Congestive heart failure - tolvaptan
If the left ventricle of the heart pumps inefficiently, it can result in heart failure. There are many causes, including coronary thrombosis, valve problems, cardiac arrhythmias and hypertension. Standard treatment includes rest, a diet low in sodium, diuretic drugs like frusemide, and digitalis derivatives.
Patients with heart failure have high levels of the hormone arginine vasopressin (AVP). This hormone is an antidiuretic and vasoconstrictor that is involved in the regulation of free water absorption, blood volume, blood pressure, body fluid osmolality, cell proliferation, cell contraction and adrenocorticotropin secretion. It is mediated by three G-protein coupled receptor subtypes, with the activation of each giving different pharmacological effects. Blocking both V1 and V2 subtypes could have an effect on patients with heart failure, and numerous such antagonists are under development.
One of these, being investigated by Japanese company Otsuka Pharmaceutical, is the benzazepine tolvaptan. 1 It is a specific, selective V2 receptor antagonist which is orally available and has been found to have a potent diuretic action. A randomised double blind placebo controlled trial has been carried out in 250 patients with heart failure and signs of congestion. 2 The subjects were also given standard therapy that included 20–200mg frusemide. Doses of 30, 45 or 60mg tolvaptan were given once a day for 25 days, and body weight reduced significantly — between two and a half and three times as much as for those patients given placebo – and urine volume increased proportionally.
A further randomised placebo controlled study in 83 patients with signs of congestion was carried out to compare the effects of the two diuretic agents alone and in combination. Patients remained on their standard therapy, but the diuretic element was removed and they were placed on a low sodium diet. Tolvaptan, in doses of 30mg, gave a significant increase in serum sodium, with reductions in leg oedema, breathlessness and enlargement of the liver. Urine output was much higher in patients given tolvaptan alone than those given 80mg frusemide or the two agents in combination. 3
Tolvaptan is currently in Phase II trials, where thus far it has proved to be well tolerated. If successful it could prove to be a significant addition to the arsenal of drugs for treating heart failure.