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Heart failure in the outpatient versus inpatient setting: findings from the BIOSTAT-CHF study.
Ferreira, JP, Metra, M, Mordi, I, Gregson, J, Ter Maaten, JM, Tromp, J, Anker, SD, Dickstein, K, Hillege, HL, Ng, LL, et al
European journal of heart failure. 2019;(1):112-120
Abstract
INTRODUCTION Patients with symptomatic heart failure (HF) require additive therapies and have a poor prognosis. However, patient characteristics and clinical outcome between HF patients treated in the outpatient setting vs. those who are hospitalized remain scarce. METHODS AND RESULTS The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with symptoms and/or signs of HF: 1694 as inpatients and 822 as outpatients. Compared to ambulatory HF patients, inpatients had higher heart rate, urea, N-terminal pro-brain natriuretic peptide, lower blood pressure, lower estimated glomerular filtration rate, sodium, potassium, high-density lipoprotein cholesterol, had more often peripheral oedema, diabetes, anaemia, and were less often treated with beta-blockers and angiotensin-converting enzyme inhibitors (ACEi). Outpatients had a more frequent history of HF hospitalization and received more frequently beta-blockers and/or ACEi/angiotensin receptor blockers up-titrated to target doses (P < 0.001). Inpatients had higher rates of the primary outcome of death or HF hospitalization: incidence rate per 100 person-years of 33.4 [95% confidence interval (CI) 31.1-35.9] for inpatients vs. 18.5 (95% CI 16.4-21.0) for outpatients; adjusted hazard ratio 1.24 (95% CI 1.07-1.43). Subdividing patients into low, intermediate and high-risk categories, the primary outcome event rates were 14.3 (95% CI 12.3-16.7), 36.6 (95% CI 32.2-41.5), and 71.3 (95% CI 64.4-79.0) for inpatients vs. 8.4 (95% CI 6.6-10.6), 29.8 (95% CI 24.5-36.2), and 43.3 (95% CI 34.7-54.0) for outpatients, respectively. These findings were externally replicated. CONCLUSIONS Marked differences were observed between inpatients and outpatients with HF. Overall, inpatients were sicker and had higher event rates. However, a substantial proportion of outpatients had similar or higher event rates compared to inpatients. These findings suggest that HF outpatients also have poor prognosis and may be the focus of future trials.
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Serial assessment of spot urine sodium predicts effectiveness of decongestion and outcome in patients with acute heart failure.
Biegus, J, Zymliński, R, Sokolski, M, Todd, J, Cotter, G, Metra, M, Jankowska, EA, Banasiak, W, Ponikowski, P
European journal of heart failure. 2019;(5):624-633
Abstract
AIMS: The clinical significance of the measurement of urine sodium concentration (UNa+ ) in response to loop diuretic administration in patients with acute heart failure (AHF) is still unsettled. We studied the association of serial measurements of spot UNa+ during the first 48 h of AHF treatment with the indices of decongestion, renal function, and prognosis. METHODS AND RESULTS We enrolled 111 AHF patients, all of whom received intravenous furosemide on admission. The mean spot UNa+ significantly increased in the 6 h sample (P < 0.05 vs. baseline) and returned to baseline values in the 24 and 48 h samples. Based on the increase or decrease/no change of UNa+ in the 6 and 48 h samples vs. baseline, patients were divided into two groups at each time point, respectively. Patients did not differ in baseline clinical and laboratory characteristics. Patients with a decrease/no change of UNa+ in the 6 and 48 h samples had a lower weight loss during hospitalization. Patients with a decrease/no change of UNa+ in the 48 h sample had a poorer diuretic response and a significant increase in the urinary levels of the tubular biomarkers: kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Low UNa+ and decrease/no change in UNa+ in the 6 and 48 h samples were independent predictors of higher risk of all-cause mortality during 1-year follow-up (all P < 0.05). CONCLUSION In AHF, low spot UNa+ and lack to increase UNa+ in response to intravenous diuretics are associated with poor diuretic response, markers of tubular injury and high risk of 1-year mortality.
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The furosemide stress test for prediction of worsening acute kidney injury in critically ill patients: A multicenter, prospective, observational study.
Rewa, OG, Bagshaw, SM, Wang, X, Wald, R, Smith, O, Shapiro, J, McMahon, B, Liu, KD, Trevino, SA, Chawla, LS, et al
Journal of critical care. 2019;:109-114
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Abstract
PURPOSE To validate the furosemide stress test (FST) for predicting the progression of acute kidney injury (AKI). MATERIALS AND METHODS We performed a multicenter, prospective, observational study in patients with stage I or II AKI. The FST (1 mg/kg for loop diuretic naïve patients and 1.5 mg/kg in patients previously exposed to loop diuretics) was administered. Subsequent urinary flow rate (UFR) recorded and predictive ability of urinary output was measured by the area under the curve receiver operatic characteristics (AuROC). Primary outcome was progression to Stage III AKI. Secondary outcomes included in-hospital mortality and adverse events. RESULTS We studied 92 critically ill patients. 23 patients progressed to stage III AKI and had significantly lower UFR (p < 0.0001). The UFR during the first 2 h was most predictive of progression to stage III AKI (AuROC = 0.87), with an ideal cut-off of less than 200mls, with a sensitivity of 73.9% and specificity of 90.0%. CONCLUSION In ICU patients without severe CKD with mild AKI, a UFR of less than 200mls in the first 2 h after an FST is predictive of progression to stage III AKI. Future studies should focus on incorporating a FST as part of a clinical decision tool for further management of critically ill patients with AKI.
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Different diuretic properties between tolvaptan and furosemide in congestive heart failure patients with diuretic resistance and renal impairment: a subanalysis of the K-STAR.
Ikeda, Y, Inomata, T, Kida, K, Shibagaki, Y, Sato, N, Izumi, T, Ako, J, ,
Heart and vessels. 2019;(3):442-451
Abstract
We attempted to identify the difference in diuretic properties between tolvaptan (TLV) and furosemide (FUR) in congestive heart failure (CHF) patients with loop diuretic resistance and renal impairment. We investigated 81 CHF patients with loop diuretic treatment and renal impairment included in t he Kanagawa Aquaresis Investigators Trial of Tolvaptan on Heart Failure Patients with Renal Impairment (K-STAR). Predictive baseline factors and their changes during treatment periods were analyzed for correlation with percentage change in urine volume (%ΔUV) after additive introduction of TLV or increasing doses of FUR. Higher urine osmolality at baseline (β = 0.355; p = 0.033) in the TLV group and a lower ratio of blood urea nitrogen to serum creatinine (BUN/Cr, β = - 0.405; p = 0.020) in the FUR group were predictive of higher %ΔUV. Higher Δfree-water clearance (β = 0.667; p < 0.0001) in the TLV group, and higher %ΔBUN/Cr (β = 0.344; p = 0.030), higher %Δurine sodium concentration (β = 0.337; p = 0.037), and lower %Δstroke volume (β = - 0.390; p = 0.017) in the FUR group were correlated with %ΔUV. In conclusion, baseline urine osmolality and change in free-water clearance with additive introduction of TLV and a changing ratio of BUN/Cr with increasing doses of FUR were identified as key clinical parameters related to diuretic response.Trial registration UMIN000009201.
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Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies.
Biegus, J, Zymlinski, R, Siwolowski, P, Testani, J, Szachniewicz, J, Tycińska, A, Banasiak, W, Halpert, A, Levin, H, Ponikowski, P
European journal of heart failure. 2019;(9):1079-1087
Abstract
AIMS: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF. METHODS AND RESULTS The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment. CONCLUSIONS The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.
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Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial).
Trippel, TD, Van Linthout, S, Westermann, D, Lindhorst, R, Sandek, A, Ernst, S, Bobenko, A, Kasner, M, Spillmann, F, González, A, et al
European journal of heart failure. 2018;(3):460-470
Abstract
AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C-terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels. METHODS AND RESULTS We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel-group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (≥110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) >29 mL/m2 and abnormal PIP levels (≥70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m2 , 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of >60%, a left ventricular mass index >120 g/m2 , an E/e' ratio of 14, and a LAVI of 40 mL/m2 with a NT-proBNP of 174 ng/L and a 6-minute walk distance of 421 m. Mean per cent change in PIP was 2.63 ± 5.68% (±SEM) in torasemide vs. 2.74 ± 6.49% in furosemide (P = 0.9898) treated patients. Torasemide was not superior to furosemide in improving functional capacity, diastolic function, quality of life, or neuroendocrine activation. CONCLUSION In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted.
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Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.
Kiernan, MS, Stevens, SR, Tang, WHW, Butler, J, Anstrom, KJ, Birati, EY, Grodin, JL, Gupta, D, Margulies, KB, LaRue, S, et al
Journal of cardiac failure. 2018;(7):428-438
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Abstract
BACKGROUND Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.
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Prevention of postcontrast acute kidney injury after percutaneous transluminal angioplasty by inducing RenalGuard controlled furosemide forced diuresis with matched hydration: study protocol for a randomised controlled trial.
Bolt, LJJ, Sigterman, TA, Krasznai, AG, Sikkink, CJM, Schurink, GH, Bouwman, LH
BMJ open. 2018;(9):e021842
Abstract
INTRODUCTION Percutaneous transluminal angioplasty (PTA) is often complicated due to postcontrast acute kidney injury (PC-AKI) in patients diagnosed with chronic kidney disease (CKD). Hydration therapy is the cornerstone in the prevention of PC-AKI. Furosemide forced diuresis with matched hydration using the RenalGuard system enables a steady balance between diuresis and hydration. A randomised controlled trial will be performed in order to investigate whether furosemide forced diuresis with matched hydration in combination with the RenalGuard system decreases incidence of PC-AKI in patients with CKD receiving a PTA of the lower extremities. Furthermore, we will investigate whether sampling of urine biomarkers 4 hours after intervention can detect PC-AKI in an earlier stage compared with the golden standard, serum creatinine 48-72 hours postintervention. METHODS AND ANALYSIS A single-centre randomised controlled trial will be conducted. Patients >18 years in need of a PTA of the lower extremities and diagnosed with CKD will be randomly assigned to receive either standard of care prehydration and posthydration or furosemide forced diuresis with matched hydration periprocedural using the RenalGuard system. Four hours postintervention, a urine sample will be collected of all participating patients. Serum creatinine will be sampled within 10 days prior to intervention as well as 1, 3 and 30 days postintervention. The primary endpoint is incidence of PC-AKI post-PTA. Secondary endpoint is the rise of urine biomarkers 4 hours postintervention. ETHICS AND DISSEMINATION Study protocol is approved by the research ethics committee and institutional review board (reference number 16 T-201 and NL59809.096.16). Study results will be disseminated by oral presentation at conferences and will be submitted to a peer-reviewed journal. It is anticipated that study results will offer a solution to contrast-induced nephropathy in patients with CKD receiving a PTA of the lower extremities. TRIAL REGISTRATION NUMBER NTR6236; Pre-results. EUDRACT NUMBER 2016-005072-10.
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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.
Makimoto, G, Ichihara, E, Hotta, K, Ninomiya, K, Oze, I, Minami, D, Ninomiya, T, Kubo, T, Ohashi, K, Tabata, M, et al
Acta medica Okayama. 2018;(3):319-323
Abstract
Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.
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Aerosol furosemide for dyspnea: Controlled delivery does not improve effectiveness.
Morélot-Panzini, C, O'Donnell, CR, Lansing, RW, Schwartzstein, RM, Banzett, RB
Respiratory physiology & neurobiology. 2018;:146-155
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Aerosolized furosemide has been shown to relieve dyspnea; nevertheless, all published studies have shown great variability in response. This dyspnea relief is thought to result from the stimulation of slowly adapting pulmonary stretch receptors simulating larger tidal volume. We hypothesized that better control over aerosol administration would produce more consistent dyspnea relief; we used a clinical ventilator to control inspiratory flow and tidal volume. Twelve healthy volunteers inhaled furosemide (40mg) or placebo in a double blind, randomized, crossover study. Breathing Discomfort was induced by hypercapnia during constrained ventilation before and after treatment. Both treatments reduced breathing discomfort by 20% full scale. Effectiveness of aerosol furosemide treatment was weakly correlated with larger tidal volume. Response to inhaled furosemide was inversely correlated to furosemide blood level, suggesting that variation among subjects in the fate of deposited drug may determine effectiveness. We conclude that control of aerosol delivery conditions does not improve consistency of treatment effect; we cannot, however, rule out placebo effect.