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BackgroundFor 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 resultsIn 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

AimsEpisodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF.Methods and resultsOn admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P

AimsCurrently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and resultsBLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.ConclusionIn this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

BackgroundAtrial fibrillation (AFib) is a common comorbidity in HF and affects patients' outcome. We sought to assess the effects of serelaxin in patients with and without AFib.MethodsIn a post hoc analysis of the RELAX-AHF trial, we compared the effects of serelaxin on efficacy end points, safety end points and biomarkers in 1161 patients with and without AFib on admission electrocardiogram.ResultsAFib was present in 41.3% of patients. Serelaxin had a similar effect in patients with and without AFib, including dyspnea relief by visual analog scale through day 5 [mean change in area under the curve, 541.11 (33.79, 1048.44), p = 0.0366 in AFib versus 361.80 (-63.30, 786.90), p = 0.0953 in non-AFib, interaction p = 0.5954] and all-cause death through day 180 [HR = 0.42 (0.23, 0.77), p = 0.0051 in AFib versus 0.90 (0.53, 1.52), p = 0.6888 in non-AFib, interaction p = 0.0643]. Serelaxin was similarly safe in the two groups and induced similar reductions in biomarkers of cardiac, renal and hepatic damage. Stroke occurred more frequently in AFib patients (2.8 vs. 0.8%, p = 0.0116) and there was a trend for lower stroke incidence in the serelaxin arm in AFib patients (odds ratios, 0.31, p = 0.0759 versus 3.88, p = 0.2255 in non-AFib, interaction p = 0.0518).ConclusionsSerelaxin was similarly safe and efficacious in improving short- and long-term outcomes and inducing organ protection in acute HF patients with and without AFib.

AimsWomen with heart failure are typically older, and more often have hypertension and a preserved left ventricular ejection fraction as compared with men. We sought to analyze if these sex differences influence the course and outcome of acute heart failure.Methods and resultsWe analyzed sex differences in acute heart failure in 1161 patients enrolled in the RELAX-AHF study. The pre-specified study endpoints were used. At baseline, women (436/1161 patients) were older, had a higher left ventricular ejection fraction, a higher rate of hypertension, and were treated differently from men. Early dyspnea improvement (moderate or marked dyspnea improvement measured by Likert scale during the first 24 h) was greater in women. However, dyspnea improvement over the first 5 days (change from baseline in the visual analog scale area under the curve (VAS AUC) to day 5) was similar between men and women. Women reported greater improvements in general wellbeing by Likert, but no such benefits were evident with the VAS score. Multi-variable predictors of moderate or marked dyspnea improvement were female sex (p = 0.0011), lower age (p = 0.0026) and lower diuretic dose (p = 0.0067). The additional efficacy endpoints of RELAX-AHF were similar between men and women and serelaxin was equally effective in men and women.ConclusionsWomen exhibit better earlier dyspnea relief and improvement in general wellbeing compared with men, even adjusted for age and left ventricular ejection fraction. However, in-hospital and post-discharge clinical outcomes were similar between men and women. This trial is registered at ClinicalTrials.gov, NCT00520806.

ObjectivesThis study sought to examine the relationships between in-hospital and post-discharge body weight changes and outcomes among patients hospitalized for acute heart failure (AHF).BackgroundBody weight changes during and after hospitalization for AHF and the relationships with outcomes have not been well characterized.MethodsA post hoc analysis was performed of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, which enrolled patients admitted for AHF regardless of ejection fraction. In-hospital body weight change was defined as the difference between baseline and discharge/day 10, whereas post-discharge body weight change was defined as the difference between discharge/day 10 and day 30. Spearman rank correlations of weight change, urine output (UOP), and dyspnea relief as assessed by a 7-point Likert scale are described. Logistic and Cox proportional hazards regression was used to evaluate the relationship between weight change and outcomes.ResultsStudy participants with complete body weight data (n = 4,172) had a mean age of 65 ± 14 years, and 66% were male. Ischemic heart disease was reported in 60% of patients and the average ejection fraction was 30 ± 13%. The median change in body weight was -1.0 kg (interquartile range: -2.1 to 0.0 kg) at 24 h and -2.3 kg (interquartile range: -5.0 to -0.7 kg) by discharge/day 10. At hour 24, there was a weak correlation between change in body weight and UOP (r = -0.381), and minimal correlation between body weight change and dyspnea relief (r = -0.096). After risk adjustment, increasing body weight during hospitalization was associated with a 16% increase per kg in the likelihood of 30-day mortality or HF readmission for patients showing weight loss ≤1 kg or weight gain during hospitalization (odds ratio per kg increase 1.16, 95% confidence interval [CI]: 1.09 to 1.27; p < 0.001). Among the subset of patients experiencing >1-kg increase in body weight post-discharge, increasing body weight was associated with higher risk of 180-day mortality (hazard ratio per kg increase 1.16; 95% CI: 1.09 to 1.23; p < 0.001).ConclusionsA substantial number of patients experienced minimal weight loss or frank weight gain in the context of an AHF trial, and increasing body weight in this subset of patients was independently associated with a worse post-discharge prognosis.

BackgroundSerelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of serelaxin.MethodsIn the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (n = 1132). Renal impairment was defined as an eGFR

Heart failure (HF) afflicts nearly 6 million Americans, resulting in one million emergency department (ED) visits and over one million annual hospital discharges. An aging population and improved survival from cardiovascular diseases is expected to further increase HF prevalence. Emergency providers play a significant role in the management of patients with acute heart failure (AHF). It is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics and alternatives to hospitalization. Further, clinical trials must be conducted in the ED in order to improve the evidence base and drive optimal initial therapy for AHF. Should ongoing and future studies suggest early phenotype-driven therapy improves in-hospital and post-discharge outcomes, ED treatment decisions will need to evolve accordingly. The potential impact of future studies which incorporate risk-stratification into ED disposition decisions cannot be underestimated. Predictive instruments that identify a cohort of patients safe for ED discharge, while simultaneously addressing barriers to successful outpatient management, have the potential to significantly impact quality of life and resource expenditures.

AimsTo examine the characteristics associated with early dyspnoea relief during acute heart failure (HF) hospitalization, and its association with 30-day outcomes.Methods and resultsASCEND-HF was a randomized trial of nesiritide vs. placebo in 7141 patients hospitalized with acute HF in which dyspnoea relief at 6 h was measured on a 7-point Likert scale. Patients were classified as having early dyspnoea relief if they experienced moderate or marked dyspnoea improvement at 6 h. We analysed the clinical characteristics, geographical variation, and outcomes (mortality, mortality/HF hospitalization, and mortality/hospitalization at 30 days) associated with early dyspnoea relief. Early dyspnoea relief occurred in 2984 patients (43%). In multivariable analyses, predictors of dyspnoea relief included older age and oedema on chest radiograph; higher systolic blood pressure, respiratory rate, and natriuretic peptide level; and lower serum blood urea nitrogen (BUN), sodium, and haemoglobin (model mean C index = 0.590). Dyspnoea relief varied markedly across countries, with patients enrolled from Central Europe having the lowest risk-adjusted likelihood of improvement. Early dyspnoea relief was associated with lower risk-adjusted 30-day mortality/HF hospitalization [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68-0.96] and mortality/hospitalization (HR 0.85; 95% CI 0.74-0.99), but similar mortality.ConclusionClinical characteristics such as respiratory rate, pulmonary oedema, renal function, and natriuretic peptide levels are associated with early dyspnoea relief, and moderate or marked improvement in dyspnoea was associated with a lower risk for 30-day outcomes.

AimsAlthough dyspnoea is the most common cause of admission for acute heart failure (AHF), more needs to be known about its clinical course and prognostic significance.Methods and resultsThe Pre-RELAX-AHF study randomized 232 subjects with AHF to placebo or four doses of relaxin and evaluated early (6-24 h Likert scale) and persistent [change in visual analogue scale area under the curve (VAS AUC) through Day 5] dyspnoea relief. Worsening heart failure (WHF) was defined as worsening AHF signs and symptoms requiring additional therapy. Patients were followed until Day 180. Early dyspnoea relief was observed in only 25% of all patients, and VAS AUC at 5 days was 45% over baseline values in all patients (32% placebo; 50% all relaxin-treated patients). Worsening heart failure to Day 5 was observed in 16% of all patients (21% placebo; 14% relaxin). Lack of persistent dyspnoea relief and WHF were associated with a longer length of initial hospital stay and worse 60-day outcomes.ConclusionDyspnoea relief in patients admitted with AHF is often incomplete, and many may show WHF after the initial stabilization. Both lack of persistent dyspnoea relief and in-hospital WHF predict a longer length of stay and worse outcome.

Relaxin is a naturally occurring peptide hormone that plays a central role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Triggering similar changes could potentially be beneficial in the treatment of patients with heart failure. The effects of relaxin include the production of nitric oxide, inhibition of endothelin, inhibition of angiotensin II, production of VEGF, and production of matrix metalloproteinases. These effects lead to systemic and renal vasodilation, increased arterial compliance, and other vascular changes. The recognition of this has led to the study of relaxin for the treatment of heart failure. An initial pilot study has shown favorable hemodynamic effects in patients with heart failure, including reduction in ventricular filling pressures and increased cardiac output. The ongoing RELAX-AHF clinical program is designed to evaluate the effects of relaxin on the symptoms and outcomes in a large group of patients admitted to hospital for acute heart failure. This review will summarize both the biology of relaxin and the data supporting its potential efficacy in human heart failure.

Aims: Heart failure (HF) guidelines recommend initiation and optimization of guideline‐directed medical therapy, including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes. Methods and results: We performed a secondary analysis of 6197 patients enrolled in the RELAX‐AHF‐2 study. Patients were divided into four groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In‐hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (43%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in‐hospital initiation of an MRA was independently associated with lower risks of mortality (multivariable hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60–0.96; p = 0.02), cardiovascular death (HR 0.77, 95% CI 0.59–1.01; p = 0.06), hospitalization for HF or renal failure (HR 0.72, 95% CI 0.60–0.86; p = 0.0003) and the composite endpoint of cardiovascular death and/or rehospitalization for HF or renal failure (HR 0.71, 95% CI 0.61–0.83; p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction. Conclusion: In patients hospitalized for acute HF, in‐hospital initiation of an MRA was associated with improved post‐discharge outcomes, independent of left ventricular ejection fraction and other potential confounders. [ABSTRACT FROM AUTHOR]

Aims: The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX‐AHF‐2) trial. Methods and results: Patients enrolled in RELAX‐AHF‐2 with available data regarding MR status were included in this analysis. Baseline characteristics, in‐hospital data, and clinical outcomes through 180‐day follow‐up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N‐terminal pro‐B‐type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03–1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91–1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone. Conclusions: In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: Istaroxime is a first‐in‐class agent which acts through inhibition of the sarcolemmal Na+/K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24 h infusion of istaroxime in patients hospitalised for acute heart failure (AHF). Methods and results: We included patients hospitalised for AHF with left ventricular ejection fraction ≤40% and E/e' > 10. Patients were randomised to a 24 h intravenous infusion of placebo or istaroxime at doses of 0.5 μg/kg/min (cohort 1: placebo n = 19; istaroxime n = 41) or 1.0 μg/kg/min (cohort 2: placebo n = 20, istaroxime n = 40). The primary endpoint of change in E/e' ratio from baseline to 24 h decreased with istaroxime vs. placebo (cohort 1: −4.55 ± 4.75 istaroxime 0.5 μg/kg/min vs. −1.55 ± 4.11 placebo, P = 0.029; cohort 2: −3.16 ± 2.59 istaroxime 1.0 μg/kg/min vs. −1.08 ± 2.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self‐reported dyspnoea and N‐terminal pro‐brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0 μg/kg/min. Conclusions: In patients hospitalised for AHF with reduced ejection fraction, a 24 h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: The effectiveness and safety of 48 h intravenous 30 μg/kg/day serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials.Methods and Results: We conducted a fixed-effect meta-analysis including all studies of intravenous serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous serelaxin 30 μg/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67-0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1-6 months), serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77-0.98; P = 0.0261).Conclusions: Administration of intravenous serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality. [ABSTRACT FROM AUTHOR]

Aims: Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30.Methods and Results: A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m2 . The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (α set at P < 0.05). Of 618 randomized patients, 578 (93.5%) had a baseline PRA. PRA was modestly, but significantly, associated with each outcome without adjustment [worsening HF or death through day 5: hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.23, P = 0.04; HF rehospitalization or death through day 30: HR 1.13, 95% CI 1.02-1.26, P = 0.02; all-cause death through day 30: HR 1.18, 95% CI 1.02-1.37, P = 0.03]. After multivariable adjustment, PRA was only significantly associated with HF rehospitalization or death through day 30 (HR 1.15, 95% CI 1.01-1.32, P = 0.04).Conclusion: Baseline PRA levels are associated with increased risk for the composite of 30-day HF rehospitalization or death in patients with AHF. [ABSTRACT FROM AUTHOR]

Aims: It remains unclear if early administration of i.v. nesiritide in patients hospitalized with acute heart failure (AHF) is associated with improved clinical outcomes. Methods and results: We analysed data from 7007 patients enrolled in ASCEND-HF to examine the associations between time to treatment with study medication (nesiritide or placebo) and clinical endpoints: (i) moderate to marked dyspnoea relief on a 7-point Likert scale at 6 h; (ii) 30-day all-cause mortality or re-hospitalization; and (iii) 30-day all-cause mortality. The median time to study drug administration was 16.7 h (25th, 75th percentiles=6.5, 23.1), with significant regional variation (e.g. median of 13.0 h in Asia-Pacific vs. 18.4 h in North America). After risk adjustment, each hour delay in study medication after the first 10 h from initial hospital presentation was associated with modestly reduced odds of dyspnoea relief [(adjusted odds ratio (OR) 0.98, 95% confidence interval (CI) 0.98-0.99; P < 0.0001]. Every hour delay in study medication was associated with modestly higher all-cause mortality or re-hospitalization (unadjusted OR 1.01, 95% CI 1.01-1.02; P < 0.001) due to pre-randomization therapies and known predictors of 30-day outcomes (adjusted P = 0.12). There was no significant association between time to study drug and all-cause mortality (P >0.08). Conclusion: In a large international AHF trial, time to treatment with study medication varied markedly across regions. Earlier administration of study medication was associated with modestly better dyspnoea relief, but not 30-day clinical outcomes. The association between timing of treatment with study medication and study endpoints may have implications for the interpretation of AHF studies and future trial design. [ABSTRACT FROM AUTHOR]

Aims: Troponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF.Methods and Results: Hs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60 days and cardiovascular mortality to 180 days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 µg/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT = 1.36, 95% confidence interval 1.15-1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels.Conclusion: Hs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Congestion is a major reason for hospitalization in acute heart failure ( HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012. [ABSTRACT FROM AUTHOR]