Congestion is the main reason for hospital admission for acute decompensated heart failure (ADHF). A better understanding of the clinical course of congestion and factors associated with decongestion ...are therefore important. We studied the clinical course, predictors and prognostic value of congestion in a cohort of patients admitted for ADHF by including different indirect markers of congestion (residual clinical congestion, brain natriuretic peptides (BNP) trajectories, hemoconcentration or diuretic response).
We studied the prognostic value of residual clinical congestion using an established composite congestion score (CCS) in 1572 ADHF patients. At baseline, 1528 (97.2%) patients were significantly congested (CCS ≥ 3), after 7 days of hospitalization or discharge (whichever came first), 451 (28.7%) patients were still significantly congested (CCS ≥ 3), 751 (47.8%) patients were mildly congested (CCS = 1 or 2) and 370 (23.5%) patients had no signs of residual congestion (CCS = 0). The presence of significant residual congestion at day 7 or discharge was independently associated with increased risk of re-admissions for heart failure by day 60 (HR 95%CI = 1.88 1.39–2.55) and all-cause mortality by day 180 (HR 95%CI = 1.54 1.16–2.04). Diuretic response provided added prognostic value on top of residual congestion and baseline predictors for both outcomes, yet gain in prognostic performance was modest.
Most patients with acute decompensated heart failure still have residual congestion 7 days after hospitalization. This factor was associated with higher rates of re-hospitalization and death. Decongestion surrogates, such as diuretic response, added to residual congestion, are still significant predictors of outcomes, but they do not provide meaningful additive prognostic information.
•The majority of hospitalized heart failure patients still have signs of residual congestion 7 days after admission•The strongest predictors of residual congestion were a poorer diuretic response and a higher blood urea nitrogen•Patients with signs of residual congestion received less often and lower doses of ACE-inhibitors and/or ARB.•Residual congestion at 7 days after admission is associated with an greater risk of death and heart failure readmission
Summary Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with ...positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo. Methods RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00520806. Findings 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120–775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients 26%; serelaxin, 156 27%; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events 60-day Kaplan-Meier estimate, 13·0%; serelaxin, 76 events 13·2%; hazard ratio HR 1·02 0·74–1·41, p=0·89 or days alive out of the hospital up to day 60 (placebo, 47·7 SD 12·1 days; serelaxin, 48·3 11·6; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42–0·93; p=0·019). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affiliate company.
Although fluid overload is one of the most prominent features of acute heart failure (AHF), its mechanism remains challenging, due to the lack of consistent data from prospective studies. ...Traditionally, fluid overload was thought to be mainly the result of either increased intake of fluid and salt or non-adherence with diuretic therapy. However, recent data showed little weight change before or during an AHF event suggesting that in many cases fluid overload is caused by other mechanisms such as fluid redistribution and neurohormonal or inflammatory activation. Redistribution may be the result of a combined vascular and cardiac process reducing capacitance in the venous system (and hence increasing preload) and increasing arterial stiffness and resistance (and hence afterload). When these vascular processes occur acutely and are superimposed on reduced cardiac function; fluid is redistributed to the lungs instigating pulmonary congestion. In this paper we elaborate on this possible pathophysiological mechanism and review its potential causes and amplifiers.
Acute heart failure (AHF) is associated with a poor prognosis regardless of left ventricular ejection fraction (LVEF). STRONG-HF showed the efficacy and safety of a strategy of rapid uptitration of ...oral treatment for heart failure (HF) and close follow-up (high-intensity care), compared with usual care, in patients recently hospitalized for AHF and enrolled independently from their LVEF.
In this study, we sought to assess the impact of baseline LVEF on the effects of high-intensity care vs usual care in STRONG-HF.
The STRONG-HF trial enrolled patients hospitalized for AHF with any LVEF and not treated with full doses of renin-angiotensin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. High-intensity care with uptitration of oral medications was performed independently from LVEF. The primary endpoint was the composite of HF rehospitalization or all-cause death at day 180.
Among the 1,078 patients randomized, 731 (68%) had LVEF ≤40% and 347 (32%) had LVEF >40%. The treatment benefit of high-intensity care vs usual care on the primary endpoint was consistent across the whole LVEF spectrum (interaction P with LVEF as a continuous variable = 0.372). Mean difference in the EQ-5D visual analog scale change from baseline to day 90 between treatment arms was slightly greater at higher LVEF values, but with no interaction between LVEF as a continuous variable and the treatment strategy (interaction P = 0.358). Serious adverse events were also independent from LVEF.
Rapid uptitration of oral medications for HF and close follow-up reduce 180-day death and HF rehospitalization after AHF hospitalization independently from LVEF. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-ProBNP Testing, of Heart Failure Therapies STRONG-HF; NCT03412201)
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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.
Aims
We evaluated the added prognostic value of a multi‐time point‐based multimarker panel of biomarkers in patients with acute heart failure (AHF).
Methods and results
Seven circulating biomarkers ...NT‐proBNP, high sensitivity cardiac troponin T (hs‐cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF‐15), cystatin‐C, galectin‐3, and high sensitivity C‐reactive protein (hs‐CRP) were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX‐AHF trial. Patients with BNP ≥350 ng/L or NT‐proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time‐dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre‐specified baseline model, was quantified with the gain in the C‐index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180‐day cardiovascular mortality except for galectin‐3. While a repeat measurement as early as day 2 was adequate for NT‐proBNP and cystatin‐C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs‐cTnT, GDF‐15, sST2, and hs‐CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT‐proBNP, hs‐cTnT, GDF‐15, and sST2, which yielded 0.08 unit absolute increment in the C‐index to 0.87 (95% confidence interval 0.83–0.91.
Conclusion
In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point‐based single marker strategy.
Summary Background Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, ...suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety. Methods In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 μg/kg (n=40), 30 μg/kg (n=43), 100 μg/kg (n=39), or 250 μg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov , number NCT00520806. Findings In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 μg/kg per day group, 42 in the relaxin 30 μg/kg per day group, 37 in the relaxin 100 μg/kg per day group, and 49 in the relaxin 250 μg/kg per day group. Dyspnoea improved with relaxin 30 μg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients 40% moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 23%; p=0·044) and visual analogue scale through day 14 (8214 mm×h SD 8712 vs 4622 mm×h 9003; p=0·053). Length of stay was 10·2 days (SD 6·1) for relaxin-treated patients versus 12·0 days (7·3) for those given placebo, and days alive out of hospital were 47·9 (10·1) versus 44·2 (14·2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2·6% 95% CI 0·4–16·8 vs 17·2% 9·6–29·6; p=0·053). The number of serious adverse events was similar between groups. Interpretation When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety. Funding Corthera (USA).
Objectives The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). ...Background Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. Methods This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. Results Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. Conclusions Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.
Background
Growth differentiation factor 15 (GDF‐15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute ...heart failure (AHF) is lacking.
Methods and results
Levels of GDF‐15 were measured at pre‐specified time‐points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo‐controlled RELAXin in Acute Heart Failure (RELAX‐AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment. Neither baseline nor changes in GDF‐15 were associated with the degree of dyspnoea or dyspnoea relief. After adjustment for baseline characteristics, baseline GDF‐15 was not associated with the composite endpoint of heart failure or renal failure (HF/RF) readmission at 60 days/cardiovascular (CV) death or CV death at 180 days. In contrast, larger increases in GDF‐15 levels at days 2 and 14 were associated with a greater risk of 60‐day HF/RF rehospitalizations/CV death and CV death at 180 days. Serelaxin treatment was associated with significantly larger decreases of GDF‐15 at days 2 and 5 than placebo.
Conclusions
In AHF patients enrolled in the RELAX‐AHF study, increases in GDF‐15 levels, but not baseline measurements, were associated with a greater likelihood of adverse outcomes. Serelaxin administration was associated with greater decreases in GDF‐15 compared with placebo.
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