Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure - ACTIV in CHF

Aug 30, 2004
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Date Presented:
01/01/2003
Date Published:
01/01/2004
Date Updated:
08/30/2004
Original Posted Date:
08/30/2004
References

Description:

The goal of the trial was to evaluate the acute and chronic effects of treatment with the vasopressin 2 antagonist tolvaptan compared with placebo in patients with congestive heart failure (CHF).

Hypothesis:

Treatment with the vasopressin 2 antagonist tolvaptan will be associated with an increase in body weight reduction at 24 hours and a reduction in worsening heart failure at 60 days compared with placebo in patients with CHF.

Study Design

Study Design:

Patients Screened: 1,159
Patients Enrolled: 319
Mean Follow Up: 60 days
Mean Patient Age: Mean age 62 years
Mean Ejection Fraction: Baseline EF 24%

Patient Populations:

Age ≥18 years; exacerbation of known CHF (ejection fraction [EF] <40%) and fluid overload requiring hospitalization

Exclusions:

Recent myocardial infarction (within 30 days) or recent cardiac surgery (within 60 days)

Primary Endpoints:

Acute: Body weight changes 24 hours after start of therapy
Chronic: Worsening heart failure, defined as rehospitalizations, visits to the emergency department, and need for new CHF therapy or death

Drug/Procedures Used:

Patients were randomized to one of three doses of tolvaptan (30 mg, n=78; 60 mg, n=84; or 90 mg, n=78) versus placebo (n=80). Patients received up to 10 days of optimal conventional CHF therapy plus randomized therapy. Treatment was continued for seven weeks.

Concomitant Medications:

Diuretics (97%), angiotensin-converting enzyme inhibitors (80%), digoxin (70%), and beta-blockers (40%)

Principal Findings:

Mean drug exposure was longer in the placebo arm (43 days) and the 30 mg tolvaptan arm (45 days) than in the higher dose tolvaptan arms (36 days in the 60 mg arm and 39 days in the 90 mg arm). Body weight reductions at 24 hours were greater in the tolvaptan arms combined compared with placebo (2.0 kg vs. 0.6 kg, p=0.008), but there was no dose response in the tolvaptan arms (1.80 kg, 2.10 kg, and 2.05 kg for the 30, 60, and 90 mg arms, respectively).

There were no significant changes in systolic blood pressure, heart rate, serum creatinine, or serum potassium in the tolvaptan arms during the study period. There was no difference in the chronic primary endpoint of worsening heart failure during follow-up (27.5% placebo vs. 26.7% for tolvaptan arms combined, p=NS; 25.6%, 34.5%, and 19.4% for 30 mg, 60 mg, and 90 mg arms, respectively). There was also no difference in total mortality at 60 days (8.7% for placebo vs. 5.4% for tolvaptan arms, p=0.18).

The decrease in the dose of diuretic use postdischarge was greater in the tolvaptan arms versus placebo (43 mg vs. 9 mg). Frequency of adverse events did not differ between tolvaptan and placebo.

Interpretation:

Among patients with CHF, treatment with the vasopressin 2 antagonist tolvaptan was associated with an increase in the acute primary endpoint of body weight reduction at 24 hours, but was not associated with a reduction in the chronic phase coprimary endpoint of worsening heart failure compared with placebo at 60-day follow-up.

The present study is the first randomized trial to evaluate both the acute and chronic effects of the vasopressin 2 antagonist tolvaptan in patients hospitalized with CHF. The larger, ongoing phase III EVEREST trial is evaluating the use of tolvaptan on mortality in patients hospitalized for heart failure. One limitation of the present study was the high treatment discontinuation rate in the tolvaptan arms.

References:

Gheorghiade M, Gattis WA, O'Connor CM, et al., on behalf of the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 2004;291:1963-71.

Presented by Dr. Mihai Gheorghiade at the November 2003 American Heart Association Annual Scientific Sessions, Orlando, FL.

Keywords: Potassium, Vasopressins, Weight Loss, Diuretics, Heart Failure, Body Weight, Blood Pressure, Creatinine, Heart Rate, Benzazepines


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