Hospital Admission For Acute Heart Failure Research Articles

Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study

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.

Association of Early Blood Pressure Decrease and Renal Function With Prognosis in Acute Heart Failure

ObjectivesThe aim of this study was to investigate the association between systolic blood pressure (SBP) drop, worsening renal function (WRF), and prognosis in patients with acute heart failure (AHF). BackgroundA large drop in SBP early after hospital admission for AHF might be associated with increased risk for WRF and prognosis. However, there is a paucity of data regarding the interaction between WRF and a drop in SBP on clinical outcomes. MethodsA post hoc analysis among 6,544 patients with AHF enrolled in the RELAX-AHF-2 (Relaxin in Acute Heart Failure-2) trial was performed. Blood pressure was uniformly and repetitively measured. Peak SBP drop was defined as the difference between baseline SBP and lowest SBP documented during the first 48 hours. WRF was defined by an increase in serum creatinine of ≥0.3 mg/dL from baseline to day 5. ResultsPeak SBP drop was independently associated with a higher risk for WRF (HR: 1.11 per 10 mm Hg SBP drop; P < 0.001), 5-day worsening heart failure (HR: 1.12 per 10 mm Hg SBP drop; P = 0.006), and 180-day cardiovascular death (HR: 1.09 per 10 mm Hg SBP drop; P = 0.026) after adjustment for potential confounders including baseline SBP. There was no interaction between the prognostic value of early SBP drop according to the presence or absence of WRF. ConclusionsIn patients hospitalized for AHF, a greater early drop in SBP was associated with a higher incidence of WRF, worsening heart failure, and an increased risk for 180-day cardiovascular death. However, the association between SBP drop and prognosis was not influenced by WRF. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778)

Acute on chronic heart failure-Which variations on B-type natriuretic peptide levels?

ObjectiveNatriuretic peptides are useful diagnostic and prognostic markers in patients presenting to the emergency department (ED) with acute shortness of breath. However, B‐type natriuretic peptide (BNP) level represents a single snapshot in time, while changes relative to a patient's baseline may be useful in risk stratification. We aimed to define the variation of BNP levels between chronic stable and acute decompensated heart failure (ADHF) that is associated with significant clinical outcomes.MethodsWe performed a retrospective cohort chart review study of chronic heart failure (HF) patients followed in an outpatient clinic from 2010 to 2013. Inclusion criteria were available hospital and clinic BNP levels and at least 1 year of follow‐up care. ADHF was defined as a hospital admission for acute HF. Dry BNP was defined as its concentration after >3 months of optimal treatment and no variations in New York Heart Association class. Dry BNP was compared to the BNP at a subsequent ED visit that was associated with hospitalization because of ADHF.ResultsOverall, 253 patients were included. Their median (interquartile range [IQR]) dry BNP was 191(83–450) pg/mL. There were 67 ADHF admissions, occurring 15 ± 15 months after patient's dry BNP was established. At subsequent ED admission, the median (IQR) BNP was 1505 (72–2620) pg/mL. Patients requiring inpatient admission had a BNP ∼250% higher than their stable BNP (404 vs 164 pg/mL, p < 0.001).ConclusionsIn this group of chronic stable HF patients, a doubling of BNP was observed in patients who required hospitalization for acute decompensated HF. BNP doubling may represent a useful parameter to reflect clinically relevant acute decompensated HF.

Patterns of dyspnoea onset in patients with acute heart failure: clinical and prognostic implications.

AimsDespite attempts to improve the management of patients with acute heart failure (HF), virtually all therapeutic agents investigated in large clinical trials failed to show any consistent reduction in mortality and morbidity. Complexity of the clinical syndrome of acute HF seems to be likely an underlying explanation. Traditionally, clinical trials studied mixed patient populations with acute HF, and only recently, better clinical characterization of patients has been proposed. Dyspnoea is the most common presenting symptom related to hospital admission for acute HF. Whether in patients with acute HF, the pattern of symptoms onset preceding hospital admission is associated with clinical characteristics, and the outcomes have not yet been established.Methods and resultsWe investigated 137 patients (mean age: 65 ± 13 years; 80% men) hospitalized due to acute HF with dyspnoea as major reported symptom, who were divided according to the time of its onset into those with acute (n = 98) vs. subacute (n = 39) onset (i.e. within 7 days vs. >7 days preceding hospital admission, respectively). On admission, the former group presented higher blood pressure (138 ± 33 vs. 121 ± 32 mmHg), more often moderate–severe pulmonary congestion (33 vs. 8%), and lower bilirubin level [1.07 (0.72–1.60) vs. 1.27 (0.87–2.06); P < 0.05 in all comparisons]. There were no other differences in baseline clinical characteristics and laboratory indices. Higher percentage of patients with an acute dyspnoea onset reported marked/moderate dyspnoea relief after 6 (18% vs. 7%), 24 (59% vs. 24%), and 48 h (80% vs. 46% assessed as an improvement of at least 5 points in self‐reported 10‐point Likert scale; P < 0.05 in all time points). In patients with an acute onset of dyspnoea after 48 h, a decrease of N‐terminal pro BNP was more frequently observed (83% vs. 65%), and the levels of endothelin‐1 were more reduced [−1.1 (−2.9–0.03) vs 0.4 (−2.2–1.4); all P < 0.05]. Patients with acute onset experienced less in‐hospital HF worsening (13% vs. 40%, P = 0.001), and 1 year cardiovascular mortality was significantly lower (20% vs. 41%, P = 0.01). On the multivariable analysis, subacute pattern of dyspnoea was independent predictor of 12 month cardiovascular mortality in patients with acute HF after adjusting for other prognostic factors: systolic blood pressure, urea, and HF de novo [hazard ratio (95% confidence interval): 2.32 (1.13–4.75), P = 0.02].ConclusionsIn patients with acute HF, the pattern of symptoms onset is associated with baseline differences in clinical characteristics, biomarker profile, response to standard treatment, and the long‐term outcomes. This is relevant information for planning future clinical trials.

MicroRNAs relate to early worsening of renal function in patients with acute heart failure

Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients. We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.3mg per deciliter or more from admission to day 3), absolute change in creatinine and Neutrophil Gelatinase Associated Lipocalin (NGAL) from admission to day 3 in 98 patients hospitalized for acute HF. At baseline, circulating levels of all miRNAs were lower in patients with WRF, with statistically significant decreased levels of miR-199a-3p, miR-423-3p, and miR-let-7i-5p (p-value<0.05). The increase in creatinine during the first 3 days of hospitalization was significantly associated with lower levels of miR-199a-3p, miR-27a-3p, miR-652-3p, miR-423-5p, and miR-let-7i-5p, while the increase in NGAL was significantly associated with lower levels of miR-18a-5p, miR-106a-5p, miR-223-3p, miR-199a-3p and miR-423-3p. MiR-199a-3p was the strongest predictor of WRF, with an Odds Ratio of 1.48 (1.061-2.065; p-value=0.021) and a C-index of 0.701. Our results show that the levels of circulating miRNAs at hospital admission for acute HF were consistently lower in patients who developed worsening of renal function. MiR-199a-3p was the best predictor of WRF in these patients.

Diuretic response in acute heart failure—an analysis from ASCEND-HF

Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. Diuretic response, defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. Mean diuretic response was -0.42 kg/40 mg of furosemide (interquartile range -1.0, -0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response (P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.

Rationale and Design of a Randomized, Double-Blind, Placebo Controlled Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure: LAICA study

BackgroundAdvanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation.MethodsThe LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo.ResultsThe main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events.ConclusionsThe LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Prevalence and prognostic role of anaemia in patients with acute heart failure and preserved or depressed ventricular function

Observations available for patients with acute heart failure (HF) show conflicting results, and the prognostic role of anaemia ascertained on hospital admission is not well defined. We investigated the database of the Italian Survey on Acute Heart Failure (IS-AHF) to analyze prevalence, factors associated with and the prognostic role of anaemia (defined as haemoglobin < 12 g/dl) in patients hospitalized for acute HF with either depressed or preserved (>40%) ejection fraction (EF). The median haemoglobin level of the 2,318 patients considered in this analysis was 13 g/dl (inter-quartile range 11.5-14.3). The prevalence of anaemia was 31%. Patients who had anaemia were older, more frequently female gender, hospitalized for a chronic destabilized HF, had higher prevalence of preserved EF, hyponatremia, elevated troponin and other comorbidities (including diabetes, peripheral artery disease, chronic renal failure) than those who did not have anaemia. During the hospital stay, they were treated with higher doses of diuretics, and more frequently required mechanical ventilation and ultrafiltration, and less frequently received ACEi/ARB, aldosterone blockers and beta-blockers at hospital discharge. In-hospital mortality was 12.1 and 5.3% in patients with and without anaemia, respectively (p < 0.0001). In the multivariable analysis, anaemia was a significant independent predictor of in-hospital mortality apart from age, low systolic blood pressure, impaired renal function, elevated troponin assay, the non use of beta-blocker and the requirement of inotropic drug. In conclusion, anaemia diagnosed at hospital admission for acute HF is a frequent comorbidity with meaningful implications on the clinical management and prognosis both in patients with reduced and preserved EF.