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Division of Cardiology, Wayne State University (J.K.G.), Detroit, Michigan 48201; Jacksonville Center for Clinical Research (M.J.K.), Jacksonville, Florida 32216; Pulmonary Consultants (J.R.T.), Tacoma, Washington 98405; Cato Research (E.B.-A., K.F., W.A.L.), Durham, North Carolina 27713; and Astellas Pharma U.S. (N.S.), Inc., Deerfield, Illinois 60015
Address all correspondence and requests for reprints to: Dr. Jalal K. Ghali, Division of Cardiology, Wayne State University, 4201 St. Antoine, Detroit, Michigan 48201. E-mail: jghali{at}med.wayne.edu.
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Abstract |
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Objective: The objective of this study was to evaluate the efficacy and safety of oral conivaptan, a vasopressin V1A/V2 receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia.
Design: The study design was a 5-d placebo-controlled, randomized, double-blind study.
Setting: The study was performed at a hospital.
Intervention: Oral conivaptan (40 or 80 mg/d) or placebo was given in two divided doses.
Patients: Seventy-four patients (average baseline serum [Na+], 115 to <130 mEq/liter) were studied.
Main Outcome Measure: The main outcome measure was the change from baseline in serum [Na+] area under the curve.
Results: The least-squares mean change from baseline in the serum [Na+] area under the curve with conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) and 2.5-fold (P < 0.001) greater, respectively, than that with placebo. The median time to achieve a confirmed increase in serum [Na+] of 4 mEq/liter or more from baseline was 71.7 h for placebo, 27.5 h for 40 mg/d conivaptan (P = 0.044), and 12.1 h for 80 mg/d conivaptan (P = 0.002). The mean total times during which patients had a serum [Na+] level of 4 mEq/liter or more above baseline were 46.5, 69.8, and 88.8 h (P = 0.001), respectively. The least-squares mean change in serum [Na+] from baseline to end of treatment was 3.4 mEq/liter for placebo, 6.4 mEq/liter for 40 mg/d conivaptan, and 8.2 mEq/liter for 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na+] (
135 mEq/liter) or increase of 6 mEq/liter or more was observed in 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014). Headache, hypotension, nausea, constipation, and postural hypotension were the most common adverse events.
Conclusion: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na+] in hyponatremia.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Hyponatremia is frequently caused by inappropriately elevated plasma AVP levels, such as in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), which is characterized by continued secretion of AVP under the condition of hypotonicity (5, 6). The causes of SIADH include neoplasms and a variety of central nervous system and pulmonary disorders.
Hypotonic hyponatremia also occurs relatively frequently in patients with heart failure (HF) and other edema-forming disorders (7, 8). Despite a hypervolemic edematous state, pronounced retention of sodium and water occurs in an attempt to maintain effective arterial blood volume (4, 7, 9). Patients who have hyponatremia with advanced HF often have inappropriately elevated plasma AVP levels (7, 8) and significantly poorer long-term prognosis than those with normal serum [Na+] (10).
Asymptomatic chronic hyponatremia, which develops over a period of more than 48 h, is usually treated with fluid restriction (<800 ml/d) and less frequently with pharmacological agents, such as demeclocyclin, and urea (1, 11). In contrast, acute or chronic symptomatic hyponatremia, which includes symptoms ranging from lethargy and headache to seizures or coma, necessitates hospitalization and immediate treatment with hypertonic saline, loop diuretics, or both (11). Regardless of the treatment, care must be taken to avoid an excessively rapid increase in serum [Na+] and resultant osmotically induced pontine demyelination, especially in patients with chronic hyponatremia (3). Increasing serum [Na+] by no more than 12 mEq/liter·d is recommended to avoid adverse effects associated with an overly rapid correction of sodium levels (3, 11). None of the currently available therapies directly addresses the effects of elevated plasma AVP, the underlying cause of many cases of hyponatremia.
The binding of AVP to V2 receptors leads to increased permeability of the renal collecting duct surface cells and reabsorption of water, which, if excessive, can lead to decreased plasma sodium levels (4, 7). The binding of AVP to V1A receptors on vascular smooth muscle causes vasoconstriction, although the AVP levels required to generate a pressor response are much higher than those necessary to produce antidiuresis (7, 12). Because AVP receptors play a key role in regulating osmolality and body fluid volume, V2 receptor blockade may be a beneficial treatment approach in patients with hyponatremia.
Several nonpeptide vasopressin receptor antagonists have been developed in recent years (7), and conivaptan is the first to be active at both V1A and V2 receptors (13). In a study of healthy volunteers, the oral bioavailability of conivaptan was 44%, and the drug’s aquaretic effects (markedly increased urine flow rate and decreased urine osmolality) persisted for at least 6 h (14). In patients with advanced HF (New York Heart Association class III or IV), a single iv dose of conivaptan increased urine output and reduced pulmonary capillary wedge pressure (15). The study reported here assessed the efficacy and tolerability of two oral doses of conivaptan (40 and 80 mg/d given in two divided doses for 5 d) in patients with euvolemic or hypervolemic hyponatremia.
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Patients and Methods |
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Patients
This double-blind, placebo-controlled, multicenter study included hospitalized patients from 21 sites in the United States, Canada, and Israel who had euvolemic (absence of pitting edema) or hypervolemic (edematous) hyponatremia. Included in the study were men and women (nonlactating and nonpregnant or practicing a barrier method of birth control) at least 18 yr of age who had a serum [Na+] of 115 to less than 130 mEq/liter, a fasting blood glucose level less than 275 mg/dl (15 mmol/liter), plasma osmolality less than 290 mosmol/kg H2O, and no evidence of extracellular volume depletion.
Excluded were patients who had uncontrolled hypertension; significant orthostatic hypotension or supine systolic blood pressure less than 85 mm Hg; uncontrolled arrhythmias; untreated severe hypothyroidism, hyperthyroidism, or adrenal insufficiency; an estimated creatinine clearance less than 20 ml/min; urinary outflow obstruction unless catheterized; an alanine aminotransferase or aspartate aminotransferase level more than five times the upper limit of normal; serum albumin of 1.5 g/dl or less; prothrombin time greater than 22 sec or an international normalized ratio greater than 2.0 without anticoagulant therapy or 3.0 or more with therapy; a white blood cell count less than 3000/µl; HIV infection; or active hepatitis. Also ineligible were patients expected to have hyponatremia necessitating emergent treatment during the study, those with any concurrent illness that could interfere with study treatment or its evaluation, and patients who had participated in a clinical trial of an investigational drug or device within 30 d of screening.
Study procedures
The baseline period lasted from 20–28 h, during which patients underwent single-blind administration of placebo twice daily. Serum [Na+] was measured at 4, 6, and 12 h and at the end of the baseline period (20–28 h). Patients whose serum [Na+] was 133 mEq/liter or greater by the end of the baseline phase were not randomly assigned to treatment.
Eligible patients were stratified by volume status and assigned randomly in a 1:1:1 ratio to receive placebo, 40 mg/d conivaptan, or 80 mg/d conivaptan in two divided doses. Before receiving medication on d 1 and after the conclusion of treatment on d 5, patients underwent electrocardiographic and clinical laboratory testing and evaluation of the following parameters: safety profile (including vital signs, weight, and volume status); serum [Na+], serum potassium concentration ([K+]), levels of AVP and other neurohormones, and osmolality; and urinary sodium, potassium, and creatinine levels, osmolality, and output. Initial assessments were performed daily before the first dose of study medication. Serum sodium and potassium concentrations and plasma osmolality were determined at 4, 6, 12, and 24 h on each treatment day. Patients returned 6–9 d after the conclusion of treatment for assessment of serum [Na+], weight, volume status, and vital signs.
Diet and concomitant therapy
Fluid intake was limited to 500 ml in a 3-h period up to a maximum of 2.0 liters in 24 h. Calorie consumption, caffeine ingestion, and 24-h sodium intake remained stable throughout the study. Consumption of alcoholic beverages or grapefruit juice was not allowed.
Because conivaptan is a substrate and potent inhibitor of the microsomal enzyme cytochrome P450 (CYP) 3A4, the concomitant use of several agents was prohibited, including chemotherapeutic agents, calcium channel blockers, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, benzodiazepines, and immunosuppressants. Other prohibited medications included any medication known to cause SIADH (e.g. vasopressin, oxytocin, desmopressin, and carbamazepine) and any medication used in the treatment of SIADH. Patients were permitted to use amiodarone (at doses not exceeding 300 mg/d), digoxin, and warfarin, provided the dosages were stable both before screening and during the study.
Efficacy end points and statistical analysis
Primary efficacy end point. The primary efficacy end point was the change from baseline in serum [Na+], as measured by area under the serum [Na+]–time curve (AUC). The serum [Na+] AUC was calculated using the trapezoidal rule, and baseline serum [Na+] was calculated as the average of all measurements obtained during the baseline period. The effect of treatment on baseline-adjusted AUC was determined according to an analysis of covariance model, in which treatment, treatment center, and each patient’s volume status were the factors and baseline serum [Na+] was the covariate. The threshold of statistical significance of the interactions between treatment and baseline serum [Na+], treatment center, and volume status was 0.1. The statistical comparisons between conivaptan and placebo were performed with Dunnett’s two-sided multiple test (threshold of significance, 0.05) (16, 17).
A sample size of 84 patients was estimated to provide 90% power to detect a change in serum [Na+] AUC of 130 mEq·h/liter, assuming a dropout rate of 20%. The analysis was performed using the full analysis set, which included all randomized patients who had at least one serum [Na+] measurement assessed at baseline, took at least one dose of study medication, and had at least one valid follow-up measurement.
Secondary efficacy end points.
Secondary efficacy parameters included the time from the first dose to a confirmed increase in serum [Na+] of 4 mEq/liter or greater above baseline, the total time from first dose to end of treatment during which serum [Na+] was 4 mEq/liter or greater above baseline, the change from baseline in serum [Na+] at the end of treatment, and the number of patients who achieved a confirmed normal (135 mEq/liter) serum [Na+] or increase of 6 mEq/liter or more from baseline. Other efficacy parameters included the change from baseline in free water clearance (FWC), effective water clearance (EWC), urine and plasma osmolality, urinary sodium levels, serum AVP, and other neurohormone levels. The log-rank test, in which patients were stratified by baseline volume status, was used for analysis of the first secondary end point, the second and third parameters were analyzed in the same manner as the primary end point, and the fourth parameter was analyzed using the Cochran-Mantel-Haenszel procedure, stratified by volume status. All other efficacy parameters were summarized using descriptive statistics.
Safety assessments
All patients who received any study medication were included in the safety analysis. The incidence of adverse events (AEs), changes in vital signs, clinical laboratory parameters, and body weight were summarized. The rate and extent of the serum [Na+] correction were also assessed as a safety parameter. Rapid serum [Na+] correction was prospectively defined with the following four criteria: 1) serum [Na+] increase of more than 12 mEq/liter in 1 d, 2) serum [Na+] increase of more than 24 mEq/liter total, 3) serum [Na+] greater than 145 mEq/liter, or 4) reduced or temporarily withheld treatment after an increase in serum [Na+] judged by the investigator to be too rapid.
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Results |
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A total of 74 patients received conivaptan (40 or 80 mg/d) or placebo (Fig. 1
). The baseline characteristics were similar in the three groups (Table 1). Most patients (68%) were 65 yr of age or older. HF, the most common underlying condition, was present in 43% of all patients. The proportions of patients with euvolemic and hypervolemic hyponatremia were similar in each of the three groups; approximately 75% of patients in the study had euvolemic hyponatremia at baseline. Only three patients, one from each treatment group, withdrew from the study.
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Conivaptan was associated with prompt increases in serum [Na+] that were sustained throughout the trial (Fig. 2). At 24 h on d 5, the least-squares (LS) mean ± SE increase from baseline in serum [Na+] was 4.7 ± 1.15 mEq/liter in the placebo group, 6.5 ± 1.08 mEq/liter in patients given conivaptan 40 mg/d, and 8.7 ± 1.06 mEq/liter in patients given conivaptan 80 mg/d. The mean change from baseline in serum [Na+] AUC was significantly greater with 40 mg/d (P = 0.03) or 80 mg/d (P < 0.001) conivaptan than with placebo (Table 2).
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). The mean total time during which patients had serum [Na+] of 4 mEq/liter or more above baseline was greater in each conivaptan group than in the placebo group; this difference was significant with 80 mg/d conivaptan (P = 0.001). The mean change from baseline in serum [Na+] at the end of treatment was 3.4 mEq/liter with placebo, 6.4 mEq/liter with 40 mg/d conivaptan, and 8.2 mEq/liter with 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na+] or increase of 6 mEq/liter or greater from baseline was achieved by 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014).
Both FWC and EWC increased dramatically on d 1, demonstrating conivaptan’s aquaretic effect (Fig. 3). The cumulative change in EWC was greater during the 5-d treatment phase with both conivaptan doses than with placebo. Serum [K+] changed little throughout the study, and the mean changes from baseline were similar across treatment groups (Tables 1 and 2).
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). Mean changes in plasma renin activity and norepinephrine, epinephrine, and aldosterone concentrations were similar across the three treatment groups. The number of patients with AVP measurements was insufficient to assess the relationship between conivaptan treatment and AVP levels. Safety and tolerability
There were four deaths among the study population (Table 3); none was considered to be related to study medication, and all were attributed to progression of underlying illness. Two deaths occurred among placebo recipients, both of whom had terminal cancer. The other two patients who died were given 40 mg/d conivaptan. One of these, who had a history of cardiovascular disease, including chronic HF (CHF), died of HF and worsening renal disease 17 d after receiving the last dose of study drug. The second patient, who had a history of severe cardiomyopathy and CHF, died of cardiac failure 5 d after withdrawing from the study on d 5. She experienced a series of AEs, including hypovolemia, and was the only patient given conivaptan whose treatment was prematurely discontinued due to AEs.
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The incidence and types of AEs associated with 40 and 80 mg/d conivaptan were similar to those observed with placebo (Table 3). Most of these events were considered by investigators to be unlikely or definitely not related to study medication. Most drug-related AEs were classified as mild. The five most frequently reported AEs were headache, hypotension, nausea, constipation, and postural hypotension. The incidence of hypotension and postural hypotension was no more frequent among those given conivaptan than among those given placebo. Hypotension was classified as a serious AE for two patients given 40 mg/d conivaptan and one patient given placebo; however, only one patient, in the 40 mg/d conivaptan group, had hypotension that was considered probably related to study treatment. This patient recovered with administration of additional fluids and a reduced dosage of study medication.
Five conivaptan recipients, three patients given 40 mg/d and two patients treated with 80 mg/d, had a rapid serum [Na+] correction as defined in the protocol (see Patients and Methods). None of these patients had AEs associated with an overly rapid correction of serum [Na+], a serum [Na+] increase of more than 24 mEq/liter total from baseline, or a serum [Na+] level that exceeded 145 mEq/liter. No patients given placebo had a rapid rise in serum [Na+].
In one patient given 40 mg/d conivaptan, serum [Na+] increased from 128 mEq/liter to 142 mEq/liter between 0 and 4 h on d 2; no dosage modifications were made, and the patient’s serum [Na+] was 124 mEq/liter at the end of treatment. In a second patient given 40 mg/d conivaptan, serum [Na+] increased from 129 mEq/liter at 6 h on d 2 to 142 mEq/liter at 24 h on d 2. The second dose of study drug was withheld on d 1, and a reduced dose was administered for the remainder of the treatment period. This patient’s serum [Na+] was 141 mEq/liter at the end of treatment. A third patient in the 40 mg/d conivaptan group had a baseline serum [Na+] of 121 mEq/liter that rose to 139 mEq/liter at 12 h on d 4. Treatment was withheld starting with the second dose on d 4. The serum [Na+] in this patient was 137 mEq/liter at the end of treatment. In one patient taking 80 mg/d conivaptan, serum [Na+] increased from 121 mEq/liter at 12 h on d 1 to 134 mEq/liter at 12 h on d 2. This patient withdrew from the study for administrative reasons on d 3. No AEs were reported. In a second patient given 80 mg/d, serum [Na+] increased too rapidly (peak, 141 mEq/liter), after which the second treatment dose was withheld on each day beginning on d 3. By the end of treatment, serum [Na+] had dropped to 133 mEq/liter.
Treatment with conivaptan at doses up to 80 mg/d for 5 d had no clinically significant AE on clinical chemistry, hematological measures, or coagulation. Elevations in blood urea nitrogen were no more frequent among those given conivaptan than among those given placebo. Three patients in each conivaptan group and one patient in the placebo group had increased serum creatinine values of clinical concern (defined as serum creatinine >1.6 mg/dl); however, the numbers of patients were too small to conclude that this was a treatment effect. At 24 h on study d 5, the mean changes from baseline in body weight were –1.5 kg in the placebo group, –1.3 kg in the 40 mg/d group conivaptan, and –0.9 kg in the 80 mg/d conivaptan group. Compared with placebo, conivaptan produced small mean decreases from baseline in supine systolic and diastolic blood pressures (Table 3); however, these decreases were not clinically significant. There were no clinically significant changes in mean heart rate across the three treatment groups. The electrocardiographic findings both at baseline and on d 5 did not differ significantly between treatment groups.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Treatment with an AVP receptor antagonist may provide specific correction for dilutional hyponatremia in patients with SIADH or CHF (3, 22). Such therapy promotes the elimination of free water while sparing electrolytes (23). In contrast, therapy with currently available diuretics does not directly address the effects of excess AVP, promotes excretion of electrolytes, and may worsen hyponatremia, particularly in the elderly (24).
In this 5-d study, oral conivaptan was significantly more effective than placebo at increasing serum [Na+] in patients with euvolemic or hypervolemic hyponatremia. All primary and secondary efficacy measures as well as other parameters, such as EWC and serum osmolality, demonstrated a clear dose-response relationship with conivaptan. Prompt increases in serum [Na+] were observed among patients in both conivaptan groups, and there was no evidence linking any AE to an overly rapid correction of serum [Na+].
Conivaptan was generally well tolerated; AEs were as likely to occur among patients given placebo as among those receiving conivaptan. Headache and constipation appeared to occur more often in patients given conivaptan than in those given placebo. The incidence of hypotension and postural hypotension was no more frequent among those given conivaptan than those given placebo. Thus, it is unlikely that the hypotension events that occurred in patients given conivaptan were a result of V1A antagonism, and it appears that the V1A antagonism had little or no clinical effect. Only one patient, given 40 mg/d conivaptan, withdrew from the study due to a series of AEs, which included hypovolemia that was classified as possibly related to the study drug. This patient had a history of severe cardiomyopathy and CHF and later died from cardiac failure, an event investigators determined was unlikely to be related to the study medication. The hypovolemia may have been due to the volume contraction associated with conivaptan’s pharmacodynamic effect. There were no meaningful changes in volume status, vital signs, or body weight over the course of treatment.
The relatively small number of patients in each treatment group may be considered a study limitation. Nevertheless, the sample sizes provided sufficient statistical power to detect differences between the conivaptan groups and placebo in serum [Na+] AUC and other efficacy measures. Comparisons across treatment groups for subpopulations of patients were limited by the small sample sizes, however.
In vitro studies confirm that conivaptan is both a substrate and potent inhibitor of CYP3A4, a major isoenzyme in the human liver and small intestine responsible for drug metabolism. In vivo pharmacokinetic drug-drug interaction studies demonstrated that oral conivaptan caused significant decreases in the metabolism of other drugs processed through CYP3A4, leading to clinically significant increases in systemic exposure of these drugs. Because of these findings, only the iv formulation is being developed.
The results of this study and another efficacy trial with iv conivaptan (25) demonstrate that conivaptan provides a targeted approach for correcting hyponatremia in euvolemic and hypervolemic patients. Conivaptan is a novel aquaretic agent that blocks AVP receptors in the kidney to increase electrolyte-free water excretion. This approach directly addresses the effects of excessive or inappropriate AVP secretion and allows serum [Na+] to increase at a rapid, but safe, rate.
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Footnotes |
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M.J.K., J.R.T., E.B.-A., K.F., and W.A.L. have nothing to declare. J.K.G. was a principal investigator from 1999–2004 for trials sponsored by Astellas Pharma US, Inc. N.S. is employed by Astellas Pharma US, Inc.
First Published Online March 7, 2006
Abbreviations: AE, Adverse event; AUC, area under the curve; AVP, arginine vasopressin; CHF, chronic HF; CYP3A4, cytochrome P450 3A4; EWC, effective water clearance; FWC, free water clearance; HF, heart failure; LS, least-squares; [Na+], sodium concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
Received October 18, 2005.
Accepted February 28, 2006.
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, P < 0.001; 
, P = 0.029; 
, P = 0.037; ||, P = 0.018 (vs. placebo).