when combined for meta-analysis, the trials were underpowered to examine differences in mortality between the intervention and control groups, which, overall, included a high-risk population. Lastly, the trials were performed in the USA or the Netherlands at sites with structured disease management programmes run by multidisciplinary teams. Whether the meta-analysis findings can be reproduced in other health-care environments (in which regulatory agencies dictate different approaches to standard care for HF) remains to be determined in future studies, such as the PASSPORT-HF trial in Germany. Treatment of acute HF remains challenging.14–18 In the ADVOR trial, acetazolamide improved decongestion in acute decompensated HF (ADHF). In another Fast Track Clinical Research article entitled ‘Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial’, Evelyne Meekers from the Ziekenhuis Oost-Limburg AV in Genk, Belgium, and colleagues point out that whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear.19 This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. On admission, median estimated glomerular filtration rate (eGFR) was 40 (30–52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of HF hospitalizations and mortality (P-interaction = .467). In contrast decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805) (Figure 2). ADHF, acute decompensated heart failure; eGFR, estimated glomerular filtration rate; HFH, heart failure hospitalization; OR, odds ratio; WRF, worsening renal function.19 Meekers et al. conclude that acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes. The manuscript is accompanied by an Editorial by Héctor Bueno from the Universidad Complutense de Madrid in Spain and Milton Packer from the Baylor University Medical Center in Dallas, Texas, USA.20 The authors note that the new analyses presented by the ADVOR investigators raise additional questions. In the original ADVOR report, when all patients were considered in the analysis, the increases in cumulative urinary sodium excretion and total urinary volume were modest. In absolute terms, when compared with placebo, acetazolamide produced an increase in urinary sodium that averaged 97 mmol of excreted sodium and an increase in urinary volume of approximately half a litre over 2–3 days. Patients with physical signs of congestion (evident as meaningful peripheral oedema, ascites, and pleural effusion) have retained at least 5 litres of fluid. Therefore, resolution of the signs of congestion in ADVOR would have necessitated an incremental diuresis of at least 2.0–2.5 litres of urine, rather than the 0.5-litre treatment effect that was reported in ADVOR. The authors of this Editorial conclude that the effects of acetazolamide in patients with acute HF and congestion clearly require further study to fully understand the mechanisms responsible for the beneficial effects of acetazolamide. Gliflozins play a key role in the treatment of HF.21–27 In a meta-analysis entitled ‘Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis’, Mainak Banerjee from the Institute of Postgraduate Medical Education and Research in Kolkata, India, and colleagues investigate the cardiovascular effects of SGLT2 inhibitors with concomitant mineralocorticoid receptor antagonist (MRA) use in HF regardless of EF and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2 inhibitors vs. placebo.28 PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2 inhibitors in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Five eligible studies were included, pooling data from about 22 000 patients with HF. Compared with placebo, randomization to SGLT2 inhibitors showed a similar reduction in HHF/CVD and HHF in patients who were or were not using MRAs (HHF/CVD: HR 0.75 vs. 0.79, P-interaction = .43; HHF: HR 0.74 vs. 0.71, P-interaction = .53), with a suggestion of greater relative reduction of CVD in patients randomized to SGLT2 inhibitors and using MRAs (HR 0.81 vs. HR 0.98, P-interaction = .034). SGLT2 inhibitors reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints (P-interaction = .73) regardless of MRA. SGLT2 inhibitors attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. Banerjee et al. conclude that MRAs do not influence SGLT2 inhibitors beneficial effects on the composite of HHF/CVD, HHF, or all-cause mortality; notably findings hint at a more pronounced relative reduction of CVD in chronic HF patients regardless of EF who are randomized to SGLT2 inhibitors and receiving an MRA compared with those randomized to SGLT2 inhibitors and not receiving MRAs. SGLT2 inhibitors attenuate the risk of MRA-associated hyperkalaemia. The contribution is accompanied by an Editorial by Johann Bauersachs and Samira Soltani from Hannover Medical School in Germany.29 The authors note that based on the well-established reduction of mortality and HHF, MRAs need to be utilized in most patients with HF. The current meta-analysis provides additional data showing that there is a synergistic effect of both SGLT-2 inhibition and an MRA for prevention of CV death as well as hyperkalaemia, also for patients with reduced kidney function (eGFR < 60 mL/min/1.73 m2). In patients with contraindications for MRAs after careful consideration, SGLT-2 inhibitor use is nevertheless mandatory in HF irrespective of EF, as there was no significant interaction observed with MRA use regarding attenuation of total mortality, HHF, as well as adverse kidney endpoints by SGLT-2 inhibition. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Detailed safety analysis of DIAMOND trial: “primum non nocere”?’, Rui Baptista from the Centro Hospitalar de Entre o Douro e Vouga in Portugal, and colleagues comment on the recent publication ‘Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial’ by Javed Butler from the University of Mississippi in Jackson, MS, USA, and colleagues.30,31 Butler et al. respond in a separate comment.32 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.