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Hyponatremia is common among hospitalized patients and has been associated with poor prognosis in those with heart failure.1 What is less clear, however, is whether low serum sodium represents a pharmacologic target or simply serves as a surrogate marker for the severity of disease. After all, efforts aimed at improving other surrogate markers in cardiovascular disease have not always conferred meaningful differences in clinical outcomes (e.g., hemoglobin, high-density lipoprotein).2,3
To date, the available evidence suggests that, while serum sodium concentrations can be improved with vasopressin antagonist therapy, these changes do not appear to confer meaningful differences in clinical outcomes. In SALT (Study of Ascending Levels of Tolvaptan in Hyponatremia), a trial evaluating the use of tolvaptan in patients with hyponatremia (a third of whom had heart failure), patients randomized to tolvaptan experienced improvements in urine output and serum sodium concentrations, but this only persisted while patients were on therapy.4 In less than a week after discontinuing tolvaptan, serum sodium concentrations returned to baseline.
In EVEREST (The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan), a trial specifically enrolling patients with acute decompensated heart failure (ADHF) irrespective of serum sodium concentrations, those randomized to tolvaptan experienced greater reductions in body weight and improvements in some but not all heart failure signs and symptoms.5 Tolvaptan failed to impart any clinically meaningful differences in mortality, hospitalizations, worsening heart failure, or quality of life.6 Serum sodium concentrations improved initially but these differences dissipated with time.
Most recently, in TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure), patients with ADHF were randomized within 24 hours of presentation to tolvaptan or placebo.7 No differences in the primary endpoint of moderate dyspnea relief was observed between the two groups. Consistent with previous trials, greater weight and volume loss was observed in the tolvaptan group although these improvements were accompanied by higher rates of worsening renal function. As with EVEREST, serum sodium concentrations improved in patients receiving tolvaptan although this was not a focus of the trial.
Thus, according to these and other trials, tolvaptan may improve serum sodium concentrations and aid in volume removal, but it does not appear to have an appreciable effect on the underlying pathophysiology of heart failure. Furthermore, recurrence of hyponatremia can be expected following cessation of therapy, especially if underlying causes for hyponatremia remain unaddressed (e.g., reduced renal perfusion, hypervolemia).
To be completely fair, the failure of tolvaptan to improve morbidity and mortality in ADHF is no different from diuretics, which also improve signs and symptoms of congestion yet fail to confer meaningful differences in other outcomes. However, diuretics have become ubiquitous in the management of ADHF due to their predictable safety and efficacy profiles and low cost. Where tolvaptan differs primarily is its expense. In TACTICS-HF, investigators reported an estimated cost of $1200 for a mere 48 hours of therapy, or $2.3 per mL of volume loss.7
Combined with the lack of overall benefit observed to date, it is doubtful that tolvaptan will become routine in the management of ADHF in the near future. Perhaps in 15-20 years (assuming the price of tolvaptan decreases substantially), the drug can become another tool in the management of patients with ADHF and refractory congestion (i.e., as thiazide-type diuretics or intravenous vasodilators are used now). Otherwise, its utility remains limited and tolvaptan should be primarily reserved for the following:
- Patients with symptomatic hypervolemic hyponatremia at any serum sodium concentration; or,
- As a temporizing measure to stabilize critically low serum sodium concentrations (e.g., < 125 mEq/L) while underlying causes are corrected, such as discontinuation of potentially offending drugs, optimization of standard heart failure therapies, addition of vasodilators or inotropes to improve renal perfusion, or aggressive diuresis to correct hypervolemia.
(That being said, evidence suggests that small boluses of hypertonic saline can improve hyponatremia in these scenarios without worsening fluid balance.8)
Given a lack of compelling benefit and excess cost, routine tolvaptan use should be avoided in ADHF, except in patients with symptomatic hypervolemic hyponatremia or in those with severe hyponatremia (< 125 mEq/L) that fails to improve with other treatment modalities.
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed
- Adams KF Jr, Fonarow GC, Horton DP, et al; ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005 Feb;149(2):209-16.
- Swedberg K, Young JB, van Veldhuisen DJ, et al; for the RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar 28;368(13):1210-9.
- Keene D, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014 Jul 18;349:g4379.
- Schrier RW, Gross P, Orlandi C, et al; for the SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112.
- Gheorghiade M, Konstam MA, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007 Mar 28;297(12):1332-43.
- Konstam MA, Gheorghiade M, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31.
- Felker GM, Mentz RJ, Cole R, et al. Efficacy and Safety of Tolvaptan in Patients Hospitalized with Acute Heart Failure.J Am Coll Cardiol. 2016 Sep 13. pii: S0735-1097(16)35321-9.
- Licata G, Di Pasquale P, Paterna S, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J. 2003 Mar;145(3):459-66.
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