The Pharmaceutical Journal
Vol 272 No 7298 p565
8 May 2004

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Promise for new “vaptan” in heart failure

A new vasopressin antagonist, or “vaptan”, one of a new class of drugs, shows promise in patients admitted to hospital with heart failure. Adding the new agent — tolvaptan — to standard treatment, such as diuretics, angiotensin converting enzyme inhibitors, beta blockers, digoxin and spironolactone, shortly after admission increases net fluid loss more effectively than standard treatment alone. So finds a study presented last year (PJ, 13 December 2003, p806), and published last week.

Tolvaptan is believed to work by blocking vasopressin V₂ receptors in the kidney. The antidiuretic hormone vasopressin modulates water reabsorption and has an important role in normal cardiovascular physiology. By blocking the V₂ receptor, the new agent appears to reduce fluid build up in patients.

The 60-day multicentre trial involved 319 patients with an ejection fraction of less than 40 per cent. They had been admitted to hospital for persistent signs and symptoms of systemic congestive heart failure, despite standard treatment. The researchers comment that diuretics can cause hypotension, electrolyte abnormalities and worsening kidney function.

After admission, patients were randomised to receive 30, 60 or 90mg daily of oral tolvaptan or placebo. The trial measured decreases in body weight to reflect net fluid loss. The increasing doses of tolvaptan led to weight losses of 1.8, 2.10 and 2.05kg, respectively, after 24 hours compared with 0.6kg for placebo. Fluid loss with tolvaptan was not associated with changes in heart rate or blood pressure, hypokalaemia or worsening renal function, the authors say.

Commenting on the trial, US cardiologists say that although ACE and ACE II inhibitors and beta blockers are the cornerstones of chronic treatment for heart failure, many patients are left with hyponatraemia and hypervolaemia poorly responsive to conventional loop diuretics.

They state that the newly published trial is an important step in the development of new drugs for congestive heart failure. However, they add that there are theoretical concerns over the long-term safety and efficacy of this class of drug. A phase III trial called EVEREST will determine the long-term efficacy of tolvaptan, they say, adding that more trials with this and other agents in this class are likely (JAMA 2004;291:1963 and 2017).