Vasopressin Excess and Hyponatremia

Vasopressin Excess and Hyponatremia Phuong-Chi T. Pham, MD, Phuong-Mai T. Pham, MD, and Phuong-Thu T. Pham, MD ● Hyponatremia is a common electrolyte disorder that frequently is overlooked and undertreated. Although the pathophysiological process of hyponatremia is complex, arginine vasopressin (AVP) is a common etiologic factor. Excess AVP release by osmotic or nonosmotic stimuli or both can lead to sodium and water imbalance. Conventional treatment options for hyponatremia, including water restriction and administration of sodium chloride with or without loop diuretics, do not directly address the underlying water retention induced by excess AVP in many cases. Clinical trials showed that AVP-receptor antagonists, including lixivaptan, tolvaptan, and conivaptan, produce aquaresis, the electrolyte-sparing excretion of free water, to correct serum sodium concentration. We review results from recent clinical trials involving AVP-receptor antagonists in the treatment of hyponatremia associated with AVP excess. Am J Kidney Dis 47:727-737. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Hyponatremia; arginine vasopressin–receptor antagonist; syndrome of inappropriate secretion of antidiuretic hormone; cirrhosis; congestive heart failure.

H

YPONATREMIA, USUALLY defined as a serum sodium concentration less than 136 mEq/L (⬍136 mmol/L), is a common, yet frequently overlooked and undertreated, condition.1,2 Depending on the definition used, the prevalence of hyponatremia in hospitalized patients was reported to range from 3% to 15%.3-5 Hyponatremia per se has been well documented as a potentially life-threatening condition, as well as an independent predictor of death in intensive care unit and geriatric patients and patients with heart failure, acute ST elevation myocardial infarction, and cirrhosis.6-12 Despite the high prevalence of hyponatremia in hospitalized patients and its association with adverse overall outcomes, many clinicians fail to address this condition at its early stage because of its nonspecific symptoms and often complex management options. For many years, sodium replacement, relatively arbitrary free-water restriction, or both, with or without the use of loop diuretics, comprised the major therapeutic options for hyponatremia. The management of hyponatremia is a multistep process that demands great focus from the clinician because he or she must determine the appropriate rate of correction according to the chronicity of the disorder, select the best therapeutic option based on the cause of hyponatremia, predict dynamic changes in salt and water balance according to the underlying cause and ongoing acute illnesses, closely monitor changes in serum sodium levels, and adjust the patient’s therapy or rate of sodium infusion accordingly. To further challenge the clinician, currently available therapeutic options may be unpredictable

and prone to complications. The use of loop diuretics and water restriction, for example, may lead to volume depletion–induced renal failure and unpleasant lifestyle changes, respectively. In the treatment of significant or life-threatening hyponatremia in patients with edematous states, another challenge arises when free-water restriction cannot provide a timely improvement. In such cases, a loop diuretic may be administered, but this approach can induce profound hypotension, hypokalemia, potentially worsening hyponatremia, and renal failure. In cases of severe hyponatremia, sodium infusion may be considered at the expense of exacerbating the preexisting hypervolemic state. Until recently, clinicians had not been able to more directly treat one of the most common causes of hyponatremia, namely, excessive secretion of antidiuretic hormone, otherwise known as arginine vasopressin (AVP).13,14 AVP-receptor From the Nephrology Division, Olive View-UCLA Medical Center, Sylmar; Department of Medicine, Kidney and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA; and Central Maine Medical Center, Lewiston, ME. Received September 13, 2005; accepted in revised form January 24, 2006. Originally published online as doi:10.1053/j.ajkd.2006.01.020 on March 23, 2006. Support: None. Potential conflicts of interest: None. Address reprint requests to Phuong-Chi T. Pham, MD, Olive View-UCLA Medical Center, Department of Medicine, Nephrology Division, 14445 Olive View Dr, 2B-182 Sylmar, CA 91342. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4705-0002$32.00/0 doi:10.1053/j.ajkd.2006.01.020

American Journal of Kidney Diseases, Vol 47, No 5 (May), 2006: pp 727-737

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728

PHAM, PHAM, AND PHAM

antagonists are a new class of drugs designed specifically to promote aquaresis, the electrolytesparing excretion of free water, and subsequently increase serum sodium levels. AVP IN WATER AND ELECTROLYTE BALANCE

Overview of AVP Release AVP is produced predominantly in magnocellular neurons in the paraventricular and supraoptic nuclei in the hypothalamus, subsequently transported down axon terminals through the supraoptic hypophyseal tract, and eventually stored in the posterior pituitary as inactive complexes with neurophysins.15,16 AVP is released quantally by exocytosis from secretory granules in response to osmotic and nonosmotic stimuli.15 An increase in serum osmolality leads to extracellular water shift in the hypothalamus osmoreceptor cells. The resultant cell-volume shrinkage or increased intracellular osmolality in osmoreceptor cells initiates a cascade of events leading to enhanced AVP synthesis and release.17 Osmotic changes that stimulate AVP release also enhance its production. In humans, the osmotic threshold for AVP release is approximately 280 to 290 mOsm/kg (280 to 290 mmol/kg).18 With serum osmolality greater than the osmotic threshold, AVP release is increased linearly. A 2- to 4-fold increase in AVP level may be observed with each 1% increase in serum osmolality.19 The exact threshold for AVP release decreases with age and during pregnancy.20,21 The slope of the AVP response to plasma osmolality tends to vary among individuals and may be genetically determined; however, the slope of AVP response within each individual may alter in response to blood volume and pressure.22 Renal water handling also is linear in response to AVP. An increasing systemic AVP level results in a proportional decrease in urine flow and increase in urine osmolality (Fig 1).23 In patients with hyponatremia associated with the syndrome of inappropriate antidiuretic hormone release (SIADH), AVP release may follow 1 of 4 distinct patterns and not necessarily reflect osmotic or volume changes (Fig 2).13,24 Type A, found in 24% of patients from a small study cohort involving 25 patients with SIADH, is characterized by erratic fluctuations in AVP release that are independent of serum osmolality. Type B, also known as “reset osmostat,” is a

Fig 1. Physiological relations between plasma osmolality, plasma AVP concentrations, urine volume, and urine osmolality in healthy humans. To convert AVP in pg/mL to pmol/L, multiply by 0.923; osmolality in mOsm/kg to mmol/kg, multiply by 1. (Adapted from Best Pract Res Clin Endocrinol Metab 17; Verbalis JG, Disorders of body water homeostasis, pp 471-503, 200314; and Clin Endocrinol Metab 14, Robinson AG, Disorders of antidiuretic hormone secretion, pp 55-88, 1985,23 with permission from Elsevier.)

pattern observed in approximately 36% of patients in whom a normal linear AVP response is preserved, but is initiated at a lower osmotic threshold than that observed in most of the population. Type C, observed in 32% of patients, is characterized by normal AVP release when serum osmolality is normal or elevated, but AVP release is not inhibited when serum osmolality is low. Type D, a pattern observed in 8% of patients, is associated with normal osmoregulated AVP release, but with an inability to dilute urine or excrete a normal water load. This condition could be caused by enhanced AVP sensitivity or the presence of other antidiuretic factors.24 Nonosmotic stimuli of AVP release include hypovolemia, a decrease in arterial blood pressure, neural regulation by various neurotransmitters and neuropeptides in the hypothalamus, and various pharmacological agents. Decreases in plasma volume exceeding 8% may exponentially stimulate the release of AVP, presumably in part

VASOPRESSIN EXCESS AND HYPONATREMIA

peutic agents, tricyclic anticonvulsants, antidepressants, clofibrate, and chlorpropamide, and such conditions as nausea, vomiting, pain, and hypoglycemia.27,28

A

Plasma AVP (pmol/L)

20

B

10

C LD D 260

729

280

300

Plasma Osmolality (mmol/kg) Fig 2. Four patterns of induced AVP release in patients with SIADH. Erratic AVP release unrelated to (A) plasma osmolality, (B) regulation of water excretion around a lower “reset osmostat” value, (C) AVP release when it cannot be “switched off” at low plasma osmolality, and (D) normal AVP release in patients with SIADH. The shaded area represents normal responses.13,24 To convert AVP in pg/mL to pmol/L, multiply by 0.923; osmolality in mOsm/kg to mmol/kg, multiply by 1. (Reprinted from Int J Biochem Cell Biol 35; Baylis PH, The syndrome of inappropriate antidiuretic hormone secretion, pp 1495-1499, 2003,13 with permission from Elsevier. Copyright 1985, The Endocrine Society.24)

by decreasing tonic inhibitory impulses from the left atrial and possibly pulmonary vein stretch receptors to the hypothalamus.19 Hypotension, particularly secondary to blood loss, serves as a potent stimulus for AVP release through activation of carotid and aortic baroreceptors.25 In addition, the decrease in arterial blood pressure also may induce AVP release through activation of the sympathetic nervous system and reninangiotensin-aldosterone system.26 Many neurotransmitters and neuropeptides in the hypothalamus, including acetylcholine, angiotensin II, histamine, bradykinin, and neuropeptide Y, also have been implicated in the stimulation of AVP release.27,28 Other nonosmotic stimuli also may have a role, including various pharmacological agents, such as morphine, nicotine, chemothera-

AVP Receptors The neurohypophyseal hormone AVP exerts its actions through G-protein–coupled membrane receptors pharmacologically subtyped as V1A (vascular), V2 (renal), and V3 (pituitary), also denoted as V1B in the literature. V1A receptors are found on vascular smooth muscle, liver, kidneys, reproductive organs, spleen, adrenal cortex, and platelets. The vasoconstrictive, mitogenic, and possibly platelet aggregative and hypercoagulable actions of AVP through V1A theoretically may contribute to the pathogenesis and progression of arterial hypertension, heart failure, and atherosclerosis.29 V2 receptors are expressed primarily in basolateral membranes of renal cortical and medullary collecting ducts and, to a lesser extent, distal tubules, where the antidiuretic effect of AVP is mediated. Binding of circulating AVP to the G-protein–coupled V2 receptor on basolateral membranes of the principal cells in collecting ducts induces the activation of adenylyl cyclase, production of cyclic adenosine monophosphate, and activation of protein kinase A. The result is enhanced production and trafficking of the water channel aquaporin-2 to the luminal membranes, where water reabsorption through osmotic equilibration with the hypertonic medullary interstitium occurs. Physiological actions of AVP through V2 receptors have a major role in plasma tonicity, volume regulation, and blood pressure maintenance.29,30 V3 (or V1B) receptors are found predominantly in the anterior pituitary corticotroph cells and, to a lesser extent, the brain, kidney, pancreas, and adrenal medulla. Physiologically, activation of V3 receptors is associated with adrenocorticotropic hormone and ␤-endorphin release.29 AVP and Water Homeostasis Total-body water content in healthy individuals is estimated to be between 55% to 65% of total-body weight and is dependent on various factors, including age, sex, and fat content.22 Two thirds of the total-body water volume is distributed in the intracellular fluid, and one

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third, in the extracellular fluid. Two thirds of the extracellular fluid volume is in interstitial tissues, and one third is in the intravascular space, of which 85% occupies the venous circulation and 15% occupies the arterial circulation.22 Maintenance of these intricate water partitions involves the movement of osmotically active solutes and passive water diffusion between the intracellular and extracellular fluid. In normal human physiological states, sodium, potassium, and glucose are the major osmotically active or effective solutes. Intercompartmental movement of any of these osmotically effective solutes necessitates either an active/facilitated reversetransport process or the obligatory parallel diffusion of water across the 2 compartments to maintain equivalent osmotic pressures.31 Solutes, such as urea, are considered ineffective because they can move freely across cell membranes bidirectionally without necessitating any other process to maintain the osmolality of either compartment. Whereas intracellular water homeostasis is dependent on osmotically active solutes, totalbody water balance is determined and maintained predominantly by the thirst center and renal water excretion.14 Thirst, a physiological response to increase free-water uptake, may be stimulated by hyperosmolality, profound volume contraction, and gastric salt loading.32 With exposure to hyperosmolality, osmoreceptor cells in the subfornical organ and organum vasculosum laminae terminalis activate neurons projecting to the paraventricular and supraoptic nuclei in the hypothalamus to stimulate thirst. In addition, profound volume contraction caused by a significant decrease in arterial blood pressure or volume depletion may induce an increase in levels of intracerebroventricular angiotensin II, a strong dipsogenic factor.33 Finally, thirst may be stimulated by gastric sodium loading, presumably through sodium receptors in the abdominal viscera (such as hepatic portal osmoreceptors), independent of any increase in systemic plasma osmolality.34 Renal free-water excretion is dependent on the integrity of nephron-diluting segments, maintenance of a hypertonic medullary interstitium, and intact AVP activity at the collecting ducts. For renal water excretion to occur, free water first is produced in the nephron-diluting seg-

PHAM, PHAM, AND PHAM

ment, the thick ascending loop of Henle, by salt extractions from the lumen through the sodiumpotassium-2 chloride cotransporter. Intraluminal free water is produced with this process because water cannot diffuse across the luminal surface in parallel with salt uptake due to the unique water-impermeable characteristic of this diluting segment. Reabsorption of salt without water continues to occur in the distal convoluted tubule, where dilution of urine is maximized. While free water is produced within the lumen, salt uptake simultaneously enhances and maintains the greater tonicity of the medullary interstitium. Subsequently, the free water formed may be either reabsorbed or excreted into urine at the collecting ducts, as dictated by AVP. In the presence of AVP and an intact hypertonic medullary interstitium, AVP, through V2 receptors, upregulates the expression and trafficking of aquaporin-2 to the luminal side of the collecting tubules and allows water to be reabsorbed efficiently down a more tonic medullary milieu. AVP-facilitated free-water reabsorption decreases urine volume and increases urine concentration.14 In the absence of AVP, the free water produced from the diluting segment is excreted and is reflected clinically as high urine output with low osmolality. AVP Excess and Hyponatremia Although AVP is the major regulatory factor in the maintenance of total-body water, its excessive production and release can result in profound water retention and hyponatremia.13 In hypovolemia, volume loss or decrease in arterial blood pressure promotes AVP release appropriately to enhance both thirst and renal water retention. Hyponatremia occurs when free water is replaced in excess of salt. In hypervolemia caused by congestive heart failure (CHF), blood volume is expanded, but cannot be translocated effectively from the venous to arterial circulation to support adequate cardiac output. As a result, effective arterial volume, pressure, or both are decreased in a manner similar to that in a hypovolemic state. To expand the effective arterial volume, AVP release is enhanced to increase thirst, water intake, and renal water retention.35 With normal renal perfusion, as much as 70% of glomerular filtrate is reabsorbed proximally, leaving the remaining volume to reach the loop of Henle, where the

VASOPRESSIN EXCESS AND HYPONATREMIA

upper limit on urine flow and output is determined. As renal perfusion decreases in association with low cardiac output, glomerular filtrate volume decreases, increased proximal filtrate reabsorption occurs, and thus a smaller remaining filtrate volume is delivered to the diluting segment for free-water production and subsequent excretion. Any free water that can be produced in the subsequent diluting segment will be reabsorbed avidly in the collecting ducts through the action of AVP on V2 receptors. The severe decrease in urine volume (salt and water retention) and free-water clearance (FWC; water retention) induced by the decreased glomerular filtrate volume and secondary excessive AVP release perpetuate the edematous state, while exacerbating hyponatremia. In addition to volume expansion and hyponatremia, the elevated AVP levels in patients with CHF secondarily may increase systemic vascular resistance through V1A vasoconstrictive activity and decrease cardiac output.30 Accordingly, the excess AVP-induced V1A vasoconstrictive effect theoretically may be harmful to some patients with CHF. As in patients with CHF, those with cirrhosis or nephrosis who have poor arterial pressure because of peripheral vasodilation, low intravascular oncotic pressure, or both may present with decreased urine output, enhanced free-water reabsorption, and significant hyponatremia caused by poor renal perfusion and enhanced AVP release.21,36 Of interest, prostaglandin synthesis inhibitors, such as nonsteroidal anti-inflammatory drugs, were observed to potentiate the antidiuretic effect of AVP, presumably through stimulation of AVP-induced generation of cyclic adenosine monophosphate, and thereby may exacerbate free-water retention and hyponatremia in patients with preexisting hypervolemia and low intravascular effective volume or pressure.37-39 Euvolemic hyponatremia accounts for 60% of all forms of chronic hyponatremia, of which SIADH, a disorder in which AVP release is independent of volume, blood pressure, and osmotic control, predominates.13,40 SIADH is defined by 5 major criteria: (1) hypotonic hyponatremia; (2) euvolemia; (3) inappropriately high urine osmolality (ie, ⬎70 to 100 mOsm/kg [⬎70 to 100 mmol/kg]) in the presence of hyponatremia; (4) normal renal, thyroid, and adrenal func-

731

tion; and (5) high renal sodium excretion (ie, ⬎40 mEq/L [⬎40 mmol/L]).41 The major categories of illnesses associated with SIADH include neoplasm, neurological disease or trauma, pulmonary disorders, and various stress states, such as nausea, vomiting, pain, and anxiety. In addition, SIADH may be caused by a number of medications, particularly tricyclic antidepressants and anticonvulsants.1,13,40,42 Impact of Age on AVP The pathophysiological processes of agerelated disturbances in water homeostasis and the resultant hyponatremia are complex and most likely multifactorial. In older individuals, totalbody water content is as much as 20% less than that in younger individuals.43 A change in salt and water balance therefore may result in a more pronounced effect on body fluid osmolality and various salt concentrations. The development of hyponatremia specifically may be attributed to the decreased capacity for free-water handling because of various factors, including a decrease in glomerular filtration rate, decrease in solute load caused by poor nutritional intake, and enhanced osmotic and nonosmotic AVP sensitivity.20,44 In addition, a blunted aldosterone response was observed in healthy elderly individuals.45 In patients in whom water balance is simultaneously altered, hyponatremia may occur. PHARMACOLOGICAL OPTIONS FOR HYPONATREMIA

Current treatment options for patients with hyponatremia, including sodium supplementation, water restriction, and concomitant diuretic therapy, usually are effective, but not without limitations. Although sodium supplementation through saline infusion is effective in patients with hypovolemic hyponatremia, its use may be problematic in patients with hypervolemic hyponatremia because of the acute volume expansion. Water restriction with or without concomitant diuretic administration in patients with euvolemic and hypervolemic hyponatremia may lead to a slow response, less predictable outcomes, and, sometimes, serious complications. For example, water restriction in patients with underlying malignancy or various other SIADH-associated conditions may lead to anxi-

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PHAM, PHAM, AND PHAM

Table 1. Overview of AVP-Receptor Antagonists

Agent

Receptor Target

Lixivaptan

V2

Tolvaptan

V2

Conivaptan

V1A/V2

Disorders Studied in Clinical Trials

CHF,49 SIADH,49 cirrhosis48,49 CHF (NYHA class I-IV),50 (LVEF ⬍ 40%)51 CHF NYHA class III and IV35 Euvolemic or hypervolemic hyponatremia52,54,55

Abbreviations: NYHA, New York Heart Association; LVEF, left ventricular ejection fraction.

ety, malnourishment, and symptomatic volume depletion. In cases of prolonged hyponatremia in which fluid restriction is not tolerated, demeclocycline, a tetracycline antibiotic, may be an option. Nevertheless, the use of demeclocycline is limited by poor results; troublesome adverse events, including azotemia, photosensitivity, and nausea; and contraindications in patients with cirrhosis or renal failure.22,46 Conventional diuretics are effective in decreasing volume overload, but may lead to excessive salt and water excretion and result in or worsen effective arterial volume depletion and hyponatremia. In addition, diuret-

ics are associated with neurohormonal activation involving the renin-angiotensin-aldosterone system and sympathetic nervous system and may be particularly harmful to elderly and cardiac patients.31 Overview of AVP-Receptor Antagonists The role of AVP-receptor antagonists in the treatment of patients with hyponatremia was evaluated in clinical trials. This novel class of agents was shown to promote aquaresis, the electrolyte-sparing excretion of free water.47 Currently, AVP-receptor antagonists directed at V2 receptors (lixivaptan and tolvaptan) are in development for clinical use in patients with euvolemic and hypervolemic hyponatremia. Conivaptan, a V1A/V2receptor antagonist, recently was approved in the United States for use in hospitalized patients with euvolemic hyponatremia (Tables 1 and 2). Lixivaptan. The efficacy and tolerability of lixivaptan (VPA-985), an oral V2-receptor antagonist, was evaluated in patients with hyponatremia secondary to CHF, SIADH, and cirrhosis with ascites. In a randomized, double-blind, multicenter trial, 60 patients with dilutional hyponatremia (serum sodium levels between 115 and 132 mEq/L [115 and 132 mmol/L]) secondary to

Table 2. Effects of AVP-Receptor Antagonists in Patients With AVP Excess Agent/Study Duration

Lixivaptan 7d Tolvaptan 25 d 60 d Conivaptan 1d 4d 5d

Urine Output*

FWC†

Urine Osmolality

Serum Sodium

Body Weight

Blood Pressure

Heart Rate

Thirst

Renal Function

60 44

1 1

1 1

2 2

1 1

2 2

NC NC

NC NC

1 1

ND NC

Gheorghiade et al50储 Gheorghiade et al51¶

254 319

1 1

NA NA

2 NA

1 1

2 2

NC NC

NC NC

1 1

NC NC

Udelson et al35# Verbalis et al52¶ Ghali et al54¶ Gross et al55¶

142 84 74 83

1 NA NA NA

NA 1 1 1

2 NA NA NA

1 1 1 1

NA NA NA NA

NC NA NA NA

NC NA NA NA

NA NA NA NA

NA NA NA NA

Reference

Gerbes et al48‡ Wong et al49§

No. of Patients

Abbreviations: 1, increase; 2, decrease (see text for actual statistical significance); NC, no change from baseline in all groups; ND, no difference— glomerular filtration rate decreased approximately 10% from baseline in all active-treatment groups and the placebo group, but the change was similar in all groups; NA, data not available. *Urine output or net fluid balance (defined as urine output ⫺ fluid intake). †In the 4- and 5-day conivaptan studies, effective water clearance was measured instead of FWC. ‡One liter per day fluid restriction. §Fluid restriction of 1.5 L/d, but may be higher for those with high urine output (⬎3 L/d). 储No fluid restriction. ¶Freedom of fluid access not stated by investigators. #Fluid restriction of 250 mL/2 h from time of insertion of pulmonary artery catheter throughout the treatment period.

VASOPRESSIN EXCESS AND HYPONATREMIA

cirrhosis were randomly assigned to administration of placebo (n ⫽ 20); lixivaptan, 100 mg/d (n ⫽ 22); or lixivaptan, 200 mg/d (n ⫽ 18).48 Treatment was continued for as long as 7 days or until the primary end point of normalization of serum sodium levels (ⱖ136 mEq/L [ⱖ136 mmol/ L]) was reached. All patients continued to take their usual medications throughout the study period. Normalization of serum sodium levels was achieved in 27% and 50% of patients administered lixivaptan, 100 and 200 mg/d, but in no patient in the placebo group, respectively. Accordingly, lixivaptan increased serum sodium levels from baseline more than placebo at study end (128.3 ⫾ 4.1 to 130.4 ⫾ 6.5 mEq/L [128.3 ⫾ 4.1 to 130.4 ⫾ 6.5 mmol/L] in patients administered 100 mg/d [P ⫽ 0.053], 126.4 ⫾ 4.4 to 132.3 ⫾ 6.9 mEq/L [126.4 ⫾ 4.4 to 132.3 ⫾ 6.9 mmol/L] in those administered 200 mg/d [P ⬍ 0.001], and 127.3 ⫾ 3.0 to 127.7 ⫾ 4.0 mEq/L [127.3 ⫾ 3.0 to 127.7 ⫾ 4.0 mmol/L] in those administered placebo). Mean changes in serum sodium levels per day were 0.8 ⫾ 0.4/L/d, 1.8 ⫾ 0.5/L/d, and 0.1 ⫾ 0.2/L/d in the 100-mg/d, 200-mg/d, and placebo groups, respectively. The maximum increase in serum sodium levels with either dose of lixivaptan was 7/L/d. Both doses of lixivaptan increased FWC significantly more than placebo (lixivaptan, 100 mg/d, 0.3 ⫾ 0.3 mL/min [P ⬍ 0.01]; lixivaptan, 200 mg/d, 1.2 ⫾ 0.4 mL/min [P ⬍ 0.001]; and placebo, ⫺0.7 ⫾ 0.2 mL/min). By the end of the study, glomerular filtration rate decreased by approximately 10% in both lixivaptan groups and the placebo group. Treatment with lixivaptan did not have an additional negative impact on renal function. Use of either dose of lixivaptan was associated with increased thirst compared with placebo.48 In another multicenter, randomized, placebocontrolled trial, lixivaptan was evaluated for its efficacy and safety in the correction of hyponatremia. The study involved 44 patients with hyponatremia (serum sodium ⬍130 mEq/L [⬍130 mmol/ L]) secondary to CHF (n ⫽ 6), SIADH (n ⫽ 5), and cirrhosis with ascites (n ⫽ 33).49 Patients were randomly assigned to administration of placebo (n ⫽ 11) or oral lixivaptan at 25 mg twice daily (n ⫽ 12), 125 mg twice daily (n ⫽ 11), or 250 mg twice daily (n ⫽ 10) during a 7-day period. All patients continued to take their usual medications, including diuretics, and followed

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dietary sodium restriction determined by each investigator and fluid restriction (1.5 L/d). The last condition was not strictly enforced because patients with urine output greater than 3 L/d were allowed to have greater fluid intake. The actual amount of fluid intake in each group was not reported in the study. Nevertheless, lixivaptan increased net fluid volume (urine output ⫺ fluid intake) and FWC significantly more than placebo (P ⬍ 0.05), in accordance with the dosage administered. At the end of the 7-day study, FWC was ⫺0.3 ⫾ 0.2 mL/min in patients administered lixivaptan, 25 mg (P ⫽ not significant), 0.5 ⫾ 0.2 mL/min in those administered 125 mg (P ⬍ 0.01), 0.3 ⫾ 0.3 mL/min in those administered 250 mg (P ⬍ 0.01), and ⫺0.7 ⫾ 0.3 mL/min in patients administered placebo. In a separate analysis of patients who had cirrhosis, serum sodium levels increased significantly more between day 1 and the end of the study in patients administered lixivaptan, 25 mg (126 ⫾ 1 mEq/L on day 1 versus 129 ⫾ 2 mEq/L on day 7 [126 ⫾ 1 versus 129 ⫾ 2 mmol/L]; P ⬍ 0.05), 125 mg (122 ⫾ 2 versus 127 ⫾ 3 mEq/L, respectively; P ⬍ 0.05), or 250 mg (125 ⫾ 1 versus 132 ⫾ 1 mEq/L; P ⬍ 0.003) than in those administered placebo (127 ⫾ 1 versus 126 ⫾ 1 mEq/L; P ⬍ 0.05). Accordingly, there was a significant decrease in urine osmolality in patients administered lixivaptan. Serum creatinine levels did not change significantly in any of the patient groups throughout the study period. However, the group administered the highest dose of lixivaptan (250 mg twice daily) consistently reported increased thirst and had significantly increased thirst scores. With respect to the vasoactive hormonal profile, including vasopressin, norepinephrine, plasma renin activity, and aldosterone, lixivaptan only increased AVP levels significantly by study end.49 Tolvaptan. The efficacy and tolerability of tolvaptan (OPC-41061), an oral V2-receptor antagonist, were evaluated in patients with CHF. In a randomized double-blind trial designed to investigate the effects of 3 doses of tolvaptan, 254 patients with a “diagnosis of CHF” were randomly assigned to administration of tolvaptan, 30 mg/d (n ⫽ 64), 45 mg/d (n ⫽ 64), and 60 mg/d (n ⫽ 63) or placebo (n ⫽ 63) in combination with standard furosemide therapy for 25 days.50 Tolvaptan was effective in increasing

734

urine output, decreasing total-body weight, and improving edema despite no fluid restriction. Although fluid intake increased in patients administered tolvaptan, 30, 45, or 60 mg, mean net fluid loss (urine output ⫺ fluid intake) was significantly greater with each of these tolvaptan doses (1,337, 988, and 1,286 mL/d, respectively) than with placebo (98 mL/d; P ⬍ 0.05). Mean change in urine osmolality from baseline to end of study also was significantly less with each tolvaptan dose (30 mg, 7.13 ⫾ 164.49 mOsm/kg [7.13 ⫾ 164.49 mmol/kg]; 45 mg, ⫺19.38 ⫾ 157.03 mOsm/kg; and 60 mg, ⫺49.51 ⫾ 152.98 mOsm/ kg) than with placebo (168.55 ⫾ 204.2 mOsm/ kg; P ⬍ 0.05). Of 254 patients, 28% had hyponatremia (serum sodium ⬍136 mEq/L [⬍136 mmol/L]) at baseline. In this subset, significantly more patients showed normalized serum sodium levels at day 1 in the tolvaptan-treated group compared with placebo (80% versus 40%, respectively; P ⬍ 0.05). Correction of hyponatremia was maintained throughout the study period (82% versus 40%; P ⬍ 0.05). Serum creatinine levels did not change in any group by the end of the study. Thirst was reported at a significantly greater frequency in tolvaptan-treated groups compared with placebo (31.3%, 40.3%, and 24.6% in the 30-, 45-, and 60-mg groups compared with 4.8% in the placebo group). Nevertheless, only 2 patients from the 60-mg group were reported to discontinue the medication because of polyuria. No significant changes in heart rate, blood pressure, serum potassium level, or renal function were observed.50 In the phase 2 clinical trial Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure, 319 patients hospitalized with CHF and a left ventricular ejection fraction less than 40% were assigned to placebo (n ⫽ 80) or tolvaptan, 30 mg/d (n ⫽ 78), 60 mg/d (n ⫽ 84), or 90 mg/d (n ⫽ 77), plus routine therapy, including diuretics, for as long as 60 days.51 Median body-weight decrease from baseline associated with placebo (⫺1.90 kg; range, ⫺4.20 to ⫺0.50 kg) was significantly smaller than that with tolvaptan, 30 mg (⫺3.30 kg; range,⫺7.30 to ⫺1.35; P ⫽ 0.006), 60 mg (⫺2.80 kg; range, ⫺5.90 to ⫺1.80; P ⫽ 0.002), and 90 mg (⫺3.20 kg; range, ⫺5.80 to ⫺1.60; P ⫽ 0.06).

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Mean urine output at 24 hours also was less with placebo (2,296.5 ⫾ 1,134.1 mL) than with each dose of tolvaptan (30 mg, 4,056.2 ⫾ 2,310.2 mL; P ⫽ 0.02; 60 mg, 4,175.2 ⫾ 2,695.4 mL; P ⬍ 0.001; and 90 mg, 4,127.3 ⫾ 2,050.8 mL; P ⬍ 0.001). This effect was maintained throughout the hospitalization period. Patients recruited into the study had only mild hyponatremia (average serum sodium level, 138.65 mEq/L [138.65 mmol/L]). Nonetheless, at 1 day after randomization, there was a trend for a slight increase in mean serum sodium levels from baseline in patients administered tolvaptan, 30 mg (2.77 ⫾ 3.56 mEq/L), 60 mg (3.38 ⫾ 4.84 mEq/L), and 90 mg (3.50 ⫾ 3.63 mEq/L), but a decrease in patients administered placebo (⫺0.20 ⫾ 3.12 mEq/L). In addition, the 68 patients with hyponatremia (serum sodium level ⬍136 mEq/L) at baseline were reported to have a rapid improvement and often normalization of serum sodium levels. The improvement in serum sodium levels was maintained throughout the study in all treated groups. As in the previous clinical trial, no significant changes in heart rate, blood pressure, serum potassium level, or renal function were observed. Thirst was a common adverse event, observed in 11.9% of patients administered tolvaptan versus 1.3% of the placebo group. Although there was no difference between the tolvaptan and placebo groups in the rate of worsening heart failure at 60 days, post hoc analysis showed lower mortality for patients with renal dysfunction or severe systemic congestion (defined as dyspnea, jugular venous distension, and edema) administered tolvaptan.51 Conivaptan. The acute efficacy of intravenous conivaptan, the first AVP-receptor antagonist with activity at both the V1A and V2 receptors, was evaluated in patients with New York Heart Association classes III and IV heart failure. In this randomized double-blind study, 142 patients were assigned to administration of a single intravenous dose of conivaptan, 10 mg (n ⫽ 37), 20 mg (n ⫽ 32), or 40 mg (n ⫽ 35), or placebo (n ⫽ 38).35 During the 4-hour period immediately after drug infusion, urine output was significantly greater in patients administered conivaptan (10 mg, 68.9 ⫾ 17.4 mL/h; 20 mg, 152.2 ⫾ 19.2 mL/h; 40 mg, 176.2 ⫾ 17.8 mL/h) than those administered placebo (11.2 ⫾ 17.3 mL/h; P ⬍

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0.001 versus all conivaptan doses). The increase in urine output was associated with a decrease in urine osmolality: ⫺249.8 ⫾ 26.9 mOsm/kg (⫺249.8 ⫾ 26.9 mmol/kg) with conivaptan, 10 mg; ⫺279.6 ⫾ 31.7 mOsm/kg with conivaptan, 20 mg; ⫺319.3 ⫾ 25.8 mOsm/kg with conivaptan, 40 mg; and ⫺2.2 ⫾ 27.9 mOsm/kg with placebo (P ⫽ 0.0001 versus all conivaptan doses). Serum sodium concentrations were not significantly different from placebo at 4 hours. Nevertheless, there was a trend for greater serum sodium level increases in the conivaptan groups (10 mg, 0.5 ⫾ 0.5 mEq/L [0.5 ⫾ 0.5 mmol/L]; 20 mg, 0.8 ⫾ 0.7 mEq/L; and 40 mg, 1.5 ⫾ 0.4 mEq/L) compared with the placebo group (0.4 ⫾ 0.7 mEq/L). In a randomized, double-blind, multicenter, placebo-controlled, parallel-group study, intravenous conivaptan (a 20-mg loading dose followed by continuous infusion of 40 [n ⫽ 29] or 80 mg/d [n ⫽ 26] for 4 days) was compared with placebo (n ⫽ 29) in patients with euvolemic or hypervolemic hyponatremia (serum sodium level, 115 to ⬍130 mEq/L [115 to ⬍130 mmol/L]).52 The primary efficacy measure was change in serum sodium level from baseline to end of study, measured by the area under the sodium level– time curve. Secondary measures included change in serum sodium level from baseline at day 4, time from first dose to achieve a 4-mEq/L or greater change in serum sodium level, number of patients achieving a 6-mEq/L or greater change in sodium level or normal sodium level, and effective water clearance (defined as electrolyte-free water clearance as opposed to solute-free water clearance for FWC—the former was suggested to more accurately explain the “physiology of the renal role in the variations in natremia”).53 Changes in serum sodium levels from baseline to end of study, measured by the area under the sodium level– time curve, were significantly greater in patients administered conivaptan than those administered placebo. Serum sodium levels increased significantly more with both conivaptan doses (6.8 and 9.0 mEq/L, respectively; P ⬍ 0.001) than placebo (2.0 mEq/L). Mean time required for serum sodium level to reach 4 mEq/L or greater was not “estimable” in the placebo group, but was 23.7 hours in the group administered conivaptan, 40 mg/d, and

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23.4 hours in the group administered 80 mg/d. In addition, a greater percentage of patients administered conivaptan, 40 mg/d (69%) or 80 mg/d (88%), than those administered placebo (21%; P ⬍ 0.01 and P ⬍ 0.001, respectively) showed an increase in serum sodium levels to 6 mEq/L or greater or normalized serum sodium level at study end. At day 1, effective water clearance also was significantly greater in patients administered conivaptan, 40 mg/d (1,984 ⫾ 1,559 mL) or 80 mg/d (1,759 ⫾ 1,748 mL), than in those administered placebo (⫺332 ⫾ 434 mL; P ⬍ 0.05 versus both doses).52 In 2 similar studies, 83 patients with euvolemic hyponatremia and 74 patients with hypervolemic hyponatremia were administered oral conivaptan, 40 or 80 mg/d, or placebo for 5 days. As in the other studies, conivaptan increased serum sodium levels and effective water clearance significantly more than placebo.54,55 Because in vivo and in vitro studies indicated that conivaptan is a substrate and potent inhibitor of cytochrome P-450 3A4, the liver and smallintestine isoenzyme responsible for drug metabolism, only the intravenous formulation of conivaptan was developed and approved in the United States for the treatment of patients with euvolemic hyponatremia. CONCLUSION

Hyponatremia is a common and potentially serious condition most often caused by excessive AVP secretion. With the exception of hypovolemic hyponatremia, for which saline infusion is appropriate and the outcome generally is easily predictable, current therapeutic options for patients with euvolemic and hypervolemic hyponatremia may result in unpredictable or undesirable outcomes. Because excessive AVP release is the key etiologic factor in perpetuating the hyponatremia observed in patients with such common clinical conditions as CHF, cirrhosis, nephrosis, and SIADH, therapy that directly antagonizes AVP receptors potentially may offer better outcomes. Current AVP-receptor antagonists were shown to increase serum sodium levels effectively at a safe dose-dependent rate and may become a promising therapeutic option in the treatment of patients with euvolemic and hypervolemic hyponatremia.47

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