La mini-revue est très bien, elle montre bien que nous n’en savons pas encore assez sur l’utilisation de ces drogues.
Elle rappelle aussi le bon rythme, ne pas dépasser 10 mmol/l pendant les 24 premières heures et pas plus de 18mmol/L pendant les 48 premières heures.
La correction de l’hyponatrémie est un sport pas si facile, le risque est surtout la correction trop rapide. C’est très bien discuté et les références données sont de qualité.
Enfin les auteurs discutent l’émergence d’une abondante littérature sur les hyponatrémies peu sévères asymptomatiques et une augmentation du risque d’ostéoporose, de fractures, de troubles cognitifs. Les vendeurs de vaptans vont les utiliser pour vendre leur soupe. Les auteurs rappellent avec justesse qu’il n’y a aucune étude montrant que la correction de l’hyponatrémie améliore ses signes et symptômes.
Je ne peux qu’appuyer leur conclusion: nous avons maintenant un marteau pour taper sur l’hyponatrémie, attention de ne pas nous taper sur les doigts et surtout sur ceux des patients avec cette arme redoutable.
Hyponatremia: Vasopressin antagonists in hyponatremia: more data needed
Richard Sterns
&
John Hix
About the authors
Two new vasopressin antagonists, conivaptan and tolvaptan have recently been licensed for the treatment of hyponatremia in the USA. Their safety and clinical effectiveness seems promising, but high costs and the lack of data regarding their use in symptomatic patients call for further studies to clarify their future clinical role.
Sustained hyponatremia usually results from water retention caused by the antidiuretic hormone, arginine vasopressin (AVP). Nephrologists have long believed that blocking AVP’s action on the kidney would be the most physiological approach to the treatment of this common electrolyte disturbance. After many years of trying, several AVP antagonists (‘vaptans’) have been developed. These agents actively compete with AVP at the vasopressin 2 receptors located in the renal collecting duct and induce an ‘aquaresis’: an increase in water excretion with no change in the excretion of sodium or potassium. This aquaresis increases the serum sodium concentration, thus correcting hyponatremia.
The FDA recently approved two aquaretic agents, conivaptan and tolvaptan, for the treatment of hyponatremia. To gain such approval, pharmaceutical companies are required to show that their new drugs are both effective and safe. Rozen-Zvi et al. have now conducted a meta-analysis of all randomized controlled trials (RCTs) that compared AVP antagonists with placebo, no treatment and/or fluid restriction, to assess the effectiveness of these agents in euvolemic and hypervolemic patients with hyponatremia.1 From their analysis, the authors of this paper concluded that AVP antagonists improve or normalize serum sodium levels without major side effects. So we know that the FDA did its job: the drugs safely do what they are approved to do in the populations studied. But does this mean they will do what we need them to do in our patients?
Rozen-Zvi et al. acknowledge several gaps in our knowledge about vaptans. Their systematic review could draw no conclusion concerning vaptan effectiveness in patients with symptomatic hyponatremia because this important group was excluded from the trials. In addition, the authors observe that although it is plausible that effective and rapid treatment of hyponatremia will shorten hospitalizations, improve quality of life, and even improve cognitive function; these outcomes (which are critical to our patients) were not assessed in any trial.1
Tolvaptan and conivaptan are both approved for the treatment of hyponatremia in hospitalized patients. What questions should we be asking about the use of these agents in the hospital? In the US, third-party payers require that a patient be symptomatic with a serum sodium concentration less than 120 mmol/l to justify reimbursement for costs of admission to an inpatient facility for the treatment of hyponatremia. As already noted, patients with serum sodium concentrations below 120 mmol/l and patients with acute hospital-acquired hyponatremia were largely excluded from RCTs in which investigators evaluated the effectiveness of the vaptans. Patients with acute or severe symptomatic hyponatremia are a clinical challenge; they require a prompt and substantial increase in serum sodium concentration to avoid serious morbidity related to the electrolyte disturbance itself, but the treatment plan and tools used must be malleable enough to allow clinicians to avert an equally undesirable overcorrection. Are vaptans suited for this dual challenge?
Hyponatremic patients with severe neurological symptoms should be corrected by 4–6 mmol/l in the first few hours of therapy.2 Published data show that as many as one-third of patients respond to vaptans with less than a 4 mmol/l increase in sodium concentration.3 We need to better understand the reasons why some patients do not respond and we need to have effective strategies for managing them. Are nonresponders patients with higher plasma AVP levels who would have responded to a higher dose? Should a high initial dose be used in patients for whom a prompt response is essential, and, if so, what dose can be counted on to elicit an adequate response in virtually all individuals with AVP-mediated hyponatremia? Can hypertonic saline and vaptans be given together for initial therapy, and, if so, what is the best regimen?
Once an initial response is achieved in a hyponatremic patient, the first 24–48 h of the treatment plan focuses on preventing overcorrection and its potential complication: osmotic demyelination syndrome.2 To be safe, daily correction should be targeted at approximately 6 mmol/l to stay clear of correction rates associated with iatrogenic injury (10 mmol/l in 24 h or 18 mmol/l in 48 h).4 Are vaptans less prone to such extremes in sodium correction?
Even in controlled trials with careful monitoring, four of 223 patients treated with tolvaptan and two of 55 patients treated with conivaptan experienced correction of greater than 12 mmol/l over 24 h.1 These numbers probably underestimate the true risk of overcorrection because many of the patients in these trials had serum sodium concentrations that were less than 12 mmol/l below the normal range; once the serum sodium level had normalized, thirst protected these mildly hyponatremic patients from overcorrection. A recent single-center, phase IV study of conivaptan reported a similar relationship between the severity of hyponatremia and the likelihood of overcorrection. In this investigation, all six patients with serum sodium concentrations ≤120 mmol/l were corrected by more than 10 mmol/l over 24 h, which most investigators now consider excessive.3 Inadvertent overcorrection of hyponatremia is common amongst patients with severe hyponatremia treated with hypertonic or isotonic saline and, in patients treated with 3% saline, the lower the serum sodium concentration, the higher the risk of overcorrection.5 During or after saline therapy, the initial cause of hyponatremia (hypovolemia, transient syndrome of inappropriate antidiuretic hormone, or a drug effect) often resolves and a water diuresis emerges, increasing the serum sodium concentration by more than intended; administration of desmopressin is an effective ‘antidote’ as it can terminate unwanted water losses.6 An important unanswered question is whether a water diuresis caused by a vaptan can be terminated with a high dose of desmopressin.
The vaptans hold great promise for the management of chronic outpatient hyponatremia because existing therapeutic options (water restriction, salt tablets, furosemide, demeclocycline, and urea) leave much to be desired.7 Mild and apparently asymptomatic hyponatremia is associated with impaired gait, osteoporosis, falls and fractures, cognitive impairment, and increased mortality—but we do not know if maintenance of a normal serum sodium concentration improves outcomes.8, 9, 10 Mild hyponatremia is extremely common among frail elderly people. Would treatment with a vaptan decrease their risk of falls and fractures, or would the increased need to get up to go to the bathroom increase the risk? Would improved performance on psychological testing translate to a decreased risk of accidental injury? Would maintenance of normonatremia improve mortality or does the association of hyponatremia and mortality merely reflect the underlying diseases responsible for hyponatremia? It is likely that budget holders and third-party payers will demand answers to these questions before agreeing to bear the high cost of vaptans.
Clinicians who manage hyponatremia have been given a valuable new tool to treat hyponatremia; we now have an effective hammer. Asking the right questions will help to ensure that we strike the nails rather than our nailbeds.
References
- Rozen-Zvi, B. et al. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am. J. Kidney Dis. 56, 325–337 (2010).
- Sterns, R. H., Nigwekar, S. U. & Hix, J. K. The treatment of hyponatremia. Semin. Nephrol. 29, 282–299 (2009).
- Velez, J. C., Dopson, S. J., Sanders, D. S., Delay, T. A. & Arthur, J. M. Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience. Nephrol. Dial. Transplant. 25, 1524–1531 (2010).
- Sterns, R. H., Hix, J. K. & Silver, S. Treating profound hyponatremia: a strategy for controlled correction. Am. J. Kidney Dis. 56, 774–779 (2010).
- Mohmand, H. K. et al. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clin. J. Am. Soc. Nephrol. 2, 1110–1117 (2007).
- Perianayagam, A. et al. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin. J. Am. Soc. Nephrol. 3, 331–336 (2008).
- Berl, T. et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J. Am. Soc. Nephrol. 21, 705–712 (2010).
- Renneboog, B. et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am. J. Med. 119, 71 e71–e78 (2006).
- Verbalis, J. G. et al. Hyponatremia-induced osteoporosis. J. Bone Miner. Res. 25, 554–563 (2010).
- Waikar, S. S., Mount, D. B. & Curhan, G. C. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am. J. Med. 122, 857–865 (2009).
