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      Conivaptan: Evidence supporting its therapeutic use in hyponatremia

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          Abstract

          Introduction:

          The available treatment options for euvolemic and hypervolemic hyponatremia are limited, and consist mainly of fluid restriction, diuresis, or hypertonic solutions. Most of these therapies are neither well tolerated nor totally effective, and many are associated with significant adverse effects. Vasopressin receptor antagonists, also known as vaptans, are a new class of agents that now offer an additional treatment option for hyponatremic patients. Conivaptan hydrochloride, a competitive antagonist of vasopressin V1a and V2 receptors, is the first agent in this class to be approved for treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients.

          Aims:

          This review critically assesses the evidence that support the use of conivaptan for the treatment of patients with euvolemic and hypervolemic hyponatremia.

          Evidence review conclusion:

          Conivaptan is effective in raising serum sodium levels in a predictable and safe fashion in euvolemic and hypervolemic hyponatremic patients. Conivaptan provides the first molecularly targeted approach for correcting hyponatremia in hospitalized patients.

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          Most cited references25

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          Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.

          Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure. To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment. Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy. Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema. During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups. Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity. clinicaltrials.gov Identifier: NCT00071331
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            Incidence and prevalence of hyponatremia.

            Hyponatremia is the most common electrolyte abnormality encountered in clinical practice. The reported frequency of the disorder is determined by a number of factors, including the definition of hyponatremia, the frequency of testing, the healthcare setting, and the patient population. This review focuses on the incidence and prevalence of hyponatremia. In acute hospital care, particular attention is given to admission versus hospital-acquired hyponatremia. Although less well studied, the epidemiology of hyponatremia in the ambulatory-based setting and the geriatric/nursing home population is also summarized. Finally, the frequency of hyponatremia occurring in special clinical conditions--including congestive heart failure, cirrhosis, pneumonia, and acquired immunodeficiency syndrome--as well as in marathon runners will be reviewed. Substantial additional work is still required to determine the true occurrence of hyponatremia in the various clinical settings. Beyond the phenomenologic value, advances in the epidemiology of hyponatremia should also provide insights in the prognostic implications as well as the preventive and management strategies of the disorder in various clinical settings.
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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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                Author and article information

                Journal
                Core Evid
                Core Evidence
                Core evidence
                Dove Medical Press
                1555-1741
                1555-175X
                15 June 2010
                2009
                2009
                : 4
                : 83-92
                Affiliations
                Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC, USA
                Author notes
                Correspondence: Joseph G Verbalis, Professor of Medicine and Endocrinology, and Chief, Endocrinology and Metabolism, Division of Endocrinology and Metabolism, Georgetown University Medical Center, Building D, Suite 232, 4000 Reservoir Road NW, Washington, DC 20007, USA, Email verbalis@ 123456georgetown.edu
                Article
                ce-4-083
                10.2147/CE.S5997
                2899773
                20694067
                c0b61582-a97f-4ef5-89c6-1f56831e85f9
                © 2009 Li-Ng and Verbalis, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 24 June 2009
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                arginine vasopressin (avp),conivaptan hydrochloride,hyponatremia,arginine vasopressin (avp) receptor antagonist

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