US and Europe Differ on Use of Vaptans in Hyponatremia

Becky McCall

May 26, 2015

DUBLIN — A heated debate about which guidelines for the treatment of hyponatremia are better — the US or European ones — ended in a victory for the Americans at the recent European Congress of Endocrinology (ECE) 2015.

Attendees initially voted in favor of the European recommendations but, after hearing from both sides, reversed their decision.

Chairing the session, Dr Mark Sherlock (Tallaght Hospital, Dublin, Ireland) explained, "There is some overlap in understanding the pathophysiology, the importance of appropriate diagnosis and etiology, the emergency treatment of symptomatic acute patients, and prevention of overcorrection in hyponatremia" between the two sets of guidelines.

But "the main area of disagreement is regarding the use of vasopressin-receptor antagonists [vaptans] and urea in the treatment of hyponatremia," he added.

While the US guidelines tend to advise using whatever therapy is judged by the treating physician to provide the best result for an individual patient, the European ones use a rigorous grading system and aim to deal with the practical issues of "what to do, what the diagnostic criteria are, [and] which tests should be requested," explained nephrologist Dr Wim Van Biesen (Ghent University Hospital, Belgium), who presented the case for the European guidelines, which were published in 2014 (Eur J Endocrinol. 2014;170:G1-G47).

Representing the US side, endocrinologist Dr Joseph Verbalis (Georgetown University Medical Center, Washington, DC) stressed there were more areas of agreement than disagreement between the two. "However there are some important differences that require discussion."

The US recommendations on the treatment of hyponatremia were published in 2013 (Am J Med. 2013;126;S1-S42).

Individualized Therapy vs Stepped Approach

Hyponatremia, defined as a serum sodium concentration of less than 135 mmol/L, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice, occurring in up to 30% of hospitalized patients. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life-threatening, and is associated with increased mortality, morbidity, and length of hospital stay in patients presenting with a range of conditions.

The excess of body water compared with sodium and potassium results in cellular edema, particularly in the brain, and because of the potential for brain damage, severe cases are medical emergencies. Complications of milder cases of hyponatremia may include impaired mobility and cognition, as well as osteoporosis and fracture.

A wide range of conditions can cause hyponatremia — including heart failure, nausea and vomiting, adrenal failure, and ectopic vasopressin secretion as part of a malignancy — and as a result, it is managed by clinicians from a broad spectrum of backgrounds, which has resulted in a variety of approaches to its diagnosis and treatment.

In the United States, Dr Verbalis pointed out that the aim is to inform physicians of the risks, benefits, and requirements of each available therapy for hyponatremia, allowing them to use their clinical judgment and knowledge of individual patients in making a treatment choice.

He stressed that the US stance is to individualize treatment of hyponatremia because each patient has different clinical characteristics that make some therapies better than others.

In contrast, in Europe, Dr Van Biesen said guideline development "forced us to consider, for each step, whether it really improves patient outcome, rather than some parameter that is only important because it can be changed [with a vaptan, for example]."

The European guidelines also considered both published and unpublished data from the US Food and Drug Administration, he added.

Use Vaptans, or Not Use Vaptans? That's the Question

As discussed by Dr Verbalis during the debate, the US guidelines recommend treatment by symptoms. For severe symptoms, all patients receive hypertonic saline (bolus or continuous infusion) followed by fluid restriction, with or without a vaptan.

In contrast, in Europe, Dr Van Biesen said, an intravenous infusion of 150-mL 3% hypertonic saline over 20 minutes, potentially repeated up to three times, is the recommended course of action.

For moderate symptoms, Dr Verbalis said the US options are vaptans, limited hypertonic saline, or urea, followed by fluid restriction. In Europe, moderate symptoms are treated by intravenous infusion of 150-mL 3% hypertonic saline over 20 minutes.

The same treatment is recommended for acute cases, without severe or moderate symptoms, Dr Van Biesen added. And in patients with the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, the first move would be to start restricting fluids, he noted.

In the United States, for no or minimal symptoms, the first move would be fluid restriction, but with consideration of pharmacologic therapy (vaptan or urea) under select circumstances — namely, an inability to tolerate fluid restriction or predicted failure of fluid restriction, Dr Verbalis said.

Dr Verbalis referred to the European recommendation against use of vaptans and the claim that they have no proven outcome benefits other than an increase in serum sodium and also can lead to an increased risk of overly rapid correction, with concerns about toxicity. To the latter point, he noted this occurs "at vaptan doses five times higher than what we use in hyponatremia."

But Dr Van Biesen argued: "The European analysis of all data referring to vaptans showed no difference [from placebo] in mortality [or] quality of life and [showed] double the risk of major side effects — for example, overly rapid correction with vaptans."

But the European guidelines do not expressly instruct physicians not to use vaptans, he pointed out, adding that they might be appropriate if the patient is self-funding and has moderate hyponatremia and as such runs a lower risk of overcorrection.

"However, in profound hyponatremia where the risk of overcorrection increases, caution is required."

Dr Van Biesen added that it would be informative to have trials of "vaptan vs existing treatment, and this has not been done," rather than the trials that have been conducted, of vaptans vs placebo, "which we know has changed very little."

Commenting on the European recommendations, Dr Verbalis observed: "Basically the EU guidelines are for two first-line therapies: either infuse a bolus of hypertonic saline or [restrict] fluid. There's no publication that has evaluated this saline as bolus to improve symptomatic hyponatremia. That evidence is nonexistent."

European Guidelines More Practical for Nonspecialists

Commenting on the discussion, Dr Mushtaqur Rahman (Northwick Park and St Mark's Hospitals, London North West Healthcare NHS Trust, United Kingdom) said he thought the European guidelines were far more practical for nonspecialists, where the bulk of patients will be seen first line.

"We need safe management of these patients. The US guidelines suggest individuality, and this is dependent on endocrinologists" being available in the first instance, which is not always the case in Europe, he said.

He continued by pointing out that just because there is a lack of randomized controlled trials with urea does not equate to a lack of evidence.

"Finally, the cost of vaptans is prohibitive, and we are unsure how long they should be taken for, due to consequences such as long-term osteoporosis and associated fracture and falls. Urea may be far more cost-effective."

Dr Verbalis is a paid consultant to Ferring and Otsuka Pharmaceuticals and has received grant support from the US National Heart, Blood, and Lung Institute; the US National Institute of Diabetes, Digestive and Kidney Diseases; the US National Institute on Aging; the US National Center for Advancing Clinical and Translational Science; and Otsuka Pharmaceuticals. Dr Van Biesen and Dr Rahman have declared no relevant financial relationships.

European Congress of Endocrinology 2015. May 17, 2015. Abstract D1.1, D1.2

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