Background: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA).Methods and Results: Eligible patients had FIF (New York Heart Association Class 11411), systolic dysfunction (left ventricular ejection fraction <= 0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosernide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 +/- 1.61, -0.54 +/- 1.59, and -1.13 +/- 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 +/- 2.42 kg versus baseline (P = .0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 +/- 1503 mL/24 hours) than with FURO (894 +/- 853 mL/24 hours, P < .001), or PLC (423 +/- 786 mL/24 hours, P < .001), and similar to TLV+FURO (2585 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P < .02 versus placebo; P < .01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated.Conclusions: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and beta-blockers. (J Cardiac Fail 2011;17:973-981)

Copyright © 2009 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/CIRCULATIONAHA.108.834424 2009;119;3093-3100; originally published online Jun 8, 2009; Circulation Mei-Chiung Shih and Phil Lavori O'Brien, Inder Anand, Alberta Warner, Brack Hattler, Mark Dunlap, John Erikson, Terrence Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Steven Goldman, Madeline McCarren, Eugene Morkin, Paul W. Ladenson, Robert Heart Failure: Phase II Trial Veterans Affairs Cooperative Study DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.834424/DC1 Data Supplement (unedited) at: http://circ.ahajournals.org/cgi/content/full/119/24/3093 located on the World Wide Web at: The online version of this article, along with updated information and services, is

Background-In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects.Methods and Results-This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2: 1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n = 57 to DITPA, n = 29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen.Conclusions-DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009; 119: 3093-3100.)

Background— In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results— This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (−20%), low-density lipoprotein cholesterol (−30%), and body weight (−11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions— DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

DITPA, a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial VA Cooperative Study Steven Goldman*, Madeline McCarren*, Eugene Morkin, Paul Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O’Brien, Inder Anand, Alberta Warner, Mark Dunlap, Brack Hattle, John Erikson, Mei-Chiung Shih, Phil Lavori; Southern Arizona VA Health Care System, Tucson, AZ; VA Center for Medication Safety, Hines, IL; University of Arizona Health Sciences, Tucson, AZ; Johns Hopkins University, Baltimore, MD; Palo Alto CSP Coordinating Center, Palo Alto, CA; CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; VA Medical Center, Charleston, SC; Minneapolis VA Medical Center, Minneapolis, MN; Greater Los Angeles Healthcare System, Los Angeles, CA; Louis Stokes VA Healthcare System, Cleveland, OH; VA Eastern Colorado Health Care System, Denver, CO; South Texas Veterans Health Care System, San Antonio, TX

Objectives This study sought to examine the effects of vasopressin V-2 receptor antagonism with tolvaptan on the changes in left ventricular (LV) volumes over time.Background Vasopressin levels may be increased in patients with heart failure (HF) and may be a factor driving the progression of HF.Methods This was a multicenter, randomized, double-blind, placebo-controlled trial conducted to evaluate the effect of long-term administration of the vasopressin V-2-receptor antagonist tolvaptan (30 mg,/day) on reducing left ventricular end-diastolic volume (LVEDV) compared with placebo in patients with HF and reduced systolic function, using quantitative radionuclide ventriculography at baseline, repeated after 1 year of therapy, and repeated again approximately 1 week after withdrawal of study drug.Results A total of 120 patients were randomized to tolvaptan and 120 were randomized to placebo. In the placebo group, there was no change in LVEDV over the course of follow-up (change of 0.0 +/- 10.0 ml/m(2)). After 1 year of tolvaptan, there was a small reduction in LV volume (decrease of 1.8 +/- 10.7 ml/m(2)); the between-group difference was not significant (p = 0.21). During the course of the trial, there were 6 deaths (5%) and 21 HF hospitalizations (18%) in the tolvaptan group, compared with 11 deaths (9%) and 34 HF hospitalizations (28%) in the placebo group. In a time-to-event analysis, there was a significant favorable effect of tolvaptan on the composite of mortality or heart failure hospitalization (p < 0.03 by log-rank test).Conclusions In a well-treated population of stable HF patients, there was no significant effect of tolvaptan therapy on LV volumes observed during 1 year of therapy. Nonprespecified natural history data favored therapy with tolvaptan, with a reduction in the combined end point of mortality and heart failure hospitalization observed. (Multicenter, Randomized, Double-Blind, Placebo Controlled, Efficacy Study on the Effects of Tolvaptan on Left Ventricuiar Dilatation in Congestive Heart Failure Patients; http://clinicaltrials.gov/ct/ show/NCT00043758?order = 1; NCT00043758).