Factors Associated With Loop Diuretic De-escalation in Patients With Acute Decompensated Heart Failure: The Influence of Guideline Directed Medical Therapy Initiation.

Use of loop diuretics in chronic heart failure: do we adhere to the Hippocratian principle 'do no harm'?

‘The road goes ever on and on, Down from the door where it began’. J.R.R. Tolkien The treatment of chronic heart failure has significantly improved over the last decades, with the introduction of beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists and the most recent addition of angiotensin receptor–neprilysin inhibition.1 This however cannot be said for the treatment of acute heart failure (AHF). Since the introduction of loop diuretics in the 1960s, they are the first-choice drug for the treatment of volume overload in AHF.2 Multiple studies have investigated different treatment strategies or modalities since, but they all failed to show decongestive or prognostic benefit. Several reasons for this have been suggested (Figure 1). First, the drugs studied might not have exhibited the desired pharmacological effects, despite positive signals in phase II trials. Second, the enrolled population, which were mostly AHF all-comers, could have contributed to neutral findings as (i) patients with other diagnoses causing dyspnoea may have also been enrolled, resulting in a mixed population in which part of the population was unlikely to benefit from the studied drug, and/or; (ii) add-on therapies to loop diuretics may not be necessary in diuretic naïve patients, or patients with a good diuretic response during the first 24 h, as these are most likely to respond well to therapy and will already exhibit a lower event rate. As such the additional effect of a novel therapy could be hampered by the law of diminishing returns. Third, the endpoints used in these trials might have contributed to neutral findings. In most trials hard clinical endpoints, such as reduction in 180-day mortality, were used. However, the expectation of a beneficial effect on such endpoint could be considered a stretch, as these drugs are often only administered during the first hours/days of an AHF hospitalization to improve decongestion. Therefore, a long-term effect beyond this time period might be unlikely. Other AHF studies have used softer, intermediate endpoints (such as improvement in dyspnoea scores, or clinical congestion), or combined endpoints of improved clinical outcome and no worsening of renal function. These endpoints have the limitations that they are notoriously difficult to assess objectively, and are hindered by several factors, such as high inter-observer variability. Finally, worsening renal function in the context of a good diuretic response has recently been suggested to be associated with improved outcomes, and could therefore also be an ambiguous endpoint to use in this setting.3 Therefore, a different approach to the study of ‘novel’ drugs in AHF is warranted. In this issue of the Journal, Verbrugge et al.4 have studied the effect of acetazolamide on natriuresis in AHF patients at high risk for diuretic resistance. In this study, 34 AHF patients admitted for decongestive treatment were enrolled. All patients had to be on an outpatient maintenance dose of loop diuretic, and had to have at least one high-risk criteria for poor diuretic response, e.g. hyponatraemia, elevated blood urea nitrogen to creatinine ratio, or worsening renal function at admission. After enrolment patients were randomized to acetazolamide on top of low-dose diuretics vs. high-dose diuretic stand-alone therapy. Even though patients randomized to acetazolamide received lower doses of loop diuretics, natriuresis after 24 h in this group was similar compared with the high-dose diuretic group, and loop diuretic efficiency (natriuresis adjusted for loop diuretic dose) was significantly better in the acetazolamide group (P = 0.048). There was however a significant increase in the incidence of worsening renal function (increase in serum creatinine > 26.5 μmol/L (0.3 mg/dL)) in the acetazolamide group. Based on these findings, the authors conclude that combination diuretic therapy of acetazolamide and loop diuretics increases the natriuretic response to loop diuretics in AHF patients at high risk for a poor diuretic response. The concept, design and results of this small study are interesting. Despite the fact that several comments can be made, e.g. the small sample size, the fact that the authors were unable to randomize the intended number of patients, only two centres enrolled patients, and that the study was not blinded, several lessons can be taken from this study (Figure 1). First, the drug under investigation in this trial is acetazolamide, a carbonic anhydrase inhibitor. Looking at the physiology of sodium reabsorption in the kidney, this occurs across all segments of the tubule, yet in AHF we only target the reabsorption in the loop of Henle.5 Acetazolamide stimulates alkaline diuresis through bicarbonate excretion with sodium and potassium by inhibiting carbonic anhydrase in the proximal tubule.2, 6 In heart failure, up to 80% of sodium is reabsorbed in the proximal tubule, and this occurs before loop diuretics even have a chance to exert their action.6 Based on this, a drug inhibiting sodium reabsorption in the proximal tubule is likely to improve natriuresis by a direct effect proximally and by improving the efficacy of loop diuretics in the loop of Henle. Prior to the findings of the study by Verbrugge et al., several small studies already found an effect of add-on acetazolamide therapy to loop diuretics on natriuresis. The current study confirms that add-on therapy with acetazolamide significantly improves loop diuretic efficiency. Interestingly, sodium–glucose co-transporter 2 (SGLT2) inhibitors have also been suggested to improve natriuresis by inhibiting proximal sodium absorption.6 Studies investigating the effect of add-on SGLT2 inhibitors to loop diuretics in AHF patients are currently ongoing. Second, the authors intentionally enrolled patients at high risk of diuretic resistance. An impaired response to diuretics is common in patients with AHF, and strongly associated with poor outcomes.2 Predictors of a poor response to diuretics are for instance poorer renal function, higher blood urea nitrogen, and lower plasma sodium levels.7 Exactly these characteristics have been selected by the authors to identify patients at an increased risk of a poor diuretic response in which addition of acetazolamide is more likely to have an additional effect. Furthermore, the primary endpoint in this study was natriuresis. From a pathophysiological perspective assessing natriuresis to determine the effectiveness of diuretics in the setting of AHF seems very logical, however until recently studies using natriuresis in AHF were scarce. Hodson et al.8 showed that poor natriuresis, even in the setting of a negative fluid balance, was associated with poor outcomes, suggesting that natriuresis is a more sensitive marker of decongestion than fluid loss. Additionally, even though urine collections are considered cumbersome, assessment of natriuresis might be more reliable and objective than net fluid loss or weight change. Possibly in the future assessment of natriuresis could be performed using spot urine samples, as one study has already shown fairly accurate prediction of 6 h natriuretic response to diuretics using spot urine samples collected 1 and 2 h after administration of diuretics.9 In the recent position statement on diuretics of the Heart Failure Association of the European Society of Cardiology, assessment of natriuresis in spot urine samples is recommended 2 h after the first administration of loop diuretics, based on which adjustment of diuretic doses should be considered.6 Finally, in the study by Verbrugge et al.,4 assessment of clinical congestion was performed by the same investigator and increases in diuretic doses in both groups were standardized based on the persistent presence of congestion and poor urine output. Despite this, only 30% of patients were considered euvolaemic after 72 h. These rates are slightly better than the number observed in the DOSE trial (11–18%), however still remain poor.10 This once again underscores the importance of additional studies assessing novel treatment strategies in AHF patients to improve decongestion. At the moment a large, multicentre, randomized controlled trial assessing the effect of acetazolamide in acute decompensated heart failure with volume overload on decongestion (ADVOR) is ongoing.11 In contrast to the paper published in this issue of the Journal, the ADVOR trial enrols all-comer AHF patients, and the primary endpoint is euvolaemia at day 4 as assessed by a clinical congestion score by local investigators. Despite these possible shortcomings, the results of this trial are eagerly awaited. An updated approach to the design of AHF trials concerning the points raised, i.e. the drugs studied, patients enrolled, study design, and endpoints, will hopefully lead to alternative roads down the door from loop diuretics (Figure 1). Acetazolamide could very well become an important additional player in the treatment of (diuretic resistant) AHF patients in the coming years. Until we are better able to adequately treat these patients and improve outcomes, the search for novel therapies in AHF goes ever on and on. Conflict of interest: none declared.

The complexity of diuretic resistance.

Introduction: Guideline-Directed Medical Therapies (GDMT) are evidence-based treatments recommended by clinical practice guidelines for the management of Cardiovascular Diseases (CVDs). While GDMT is foundational for treating Heart Failure (HF), its adoption promotes uniform, evidence-driven practices across various cardiovascular conditions. This therapy includes drug classes such as Beta-Blockers (BB), AngiotensinConverting Enzyme inhibitors, Angiotensin-Receptor Blockers, and Angiotensin Receptor-Neprilysin Inhibitors (ACEi/ARB/ ARNI), Mineralocorticoid Receptor Antagonists (MRAs), and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i). Implementing GDMT can enhance cardiac function, improve quality of life and reduce hospitalisation and mortality risks. Aim: To understand the preferences of drug choice among Indian Healthcare Practitioners (HCPs) regarding the adaptation of GDMT in CVD management. Materials and Methods: A cross-sectional, questionnairebased study was conducted in India from December 2022 to March 2023. Participants (n=93) included cardiologists, electrophysiologists and cardiophysicians, who were actively involved in managing CVD. A predefined questionnaire consisting of seven questions, developed from existing literature, guidelines and expert opinions, was used. Responses were digitally analysed, with descriptive statistics presented as numbers and percentages. Results: For hypertension management in Acute Coronary Syndrome (ACS), telmisartan (60.22%) was the most preferred ARB, followed by metoprolol (48.39%; BB), amlodipine (39.78%; Calcium Channel Blockers [CCB]), and torsemide (32.26%; diuretics). For patients with diabetes and ACS, SGLT2i (89.29%) were favoured. Clopidogrel (56.99%) was the preferred oral antiplatelet drug alongside aspirin in ACS. In Acute Decompensated HF (ADHF), the preferred sequential addition of GDMT includes loop diuretics (44.74%) as the first choice, followed by ARB, SGLT2i, and MRAs as subsequent choices. One in four HF patients was on ARNI (37.36%) and SGLT2i (35.62%), while three in four HF patients were on BB (36.99%) and ACEi/ARBs (34.28%). In HF patients on loop diuretics and MRAs, the preferred doses were torsemide 10 mg with spironolactone 25 mg (57.32%) and torsemide 10 mg with spironolactone 50 mg (37.80%). In addition to symptomatic treatment with loop diuretics in HF patients, 72.50% of HCPs preferred ARNI, and 35.0% preferred ARBs as combination therapy. Conclusion: ARBs and BBs were preferred for hypertension in ACS, while SGLT2i were favoured for diabetes. Clopidogrel was the most popular P2Y12 inhibitor in ACS. For HF, HCPs favoured sequential therapy, with loop diuretics and ACEi/ARBs as the first and second choices and preferred combinations of ARNI or ARBs with loop diuretics for symptomatic HF.

Recent Trends in the Incidence, Treatment, and Prognosis of Patients With Heart Failure and Atrial Fibrillation (the Worcester Heart Failure Study)

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

IntroductionCardiovascular disease is the most common cause of death worldwide (1). Heart failure is a major contributor to this (2), with mortality rates particularly high in those hospitalised due to...

Background: The association of prior to admission guideline-directed medical therapy (GDMT) with outcomes among patients hospitalized with Heart Failure with Reduced Ejection Fraction (HFrEF) and COVID-19, as well as overall GDMT prescription patterns during the pandemic, is not well known. Methods: HFrEF patients (left ventricular ejection fraction ≤40%) admitted with acute decompensated heart failure (ADHF) were identified from the American Heart Association’s Get With The Guidelines Heart Failure Registry. We analyzed the association of prior to admission GDMT use with odds of in-hospital mortality, and with odds of severe COVID-19, using adjusted logistic regression models. GDMT was defined as prescription of angiotensin converting enzyme inhibitor/angiotensin II receptor blocker/angiotensin receptor-neprilysin inhibitor (ACEI/ARB/ARNI), beta blocker (BB), or mineralocorticoid receptor antagonist (MRA). We further evaluated GDMT prescription trends during the pandemic. Results: We identified 23,899 HFrEF patients admitted with ADHF (2/16/20-3/24/21) during the pandemic, of which 333 had a diagnosis of COVID-19. We also identified 26,459 HFrEF patients admitted with ADHF in the year prior to the pandemic (2/16/19-2/15/20). Prior to admission ACEI/ARB/ARNI, BB, or MRA use was not associated with odds of in-hospital mortality or severe COVID-19. Among all HFrEF patients, prior to admission ACEI/ARB/ARNI and BB use was lower during the pandemic compared to the year prior (Figure 1, Panel A). Prior to discharge prescription of ACEI/ARB/ARNI, MRA, and triple therapy (ACEI + BB + MRA) was higher during the pandemic compared to the year prior (Figure 1, Panel B). Conclusion: Among patients with HFrEF admitted with ADHF and COVID-19, prior to admission GDMT use was not associated with in-hospital mortality or severe COVID-19. GDMT prescription rates at discharge were similar to or improved during the pandemic compared with the preceding year.

Heart failure treatment and the art of medical decision making.

Background: Diuretic administration is a cornerstone of acute decompensated heart failure (ADHF) treatment. Prior research suggest that delays in initial therapy in the emergency department may be linked to higher risk of in-hospital mortality, but this has not been examined in large contemporary cohorts and in the context of guideline directed medical therapy (GDMT). Methods: We analyzed ADHF hospitalizations from 2013-2020 across two large health systems in New York (University of Rochester) and Texas (Baylor, Scott&White). Inclusion criteria were age ≥18, a primary diagnosis of ADHF, and intravenousbadministration of loop diuretics within 16 hours of admission. Door-to-diuretic (D2D) time was calculated in hours as the time between hospital arrival and administration of the first IV loop diuretic. The primary outcome was in-hospital mortality. We fit a logistic regression (LR) model adjusting for gender, number of hospital beds, and Get With the Guidelines-HF (GWTG-HF) risk score. Subgroup analysis for patients with EF ≤ 35% included GDMT score (ACE/ARB/ARNI, beta-blocker, mineralocorticoid receptor antagonist, SGLT2 inhibitor, 1 point for each). We fit a Kaplan-Meir curve for time-to-event analysis and visualized survival by D2D quartiles. Analyses were performed in R (version 4.4.0)with p<0.05 set for significance. Results: Our cohort included 14,448 patients (52.2%, n = 7,544 female; 78.0%, n = 11,268 White; 92.4%, n = 13,356 non-Hispanic) with a mean age of 72.9 ± 14.2 years. D2D time was 8.7 ± 4.7 hours, with only 2.1% (n = 308) of patients receiving diuretics within the first hour. In the LR model, each additional hour of D2D time was associated with a 3.8% increase in the odds of in-hospital mortality (OR = 1.038, 95% CI: 1.024-1.053, p < .001). Patients in the fastest quartile of D2D time had the highest survival probability across the hospital stay (p < .01; Figure 1). Sensitivity analysis in the EF ≤ 35% subgroup confirmed that D2D time remained a significant predictor of in-hospital mortality (OR = 1.064, 95% CI: 1.026-1.106, p = .001) despite GDMT use. Conclusion: Shorter D2D time is associated with lower in-hospital mortality in ADHF, after adjusting for clinical risk and hospital-level factors. While the effect size per hour is modest, cumulative delays may meaningfully increase mortality risk. These findings support prioritizing early IV diuretic initiation in ADHF care, and a prospective trial is warranted.

Guideline-directed medical therapy (GDMT) is recommended for all patients with heart failure with reduced ejection fraction (HFrEF). Despite this, little data exist describing GDMT use in diverse, real-world populations including the use of vasodilators, prescribed primarily to Black populations. We sought, among a diverse population of HFrEF patients, to determine (1) GDMT use rates and target dosing by medication class and (2) predictors of GDMT use and target dosing by medication class. We utilized electronic health records (EHRs) from Kaiser Permanente (KP) Mid-Atlantic States, a large integrated health system. Included patients had heart failure and left ventricular ejection fraction (EF) of ≤40% between 2015 and 2021. GDMT was defined by five medication classes-angiotensin-converting enzyme (ACE) inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors (ARNis), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is) and vasodilators (Black patients only). Proportions of patients on GDMT and target dose rates were examined. Logistic regression determined, within each class, predictors of medication use and being at ≥80% of the target dose. A total of 3154 patients were included. Among the 93.8% on some form of GDMT, 82.8%, 81.4%, 23.5%, 3.6% and 13.4% were on ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators (Black patients only), respectively. Among treated patients, 45.8%, 21.4%, 77.6%, 100% and 14.7% were treated at ≥80% of the target dose for ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators, respectively. Overall, increasing age, higher EF, atrial fibrillation/flutter, chronic obstructive pulmonary disease (COPD), prior stroke and dementia were associated with decreased odds of GDMT use. Conversely, higher body mass index (BMI), Black race, higher glomerular filtration rate (GFR), recent echo and cardiac defibrillator were associated with increased odds of GDMT use. Among treated, higher BMI, higher systolic blood pressure, haemoglobin A1C≥6.5% and cardiac defibrillator were associated with higher odds of being at ≥80% of the target dose. Our study using real-world data from a diverse health system demonstrated gaps in GDMT use among patients with HFrEF, specifically older patients with more comorbidities.

Background Heart failure with reduced ejection fraction (HFrEF) requires adherence to guideline-directed medical therapy (GDMT) for optimal outcomes. This study aimed to assess GDMT adherence at a teaching hospital and compare discharge prescriptions by residents and attending physicians. Methods A retrospective cohort study was conducted at Spring Valley Hospital from August 2023 to March 2024. Patients with HFrEF and decompensated heart failure as the primary reason for admission were identified through electronic health records. Adherence to GDMT at discharge was evaluated based on 2022 American Heart Association (AHA) guidelines, focusing on beta-blockers (BB), angiotensin receptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). The primary outcome was comparing GDMT adherence between residents and attending physicians. Secondary outcomes included adherence to individual medications, combination regimens, and reasons for non-adherence. Results Among 243 patient charts reviewed, 80 met inclusion criteria (33 residents, 47 attendings). Adherence to beta-blockers was significantly higher than to other GDMT medications (p<0.0001). Residents showed slightly higher adherence to BB, MRA, and SGLT2i, though differences were not statistically significant. Double and triple therapies were prescribed more often than quadruple therapy (p=0.002, p=0.01). Residents demonstrated higher adherence to double therapy with BB and MRA (55% vs. 28%, p=0.02). Conclusion Adherence to GDMT for HFrEF was comparable between residents and attending physicians. Improving adherence to key medications can further enhance HFrEF management and patient outcomes.

Biomarkers represent useful tools in the management of patients with heart failure (HF). 1-3 Antigen carbohydrate 125 (CA125) is a novel marker of congestion, inflammation and right-sided HF. It emerged as an affordable and widely available tool for tailoring HF therapies and prognostic stratification, since high serum levels are associated with an increased risk of death and HF hospitalization.4 The role of cardiac troponin in HF is well-established.5 In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), increasing levels of high-sensitivity cardiac troponin T (hs-cTnT) were associated with higher rates of comorbidities (i.e. diabetes and atrial fibrillation), more advanced New York Heart Association functional class, decreased renal function, higher concentrations of natriuretic peptides and worse clinical course. However, empagliflozin reduced the primary endpoint of cardiovascular death or HF hospitalization, regardless of baseline hs-cTnT levels,6 confirming the role of sodium–glucose co-transporter 2 (SGLT2) inhibitors as an essential treatment for patients with HF with reduced ejection fraction (HFrEF).7-9 Sex-based differences exist among patients with HF.10, 11 In the Effects of High-Dose versus Low-Dose Losartan on Clinical Outcomes in Patients with Heart Failure (HEAAL) trial, women appeared to respond similarly to low and high doses of losartan, whereas men had more benefits with high doses. However, women were older compared with men and more frequently presented severe symptoms and renal dysfunction.12 Sex differences were also investigated in the Patient-centered Care Transitions in Heart Failure: A Pragmatic Cluster Randomized (PACT-HF) study, enrolling 986 patients with the aim to test the effect of a patient-centred transitional care model. Such model improved discharge preparedness, transition quality, and the health-related quality of life both at 6 weeks and 6 months, with no differences between men and women. Women had a lower quality of life score at discharge, but experienced more benefits from treatment compared with men.13 Dietary interventions are related to HF incidence and outcome.14, 15 A meta-analysis, including 122 randomized controlled trials and 176 097 participants, summarized and confirmed the impact of nutritional and dietary interventions on HF-related outcomes. In particular, coenzyme Q10 was associated with lower all-cause mortality, whereas Mediterranean diet was related with a lower risk of developing HF.16 Ergoreflex is a cardiorespiratory reflex activated during physical effort. HF patients often develop skeletal myopathy,17 which is associated with increasing ergoreflex sensitivity and dyspnoea on effort. Exercise training represents a valuable strategy to reduce such sensitivity and increase exercise tolerance.18 Among the quality of life measures tested in the PARALLAX trial (a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure with mildly reduced and preserved ejection fraction), the Short Form Health Survey-36 physical functioning score was the most closely correlated with 6-min walk test (6MWT). A modest correlation was found between 6MWT and Kansas City Cardiomyopathy Questionnaire clinical summary score. Many factors were associated with worse values in both quality of life and exercise capacity (i.e. female sex, higher body mass index, higher levels of N-terminal pro-B-type natriuretic peptide and coronary artery disease).19 Adherence to guideline-directed medical therapy (GDMT) improves outcome in patients with HFrEF.20, 21 However, GDMT remains suboptimal in a large proportion of patients.22 A recent multinational observational study confirmed strong patterns of GDMT low-titration in HF patients. Target dose of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers, beta-blockers, and angiotensin receptor–neprilysin inhibitors, was achieved in 15%, 10%, 12%, and 30% of patients, respectively. An early discontinuation of therapy was frequently observed, with ACEi being the most withdrawn agent (55% at 12 months), followed by mineralocorticoid receptor antagonists (MRA) (40% at 12 months).23 Bhatt et al.24 evaluated the effects of both sacubitril/valsartan and enalapril on co-prescribed beta-blockers and MRA in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HH) trial. Sacubitril/valsartan did not influence beta-blocker treatment nor MRA initiation, but led to fewer MRA discontinuation compared to enalapril. The coronavirus disease 2019 (COVID-19) pandemic represented a great burden for the HF community.25-30 Management of heart transplant recipients require even tighter precautionary measures in this historical era.31 In a prospective single centre cohort study, including heart transplant recipients, short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has been evaluated. Only 15% of patients displayed the presence of anti-spike IgG antibodies after the first dose, and a total of 49% responded to the full two-dose vaccine schedule. Older age and anti-metabolite-based immunosuppression were associated with lower immunogenicity.32

To assess ethnic disparities in 90-day outcomes among patients hospitalized with acute decompensated heart failure (ADHF), and in the use of guideline-directed medical therapy (GDMT) among those with heart failure with reduced ejection fraction (HFrEF). This retrospective cohort study included patients hospitalized with ADHF at a medium-sized health system between January 2018 and May 2024. Primary outcomes were 90-day mortality and readmission. Among patients with HFrEF, GDMT use was assessed as a secondary outcome. Multilevel logistic regression was used to evaluate associations between ethnicity and outcomes. A total of 14,644 patients with ADHF were included. No significant differences were observed in 90-day mortality (OR 0.69, 95% CI 0.21-2.24, P = 0.540) or 90-day readmission (OR 0.78, 95% CI 0.51-1.19, P = 0.267) between Hispanic and non-Hispanic patients. Among HFrEF patients, Hispanic patients had higher odds of receiving beta blockers (OR 1.32, 95% CI 1.04-1.68, p = 0.023), mineralocorticoid receptor antagonists (OR 1.37, 95% CI 1.05-1.79, p = 0.021), and renin-angiotensin system blockers (OR 1.51, 95% CI 1.17-1.95, p = 0.002). In contrast, no significant difference was observed in the use of sodium-glucose cotransporter-2 inhibitors between the two groups (OR 1.67, 95% CI 0.69-4.05, p = 0.254). Additionally, patients with Medicare (OR 0.65, 95% CI 0.57-0.74, p < 0.001) or unspecified insurance (OR 0.18, 95% CI 0.11-0.28, p < 0.001) had lower odds of receiving GDMT compared to self-pay patients. This study reveals a counterintuitive pattern of higher GDMT use among Hispanic HFrEF patients, underscoring the need to leverage community-based resources and patient assistance programs to address disparities. Further prospective studies are needed to confirm these findings or policy changes to reduce insurance-related barriers to GDMT.

The optimal timing for prescribing guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) during acute decompensated heart failure (ADHF) remains uncertain. This study evaluated the real-world impact of early in-hospital quadruple GDMT prescription in ADHF patients with HFrEF. In this retrospective cohort study using the Institutional aCute descompensAted heaRt failUre regiStry (ICARUS), we analysed 2051 HFrEF patients (71% male, median age 68years) hospitalized for ADHF between June 2022 and March 2024. Early quadruple therapy was defined as the prescription of beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) within 48h of admission. Among included patients, 898 (43.8%) received early quadruple therapy. Using optimal full matching propensity score methodology, early quadruple therapy was associated with lower 30day mortality/rehospitalization [relative risk (RR) 0.73; 95% confidence interval (CI) 0.55-0.97, P=0.028], reduced in-hospital mortality (RR 0.29; 95% CI 0.15-0.56, P<0.001) and shorter hospital stay (β=-2.65days; 95% CI -3.67 to -1.63, P<0.001). Patients receiving early quadruple therapy showed higher rates of GDMT continuation at discharge (RR 3.82; 95% CI 3.01-4.86, P<0.001). In this HFrEF cohort, early initiation of comprehensive GDMT during ADHF hospitalization was associated with improved clinical outcomes. Future randomized trials including patients across the full spectrum of ejection fraction are needed to validate these findings and determine their applicability to other heart failure phenotypes.