Hospitalizations for heart failure are common in the United States, with 995,000 hospital discharges for heart failure in 2001, according to background information in the article. Pharmacological management of systemic congestion in heart failure (buildup of excess fluid in the lungs and some other body tissues) is often inadequate; the 6-month postdischarge readmission rates are as high as 50 percent. Although diuretics are the mainstay therapy for congestion, their use has been associated with hypotension (abnormally low blood pressure), electrolyte abnormalities and worsening kidney function. The medication tolvaptan is thought to help treat heart failure without adversely affecting electrolytes and kidney function.
Mihai Gheorghiade, M.D., of Northwestern University Feinberg School of Medicine, Chicago, and investigators with the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial evaluated the clinical effects of tolvaptan in patients hospitalized for heart failure. This randomized, double blind, placebo-controlled trial was conducted at 45 centers in the United States and Argentina, and enrolled 319 patients who were hospitalized for heart failure and who had persistent signs and symptoms of systemic congestion despite standard therapy.
After admission, patients were randomized to receive 30, 60, or 90 mg of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days.
The researchers found that "tolvaptan in addition to standard therapy including diuretics increased net fluid loss resulting in decreased body weight more effectively than standard therapy alone in patients hospitalized for heart failure. This desirable effect was achieved without adversely affecting blood pressure, heart rate, electrolyte levels, or renal [kidney] function," they write. "Tolvaptan also improved serum sodium levels in patients with hyponatremia [abnormally low level of sodium in the blood; associated with dehydration]. Although tolvaptan did not reduce the rate of worsening heart failure after discharge, post hoc analysis suggested that mortality might be reduced in high-risk patients treated with tolvaptan."
(JAMA. 2004;291:1963-1971. Available post-embargo at JAMA.com)
Editor's Note: The study was sponsored by the Otsuka Maryland Research Institute, Rockville, Md. All authors served as consultants for Otsuka Maryland Research Institute, received grants or honoraria from the company, or both.
EDITORIAL: VASOPRESSIN RECEPTOR ANTAGONISTS
In an accompanying editorial, Gary S. Francis, M.D., and W. H. Wilson Tang, M.D., of the Cleveland Clinic Foundation, write that tolvaptan is one of a new class of drugs that may be helpful for addressing important problems in acute heart failure, e.g., hyponatremia, water retention, and renal dysfunction.
"The study by Gheorghiade et al also raises important regulatory issues. The question arises as to what should be measured to demonstrate efficacy in clinical trials of such new therapy for the treatment of acute or decompensated heart failure. Payers such as the Center for Medicare and Medicaid Services (CMS) and insurance carriers have a stake in this question, as new agents are likely to be expensive. Some demonstration of physiologic improvement, such as weight loss and correction of hyponatremia, is necessary but should be coupled to some index of improvement in clinical outcome. Heart failure researchers are still struggling to identify a measure of improved clinical outcome in the setting of acute heart failure that is objective, quantitative, reproducible, relevant, and reliable."
(JAMA. 2004;291:2017-2018. Available post-embargo at JAMA.com)
Editor's Note: Dr. Francis has served as a consultant to Yamanouchi Pharmaceuticals, which is developing conivaptan, a dual vasopressin V1A and V2 receptor antagonist.
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