Mihai Gheorghiade

BACKGROUND: Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia. METHODS: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. RESULTS: Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. CONCLUSIONS: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [ClinicalTrials.gov] [SALT-1] and NCT00201994 [ClinicalTrials.gov] [SALT-2].).

CONTEXT: The association between systolic blood pressure (SBP) at admission, clinical characteristics, and outcomes in patients hospitalized for heart failure who have reduced or relatively preserved systolic function has not been well studied. OBJECTIVE: To evaluate the relationship between SBP at admission, clinical profile, and outcomes in patients hospitalized for acute heart failure. DESIGN, SETTING, AND PATIENTS: Cohort study using data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry and performance-improvement program for patients hospitalized with heart failure at 259 US hospitals between March 2003 and December 2004. Patients were divided into quartiles by SBP at hospital admission (<120, 120-139, 140-161, and >161 mm Hg). In-hospital outcomes were based on 48,612 patients aged 18 years or older with heart failure. Of the 41,267 patients with left ventricular function assessed, 21,149 (51%) had preserved left ventricular function. Postdischarge outcomes were based on a prespecified subgroup (n = 5791, 10% of patients) with follow-up data assessed between 60 and 90 days. MAIN OUTCOME MEASURES: In-hospital and postdischarge mortality. RESULTS: Patients with higher SBP were more likely to be female and black and to have preserved systolic function. Fifty percent of the patients had SBP higher than 140 mm Hg at admission. Patients with lower SBP at admission had higher in-hospital and postdischarge mortality rates. Higher SBP at admission was associated with lower in-hospital mortality rates: 7.2% (<120 mm Hg), 3.6% (120-139 mm Hg), 2.5% (140-161 mm Hg), and 1.7% (>161 mm Hg) (P<.001 for overall difference). Postdischarge mortality rates in the follow-up cohort by SBP at admission were 14.0%, 8.4%, 6.0%, and 5.4%, respectively (P<.001 for overall difference). CONCLUSIONS: Systolic hypertension is common in patients hospitalized for heart failure. Systolic blood pressure is an independent predictor of morbidity and mortality in patients with heart failure with either reduced or relatively preserved systolic function. Low SBP (<120 mm Hg) at hospital admission identifies patients who have a poor prognosis despite medical therapy. These findings may have important therapeutic implications because characteristics and outcomes differ greatly among patients with heart failure with varying SBP.

BACKGROUND: Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents, it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors, as is often the case in current practice. METHODS: We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinically stable while receiving digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor (captopril or enalapril). The patients were randomly assigned in a double-blind fashion either to continue receiving digoxin (85 patients) or to be switched to placebo (93 patients) for 12 weeks. Otherwise, their medical therapy for heart failure was not changed. RESULTS: Worsening heart failure necessitating withdrawal from the study developed in 23 patients switched to placebo, but in only 4 patients who continued to receive digoxin (P < 0.001). The relative risk of worsening heart failure in the placebo group as compared with the digoxin group was 5.9 (95 percent confidence interval, 2.1 to 17.2). All measures of functional capacity deteriorated in the patients receiving placebo as compared with those continuing to receive digoxin (P = 0.033 for maximal exercise tolerance, P = 0.01 for submaximal exercise endurance, and P = 0.019 for New York Heart Association class). In addition, the patients switched from digoxin to placebo had lower quality-of-life scores (P = 0.04), decreased ejection fractions (P = 0.001), and increases in heart rate (P = 0.001) and body weight (P < 0.001). CONCLUSIONS: These findings indicate that the withdrawal of digoxin carries considerable risks for patients with chronic heart failure and impaired systolic function who have remained clinically stable while receiving digoxin and angiotensin-converting-enzyme inhibitors.