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      Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

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          Background: Most cases of hyponatremia – serum sodium concentration ([Na<sup>+</sup>]) <135 mEq/l (<135 m M) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V<sub>1A</sub>/V<sub>2</sub>-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na<sup>+</sup>] 115 to <130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na<sup>+</sup>], measured by the baseline-adjusted area under the [Na<sup>+</sup>]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na<sup>+</sup>] increase, total time patients had serum [Na<sup>+</sup>] ≧4 mEq/l higher than baseline, change in serum [Na<sup>+</sup>] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na<sup>+</sup>] or normal [Na<sup>+</sup>] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na<sup>+</sup>]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na<sup>+</sup>] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. Conclusion: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na<sup>+</sup>] and was well tolerated.

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          Most cited references 17

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            Introduction to sample size determination and power analysis for clinical trials.

            The importance of sample size evaluation in clinical trials is reviewed and a general method is presented from which specific equations are derived for sample size determination or the analysis of power for a wide variety os statistical procedures. The method is discussed and illustrated in relation to the t test, tests for proportions, tests of survival time, and tests for correlations as they commonly occur in clinical trials. Most of the specific equations reduce to a simple general form for which tables are presented.
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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. Identifier: NCT00071331

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                September 2007
                26 July 2007
                : 27
                : 5
                : 447-457
                aDepartment of Internal Medicine ‘D’, Sourasky Medical Center, Tel Aviv, Israel; bDepartment of Internal Medicine, WJB Dorn Veterans Hospital, Columbia, S.C., cDepartment of Medicine, Georgetown University Hospital, Washington, D.C., dAstellas Pharma US, Inc., Deerfield, Ill., USA; eUnitas Hospital, Lyttelton Manor, South Africa
                106456 Am J Nephrol 2007;27:447–457
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 4, References: 26, Pages: 11
                Original Report: Patient-Oriented, Translational Research


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