Search

The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229) [Display omitted] [ABSTRACT FROM AUTHOR]

• Inotrope formulations avoiding the burdens of continuous IV infusion are needed. • We tested a novel, concentrated formulation of milrinone for inhalation. • Nebulized milrinone was well tolerated and without adverse events. • Intermittent inhalation of milrinone produced therapeutic serum concentrations. • Nebulized milrinone improved invasive hemodynamic parameters. Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17–66) ng/mL and a median peak concentration of 207 (134–293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%–65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2–2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF. [ABSTRACT FROM AUTHOR]

Aims: Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness. Methods and results: We conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol‐derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03–35.89] vs. 29.70 [18.19–34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 μg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005). Conclusions: Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery. [ABSTRACT FROM AUTHOR]

Background Achieving pharmacologic rate control in patients with atrial fibrillation (AF) with rapid ventricular response (RVR) can be tricky when the patient's underlying cardiac function is decreased. We present a case illustrating how ivabradine can be useful in this clinical scenario. Case summary A 95-year-old woman with a history of systolic heart failure (HF) presented with acute decompensated HF in AF with RVR. Beta blockade and calcium channel blockade were avoided given her cardiac history, and diuresis with high doses of furosemide was ineffective. Her ventricular response slowed with ivabradine, allowing for rapid decongestion and a safe discharge home. Discussion Ivabradine acts on the I f current of cardiac pacemaker cells to slow heart rate (HR), and it currently carries a class IIa recommendation to reduce the risk of HF hospitalization and cardiac death in patients with left ventricular ejection fraction ≤35% and a symptomatic HR ≥70 b.p.m. Although current recommendations are for patients in sinus rhythm, ivabradine has a theoretical benefit in patients with AF given its mechanism of action. Because it does not negatively affect inotropy or blood pressure, ivabradine was used in our patient with a good clinical outcome. Our case provides an example of ivabradine's usefulness in patients with AF in RVR with a history of depressed systolic function. [ABSTRACT FROM AUTHOR]

Background: The concept of multinephron segment diuretic therapy (MSDT) has been recommended in severe diuretic resistance with only expert opinion and case-level evidence. The purpose of this study was to investigate the safety and efficacy of MSDT, combining 4 diuretic classes, in acute heart failure (AHF) complicated by diuretic resistance.Methods and Results: A retrospective analysis was conducted in patients hospitalized with AHF at a single medical center who received MSDT, including concomitant carbonic anhydrase inhibitor, loop, thiazide, and mineralocorticoid receptor antagonist diuretics. Subjects served as their own controls with efficacy evaluated as urine output and weight change before and after MSDT. Serum chemistries, renal replacement therapies, and in-hospital mortality were evaluated for safety. Patients with severe diuretic resistance before MSDT were analyzed as a subcohort. A total of 167 patients with AHF and diuretic resistance received MSDT. MSDT was associated with increased median 24-hour urine output in the first day of therapy compared with the previous day (2.16 L [0.95-4.14 L] to 3.08 L [1.74-4.86 L], P = .003) in the total cohort and in the Severe diuretic resistance cohort (0.91 L [0.43-1.43 L] to 2.08 L [1.13-3.96 L], P < .001). The median cumulative weight loss at day 7 or discharge was -7.4 kg (-15.3 to -3.4 kg) (P = .02). Neither serum sodium, chloride, potassium, bicarbonate, or creatinine changed significantly relative to baseline (P > .05 for all).Conclusions: In an AHF cohort with diuretic resistance, MSDT was associated with increased diuresis without changes in serum chemistries or kidney function. Prospective studies of MSDT in AHF and diuretic resistance are warranted. [ABSTRACT FROM AUTHOR]

Aims In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. Methods and results Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13–17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r  = 0.7, P  < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r  = 0.37, P  < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n  = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P  = 0.47). Conclusion On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF. [ABSTRACT FROM AUTHOR]

Introduction: Diuretic resistance is a common complication impairing decongestion during hospitalization for acute decompensated heart failure (ADHF). The current understanding of diuretic resistance mechanisms in ADHF is based upon extrapolations from other disease states and healthy volunteers. However, accumulating evidence suggests that the dominant mechanisms in other populations have limited influence on diuretic response in ADHF. Additionally, the ability to rapidly and reliably diagnose diuretic resistance is inadequate using currently available tools. Aims: The Mechanisms of Diuretic Resistance (MDR) Study is designed to rigorously investigate the mechanisms of diuretic resistance and develop tools to rapidly predict diuretic response in a prospective cohort hospitalized with ADHF. Methods: Study assessments occur serially during the ADHF hospitalization and after discharge. Each assessment includes a supervised 6‐hour urine collection with baseline blood and timed spot urine collections following loop diuretic administration. Patient characteristics, medications, physical exam findings, and both in‐hospital and post‐discharge HF outcomes are collected. Patients with diuretic resistance are eligible for a randomized sub‐study comparing an increased loop diuretic dose with combination diuretic therapy of loop diuretic plus chlorothiazide. Conclusions: The Mechanisms of Diuretic Resistance Study will establish a prospective patient cohort and biorepository to investigate the mechanisms of diuretic resistance and urine biomarkers to rapidly predict loop diuretic resistance. [ABSTRACT FROM AUTHOR]

Admission blood glucose (BG) has demonstrated contradictory association with 30-day mortality in acute heart failure (AHF) hospitalization. To explore these contradictory findings, we aimed to determine if admission BG reflects an acute change from chronic glucose control and investigate the association between the admission and chronic BG change (ΔBG) with 30-day mortality in AHF. We analyzed patients (n = 1045) age ≥ 65 with Centers of Medicare Services benefits and known 30-day all-cause mortality hospitalized with AHF at an academic medical center from 2009 to 2016. We included diabetic (n = 736) and non-diabetic (n = 309) patients with recent Hemoglobin A1c (HbA 1c). We defined ΔBG as the difference in the admission and chronic BG, calculated from HbA 1c. Admission BG was 126 (101, 167) mg/dl and was moderately elevated (≥170 mg/dl) in 25% of admissions. The median (IQR) ΔBG was −7 (−29, 26) mg/dl, with 74% of all admissions (66% diabetic, 92% non-diabetic) presenting within ±50 mg/dl of the chronic BG. Admission BG was not associated with mortality. ΔBG > +100 mg/dl displayed increased 30-day mortality (18.6% vs 6.9%, p < 0.001) compared to −26 to +25 mg/dl. When admission BG was >200 mg/dl (n = 166), a ΔBG > +100 mg/dl was present in 77% of those deceased vs 31% of those alive at 30 days (p = 0.003; positive likelihood ratio = 5.7). ΔBG > +100 mg/dl was strongly associated with 30-day mortality risk (OR 6.4, 95% CI 2.3–18.9; p = 0.0005) after multivariate adjustment. Admission BG predominantly reflects chronic glycemic status. Increased change in admission from chronic BG was associated with increased 30-day mortality. • Elevated blood glucose at AHF hospital admission reflects chronic hyperglycemia. • Change from chronic glucose values further identifies a high-risk cohort. • Admission hyperglycemia should be interpreted in context of chronic glucoses. [ABSTRACT FROM AUTHOR]

Loop diuretics are a cornerstone of symptom management for nearly all patients with heart failure. Diuretic resistance is a clinical problem with similar presentation despite diverse and multiple etiologies. Although the exact incidence is not known, diuretic resistance occurs frequently and can increase the length of hospitalization. Despite the prevalence of loop diuretic prescription in heart failure and frequency of diuretic resistance, current heart failure guidelines provide nonspecific guidance on strategies to restore diuretic efficacy. Providers are left with many questions regarding the optimum diuretic titration strategy in the setting of diuretic resistance. In light of these highly prevalent uncertainties, we present a case vignette-structured literature review of the mechanisms of diuretic resistance and recommend therapeutic strategies based on the resistance etiology to improve diuretic response in acute decompensated heart failure. [ABSTRACT FROM AUTHOR]