Diuretic Treatment in Heart Failure Ellison, David H; Felker, G Michael
New England journal of medicine/The New England journal of medicine,
2017-Nov-16, Letnik:
377, Številka:
20
Journal Article
Abstract Background Classification of chronic heart failure (HF) is on the basis of criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and ...therapeutic strategies. Objectives This study used cluster analysis to explore clinical phenotypes in chronic HF patients. Methods A cluster analysis was performed on 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, which evaluated exercise training versus usual care in chronic systolic HF. An association between identified clusters and clinical outcomes was assessed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing. Results Four clusters were identified (ranging from 248 to 773 patients in each), in which patients varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life, cardiopulmonary exercise testing parameters, and biomarker levels. Differential associations were observed for hospitalization and mortality risks between and within clusters. Compared with cluster 1, risk of all-cause mortality and/or all-cause hospitalization ranged from 0.65 (95% confidence interval 95% CI: 0.54 to 0.78) for cluster 4 to 1.02 (95% CI: 0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had a disproportionately lower risk of 0.61 (95% CI: 0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak oxygen consumption and clinical outcomes between clusters (p for interaction <0.04). Conclusions Cluster analysis of clinical variables identified 4 distinct phenotypes of chronic HF. Our findings underscore the high degree of disease heterogeneity that exists within chronic HF patients and the need for improved phenotyping of the syndrome. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
Congestion and volume overload are the hallmarks of acute decompensated heart failure (ADHF), and loop diuretics have historically been the cornerstone of treatment. The demonstrated efficacy of loop ...diuretics in managing congestion is balanced by the recognized limitations of diuretic resistance, neurohormonal activation, and worsening renal function. However, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial suggests that previous concerns about the safety of high-dose diuretics may not be valid. There has been a growing interest in alternative strategies to manage volume retention in ADHF with improved efficacy and safety profiles. Peripheral venovenous ultrafiltration (UF) represents a potentially promising approach to volume management in ADHF. Small studies suggest that UF may allow for more effective fluid removal compared with diuretics, with improved quality of life and reduced rehospitalization rates. However, further investigation is needed to completely define the role of UF in patients with ADHF. This review summarizes available data on the use of both diuretics and UF in ADHF patients and identifies challenges and unresolved questions for each approach.
Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity ...and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown.
To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency.
Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites.
Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks.
The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life).
Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range IQR, 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min 95% CI, -34 to +76 mL/min; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05.
Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF.
clinicaltrials.gov Identifier: NCT02188784.
Natriuretic peptides have led the way as a diagnostic and prognostic tool for the diagnosis and management of heart failure (HF). More recent evidence suggests that natriuretic peptides along with ...the next generation of biomarkers may provide added value to medical management, which could potentially lower risk of mortality and readmissions. The purpose of this scientific statement is to summarize the existing literature and to provide guidance for the utility of currently available biomarkers.
The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through December 2016. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or contemporary clinical practice recommendations.
A number of biomarkers associated with HF are well recognized, and measuring their concentrations in circulation can be a convenient and noninvasive approach to provide important information about disease severity and helps in the detection, diagnosis, prognosis, and management of HF. These include natriuretic peptides, soluble suppressor of tumorgenicity 2, highly sensitive troponin, galectin-3, midregional proadrenomedullin, cystatin-C, interleukin-6, procalcitonin, and others. There is a need to further evaluate existing and novel markers for guiding therapy and to summarize their data in a standardized format to improve communication among researchers and practitioners.
HF is a complex syndrome involving diverse pathways and pathological processes that can manifest in circulation as biomarkers. A number of such biomarkers are now clinically available, and monitoring their concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies.
Background
Whereas heart failure (HF) is a complex clinical syndrome, conventional approaches to its management have treated it as a singular disease, leading to inadequate patient care and ...inefficient clinical trials. We hypothesized that applying advanced analytics to a large cohort of HF patients would improve prognostication of outcomes, identify distinct patient phenotypes, and detect heterogeneity in treatment response.
Methods and Results
The Swedish Heart Failure Registry is a nationwide registry collecting detailed demographic, clinical, laboratory, and medication data and linked to databases with outcome information. We applied random forest modeling to identify predictors of 1‐year survival. Cluster analysis was performed and validated using serial bootstrapping. Association between clusters and survival was assessed with Cox proportional hazards modeling and interaction testing was performed to assess for heterogeneity in response to HF pharmacotherapy across propensity‐matched clusters. Our study included 44 886 HF patients enrolled in the Swedish Heart Failure Registry between 2000 and 2012. Random forest modeling demonstrated excellent calibration and discrimination for survival (C‐statistic=0.83) whereas left ventricular ejection fraction did not (C‐statistic=0.52): there were no meaningful differences per strata of left ventricular ejection fraction (1‐year survival: 80%, 81%, 83%, and 84%). Cluster analysis using the 8 highest predictive variables identified 4 clinically relevant subgroups of HF with marked differences in 1‐year survival. There were significant interactions between propensity‐matched clusters (across age, sex, and left ventricular ejection fraction and the following medications: diuretics, angiotensin‐converting enzyme inhibitors, β‐blockers, and nitrates, P<0.001, all).
Conclusions
Machine learning algorithms accurately predicted outcomes in a large data set of HF patients. Cluster analysis identified 4 distinct phenotypes that differed significantly in outcomes and in response to therapeutics. Use of these novel analytic approaches has the potential to enhance effectiveness of current therapies and transform future HF clinical trials.
Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a ...constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.
Abstract Background The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of ...patients with acute heart failure (AHF). Objectives To address the acute use of tolvaptan to improve congestion in AHF, we conducted the Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF, NCT01644331) study. Methods TACTICS-HF randomized patients within 24 hours of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 hours, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 hours. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. Results A total of 257 patients were randomized. Dyspnea relief by Likert scale was similar between tolvaptan and placebo at 8 hours (25% moderately or markedly improved for tolvaptan vs. 28% placebo, p=0.59) and at 24 hours (50% tolvaptan vs. 47% placebo, p=0.80). Need for rescue therapy was also similar at 24 hours (21% tolvaptan, 18% placebo, p=0.57). The proportion defined as responders at 24 hours (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p=0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared to placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. Conclusions In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 hours despite greater weight loss and fluid loss.
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