The vaptans: just landed. But how was the trip?

Vaptans is a collective term for a novel class of compounds: orally available vasopressin antagonists. They have been developed primarily for the treatment of hyponatraemia. Although this is a plausible concept, the details of the treatment could be less straightforward than it might appear. For instance, the secondary thirst of a vaptan treatment [1] could increase the fluid intake substantially and thereby jeopardize the therapeutic effect. On the other hand, overcorrection of hyponatraemia might be difficult to prevent once the vaptan is used in the real world (overcorrection: ≥0.5 mmol/L/h in the setting of chronic hyponatraemia). Until recently, no such problems had surfaced—but the use of vaptans had been restricted to binding scientific protocols. This has changed, and two approved vaptans are now available for general use [conivaptan, only available as an intravenous (i.v.) preparation; tolvaptan, a tablet]. In this issue of the journal, Velez et al. describe the treatment of hyponatraemia using conivaptan as a routine measure in their hospital [2]. How did the vaptan do? The i.v. conivaptan, given as recommended by the manufacturer, was indeed effective. All 18 patients diagnosed with the syndrome of inadequate antidiuresis (SIAD) responded. All showed a clear increase of the serum sodium level: the mean value rose from 121.7 ± 3.3 mmol/L at baseline to 129.2 ± 2.6 mmol/L within the first 24 h of treatment. Concomitantly, the urinary osmolality dropped in all, from 476.8 ± 132 to 243.2 ± 151.8 m0sm/kg. As expected, the urinary output increased; in fact, it almost doubled from 1.5 ± 0.29 to 2.7 ± 0.5 L/day. Due to these robust responses, the mean treatment time (the duration of conivaptan infusions) could be kept down at only 13 h. The improved serum sodium level was well maintained even at 48 and 72 h after discontinuation of conivaptan. (All patients were on a fluid restriction to 1 L/day). Finally, the authors succeeded in predicting the individual correction rate of the given hyponatraemia: the lower the baseline serum sodium and the higher the estimated glomerular filtration rate (eGFR), the faster the correction rate which is compatible with a previously published work [3]. Considering our previous standard therapy for hyponatraemia—time-consuming and frustrating fluid restrictions—conivaptan was clearly more efficient, more specific and more time saving. I assume this is what a hospital administrator must consider the equivalent of paradise. But was it ideal to the doctor, too? From a medical standpoint, safety could be an issue. In this respect, Figure 1 of [2] shows that 5 or 6 of the 18 patients had a correction rate of 10 mmol/L or more in the first 24 h, disturbingly close to the limit. In four patients, the authors had to interrupt the infusions of conivaptan prematurely because of a too rapid correction. Since the paper does not give a very detailed report, it is possible that not all of these four patients belong to the group of six patients; in other words, the incidence of potentially risky treatments may have been larger than six out of 18. Fortunately, in most patients, the serum sodium was measured every 6 h—which must have caused extra ‘discomfort’. But without this extra attention, the four patients who had their infusions interrupted might have progressed to severe overcorrection. In a single patient, the serum sodium apparently rose by 16 mmol/L (from 119 to 135 mmol/L) within the first 24 h—not quite a safe result if this patient would have had chronic hyponatraemia. One patient experienced a drop of the systolic blood pressure from 110 to 88 mmHg, necessitating a saline infusion. In two patients, the serum creatinine increased >25%, though this was still within normal limits. Clearly then, adequate safety was problematic. We seem to be paying a price for the efficiency of conivaptan in the majority of patients by overcorrection in some. Perhaps, it would have helped to avoid these unwanted effects if a more liberal fluid intake had been permitted or if the dose of conivaptan had been lower. But for the time being, meticulous care and close follow-up of the patients are strictly indicated to prevent risky correction rates. Isn’t there something else missing? Wasn’t the doctor the one who alleviated the symptoms and prevented the suffering? Well then, how did conivaptan benefit the well-being of the patients? Or was it basically given to correct the numbers printed on lab reports? How symptomatic were these patients at baseline? Did they have confusion, headache, loss of balance or impaired memory, and if so, what effect did conivaptan have on these symptoms? What did the patients have to say about the thirst in response to conivaptan? Were there any other indications for conivaptan than symptoms and complaints, such as prevention of relapse, reduction in the length of hospital stay in refractory cases or prophylaxis against the worsening of hyponatrae-