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AQUARESIS UTILITY FOR HYPONATREMIC ACUTE HEART FAILURE (AQUA-AHF) STUDY

Description

Hyponatremia is a common finding in acute heart faiilure (HF) patients and is associated with worse prognosis. In addition to its prognostic value, hyponatremia may have importance during the acute management of HF. Weve recently shown that acute or chronic hyponatremia, especially <130 mEq/L, was associated with higher loop diuretic dose requirements and more frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as normornatremic HF patients. Loop diuretics such as furosemide exert a diuretic effect through blockade of sodium reabsorption in the thick ascending limb of the Loop of Henle (natriuesis). Furosemide is the most common loop diuretic used for diuresis in HF and is an FDA approved drug. Vasopressin receptor antagonists such as tolvaptan cause diuresis through blockade of aquaporin channels in the collecting duct leading to free water elimination (aquaresis). Aquaresis with tolvaptan represents a potentially advantageous approach to the management of volume overload in HF, especially in patients presenting with concomitant hyponatremia. Tolvaptan is FDA approved for the treatment of euvolemic and hypervolemic hyponatremia (including SIADH and HF). The purpose of the current study is to prospectively evaluate the comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to conventional diuresis with a furosemide-based regimen on short-term clinical and treatment outcomes in hyponatremic acute HF patients.This will be a prospective, open-label, parallel-group, randomized study comparing a tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based regimen of furosemide. Up to 50 (target sample size of 50) adult subjects admitted with acute HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomzied to tolvaptan or furosemide treatment arms (maximum of 25 subjects will be enrolled with serum sodium in the range of 130-134 mEq/L). The initial 24 hours of study treatment will compare tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment regimens may be altered to achieve desired clinical goals. Patients will be followed for up to 96 hours and at discharge for study purposes. The primary efficacy endpoint is mean urine output at 24 hours post randomization. Secondary efficacy endpoints include mean urine output at time points up to 96 hours, serum sodium changes, weight change and cumulative furosemide dose. The primary safety endpoint is mean change in serum creatinine at 24 hours post randomization. Patients will also have blood drawn to assess changes in plasma renin activity, copeptin, NT-proBNP, and cystatin C. Descriptive statistics will be computed for each treatment group. For all comparative analyses between the two treatment groups, independent samples t-test and Chi-Square test (or Fishers exact test) will be performed for continuous variables or categorical variables, respectively. If either the normality or equal-variance assumptions underlying the traditional t-tests are violated, a non-parametric test will be used.

Phase

N/A

Inclusion and Exclusion Criteria

  • Acute HF with signs or symptoms of volume overload [i.e. elevated jugular venous pulsation (JVP), rales, edema]
  • Serum sodium < 135 mEq/L at time of or within first 48 hours of hospitalization
  • Randomized within 48 hours of presentation to hospital
  • ≥ 18 years of age
  • Informed consent

  • Severe symptomatic hyponatremia requiring acute treatment
  • Severe renal impairment upon admission (creatinine clearance < 20 mL/min)
  • Renal replacement therapy dependent, or requiring upon admission
  • Acute coronary syndrome on admission
  • Requires or has a mechanical circulatory support device
  • Evidence of cardiogenic shock requiring intravenous vasopressors
  • Pregnancy
  • Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin)

Sites

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