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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 7

Efficacy and Safety of Conivaptan versus Tolvaptan in Neurocritically Ill Patients


1 Department of Pharmacy, The Ohio State University Wexner Medical Center, Ohio, Columbus, United States
2 Department of Pharmacy, Saint Thomas West Hospital, Nashville, Tennessee, United States

Date of Submission11-Oct-2021
Date of Acceptance01-Mar-2022
Date of Web Publication24-Mar-2022

Correspondence Address:
Dr. Keaton S Smetana
410 W. 10th Ave, Doan Hall Room 368, Columbus, Ohio 43210
United States
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JTCCM-D-21-00018

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  Abstract 


Background: Vasopressin receptor antagonists increase serum sodium through increased aquaresis via inhibition of V2 receptors. The purpose of this study was to compare the efficacy and safety of conivaptan versus tolvaptan for the treatment of hyponatremia. Subject and Methods: This was a retrospective study of patients who received conivaptan or tolvaptan for hyponatremia admitted to the neurocritical care unit. Serum sodium values were collected at baseline and daily up to 4 days after the last dose. The primary efficacy outcome was an increase in serum sodium ≥4 mEq/L in 24 h after the first vaptan dose. The primary safety outcome was overcorrection defined by an increase in serum sodium >12 mEq/L in 24 h. Results: Thirty-four encounters (14 conivaptan and 20 tolvaptan) were included. Baseline serum sodium was similar between groups (conivaptan 126 mEq/L and tolvaptan 125 mEq/L). Each group received a median of one vaptan dose received on days 5 and 7 of hospitalization for conivaptan and tolvaptan, respectively. The primary efficacy outcome was similar between conivaptan (9 of 14, 64.3%) and tolvaptan (14 of 20, 70%) groups, P = 1.0, and the median change in serum sodium 24 h after the first vaptan dose was 5 versus 7 mEq/L (P = 0.377), respectively. The rate of overcorrection was similar between conivaptan and tolvaptan patients (7.1% vs. 15% P = 0.627). Conclusion: In this study, conivaptan compared to tolvaptan for the treatment of hyponatremia in patients admitted with a primary neurological diagnosis appears efficacious and safe. Further studies are warranted given the sample size of this cohort.

Keywords: Conivaptan, critical care, hyponatremia, neurointensive care unit, syndrome of inappropriate antidiuretic hormone secretion, tolvaptan, vasopressin receptor antagonist


How to cite this article:
Smetana KS, Wiss AL, May CC. Efficacy and Safety of Conivaptan versus Tolvaptan in Neurocritically Ill Patients. J Transl Crit Care Med 2022;4:7

How to cite this URL:
Smetana KS, Wiss AL, May CC. Efficacy and Safety of Conivaptan versus Tolvaptan in Neurocritically Ill Patients. J Transl Crit Care Med [serial online] 2022 [cited 2022 Dec 7];4:7. Available from: http://www.tccmjournal.com/text.asp?2022/4/1/7/340648




  Introduction Top


Aberrations in serum sodium concentrations are common in neurological patients, and depending on the severity and rate at which abnormalities occur, patients may present with a myriad of clinical manifestations ranging from anorexia, nausea and vomiting, muscle weakness, lethargy, and altered mental status to seizures, coma, and death.[1] Hyponatremia is a feared electrolyte abnormality in those with neurologic injury and etiologies of this dysnatremia can be due to syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, adrenal insufficiency, and iatrogenic causes.[2],[3],[4] For patients with euvolemic or hypervolemic hypernatremia, numerous treatment options have been described including fluid restriction, salt tablets, oral urea, hypertonic saline, and vasopressin receptor antagonists.[1],[5]

Arginine vasopressin is an endogenous hormone produced in the hypothalamus, stored in the posterior pituitary, and released in response to decreased blood volume and increased plasma osmolality.[6] Vasopressin receptors belong to a class of G-protein-coupled receptors with actions that vary in response to the different type of receptor subtype. V1a receptors are located primarily in vascular smooth muscle and when stimulated leads to vasoconstriction. Whereas, V1b receptors play a larger neurohormonal role of the stress response and lead to adrenocorticotrophic hormone release. V2 receptors are located in the renal collecting duct, and stimulation leads to production and insertion of aquaporin-2 channels, which results in resorption of free water.[6] Conivaptan and tolvaptan are vasopressin receptor antagonists, known as “vaptans,” approved for the treatment of euvolemic and hypervolemic hyponatremia. The primary mechanism of action of vaptans is through inhibition of aquaresis via V2 inhibition. Tolvaptan is an orally active V2 selective antagonist administered every 24 h with usual doses ranging from 15 to 60 mg.[7],[8] Whereas, conivaptan, a V1a/V2 nonselective antagonist, is available as an intravenous (IV) formulation with a recommended dosing strategy of a 20 mg IV bolus over 30 min followed by a continuous infusion of 20–40 mg for one to 4 days.[9] While the latter is an attractive option for neurological patients unable to receive oral medications, it is less selective to the V2 receptor. This lack of selectivity may be a cause for concern with adverse effects that may be elicited by V1 antagonism. However, conivaptan has been found in preliminary data to reduce cerebral edema and in turn intracranial pressure (ICP) via the V1a receptor and the aquaporin channel expressed by astrocytes.[10],[11]

Several studies have evaluated the safety and efficacy of vaptan administration in those with neurologic injury.[12],[13],[14],[15] Most evaluated either conivaptan or tolvaptan individually and found promising results for their use as single-dose options in the management of hyponatremia in this setting. While one of the studies compared both agents, only 14% (5/36) received conivaptan.[15] Given this limited data, the purpose of this study was to compare the efficacy and safety of conivaptan versus tolvaptan for the treatment of hyponatremia among patients hospitalized in a neurocritical care unit with a primary neurological diagnosis.


  Methods Top


A single-center, retrospective study was conducted at a 1382-bed academic medical center. Patients greater than or equal to 18 years of age admitted between 2011 and 2017 were identified for inclusion. Patients hospitalized in the neurocritical care unit were eligible for study inclusion if they received conivaptan or tolvaptan for the management of hyponatremia. Initial dosing was provider dependent. Institutional review board (IRB) review was not required per the Ohio State University IRB, and in accordance with federal regulations, this study did not constitute human subjects research. We excluded prisoners, patients known to be pregnant or lactating, or if they received both agents within 96 h of each other.

The primary efficacy outcome was an increase in serum sodium concentration of ≥4 mEq/L in 24 h after the first vaptan administration. If a patient received an additional vaptan dose >96 h from previous administration, a new encounter was created. The primary safety outcome was overcorrection of serum sodium defined by an increase in serum sodium concentration >12 mEq/L in 24 h. Additional safety outcomes were incidence of the following within 24 h after receiving the first dose: hypernatremia (serum sodium >145 mEq/L), hypotension (defined as systolic blood pressure <90 mmHg or >20% decrease), hypokalemia (serum potassium <3.5 mmol/L), and infusion site reactions with conivaptan.

Patient characteristics collected via chart review included age, height, weight, gender, type of neurologic injury, Glasgow Coma Score (GCS), and discharge disposition. To assess effectiveness, we collected the vaptan dose and serum sodium levels at baseline and 24 h after administration. Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at The Ohio State University of Wexner Medical Center.[16],[17] REDCap is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources. The utilization of REDCap for this project was supported by Award Number Grant UL1TR002733 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors.

Continuous parametric data were analyzed using the Student's t-test and presented as a mean (±standard deviation), and continuous nonparametric data were assessed using the Mann–Whitney U-test and presented as median (25%–75% interquartile range [IQR]). Nominal data were analyzed using the Chi-squared or the Fisher's exact test. P < 0.05 was used to determine statistical significance. SPSS Software, version 27.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analysis.


  Results Top


A total of 29 patients were included which accounted for 34 encounters in the analysis. No differences in baseline characteristics were observed between those who received conivaptan (n = 14) or tolvaptan (n = 15) [Table 1]. The baseline serum sodium was similar between groups (conivaptan 126 mEq/L [IQR: 122–128] vs. tolvaptan 125 mEq/L [IQR: 123–131]; P = 0.914) as well as the median number of doses administered (1 [IQR: 1–2] vs. 1 [IQR: 1–3]; P = 0.396). The median time from hospital admission to vaptan administration was day 5 (IQR: 2–7) and day 7 (IQR: 4–15) (P = 0.138). The median first dose was 20 mg (IQR: 10–20) with conivaptan and 15 mg (IQR: 7.5–15) with tolvaptan [Table 2].
Table 1: Baseline characteristics of patients


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Table 2: Treatment characteristics


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For the primary efficacy outcome, there was no statistically significant difference in the increase in serum sodium ≥4 mEq/L in the first 24 h of vaptan administration between the conivaptan and tolvaptan groups, 9 of 14 (64.3%) versus 14 of 20 (70%), P = 1.0, respectively. Similarly, there was no difference in the absolute change in serum sodium 24 h after the first vaptan dose (5 mEq/L [IQR: 2–8] vs. 7 mEq/L [IQR: 2–11]; P = 0.377) [Figure 1]. Concomitant therapies received during admission that would have increased serum sodium were as follows: fludrocortisone 8 (23.5%), sodium chloride tablets 29 (85.3%), free water restriction 21 (61.8%), and hypertonic saline 8 (23.5%).
Figure 1: Change in serum sodium 24 h after first vaptan dose

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The primary safety outcome, serum sodium overcorrection >12 meq/L in a 24 h period after the first dose, was not different between conivaptan and tolvaptan patients (7.1% [1 of 14] vs. 15% [3 of 20], P = 0.627). These 4 patients had the following characteristics: Patient 1– tolvaptan 30 mg, baseline to 24 h serum sodium 125–139 mEq/L, discharged home; Patient 2 – tolvaptan 15 mg, serum sodium 114–132 mEq/L, discharged to inpatient rehab; Patient 3 – tolvaptan 7.5 mg, serum sodium 122–138 mEq/L, discharged home; and Patient 4 – conivaptan 20 mg, serum sodium 125–138 mEq/L, discharged to skilled nursing facility. The median baseline sodium between those who did or did not overcorrect was 122 meq/L (IQR: 116–125) and 127 mEq/L (IQR: 123–129), respectively, and was not statistically different (P = 0.070). There was also no difference in development of hypotension (14.3% [2 of 14] vs. 35% [7 of 20], P = 0.250) or hypokalemia (14.3% [2 of 14] vs. 5% [1 of 20], P = 0.555), and no patient developed hypernatremia or infusion site reactions within 24 h after receiving the first vaptan dose.

Given the variance in dosing strategies, we also evaluated the primary safety and efficacy endpoints on the doses most often used. Conivaptan 20 mg was used as the initial dose in 71.4% (10/14) of cases and tolvaptan 15 mg in 60% (12/20). There was no statistically significant difference in the increase in serum sodium ≥4 mEq/L in the first 24 h of vaptan administration between the conivaptan and tolvaptan subgroups, 5 of 10 (50%) versus 8 of 12 (66.7%), P = 0.666, respectively. Nor was there a difference in the primary safety outcome of serum sodium overcorrection after 24 h between conivaptan or tolvaptan subgroups (8.3% [1 of 12] vs. 10% [1 of 10], P = 1.0).


  Discussion Top


We found that after a single dose of either conivaptan or tolvaptan that most encounters (68%, 23 of 34) achieved an increase in serum sodium >4 mEq/L. This supports the findings of previous studies with a median increase in serum sodium of 5 or 7 mEq/L in those who received conivaptan or tolvaptan, respectively. No statistical differences were observed between agents in attaining the efficacy outcomes. Overcorrection (>12 mEq/L in 24 h) was observed in both groups, but there was no reported incidence of osmotic demyelination syndrome upon chart review.

There are several studies that have evaluated the therapeutic benefit of vaptans for treatment of hyponatremia in those with neurologic injuries. Jeon et al. evaluated the safety and efficacy of tolvaptan in 17 nontraumatic neurologically injured patients. They found that after a single dose of 15 mg, the serum sodium increased by roughly 6 and 8 mEq/L at 24 and 48 h, respectively. Tolvaptan appeared safe as the authors appreciated no signs of hypovolemia despite an increase in urine output, changes in GCS, nor significant variations in ICP or cerebral perfusion pressure (CPP).[12] Murphy et al. observed a more robust response after a single dose of 20 mg or 40 mg of conivaptan. At 12 h, 75% (12/16) of patients had an increase in serum sodium of at least 4 mEq/L and 56% (9/16) of at least 6 mEq/L. No difference was observed on the dose administered and efficacy.[13] A subsequent study by the same group evaluated the efficacy of conivaptan administered as either a 10, 20, or 40 mg bolus. Most patients received a 20 mg dose and 60% (74/123) attained a serum sodium increase of at least 4 meq/L. Only 4% (5/123) had a rapid correction over 12 mEq/L within 24 h and was associated with lower baseline sodium (<130 mEq/L).[14] This supports our findings and may indicate the need for a lower first dose in those with initial serum sodium below 130 mEq/L. More recently, a comparison of conivaptan (n = 5) and tolvaptan (n = 31) was performed to assess differences in safety and efficacy. Most patients in the tolvaptan group received a single dose of 15 mg and conivaptan was administered as either a 20 mg IV bolus (n = 2) or bolus followed by an infusion (n = 5). At 24 h, the increase in serum sodium between those who received conivaptan versus tolvaptan was 5 mEq/L and 8 mEq/L, respectively. Overcorrection (>12 mEq/L in 24 h) was observed in 6 patients (19%) in the tolvaptan group and none experience osmotic demyelination syndrome.[15]

Vaptans are attractive agents for the management of hyponatremia in the acute setting of neurologic injury. Fluid restriction is often avoided as volume status is directly related to cerebral blood flow and CPP. Fludrocortisone has been shown to have an appreciable effect on increasing serum sodium in the management of cerebral salt wasting, but can take several days to achieve the desired effect and can induce hypokalemia.[18] Hypertonic saline is commonly used but is limited by a less predictable increase in serum sodium, risk of volume overload in certain populations (e.g., congestive heart failure), and dependent on institution policy may be limited to central line administration only. Demeclocycline has a similar mechanism to vaptans in inhibiting V1 receptors, but is limited by a delayed onset of up to 7 days, gastrointestinal upset, hepatotoxicity, and photosensitivity. Given our findings and those in previous literature, a one-time dose of 20 mg conivaptan IV or 15 mg of tolvaptan orally appears to be safe and provides a predictable increase in serum sodium. It is important to note the tablet size and premixed IV dose that are manufactured in addition to associated costs. Tolvaptan is manufactured as tablets in increments of 15 mg (15, 30, 60, and 90), and the cost per tablet ranges from $344.50 to $647.57 US dollars (USD).[19] Conivaptan is manufactured as a premix of 20 mg in 100 mL of D5W and costs around $1000 USD.[19] The package insert of conivaptan recommends a loading dose followed by a continuous infusion with a total duration of therapy not to exceed 4 days.[9] Implementation of a single-bolus dose, which was used in this study, may be less cost prohibitive in addition to reduce infusion site reactions.[15] However, when compared to the daily cost of IV infusion of hypertonic solutions (e.g., 3% Sodium Chloride) being a fraction of the cost, it is difficult to argue vaptans are a cost-effective alternative.

There are several limitations to this study. Given the retrospective nature of this study, it was difficult to discern the true cause of hyponatremia and if treatment was warranted or appropriate. In addition, medications may have been administered that may have impacted the degree to which serum sodium was increased after receiving therapy. Finally, although no difference was seen in efficacy or safety between conivaptan and tolvaptan, we had a relatively small sample size and were likely underpowered to detect a difference. A strength of this study is that this is one of the largest comparative studies evaluating vaptans in the neurocritical care population. Thirty-four encounters were evaluated and a similar dose response was found after receiving a one-time dose of either agent. In addition, our report supports previous findings in that a single-bolus dose of conivaptan can be used in the treatment of hyponatremia in this setting.


  Conclusion Top


In this study, conivaptan compared to tolvaptan for the treatment of hyponatremia in patients admitted with a primary neurological diagnosis appears efficacious and safe. However, it is important to note that these findings are limited given the sample size. Tolvaptan may provide a more cost-effective alternative within the class as well as its ease of administration given the oral formulation. Further studies are warranted to understand the changes in serum sodium with repeat dosing strategies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Der-Nigoghossian C, Lesch C, Berger K. Effectiveness and tolerability of conivaptan and tolvaptan for the treatment of hyponatremia in neurocritically ill patients. Pharmacotherapy 2017;37:528-34.  Back to cited text no. 15
    
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