Hospitalization rates for heart failure are high, and six-month readmission rates approach 50 percent. Because volume expansion often leads to exacerbation, diuretics are the mainstay of therapy, but these drugs can have adverse effects and do not prolong survival. A medication that blocks arginine-vasopressin might have long-term pharmacologic benefits similar to those of other medications for congestive heart failure (CHF), such as angiotensin-converting enzyme inhibitors and beta blockers, but it also may have an added benefit of relieving volume overload and congestion immediately when combined with diuretics. In this study, Gheorghiade and colleagues compared the vasopressin V₂ receptor antagonist tolvaptan with placebo in the usual acute care of patients hospitalized for CHF.

In the double-blind, controlled Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, patients 18 years or older with CHF and an ejection fraction of less than 40 percent were randomized to one of three doses (i.e., 30, 60, or 90 mg) of tolvaptan or placebo, with all groups receiving concomitant standard care, including diuretics. The primary outcomes included acute (in-hospital) and intermediate-term (outpatient and after discharge) effects of tolvaptan. Acute effects were measured by changes in body weight after 24 hours following the first ingestion of the drug. Intermediate effects were measured by readmission, or urgent clinic or emergency department visits resulting in more intensive therapy or a change in therapy 60 days after randomization, indicating worsening heart failure. Other end points included secondary symptoms and laboratory abnormalities.

Of the 319 patients enrolled, a significantly greater body weight reduction was observed in the tolvaptan groups compared with the placebo group during the first day of hospitalization. This change was greater in the treatment groups from baseline to discharge compared with the placebo-treated group. All patients lost weight and had improved symptoms during this phase; only dyspnea was improved significantly in the tolvaptan group at discharge. In the outpatient phase, there was no significant difference between treatment and placebo groups in worsening heart failure. A post-hoc analysis showed that event-free survival tended to be longer in the combined tolvaptan groups compared with placebo, with a lower total mortality in the most severe subgroups. Tolvaptan was well tolerated, but it caused thirst in a large percentage of patients.

This study showed improvements with tolvaptan in the acute phase in patients with CHF, with greater volume loss in treated patients than in those given placebo, confirming tolvaptan’s potential advantage—although it has yet to show clinical benefit—of rapid action. The study was not designed to measure mortality, but a post-hoc analysis found a trend toward lower mortality in the most severely affected patients taking tolvaptan. This finding would require corroboration by studies focused on mortality outcomes.