Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia

Abstract

Introduction and objective:

As evidence grows about the management of hyponatremia, a number of different international and national recommendations/guidelines from professional organizations have recently been published that offer guidance on decision-making. However, they include several important differences that could confuse practising physicians. This article summarizes the key differences in guideline recommendations by various independent groups, taking the marketing authorizations granted by different regulatory agencies into account. It proposes a synthesis of implications for practising physicians as a practical method for resolving these differences as they relate to everyday clinical practice.

Methods:

The authors reviewed all recent guidelines and consensus documents worldwide to assess differences and similarities. They also reviewed licensed indications for therapeutic agents in hyponatremia.

Results:

The actual indications for the only pharmacological therapy approved across three continents for the treatment of hyponatremia—the vaptans—differ substantially around the world. The numerous treatment guidelines published to date also fail to achieve agreement on hyponatremia management. The possible reasons for these differences are explored in this paper. The authors emphasize the crucial role that clinical judgment must continue to play in decision-making about the management of hyponatremia in individual patients. Such judgments should take into account appropriate appraisals of evidence by authoritative experts in the field, as well as the decisions of regulatory agencies that have based their approvals on a critical review of the efficacy and safety data for approved treatments for hyponatremia.

Conclusion:

It is clinical judgment rather than guidelines that should dictate the ultimate choices physicians make for their patients, not only in hyponatremia, but in all aspects of medicine.

Keywords::

• Hyponatremia
• Tolvaptan
• Mozavaptan
• Conivaptan
• Syndrome of inappropriate anti-diuretic hormone secretion (SIADH)
• Sodium
• Guidelines

Introduction

Hyponatremia is the most common electrolyte imbalance encountered in clinical practice, and is especially common in elderly patients1,2. Hyponatremia often progresses to a chronic disorder found in up to 7–11% of ambulatory outpatients3, and hyponatremia of multiple etiologies and in heterogeneous clinical settings is associated with increased morbidity and mortality4–7. Although some of the adverse outcomes associated with hyponatremia can be accounted for by the underlying medical illness causing the hyponatremia, hyponatremia itself is associated with adverse outcomes independently of the co-morbid condition8. It is also becoming increasingly apparent that patients with even mild hyponatremia, which was historically thought to be relatively asymptomatic, also have excess mortality compared with patients with a normal serum sodium concentration ([Na⁺])8,9.

New data on the association of hyponatremia with increased mortality, morbidity and length of hospital stay in diverse patient populations continue to be published with increasing frequency. As this evidence grows, the need for more effective management of hyponatremia has become more apparent. As typically occurs in such situations, practising physicians look to the recommendations of content experts in a particular field to guide their treatment decisions. Over the past year, a number of different international and national recommendations/guidelines from professional organizations have been published that offer guidance on decision-making in the management of hyponatremia. These include:

International:

• October 2013: Expert Panel Recommendations (Verbalis et al.10);

• February 2014: European Clinical Practice Guideline (Spasovski et al.11).

National:

• January 2012: Sweden (Chantzichristos et al.12);

• December 2013: Spain (Runkle et al.13); and

• In progress: UK (Grossman et al.14).

It has become apparent that these publications differ in some of their basic recommendations. While it is not uncommon that expert groups differ somewhat in recommendations for treatment of specific diseases, in the case of hyponatremia these differences are substantial and not just related to different thresholds for initiation of various therapies. Conflicting recommendations may cause confusion for treating physicians who may be less well versed on the intricacies involved in the management of hyponatremia.

Compounding this problem are quite different approved indications and treatment traditions for pharmacological therapies of hyponatremia across different continents and countries. This article will summarize the important differences in approved drugs for treatment of hyponatremia by various regulatory agencies, and the differences in guideline recommendations by various independent groups. A synthesis of implications for practising physicians will be proposed as a practical recommendation for resolving these differences as they relate to everyday clinical practice.

Differing regulatory approvals for pharmacological therapy of hyponatremia

Variances in the management of hyponatremia are exemplified by the different pharmacological agents approved for the treatment of hyponatremia across the world. Table 1 summarizes differences in approvals for pharmacological therapy of hyponatremia by different regulatory agencies.

Table 1. Approved pharmacological agents for the treatment of hyponatremia.

	Canada	Europe	Japan	US
Demeclocycline	No licence	No EMA authorization Approved in UK (SIADH secondary to malignancy, if fluid restriction ineffective and no cirrhosis) Approved in France (SIADH particularly secondary to malignancy, if fluid restriction ineffective)	No licence	No licence
Lithium	No licence	No licence	No licence	No licence
Loop diuretics	No licence	No licence	No licence	No licence
Urea	No licence	No licence	No licence	No licence
Vaptans	Tolvaptan (clinically significant non-hypovolemic hyponatremia)	Tolvaptan (hyponatremia secondary to SIADH)	Mozavaptan (SIADH secondary to malignancy)	Tolvaptan (clinically significant hypervolemic and euvolemic hyponatremia, incl. heart failure and SIADH) Conivaptan (euvolemic and hypervolemic hyponatremia)

EMA, European Medicines Agency; SIADH, syndrome of inappropriate anti-diuretic hormone secretion.

The only pharmacological therapy approved across three continents for the treatment of hyponatremia is the class of vasopressin receptor antagonists (vaptans). However, the actual indications for the use of these agents differ substantially in each location. The European Medicines Agency (EMA) has only approved tolvaptan for the treatment of hyponatremia caused by the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The Japanese Ministry of Health, Labour and Welfare has only approved mozavaptan for the treatment of a specific etiology of SIADH, namely tumors; although tolvaptan is also approved in Japan, it is approved for treatment of cardiac edema, and for autosomal dominant polycystic kidney disease (ADPKD), but not for hyponatremia. The US Food and Drug Administration (FDA) originally approved two vaptans, tolvaptan and conivaptan, for treatment of both euvolemic (i.e., SIADH) and hypervolemic (i.e., edema-forming states such as heart failure and cirrhosis) hyponatremia, but has recently restricted the use of tolvaptan in patients with liver disease because of potential hepatotoxicity15. Approval of vaptans in Canada is for clinically significant non-hypovolemic hyponatremia, similar to the US.

Since the only commonality for approved use of pharmacological therapy for hyponatremia is in SIADH, further discussion will be directed at this indication. Despite approval for hyponatremia due to SIADH by all regulatory agencies that have reviewed the clinical trial data of various vaptans, the actual indications vary substantially. The EMA has approved tolvaptan for all SIADH patients with clinically significant hyponatremia. Japan has only approved mozavaptan for hyponatremia associated with tumors >3.5 cm. The FDA has limited tolvaptan use to patients with serum [Na⁺] less than 125 mmol/L, unless patients are symptomatic and have resisted attempts to correct hyponatremia by fluid restriction. Health Canada set a higher limit of <130 mmol/L for initiation of therapy with tolvaptan.

Differing recommendations for treatment of SIADH

The previous summary indicates that not even the world regulatory agencies agree on the appropriate therapies and indications for hyponatremia in different disease states. So it is perhaps not surprising that the various treatment guidelines published to date fail to achieve agreement either. The clearest example of published recommendations differing on the management of this disorder was recently unveiled by the European Society of Endocrinology (ESE), the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA), and the European Society of Intensive Care Medicine (ESICM), represented by European Renal Best Practice (ERBP) publication. These European guidelines have prompted discussion over their decision to not recommend a place for use of vaptans in the treatment of hyponatremia secondary to SIADH. This stands in marked contrast with all of the other recent recommendations and guidelines, which recommend vaptans as treatment for patients not suitable for fluid restriction or who are resistant to fluid restriction (Table 2).

Table 2. International and national treatment recommendations for SIADH.

	Fluid restriction	Vaptans (tolvaptan)	Urea	Loop diuretics	Demeclocycline	Lithium
International
European Clinical Practice Guideline	First-line treatment in moderate or profound hyponatremia	Not recommended in moderate hyponatremia; Recommended against in profound hyponatremia	Equal second-line treatment	Equal second-line treatment (combined with oral NaCl)	Recommended against in moderate or profound hyponatremia	Recommended against in moderate or profound hyponatremia
Expert Panel Recommendations	Generally first-line treatment; Consider alternative treatments in the presence of predictors of failure of fluid restriction	Recommended: ‘Have the potential to replace water restriction as first-line treatment’	Recommended as an alternative oral treatment	*	Recommended as an alternative oral treatment	*
National
Spain	First-line treatment	Recommended in patients not suitable for fluid restriction or furosemide	Recommended as an option; Could be therapy of choice in children with SIADH	Recommended as short-term treatment when urinary osmolality is sufficiently high; NaCl supplements recommended	*	*
Sweden	First-line treatment; Calculate electrolyte-free water clearance prior to initiation	First-line treatment in patients not suitable for fluid restriction	*	*	*	*
UK	First-line treatment; Calculate electrolyte-free water clearance prior to initiation	Consider if fluid restriction is not advised, or has a poor response	*	*	Consider if fluid restriction is not advised, or has a poor response	*

*Treatment option was not mentioned by the recommendation/guideline.

SIADH, syndrome of inappropriate anti-diuretic hormone secretion

This seems unusual, since tolvaptan is a specific treatment for SIADH, and is the only drug with a demonstrated efficacy and safety profile supported by data from randomized placebo-controlled trials. This has prompted approval by regulatory agencies in both Europe and North America following rigorous, multidisciplinary review. It can be reasonably argued that the lack of a recommendation for tolvaptan in any patient population removes the most evidence-based treatment option from the armamentarium of physicians dealing with this disorder. It is, therefore, important to try to understand the basis for these quite different sets of recommendations.

The recommendations regarding other treatments, both in terms of efficacy and safety, are not as dramatically different (Table 2). All are in agreement that the evidence database for alternative therapies such as demeclocycline, lithium, and urea are limited, and provide weak support for the generalized use of these therapies. However, by eliminating vaptans from consideration as a viable therapy for hyponatremia, this recommendation by default moves these alternative therapies into prime consideration for those patients who fail to respond adequately to fluid restriction.

Because fluid restriction has been the mainstay of therapy for hyponatremia due to SIADH since the first description of this disease by Schwartz et al.16 in 1957, one could argue that pharmacological therapy of hyponatremia is generally not necessary anyway. However, despite a lack of evidence-based studies of the effectiveness of fluid restriction across diverse groups of patients with different etiologies of hyponatremia, in clinical practice fluid restriction is well known to be ineffective in substantial numbers of patients with SIADH. Recent guideline recommendations have summarized predictors of failure of fluid restriction based on simple measures of urine volume, osmolality and electrolyte concentrations (Table 3)10.

Table 3. General recommendations for employment of fluid restriction and predictors of the increased likelihood of failure of fluid restriction10.

General recommendations:

• Restrict all intake that is consumed by drinking, not just water;

• Aim for a fluid restriction that is 500 mL/day below the 24-hour urine volume; and

• Do not restrict sodium or protein intake unless indicated.

Predictors of the likely failure of fluid restriction:

• High urine osmolality (>500 mOsm/kg H2O);

• Sum of the urine Na^+ and K^+ concentrations exceeds the serum Na^+ concentration;

• 24-hour urine volume <1500 mL/day; and

• Increase in serum Na^+ concentration <2 mmol/L/day in 24–48 hours on a fluid restriction of ≤1 L/day.

In addition, many hospitalized patients cannot be effectively fluid restricted (e.g., patients requiring intravenous therapies, or parenteral or enteral nutrition). Furthermore, even those patients who respond adequately to fluid restriction often have difficulty maintaining this therapy over long periods of time due to the increased thirst that often accompanies restricted oral fluid intake. Consequently, there is clearly a need for pharmacological therapies for hyponatremia in patients who either fail, or are predicted to fail, attempts at fluid restriction, those who cannot realistically be fluid restricted, and those who find long-term fluid restriction intolerable and, therefore, ineffective.

Why can treatment recommendations and guidelines differ?

The above analysis logically leads to the question of why treatment recommendations and guidelines can differ so dramatically, and what individual practising physicians should do about this seeming dilemma. Consensus clinical practice guidelines are generally developed based on a critical analysis of published medical literature and supplemented by expert opinion, where necessary. Consequently, there are a number of obvious reasons why guidelines and recommendations may diverge in different countries and by different organizations:

1. The availability of drugs may differ between countries, thus leading to different experiences, or lack of experience, with the use of particular agents;

2. Different groups may utilize differing methodologies and scope in their review of existing data; and

3. There may be divergent interpretations of evidence, both in terms of the magnitude and the quality of the evidence.

With regard to point 1, it is noteworthy that vaptans were approved in the US (conivaptan in 2005 and tolvaptan in 2008) several years before approval in the EU (tolvaptan in 2009). As a result, there has been greater clinical experience with use of vaptans in the US than in other parts of the world17. Conversely, urea has been predominantly used in Belgium, with very little use in the US or other parts of the EU, in large part owing to the lack of general availability of a preparation approved for human use. Consequently, it is not surprising that there are relative differences in perceptions about both efficacy and safety of these agents based on the quite different clinical experiences of the physicians writing the respective recommendations/guidelines.

With regard to point 2, it is important to recognize that recommendations for the management of hyponatremia are made more difficult by a general paucity of available randomized controlled trials with clinical outcome measures for most of the available therapies other than vaptans18,19. The European guidelines group adopted a methodology of numerically rating the quality of data for different therapies, and as a result gave uniformly low grade rankings to all therapies other than vaptans, which they chose not to grade at all11. In contrast, the Expert Panel Recommendations acknowledged the paucity of evaluable outcomes data other than correction of serum [Na⁺], and because of this declined to attempt this approach:

As such, the use of a quality-of-evidence scoring system to grade the strength of supporting data for each recommendation was not feasible. The panel recognizes the need for expert guidance in hyponatremia management in the absence of such literature, and the need for future studies to evaluate management strategies not currently supported by evidence from high-quality randomized controlled trials10 (page S6).

The various national guidelines also evaluated treatments based on the available literature, but also chose not to attempt to grade the strength of specific recommendations. Once again, it is not surprising that there could be relative differences in perceptions about both the efficacy and safety of various agents based on the different roles that more subjective expert opinion played in generating the recommendations of the respective groups.

Finally as mentioned in point 3, it must be acknowledged that a major reason for the differences was based upon divergent interpretations of evidence, and particularly the quality of the evidence for the use of vaptans in SIADH. In this regard, it is notable that the European guidelines group downgraded the quality of evidence of the vaptan clinical trials based largely on the fact that they were industry sponsored. In addition, they relied upon existing meta-analyses of combined clinical trials of multiple vaptans, including those not licensed for use anywhere in the world11. The remaining groups chose to focus instead on the Phase III pivotal studies of only those vaptans that succeeded in gaining regulatory approval in Canada, the EU, and the US. Similar to the EMA, FDA, and Health Canada, these groups rated the quality of the Phase III clinical trials for both conivaptan and/or tolvaptan to be high, and there was not felt to be a need to downgrade the level of evidence for well-constructed, placebo-controlled, randomized trials10. Indeed, if this standard were to be uniformly applied to drugs currently in clinical use, we would have few drugs that could be recommended today.

The crucial importance of clinical judgment

For all of the reasons summarized above, it is not surprising that disparate groups using quite different methodologies and very different standards for acceptable evidence have come to different conclusions. The dilemma is what individual practising physicians should believe, but more so what they should do. The answer must ultimately be predicated upon reason and logic, not on blind adherence to one set of recommendations or another. Hyponatremia guidelines and recommendations are an important source of knowledge; however, they have inherent limitations owing to the lack of an adequate evidence base for most treatments for hyponatremia. The authors of this article, many of whom were involved in the development of the recommendations/guidelines in Table 2, would therefore emphasize the crucial role that clinical judgment must continue to play in decision-making about the management of hyponatremia in individual patients. Such judgments should take into account appropriate appraisals of evidence by authoritative experts in the field, as well as the decisions of regulatory agencies that have based their approvals on a critical review of the efficacy and safety data for approved treatments for hyponatremia. Most importantly, however, physicians bear the responsibility of using their clinical judgment to decide what therapy is most appropriate for individual patients under their care. Differing situations mandate different therapeutic approaches, which is a prominent aspect of caring for hyponatremic patients. A patient with transient SIADH secondary to pneumonia may well be treated with just a few days of fluid restriction while waiting for the SIADH to resolve. Conversely, a patient with an unresectable small cell carcinoma of the lung and a urine osmolality >500 mOsm/kg H₂O will predictably not respond to any reasonable degree of fluid restriction, and therefore is clearly a candidate for pharmacological therapy. Which therapy is chosen should be determined by the circumstances of that individual patient. A patient with chronic stable hyponatremia can potentially be treated with demeclocycline, urea, or a vaptan. However, the same patient receiving chemotherapy with aggressive hydration to prevent nephrotoxicity would not be well served by a bitter-tasting therapy such as urea if they are already nauseated20, nor with furosemide and NaCl with the attendant risk of volume depletion and renal injury; in that case, a vaptan would be a more reasonable choice. These examples hardly cover the wide spectrum of clinical scenarios of hyponatremic patients, but they serve to highlight the fact that, when caring for complex hyponatremic patients, there is no ‘one size that fits all’; rather therapy should be individualized to the patient’s unique situation. In that setting, to eliminate the possibility of any of the potential pharmacological therapies for hyponatremia represents a disservice to the patients we have the responsibility to care for in the best way available. It is clinical judgment rather than guidelines that should, and must, dictate the ultimate choices physicians make for their patients.

Finally, future decisions will also need to take into account increasingly available new data from the rapidly evolving evidence base in hyponatremia; recommendations and guidelines that attempt to address best perceived practices in 2014 are not static, and will likely change significantly over the next several years. For all these reasons, physicians would be best served by maintaining an open mind about all therapies for hyponatremia, each with their individual attendant benefits and risks. To do less would be shirking our responsibilities as physicians to use the best clinical judgment possible for the welfare of our patients.

Conclusion

The indications for the only pharmacological therapy approved across three continents for the treatment of hyponatremia, vasopressin receptor antagonists, differ substantially around the world. Treatment guidelines published to date also fail to achieve agreement on appropriate hyponatremia management. The likely reasons for this failure to achieve consensus include: differing availability of drugs between countries leading to different experiences, or lack of experience, with the use of particular agents; utilization of differing methodologies and scope in the review of existing data; and divergent interpretations of evidence, both in terms of the magnitude and the quality of the evidence. The authors conclude that the only rational way for clinicians to integrate these divergent approved indications and guideline recommendations is to recognize the primary role that clinical judgment must continue to play in decision-making about the management of hyponatremia in individual patients. Such judgments should take into account appropriate appraisals of evidence by authoritative experts in the field, as well as the decisions of regulatory agencies that have based their approvals on a critical review of the efficacy and safety data for approved treatments for hyponatremia. In this context, the exclusion of any of the available effective treatments for hyponatremia from consideration for the treatment of individual patients constitutes a disservice to the patients that physicians are responsible to care for in the best possible manner. Consequently, it is clinical judgment rather than guidelines that should dictate the ultimate choices physicians make for their patients, for hyponatremia just as for all aspects of medicine.

Transparency

Declaration of funding

This paper was commissioned by Otsuka Pharmaceutical Europe Ltd. and publication costs for this article were supported by the company. The authors have not received any honorarium in relation to this paper.

Declaration of financial/other relationships

Charlotte Höybye has been an investigator for Otsuka and has received lecture fees from Otsuka for lectures on hyponatremia. Ashley Grossman is on the Otsuka Speakers’ Bureau, and receives funds for research from Otsuka. Isabelle Runkle has received research funding from Otsuka and has been an advisor and speaker for Otsuka. She has also given talks for Novo Nordisk. Dr Verbalis has served as a consultant, Advisory Board and Speaker Bureau member, and has received both research grants and travel support from Otsuka Pharmaceuticals for development and educational programs related to the use of tolvaptan for treatment of hyponatremia. He has also served as a consultant and provided expert testimony on behalf of Cornerstone Pharmaceuticals related to their application to the FDA for approval of lixivaptan for the treatment of hyponatremia.

CMRO Peer Reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

The authors would like to thank Lorraine Law from apothecom for proofreading the manuscript, and Eman Zaman and James Williams from apothecom for their assistance in compiling the tables.