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      Differential Effects of Levosimendan and Dobutamine on Glomerular Filtration Rate in Patients With Heart Failure and Renal Impairment:A Randomized Double‐Blind Controlled Trial

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          Abstract

          Background

          The management of the cardiorenal syndrome in advanced heart failure is challenging, and the role of inotropic drugs has not been fully defined. Our aim was to compare the renal effects of levosimendan versus dobutamine in patients with heart failure and renal impairment.

          Methods and Results

          In a randomized double‐blind study, we assigned patients with chronic heart failure (left ventricular ejection fraction <40%) and impaired renal function (glomerular filtration rate <80 mL/min per 1.73 m 2) to receive either levosimendan (loading dose 12 μg/kg+0.1 μg/kg per minute) or dobutamine (7.5  μg/kg per minute) for 75 minutes. A pulmonary artery catheter was used for measurements of systemic hemodynamics, and a renal vein catheter was used to measure renal plasma flow by the infusion clearance technique for PAH (para‐aminohippurate) corrected by renal extraction of PAH. Filtration fraction was measured by renal extraction of chromium ethylenediamine tetraacetic acid. A total of 32 patients completed the study. Following treatment, the levosimendan and dobutamine groups displayed similar increases in renal blood flow (22% and 26%, respectively) with no significant differences between groups. Glomerular filtration rate increased by 22% in the levosimendan group but remained unchanged in the dobutamine group ( P=0.012). Filtration fraction was not affected by levosimendan but decreased by 17% with dobutamine ( P=0.045).

          Conclusions

          In patients with chronic heart failure and renal impairment, levosimendan increases glomerular filtration rate to a greater extent than dobutamine and thus may be the preferred inotropic agent for treating patients with the cardiorenal syndrome.

          Clinical Trial Registration

          URL: https://www.clinicaltrials.gov. Unique identifier: NCT02133105.

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          Most cited references24

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          Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease.

          We sought to investigate the relationship between increased central venous pressure (CVP), renal function, and mortality in a broad spectrum of cardiovascular patients. The pathophysiology of impaired renal function in cardiovascular disease is multifactorial. The relative importance of increased CVP has not been addressed previously. A total of 2,557 patients who underwent right heart catheterization in the University Medical Center Groningen, the Netherlands, between January 1, 1989, and December 31, 2006, were identified, and their data were extracted from electronic databases. Estimated glomerular filtration rate (eGFR) was assessed with the simplified modification of diet in renal disease formula. Mean age was 59 +/- 15 years, and 57% were men. Mean eGFR was 65 +/- 24 ml/min/1.73 m(2), with a cardiac index of 2.9 +/- 0.8 l/min/m(2) and CVP of 5.9 +/- 4.3 mm Hg. We found that CVP was associated with cardiac index (r = -0.259, p < 0.0001) and eGFR (r = -0.147, p < 0.0001). Also, cardiac index was associated with eGFR (r = 0.123, p < 0.0001). In multivariate analysis CVP remained associated with eGFR (r = -0.108, p < 0.0001). In a median follow-up time of 10.7 years, 741 (29%) patients died. We found that CVP was an independent predictor of reduced survival (hazard ratio: 1.03 per mm Hg increase, 95% confidence interval: 1.01 to 1.05, p = 0.0032). Increased CVP is associated with impaired renal function and independently related to all-cause mortality in a broad spectrum of patients with cardiovascular disease.
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            Renal function as a predictor of outcome in a broad spectrum of patients with heart failure.

            Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced ( 40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 micromol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.
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              Renal function, neurohormonal activation, and survival in patients with chronic heart failure.

              Because renal function is affected by chronic heart failure (CHF) and it relates to both cardiovascular and hemodynamic properties, it should have additional prognostic value. We studied whether renal function is a predictor for mortality in advanced CHF, and we assessed its relative contribution compared with other established risk factors. In addition, we studied the relation between renal function and neurohormonal activation. The study population consisted of 1906 patients with CHF who were enrolled in a recent survival trial (Second Prospective Randomized study of Ibopamine on Mortality and Efficacy). In a subgroup of 372 patients, plasma neurohormones were determined. The baseline glomerular filtration rate (GFR(c)) was calculated using the Cockroft Gault equation. GFR(c) was the most powerful predictor of mortality; it was followed by New York Heart Association functional class and the use of angiotensin-converting enzyme inhibitors. Patients in the lowest quartile of GFR(c) values ( 76 mL/min). Impaired left ventricular ejection fraction (LVEF) was only modestly predictive (P=0.053). GFR(c) was inversely related with N-terminal atrial natriuretic peptide (ANP; r=-0.53) and, to a lesser extent, with ANP itself (r=-0.35; both P<0.001). Impaired renal function (GFR(c)) is a stronger predictor of mortality than impaired cardiac function (LVEF and New York Heart Association class) in advanced CHF, and it is associated with increased levels of N-terminal ANP. Moreover, impaired renal function was not related to LVEF, which suggests that factors other than reduced cardiac output are causally involved.
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                Author and article information

                Contributors
                lukas.lannemyr@vgregion.se
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                16 August 2018
                21 August 2018
                : 7
                : 16 ( doiID: 10.1002/jah3.2018.7.issue-16 )
                : e008455
                Affiliations
                [ 1 ] Department of Anesthesiology and Intensive Care Medicine University of Gothenburg Sahlgrenska University Gothenburg Sweden
                [ 2 ] Department of Cardiology Sahlgrenska University Hospital Gothenburg Sweden
                [ 3 ] Department of Transplantation Sahlgrenska University Hospital Gothenburg Sweden
                Author notes
                [*] [* ] Correspondence to: Lukas Lannemyr, MD, Department of Anaesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Bla Straket 7, van 5. 41345 Gothenburg, Sweden. E‐mail: lukas.lannemyr@ 123456vgregion.se
                Article
                JAH33403
                10.1161/JAHA.117.008455
                6201411
                30369310
                08d8418e-9425-4540-9d43-9e5614292788
                © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 26 April 2018
                : 02 July 2018
                Page count
                Figures: 2, Tables: 4, Pages: 9, Words: 6285
                Funding
                Funded by: Swedish State Support for Clinical Research
                Funded by: Swedish Heart‐Lung Foundation
                Funded by: Gothenburg Medical Society
                Categories
                Original Research
                Original Research
                Kidney in Cardiovascular Disease
                Custom metadata
                2.0
                jah33403
                21 August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:21.08.2018

                Cardiovascular Medicine
                dobutamine,heart failure,hemodynamics,levosimendan,renal function,clinical studies,nephrology and kidney

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