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      Early treatment with tolvaptan improves diuretic response in acute heart failure with renal dysfunction

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          Abstract

          Background

          Poor response to diuretics is associated with worse prognosis in patients with acute heart failure (AHF). We hypothesized that treatment with tolvaptan improves diuretic response in patients with AHF.

          Methods

          We performed a secondary analysis of the AQUAMARINE open-label randomized study in which a total of 217 AHF patients with renal impairment (eGFR < 60 mL/min/1.73 m 2) were randomized to either tolvaptan or conventional treatment. We evaluated diuretic response to 40 mg furosemide or its equivalent based on two different parameters: change in body weight and net fluid loss within 48 h.

          Results

          The mean time from patient presentation to randomization was 2.9 h. Patients with a better diuretic response showed greater relief of dyspnea and less worsening of renal function. Tolvaptan patients showed a significantly better diuretic response measured by diuretic response based both body weight [−1.16 (IQR −3.00 to −0.57) kg/40 mg vs. −0.51 (IQR −1.13 to −0.20) kg/40 mg; P < 0.001] and net fluid loss [2125.0 (IQR 1370.0–3856.3) mL/40 mg vs. 1296.3 (IQR 725.2–1726.5) mL/40 mg; P < 0.001]. Higher diastolic blood pressure and use of tolvaptan were independent predictors of a better diuretic response.

          Conclusions

          Better diuretic response was associated with greater dyspnea relief and less WRF. Early treatment with tolvaptan significantly improved diuretic response in AHF patients with renal dysfunction.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00392-017-1122-1) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries.

          Heart failure is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in both the United States and Europe. Although the outcomes for ambulatory HF patients with a reduced ejection fraction (EF) have improved with the discovery of multiple evidence-based drug and device therapies, hospitalized heart failure (HHF) patients continue to experience unacceptably high post-discharge mortality and readmission rates that have not changed in the last 2 decades. In addition, the proportion of HHF patients classified as having a preserved EF continues to grow and may overtake HF with a reduced EF in the near future. However, the prognosis for HF with a preserved EF is similar and there are currently no available disease-modifying therapies. HHF registries have significantly improved our understanding of this clinical entity and remain an important source of data shaping both public policy and research efforts. The authors review global HHF registries to describe the patient characteristics, management, outcomes and their predictors, quality improvement initiatives, regional differences, and limitations of the available data. Moreover, based on the lessons learned, they also propose a roadmap for the design and conduct of future HHF registries. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.

            Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, shows promise in this condition. To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure. Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied. Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission. Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge). Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events. clinicaltrials.gov Identifier: NCT00071331
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              Diuretic response in acute heart failure: clinical characteristics and prognostic significance.

              Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for diuretic response, examine associated patient characteristics and relationships with outcome. We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 response was used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses. We investigated predictors of diuretic response and relationships with outcome. The median diuretic response was -0.38 (-0.80 to -0.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P < 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11-1.81, P = 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14-1.59, P < 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24-2.01, P < 0.001) in multivariable models. The proposed metric-weight loss indexed to diuretic dose-better captures a dose-response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal. Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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                Author and article information

                Contributors
                +81-4709-2211 , yuya8950@gmail.com
                Journal
                Clin Res Cardiol
                Clin Res Cardiol
                Clinical Research in Cardiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1861-0684
                1861-0692
                24 May 2017
                24 May 2017
                2017
                : 106
                : 10
                : 802-812
                Affiliations
                [1 ]Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [2 ]ISNI 0000 0004 0378 2140, GRID grid.414927.d, Department of Cardiology, , Kameda Medical Center, ; 929, Higashi-Cho, Kamogawa, Chiba Japan
                [3 ]ISNI 0000 0001 1516 6626, GRID grid.265061.6, Department of Cardiology, , Tokai University School of Medicine, ; Kanagawa, Japan
                [4 ]GRID grid.460111.3, Department of Cardiology, , Tomishiro Central Hospital, ; Okinawa, Japan
                [5 ]ISNI 0000 0000 9912 5284, GRID grid.417093.8, Department of Cardiology, , Tokyo Metropolitan Hiroo Hospital, ; Tokyo, Japan
                [6 ]ISNI 0000 0004 1764 8671, GRID grid.416773.0, Department of Cardiology, , Ome Municipal General Hospital, ; Tokyo, Japan
                [7 ]ISNI 0000 0004 0641 1505, GRID grid.417365.2, Department of Cardiology, , Yokohama Minami Kyosai Hospital, ; Kanagawa, Japan
                [8 ]ISNI 0000 0004 0466 8016, GRID grid.410843.a, Department of Cardiovascular Medicine, , Kobe City Medical Center General Hospital, ; Kobe, Japan
                [9 ]Department of Cardiology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
                [10 ]GRID grid.470115.6, Division of Cardiovascular Medicine, , Toho University Ohashi Medical Center, ; Tokyo, Japan
                [11 ]ISNI 0000 0004 0618 7777, GRID grid.414150.5, Department of Cardiology, , Hiratsuka Kyosai Hospital, ; Kanagawa, Japan
                [12 ]ISNI 0000 0004 1775 3041, GRID grid.416085.e, Department of Cardiology, , Tokyo Yamate Medical Center, ; Tokyo, Japan
                [13 ]GRID grid.413411.2, Department of Cardiology, , The Sakakibara Heart Institute of Okayama, ; Okayama, Japan
                [14 ]ISNI 0000 0004 0569 9594, GRID grid.416797.a, Department of Cardiology, , National Disaster Medical Center, ; Tokyo, Japan
                [15 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, , Harvard T. H. Chan School of Public Health, ; Boston, MA USA
                [16 ]ISNI 0000 0000 9206 4546, GRID grid.414021.2, Division of Cardiology, , Hennepin County Medical Center and University of Minnesota, ; Minneapolis, MN USA
                Author information
                http://orcid.org/0000-0003-2456-8525
                Article
                1122
                10.1007/s00392-017-1122-1
                5613036
                28540483
                daca6127-9137-4e93-8580-13df0ca1d7d7
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 8 March 2017
                : 19 May 2017
                Funding
                Funded by: Japan Heart Foundation Multicenter Study Grant
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag GmbH Germany 2017

                Cardiovascular Medicine
                acute heart failure,diuretics,worsening renal function,dyspnea relief
                Cardiovascular Medicine
                acute heart failure, diuretics, worsening renal function, dyspnea relief

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