ECLIPSE Casts Light on Mechanisms Behind Tolvaptan's Relief of Heart Failure Symptoms

September 21, 2007

September 21, 2007 (Washington, DC) - One frustration heart-failure specialists are quick to discuss when they get together at scientific meetings centers on the short list of drug therapies available to relieve symptoms in patients with acute decompensated heart failure (ADHF) that don't come with nagging safety concerns. So it's with some interest that they are following the slow but steady progress of tolvaptan (Otsuka America Pharmaceuticals), a vasopressin receptor antagonist, in its march toward possible market approval.

A small, placebo-controlled dose-ranging study in patients with severe chronic heart failure [ 1] has provided what seems to be a portrait of the hemodynamic changes that went with the volume reduction and alleviation of dyspnea and other signs of congestion tolvaptan had previously demonstrated in larger randomized ADHF studies.

In the Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure (ECLIPSE) trial, a single dose of tolvaptan at any of three dose levels was associated with modest but significant declines in pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure, and right atrial pressure, reported Dr James E Udelson (Tufts University School of Medicine, Boston, MA) here at the Heart Failure Society of America 2007 Scientific Meeting.

The early, dose-dependent increases in urine output were more pronounced than the hemodynamic changes, comparable to what might be expected with loop diuretics, Udelson told heartwire . They were paralleled by significant declines in urine osmolality at all three dosages (p<0.0001); tolvaptan is also under investigation as a treatment for hyponatremia.

The drug showed it might have a future as an ADHF therapy in the randomized Efficacy of Vasopressin Antagonism in Heart Failure Trial (EVEREST), which was published earlier this year, presented at the American College of Cardiology 2007 Scientific Sessions, and covered then by heartwire . In the placebo-controlled trial with more than 4000 patients with ADHF, those who received tolvaptan on top of standard IV therapy showed in-hospital improvements in body weight and a composite end point reflecting clinical status, but no significant clinical effect over one year [ 2, 3].

Also previously reported by heartwire were the transatlantic twin trials, the Studies of Ascending Levels of Tolvaptan in Hyponatremia (SALT 1 and SALT 2), which showed that the drug could raise serum sodium levels in euvolemic or hypervolemic patients with hyponatremia associated with heart failure, cirrhosis, or other disorders. The results had been presented at the American Heart Association 2006 Scientific Sessions and published online the same day [ 4].

As for ECLIPSE, the trial randomized 181 patients in stable NYHA class 3-4 heart failure and with an LVEF <40% to receive a single dose of tolvaptan at 15 mg, 30 mg, or 60 mg or placebo during continuous monitoring with a Swan-Ganz pulmonary-artery catheter. Patients could be randomized only if their PCWP was at least 18 mm Hg; their baseline mean was 25 mm Hg. The tested dosage levels reflected those studied in EVEREST and the two SALT trials. Hemodynamics were measured regularly for 12 hours, and the patients were followed for a total of seven days.

Virtually all patients were on beta blockers and diuretics; 90% were on either ACE inhibitors or angiotensin receptor blockers, Udelson reported.

Primary hemodynamic finding after a single oral tolvaptan dose in ECLIPSE

End point 15 mg, n=44 30 mg, n=43 60 mg, n=46 Placebo, n=48
Peak PCWP change by 3–8 hours (mm Hg) -6.4 a -5.7 b -5.7 b -4.2

a. p=0.003 vs placebo
b. p<0.05 vs placebo

PCWP=pulmonary capillary wedge pressure

No significant differences were observed in the secondary end points of systolic blood pressure, systemic or pulmonary vascular resistance, cardiac index, or heart rate.

All tolvaptan dosages were associated with significant and sustained increases in urine output (p<0.01 vs placebo) that were most pronounced at the 60-mg level and the least at 15 mg.

About 54% of tolvaptan recipients and 33% of those receiving placebo experienced adverse effects apparently associated with "treatment." The most common of these effects--as already well characterized in the EVEREST data, Udelson observed--were thirst and dry mouth.

During the question-and-answer period following his presentation, Udelson said serum sodium levels remained stable in the placebo group but increased somewhat in the tolvaptan groups, to the greatest extent at the 60-mg dose. That effect has also been well characterized in the SALT trials and other studies. Together, the different trials suggest that tolvaptan can be a useful therapy in patients with hyponatremia and also alleviate congestion in those with ADHF, he said, "whether they're hyponatremic or not."

ECLIPSE was funded by Otsuka America Pharmaceuticals, from which its investigators received research support. Several coauthors are employees of the company. In addition, Udelson reports being a consultant for and receiving honoraria from Otsuka and being a consultant for Acusphere and Molecular Insight Pharmaceuticals.

  1. Udelson JE, Orlandi C, Ouyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: the ECLIPSE international, multicenter, randomized, placebo-controlled trial. Heart Failure Society of America 2006 Scientific Meeting; September 19, 2007; Washington, DC. Recent and Late-Breaking Trials session.

  2. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007; 297:1319-1331. Abstract

  3. Gheorghiade M, Konstam MA, Burnett, JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA 2007; 297:1332-1343. Abstract

  4. Schrier RW, Gross P, Gheorghiade M, et al for the SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099-2112. Abstract

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