Aims
Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure ...(AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for
AHF.
Methods and results
The 6128 patients from the RELAX‐AHF‐2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93–0.98 per 5% LVEF increase, P < 0.001) that was driven predominantly by decreased risk for rehospitalization. The smoothed spline curve depicting risk remained stable as LVEF decreased until reaching approximately 40%, at which point risk increased progressively with further reductions in LVEF. Significant differences between LVEF quartiles for post‐discharge CV risk were seen in patients with an ischaemic aetiology or with a history of HF preceding index hospitalization, but were less robust in patients with non‐ischaemic aetiology and absent in those with de novo
HF.
Conclusion
In patients hospitalized with AHF, CV events over 180 days were more frequent in patients with lower LVEF. This was due predominantly to a significant increase in risk for HF/renal failure rehospitalization but not in either CV or all‐cause mortality. LVEF had greater prognostic value in patients with ischaemic aetiology or pre‐existing
HF.
The prognostic impact of high concentration of interleukin-6 (IL-6) or C-reactive protein (CRP), two routinely available markers of systemic inflammation in the general population of critically ill ...patients, remains unclear. In a large cohort of critically ill patients including septic and non-septic patients, we assessed the relationship between baseline IL-6 or CRP and mortality, organ dysfunction, and the need for organ support.
This was an ancillary analysis of the prospective French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study including patients with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following intensive care unit (ICU) admission. The primary objective was to determine the association between baseline IL-6 or CRP concentration and survival until day 90. Secondary outcomes included organ dysfunction as evaluated by the Sequential Organ Failure Assessment (SOFA) score, and the need for organ support, including vasopressors/inotropes and/or renal replacement therapy (RRT).
Median IL-6 and CRP concentrations (
= 2,076) at baseline were 100.9 pg/ml (IQR 43.5-261.7) and 143.7 mg/L (IQR 78.6-219.8), respectively. Day-90 mortality was 30%. High IL-6 or CRP was associated with worse 90-day survival (hazard ratios 1.92 1.63-2.26 and 1.21 1.03-1.41, respectively), after adjustment on the Simplified Acute Physiology Score II (SAPS-II). High IL-6 was also associated with the need for organ-support therapies, such as vasopressors/inotropes (OR 2.67 2.15-3.31) and RRT (OR 1.55 1.26-1.91), including when considering only patients independent from those supports at the time of IL-6 measurement. Associations between high CRP and organ support were inconsistent.
IL-6 appears to be preferred over CRP to evaluate critically ill patients' prognoses.
Reports are mixed on the efficacy of omega-3 fatty acids (O3FA) for the treatment of major depressive disorder (MDD), with only limited data in adolescents. The present trial aimed to investigate ...systematically the efficacy of O3FA as a monotherapy, compared to a placebo, in adolescents with MDD. Secondarily, we explored O3FA effects on anhedonia, irritability, and suicidality-all key features of adolescent MDD.
Fifty-one psychotropic medication-free adolescents with DSM-IV-TR diagnoses of MDD (aged 12-19 years; 57% female) were randomized to receive O3FA or a placebo for 10 weeks. Data were collected between January 2006 and June 2013. O3FA and a placebo were administered on a fixed-flexible dose titration schedule based on clinical response and side effects. The initial dose of 1.2 g/d was increased 0.6 g/d every 2 weeks, up to a maximum of 3.6 g/d. Clinician-rated and self-rated depression severity, along with treatment response, served as primary outcome measures. Additionally, we examined O3FA effects on depression-related symptoms, including anhedonia, irritability, and suicidality. Treatment differences were analyzed via intent-to-treat analyses.
O3FA were not superior to a placebo on any clinical feature, including depression severity and levels of anhedonia, irritability, or suicidality. Additionally, response rates were comparable between treatment groups. Within-treatment analyses indicated that both treatments were associated with significant improvement in depression severity on self- (O3FA: t = -4.38, P < .001; placebo: t = -3.52, P = .002) and clinician (O3FA: t = -6.47, P < .001; placebo: t = -8.10, P < .001) ratings.
In adolescents with MDD, O3FA do not appear to be superior to placebo.
ClinicalTrials.gov identifier: NCT00962598.
The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown.
We have explored ...changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 17.38 ml, p = 0.0040, and 9.6 2.02 mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 5.13 mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 -12.7, 7.4 kg at 2 months, and -0.75 -15.9, 7.5 kg at 3 months; both p < 0.0001).
The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.
Aim
Recent data suggest that guideline‐directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a ...left ventricular ejection fraction (LVEF) of 55–65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U‐shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients.
Methods and results
RELAX‐AHF‐2 was a multicentre, placebo‐controlled trial on the effects of serelaxin on 180‐day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50–65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non‐ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta‐blockers and had higher blood urea nitrogen plasma levels. All‐cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180‐day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non‐CV causes. No treatment effect of serelaxin was observed in any of the subgroups.
Conclusions
In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non‐CV death.
Acute heart failure is a common and increasingly prevalent condition, affecting >10 million people annually. For those patients who survive to discharge, early readmissions and death rates are >30% ...everywhere on the planet, making it a malignant condition. Beyond these adverse outcomes, it represents one of the largest drivers of health care costs globally. Studies in the past 2 years have demonstrated that we can induce remissions in this malignant process if therapy is instituted rapidly, at the first acute heart failure episode, using full doses of all available effective medications. Multiple studies have demonstrated that this goal can be achieved safely and effectively. Now the urgent call is for all stakeholders, patients, physicians, payers, politicians, and the public at large to come together to address the gaps in implementation and enable health care providers to induce durable remissions in patients with acute heart failure.
Aims
We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).
Methods and results
...RELAX‐AHF was a double‐blind, placebo‐controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/(total i.v. dose)/40 mg + (total oral dose)/80 mg) furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was −0.42 (−1.00, −0.14) kg/40 mg. A poor diuretic response was independently associated with Western‐like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180‐day cardiovascular mortality (P = 0.507).
Conclusions
In patients hospitalized for AHF, a poor diuretic response was associated with a poor in‐hospital and early post‐discharge clinical outcome. Serelaxin had a neutral effect on diuretic response.
Trial registration: NCT00520806
Aims
The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay ...(LOS), 30‐day post‐discharge readmission and 90‐day post‐discharge mortality in 1990 patients enrolled in the PROTECT study.
Methods and results
PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment. Geographic‐region‐adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R2 0.27). Addition of in‐hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS R2 difference 0.050, 95% confidence interval (CI) 0.0282–0.072. Thirty‐day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97–1.04). Death within 90 days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90‐day post‐discharge mortality.
Conclusions
In patients admitted for AHF, LOS is not well‐predicted by traditional markers of disease severity, but strongly associated with the occurrence of in‐hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post‐discharge outcomes on patients' subgroups at increased risk.
Aims
Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF).
Methods and results
Plasma miRNA profiling included 137 patients with AHF from 3 different ...cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR‐18a‐5p, miR‐26b‐5p, miR‐27a‐3p, miR‐30e‐5p, miR‐106a‐5p, miR‐199a‐3p, and miR‐652‐3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180‐day mortality in a subset of the identified miRNAs.
Conclusions
Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in‐hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch‐pad for molecular pathway studies to identify new pharmacological targets and miRNA‐based therapies.
Background
For patients with acute heart failure (AHF), substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to ...rise, suggesting renal function decline. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF.
Methods and results
In two AHF cohorts (PROTECT, n = 1698 and RELAX‐AHF‐2, n = 5586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dl increase baseline—day 4; sensitivity analyses incorporated baseline renal function) by diuretic response (kg weight loss/40 mg furosemide equivalent baseline—day 4) was investigated with regard to (cardiovascular) death or cardiovascular/renal hospitalization using subpopulation treatment effect pattern plots (STEPP) and survival analyses. WRF occurred in 286 (16.8%) and 1031 (18.5%) patients in PROTECT and RELAX‐AHF‐2, respectively. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (p < 0.05), and received higher doses of loop diuretics and had a worse diuretic response (p < 0.001). In patients with a poor diuretic response (≤0.35 kg weight loss/40 mg furosemide equivalent as identified by STEPP), WRF was associated with higher risk of (cardiovascular) death or cardiovascular/renal hospitalization (p < 0.001 both cohorts), but this was not the case for patients with a good diuretic response (p = 0.900 both cohorts).
Conclusion
In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response.
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