Late breaking trials in heart failure

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 Fast Track Clinical Research article ‘Conventional heart failure therapy in cardiac ATTR amyloidosis’ by Adam Ioannou from the University College London, and colleagues.1 There is growing interest in amyloidosis mainly related to improved diagnosis and introduction of disease-modifying drugs.2–6 The authors assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional HF medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of HF medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57%, and mineralocorticoid receptor antagonists (MRAs) in 39% of cases. During a median follow-up of 28 months, 22% had beta-blockers discontinued, and 33% had ACEis/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77, P < 0.001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% (HR 0.75, P = 0.002). Treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% (HR 0.61, P = 0.002). No convincing differences were found for treatment with ACEis/ARBs (Figure 1). Discontinuation rates of heart failure medications in patients with cardiac ATTR amyloidosis. Kaplan–Meier curves comparing survival in patients treated with heart failure medications with propensity score-matched patients not treated with heart failure medications, followed by a Cox proportional hazards regression analysis. ACEi, angiotensin-converting enzyme inhibitor; ARBs, angiotensin II receptor blockers; MRAs, mineralocorticoid receptor antagonists; LVEF, left ventricular ejection fraction; HR, hazard ratio; CI, confidence interval.1 The authors conclude that conventional HF medications are currently not widely prescribed in ATTR-CA, and that those who receive these medications have more severe cardiac disease. Beta-blockers and ACEis/ARBs are often discontinued, but low-dose beta-blockers are associated with reduced risk of mortality in patients with an LVEF ≤40%. In contrast, MRAs are rarely discontinued and are associated with reduced risk of mortality in the overall population. The contribution is accompanied by an Editorial by Richard Cheng from the University of Washington in Seattle, WA, USA and Sarah Cuddy from the Brigham and Women’s Hospital in Boston, MA, USA.7 The authors note that to fully understand the role of neurohormonal (NH) blockade in ATTR-CA, we need to consider what we can do to move the field forward. Most importantly, this study serves as a call to action regarding the need for a randomized clinical trial of NH blockade in patients with ATTR-CA. Benefit may not be a ‘one size fits all’ and we will need to be selective about whom we treat. The current study suggests that benefit is most likely in those with LVEF ≤40% with beta-blockers and in all-comers with MRAs; additionally, if the benefit is from NH blockade, perhaps there will be a signal of benefit with low-dose ACEis/ARBs. In the interim, the authors recommend consideration of pragmatic trials with close collaboration between amyloid centres of expertise worldwide to expand the sample size and include a more diverse cohort. Such collaborations will be needed not only to evaluate conventional HF therapies, but also to assess more novel therapies that may have potential benefit in ATTR-CA, such as sodium–glucose co-transporter 2 (SGLT2) inhibitors, and address the unmet needs in the management of CA. Telemonitoring modalities in HF have been proposed as being essential for future organization and transition of HF care; however, efficacy has not been proven. In a Fast Track Clinical Research article entitled ‘Telemonitoring for heart failure: a meta-analysis’, Niels Scholte from the University Medical Centre Rotterdam in the Netherlands, and colleagues provide a comprehensive meta-analysis of studies on home telemonitoring systems (hTMS) in HF and the effect on clinical outcomes.8 A systematic literature search was performed in four bibliographic databases, including randomized trials and observational studies that were published during January 1996–July 2022. A random effects meta-analysis was carried out comparing hTMS with standard of care. All-cause mortality, first HF hospitalization, and total HF hospitalizations were evaluated as study endpoints. Sixty-five non-invasive hTMS studies and 27 invasive hTMS studies enrolled 36 549 HF patients, with a mean follow-up of 11.5 months. In patients using hTMS compared with standard of care, a significant 16% reduction in all-cause mortality was observed [pooled odds ratio (OR) 0.84], as well as a significant 19% reduction in first HF hospitalization (OR 0.81) and a 15% reduction in total HF hospitalizations (pooled incidence rate ratio 0.85). Scholte et al. conclude that these results are an advocacy for the use of hTMS in HF patients to reduce all-cause mortality and HF-related hospitalizations. Still, the methods of hTMS remain diverse, so future research should strive to standardize modes of effective hTMS. The contribution is accompanied by an Editorial by Friedrich Koehler and Gerhard Hindricks from the Deutsches Herzzentrum der Charité (DHZC) in Berlin, Germany.9 The authors note that the results of the primary endpoint of the 73 telemedicine randomized controlled trials included in the meta-analysis are exceedingly heterogeneous. There are four main reasons that may help to explain the heterogeneity of study outcomes in the primary study endpoints of telemonitoring studies. (i) Communication pathways: in contrast to drugs that act directly on the pathogenesis of the disease, e.g. via receptor blockade, telemonitoring is a digital care intervention whose effects are strongly influenced by communication processes and interactions between the caregiver and patient. (ii) Patient selection: of all HF patients, only certain subpopulations may benefit from telemonitoring. (iii) Technology: the telemedical sensor technologies used differ significantly with respect to the type of signal obtained remotely and the usefulness of the signal to guide/improve therapy. (iv) Time to intervention: one critical factor for the clinical effectiveness of telemonitoring to affect the endpoints of hospitalization and death in HF is the speed at which transmitted diagnostic information is translated into medical action by the caregiver. Gliflozins play a key role in the treatment of HF.10–16 In another Fast Track Clinical Research article entitled ‘Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial’, Safia Chatur from Harvard Medical School in Boston, MA, USA, and colleagues indicate that dapagliflozin reduces the combined risk of worsening HF or cardiovascular death among patients with HF with mildly reduced or preserved ejection fraction.17 In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. The effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg. Of the 6263 randomized patients, 10.9% were on no diuretic, 12.3% were on a non-loop diuretic, and 76.8% were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (P-interaction = 0.64) or loop diuretic dose (P-interaction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% (HR 0.68, P < 0.001) but did not influence discontinuations/disruptions (HR 0.98, P = 0.83) during follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of −6.5% (P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of −2.5 mg/year, P < 0.001). The authors conclude that in patients with HF with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo are consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduces new loop diuretic requirement over time. The contribution is accompanied by an Editorial by Barry Borlaug from the Mayo Clinic in Rochester, MN, USA and Jeffrey Testani from Yale University in New Haven, CT, USA.18 The authors note that the proximal tubular location of SGLT2 probably drives the paradox observed in trials such as DELIVER, where a diuretic/diuretic-sparing effect is seen, without the downsides of a drug that induces a diuretic/diuretic-sparing effect. It is as if the drug is working by making the kidney operate more ‘normally’ in handling sodium, rather than the ‘brute-force’ addition of a second diuretic such as a thiazide. Blocking a large amount of sodium reabsorption in the proximal nephron probably provides this opportunity by (i) increasing delivery of salt-rich fluid to salt-sensing elements spanning the entire remainder of the nephron, and (ii) having the entire remainder of the nephron available to compensate and reabsorb this salty fluid (if required). For example, enhanced sodium chloride delivery to the macula densa results in a relative suppression of renin–angiotensin–aldosterone system activation and other compensatory mechanisms, but this salt and fluid then traverse the remaining nephron segments to undergo compensatory reabsorption as needed, avoiding overdiuresis. The role of NT-proBNP in patients receiving high intensity care (HIC) after hospital admission for acute heart failure. This analysis from the STRONG-HF trial includes 1077 patients. The treatment effect of a HIC strategy vs. usual care (UC) reduced the primary endpoint regardless of baseline NT-proBNP concentrations. In the 542 patients included in the HIC group, an increase in NT-proBNP levels was associated with a poorer outcome up to 90-day follow-up, but not at 180 days. CI, confidence interval; HF, heart failure; HR, hazard ratio; NT-proBNP, N-terminal probrain natriuretic peptide.19 STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared with usual care in patients hospitalized with acute HF. In a Fast Track Clinical Research article entitled ‘NT-proBNP and high intensity care for acute heart failure: the STRONG-HF trial’, Marianna Adamo from the University of Brescia in Italy, and colleagues assessed the role of N-terminal probrain natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration.19 A total of 1077 patients hospitalized for acute HF and with a > 10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge) were included. Patients receiving HIC were stratified by further NT-proBNP changes, from randomization to 1 week later, as decreased (≥30%), stable (<30% decrease to ≤10% increase), or increased (>10%). The primary endpoint was 180-day HF readmission or death. The benefit of HIC vs. usual care was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months, they reached 70.4% optimal GRMT doses, compared with 80.3% for those with an NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs. 2.2% and 4.0% in those with decreased NT-proBNP (P = 0.039 and P = 0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; P = 0.93) (Figure 2). The authors conclude that among patients with acute HF enrolled in STRONG-HF, HIC reduces 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge, utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate, results in the same 180-day outcomes regardless of early post-discharge NT-proBNP change. The contribution is accompanied by an Editorial by Antoni Bayes-Genis from the University Hospital Germans Trias i Pujol in Badalona, Spain, and Domingo Pascual-Figal from the Instituto de Salud Carlos III from Madrid, Spain.20 The authors highlight that it is crucial to ensure that patients with HF receive the best possible medical treatment. Making the transition period STRONGer by monitoring NT-proBNP can give clinicians the confidence they need to titrate GDMT at the appropriate pace for each patient. In a Fast Track Congress article entitled ‘Dapagliflozin versus metolazone in heart failure resistant to loop diuretics’, Su Ern Yeoh from the University of Glasgow, UK, and colleagues examine the decongestive effect of the SGLT2 inhibitor dapagliflozin compared with the thiazide-like diuretic metolazone in patients hospitalized for HF and resistant to treatment with intravenous furosemide.21 The authors undertook a multicentre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5–10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. A total of 61 patients were randomized. The mean cumulative dose of furosemide at 96 hours was 976 mg in the dapagliflozin group and 704 mg in patients assigned to metolazone. The mean decrease in weight at 96 hours was 3.0 kg with dapagliflozin compared with 3.6 kg with metolazone (P = 0.11). Loop diuretic efficiency was similar with dapagliflozin and with metolazone. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. The authors conclude that in patients with HF and loop diuretic resistance, dapagliflozin is not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. The contribution is accompanied by an Editorial by Pieter Martens from Cleveland Clinic in New York City, USA.22 Martens notes that this trial does seem to challenge the current dogma that thiazides are the superior agents as first add-on choice on top of loop diuretics, rejuvenating the question of how to use combinational diuretics best. With SGLT2 inhibitors being a well-established disease-modifying therapy that will probably be prescribed and continued throughout the AHF admission, the incremental diuretic effects of SGLT2 inhibitors becomes a moot point as they should be prescribed regardless of the effects on diuretic responsiveness. Different diuretics might have different goals. Acetazolamide as an upfront agent lowers the loop diuretic threshold to invoke natriuresis with several theoretical by which it can the of loop diuretic can diuretic if loop diuretics a dose but at the of of a after the of loop diuretics, and we are to understand how to use these agents in to and diuretic in patients with acute HF. play a key role in the treatment of The trial demonstrated in natriuretic with compared with in patients with HF with mildly reduced or preserved ejection fraction who had a worsening HF but was not to examine clinical In a Fast Track Congress article entitled in heart failure with mildly reduced or preserved ejection fraction: a pre-specified analysis of and from Harvard Medical School in Boston, MA, USA, and colleagues point out that included a of patients who were hospitalized for from and were to better the efficacy and safety of in cardiovascular and renal events in HF with mildly reduced or preserved ejection and were multicentre, randomized, trials of vs. in patients with HF with mildly reduced or preserved LVEF in and in In the pre-specified primary the authors in of whom were enrolled during or days of a worsening HF with a of hospitalized for HF The authors also the entire and for a The primary endpoint for this analysis was the composite of total worsening HF events first and HF hospitalizations and and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for studies in rate from renal disease, or renal with significantly reduced total worsening HF events and cardiovascular death in the primary analysis of with worsening HF = rate ratio P = and in the analysis of all = P = In the analysis of all first was reached by day after and treatment benefits were larger in those with LVEF compared with those with LVEF = was also associated with rates of the renal composite endpoint in the primary analysis (HR P = and the analysis of all (HR P = 0.002). The authors conclude that in of and reduce cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection provide for use of in patients with HF with mildly reduced or preserved ejection fraction, among those with an LVEF regardless of care The is accompanied by an Editorial by from Clinical Research in USA and from the University of Medical The authors note that the of as having incremental efficacy over in a population of patients with HF and ejection fraction the current analysis from et al. the where the of the therapy will be at the current time. of worsening HF are a consistent of associated with of hospitalization, and one can that patients with HF are across the and should be treated with a of patients with are at the and where of and hospitalizations. SGLT2 inhibitor is the therapy for all patients with mildly reduced or preserved ejection fraction, including those with or without a where do we in the treatment use of can be among all patients with HF and ejection fraction it can be and among those with ejection fraction and In a Clinical Research article entitled in patients with heart failure and reduced or preserved ejection from the University of Glasgow, UK, and colleagues that is an in patients with HF, but the between the is across the range of ejection The of of and related outcomes were in patients with HF in an meta-analysis of clinical trials patients with HF with reduced or preserved ejection Of the patients with reduced ejection fraction, 8.3% had a of and of the patients with preserved ejection fraction, had a of of ejection fraction, patients with a of had more and worse HF. those with reduced ejection fraction, the incidence of the composite of cardiovascular HF hospitalization, or was per in those with vs. in those without (HR P < 0.001). The rates in patients with preserved ejection fraction were and (HR P < 0.001). of the composite was more frequent in patients with and the risk of future was in patients with patients with with were not and with were not The authors conclude that HF patients with a of are at high risk of cardiovascular and of guideline-recommended might be a to outcomes in this population. The contribution is accompanied by an Editorial by and from The authors point out that the of et al. not only the that a risk in patients with HF with reduced ejection fraction, by that ejection fraction may be an to the risk of in HF, but they also about the role of HF in HF with reduced or preserved ejection fraction may to risk factor rather than as a of studies will help the question of secondary can be to the cardiac The is also by In a entitled call for in from the University of in the and from Research Hospital in USA on the on in collaboration with the the for and and the by the on of the of of the and in a The that this of the Heart will be of interest to its from the With to and for help with of this