Tolvaptan Reduces Fluid Volume in Congestive Heart Failure

Peggy Peck

November 11, 2003

Nov. 11, 2003 (Orlando) — Results of a phase II trial of the investigational agent tolvaptan suggest that the drug may improve clinical symptoms in patients hospitalized due to worsening heart failure, according to the results of Acute and Chronic Therapeutic Impact of Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF), a late-breaking clinical trial presented here at the American Heart Association Scientific Sessions.

Fluid overload is a symptom of worsening heart failure and is usually monitored by measuring patient weight at least once a day. Diuretics are typically the mainstay of treatment, but they are associated with electrolyte abnormalities and impaired kidney function. Use of tolvaptan, an oral vasopressin V 2 receptor blocker, is known to decrease fluid overload without adversely affecting electrolytes or renal function.

The ACTIV in CHF study was undertaken to evaluate the acute (in-hospital) and chronic (60 days after discharge) effects of tolvaptan in patients with worsening heart failure (ejection fraction <40%) and fluid retention requiring hospitalization. Changes in body weight and worsening heart failure were the study's primary endpoints.

Patients treated with tolvaptan lost an average of 2 kg during hospitalization compared with about a 1 kg gain among patients randomized to placebo, reported principal investigator Mihai Georghiade, MD, associate chief of the division of cardiology at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

"These results are encouraging and may provide hope for a field that has not seen a new treatment option in a long time," said Dr. Georghiade. "This is the first trial to assess the acute and chronic effects of an oral investigative agent in patients hospitalized with congestive heart failure."

Robert O. Bonow, MD, chief of cardiology at Northwestern University, called the study results encouraging. "This may be the first pure water drug, meaning that [tolvaptan] reduces fluid volume without disturbing electrolytes." He noted that there are "very few drugs for heart failure — beta-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, digoxin, and now [angiotensin receptor blockers], but that's about it — so the prospect of a new agent is exciting." Dr. Bonow was not involved in the study.

The study enrolled 319 patients who were randomized to tolvaptan or placebo in addition to standard therapy (digitalis, digoxin, ACE inhibitors, and beta-blockers). Eighty patients were assigned to receive placebo while patients in the active treatment group received tolvaptan: 30 mg (n=78), 60 mg (n=84), or 90 mg (n=77). The oral agents were administered once a day in the hospital and then daily for seven weeks after discharge.

Weight loss with tolvaptan continued after discharge, with patients losing an average of an additional 4 kg during the seven-week treatment period. Patients receiving placebo lost an average of 2 kg after discharge.

Raymond Gibbons, MD, the Arthur M. and Gladys D. Gray professor of medicine at Mayo Medical School in Rochester, Minnesota, and chair of the AHA Scientific Sessions, said the loss of body weight in these patients suggests improvement in the patient's general condition. Dr. Gibbons was not involved in the study, but he chaired an AHA press conference at which the data were presented.

Although tolvaptan had a significant impact on weight, the weight loss was not dose-dependent; patients in all three treatment groups lost the same amount. Tolvaptan did not affect worsening heart failure, which was the same at 60 days in both the placebo and all treatment groups. All-cause mortality was 5.4% in the tolvaptan groups and 8.7% in the placebo group, a difference that did not reach statistical significance, he said. A larger phase III trial, EVEREST (Effects of Vasopressin antagonists inhEart failuRE: outcome Study with Tolvaptan), plans to test only the lowest dose (30 mg) of the drug.

Dr. Georghiade noted that tolvaptan treatment did not affect blood pressure, heart rate, or serum potassium levels. The use of tolvaptan also did not increase blood urea nitrogen (BUN) or creatinine.

Summing up the potential clinical implications of tolvaptan, Dr. Bonow said, "It is like the story about a sick horse pulling a wagon up hill: you can either whip the horse or lighten the load. This drug lightens the load without whipping the failing heart."

Otsuka Pharmaceutical Co., Ltd., funded the research.

AHA 2003 Scientific Sessions: Late Breaking Clinical Trials. Presented Nov. 10, 2003.

Reviewed by Gary D. Vogin, MD

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