Abstract
We aimed to survey the status of tolvaptan administration in routine clinical practice since the approval of a novel indication for treating syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in Japan. Data from a population of 3,152 patients aged ≥18 years and diagnosed with SIADH between July 1, 2020 and June 30, 2021 were extracted from a Japanese database. Tolvaptan was administered to 586 patients while 2,566 patients were followed up without tolvaptan. In the tolvaptan-treated group, the standard initial doses were 3.75 mg and 7.5 mg in 290 (49.5%) and 250 (42.7%) patients, respectively. The dose was increased in 112 (38.6%) and 71 (28.4%) and decreased in 8 (2.8%) and 46 (18.4%) of patients with 3.75 and 7.5 mg initial doses, respectively. Of the total 586 SIADH patients treated with tolvaptan, serum sodium concentrations were analyzed in 60 patients. In both treatment groups of 3.75 and 7.5 mg initial doses, the serum sodium concentration was elevated from the second day of treatment and reached 135 mEq/L on the fourth day, which was maintained for 2 weeks. Rapid correction of hyponatremia (>10 mEq/L increase in serum sodium concentration over 1 day or >18 mEq/L increase over 2 days) occurred in 26.7% patients with a 7.5 mg initial dose (4 of 15 patients) but not in the patients with a 3.75 mg initial dose (n = 16), suggesting that an initial dose of 3.75 mg of tolvaptan may be a better choice for the safe and proper correction of hyponatremia.
SYNDROME OF INAPPROPRIATE SECRETION of antidiuretic hormone (SIADH) is a clinical condition characterized by a continuing antidiuretic effect due to unsuppressed secretion of arginine vasopressin (AVP) despite euvolemic hyponatremia. According to the most recent Japanese guideline on the diagnosis and treatment of SIADH (revised in 2019) [1], a patient is diagnosed with SIADH when AVP release is not suppressed despite hyponatremia and hypo-osmolar state, the sodium concentration in the urine is relatively high (≥20 mEq/L), and renal and adrenal functions are intact. In addition, diseases that present symptoms of dehydration or an increase in the extracellular fluid volumes should be distinguished from SIADH. The known causes of SIADH include diseases of the central nervous system, lung diseases, and ectopic AVP-producing tumor as well as some drugs [1, 2].
Tolvaptan suppresses water re-absorption in the collecting duct by inhibiting the AVP V2-receptor [3] and has been approved in over 40 countries and regions, including the US and the EU, for the treatment of hyponatremia associated with SIADH. In Japan, tolvaptan was first approved for the treatment of fluid retention in cardiac failure in 2010, and hepatic cirrhosis in 2013, followed by the approval for autosomal dominant polycystic kidney disease in 2014. The Japan Endocrine Society requested the approval of tolvaptan for treating the SIADH indication in 2013, and after a clinical trial [4], “hyponatremia associated with SIADH” was recognized in Japan as a novel indication for tolvaptan therapy in June 2020.
Although the recommended initial dose of tolvaptan is 15 mg/day in countries other than Japan (e.g., US and EU), the Japanese clinical trial was conducted with an initial dose of 7.5 mg, in which some patients displayed rapid increases in the serum sodium concentration from the first day (increase of >10 mEq/L in 24 h in 4 out of 16 patients) [4]. Based on this clinical trial, 7.5 mg/day was employed for the initial dose of tolvaptan, and a half of the initial dose (3.75 mg) has been recommended for patients with serum sodium concentration levels <125 mEq/L, patients requiring a slower correction of the serum sodium concentration (those with hypokalemia, undernutrition, alcohol abuse, or liver disorder), or patients in whom a rapid decrease in circulating plasma volumes should be avoided. However, as the sample size was small in the Japanese clinical trial for the approval of the SIADH indication [4], more data and evidence are required to address the question as to the initial doses of tolvaptan: that is, which dose (3.75 mg or 7.5 mg) is more appropriate for Japanese patients with SIADH.
In the current study, we aimed to analyze the data on the use of tolvaptan in the daily clinical setting by investigating the prescription details (the initial doses, the presence of increase/decrease in doses, the length of prescription, and re-administration of tolvaptan), comorbidities, patient characteristics, serum sodium concentrations, and the frequency of the rapid correction of hyponatremia.
Materials and Methods
Data sources
A Japanese medical database maintained by Medical Data Vision Co., Ltd was used in the present study. The Medical Data Vision (MDV) database is a centralized insurance claims database that comprises anonymized data on all medical practices performed on inpatients and outpatients of acute care hospitals using the diagnosis procedure combination (DPC) fixed-payment reimbursement system. As of May 2022, the MDV database contained data on 40 million patients from over 460 hospitals using the DPC/per-diem payment system (PDPS).
Study population
The SIADH population was defined as patients aged ≥18 years diagnosed with SIADH (ICD10 code: E222) between July 1, 2020 and June 30, 2021. Patients in the tolvaptan-treated group were defined as those in the SIADH population who were administered tolvaptan and confirmed not to have been prescribed tolvaptan or mozavaptan in the previous 90 days. If tolvaptan was administered more than once during the enrollment period, the first administration phase was used for the analysis. The follow-up period began on the first day of tolvaptan administration in the tolvaptan-treated group and on the first day of the month when patients were diagnosed with SIADH in the non-tolvaptan-treated group. The follow-up lasted for 90 days. If a patient was in hospital or in-hospital death, follow-up lasted until discharge or date of in-hospital death, respectively.
We examined the clinical parameters such as sex, age, and body mass index (BMI), comorbidities contributing to SIADH, conditions increasing risk of osmotic demyelinating syndrome (ODS) due to rapid correction of hyponatremia (liver disorder, hypokalemia, and alcohol abuse), and clinical departments. Comorbidities contributing to SIADH were defined as diseases extracted from “diseases requiring the most medical resource,” “diseases requiring hospitalization,” or “primary disease” documented in the medical records within 2 years from the first day of tolvaptan administration and corresponded to the primary diseases listed in the guidelines on the diagnosis and treatment of SIADH [1]. Clinical departments were defined where tolvaptan was prescribed in the tolvaptan-treated group and where diseases leading to hospitalization were diagnosed in the non-tolvaptan-treated group. We also collected laboratory data including serum sodium, serum potassium, serum chloride, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (γ-GTP), alkaline phosphatase (ALP), albumin (Alb), and uric acid. Except for serum sodium concentrations, laboratory data were obtained on the day with the lowest recorded serum sodium concentration during 90 days before tolvaptan administration in the tolvaptan-treated group, and during 90 days before diagnosis of SIADH in the non-tolvaptan-treated group. The significant digits of the baseline laboratory data extracted from the MDV database are summarized and presented in Supplementary Table 1.
Outcomes
To gain an understanding of the details of tolvaptan prescription in routine clinical practice, we assessed the initial doses, the presence of increase/decrease in dose, the length of prescription, and the presence of tolvaptan re-administration in the tolvaptan-treated group. Re-administered patients were defined as those who received tolvaptan after more than 1 day of a temporary discontinuation of administration.
Summary statistics of the serum sodium concentrations were calculated before tolvaptan prescription, on the first, second, third, and fourth days of administration, and at 1 and 2 weeks after administration. The “Before prescription” values used were the serum sodium concentrations from 3 days to 1 day before tolvaptan prescription that were closest to the Day 1 serum sodium concentration. The “Week 1” values used were the serum sodium concentrations from Day 4 to 11 after prescription that were closest to the Day 8 serum sodium concentration. The “Week 2” values used were the serum sodium concentrations from Day 12 to 19 after prescription that were closest to the Day 15 concentration. Changes in serum sodium concentrations were analyzed in patients with serum sodium concentration levels <135 mEq/L before prescription. Rapid correction of hyponatremia was defined as more than 10 mEq/L increases in serum sodium concentrations in 1 day or more than 18 mEq/L increases in 2 days during the treatment.
Statistical analyses
Categorical data are summarized using the number of patients and percentages, whereas continuous data are presented with descriptive statistics. The occurrence of the rapid correction of hyponatremia was expressed with frequencies and percentages. We calculated the statistical significance of the differences between the groups (tolvaptan-treated vs. non-tolvaptan-treated groups, and initial dose of tolvaptan of 3.75 mg vs. 7.5 mg) using the two samples t-test or Wilcoxon rank sum test for continuous variables, the Fisher’s exact test for binary data and Wilcoxon rank sum test for ordinal categorical data. Statistical Analysis Software version 9.4 (SAS Institute, Inc., Cary, NC, USA) was used for all statistical analyses.
Ethical approval and informed consent
The study about objective descriptions of the database was approved by the Ethics Committee of the Research Institute of Healthcare Data Science (RIHDS) (RI2021021). The study was also registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/): UMIN000046985. Informed consent was not obtained for the present study because personal information was not handled.
Results
Patient disposition
A total of 3,214 patients with SIADH were registered in the MDV database. After exclusion of 62 patients who were younger than 18 years, 3,152 patients were included in the SIADH population. Of these patients, 586 received tolvaptan (tolvaptan-treated group) whereas 2,566 did not (non-tolvaptan-treated group). The initial doses of tolvaptan were 1.875 mg, 3.75 mg, 7.5 mg, and 15 mg in 8 (1.4%), 290 (49.5%), 250 (42.7%), and 21 (3.6%) patients, respectively. Serum sodium levels were analyzed in 187 patients (tolvaptan-treated group; N = 60, non-tolvaptan-treated group; N = 127) out of the total 3,152 SIADH patients due to the accessibility to laboratory data only provided by some hospitals according to the contract between the data provider and hospitals (Fig. 1).
Clinical characteristics of SIADH patients treated with tolvaptan
Table 1 shows the clinical characteristics of all patients with SIADH in the tolvaptan-treated and non-tolvaptan-treated groups. Patients in the tolvaptan-treated group had significantly higher proportion of male patients, older ages, and higher body weight than in the non-tolvaptan-treated group, while there was no significant difference in BMI between the groups. The levels of serum sodium, serum chloride, Alb, and uric acid were significantly lower and the levels of eGFR, ALT, AST and γ-GTP were significantly higher in the tolvaptan-treated group than in the non-tolvaptan-treated group. There were no significant differences between the groups in the comorbidities that occurred during admission nor any great differences in the comorbidities that occurred during the previous 2 years, including those which could cause SIADH (Supplementary Table 2). Treatment with sodium chloride was administered to 46.8% of the patients in the tolvaptan-treated group prior to tolvaptan administration. The same treatment was administered to 29.6% of patients in the non-tolvaptan-treated group within 90 days from the diagnosis of SIADH.
Table 1
Baseline characteristics of patients in the tolvaptan-treated and non-tolvaptan-treated groups
|
Tolvaptan-treated group |
Non-tolvaptan-treated group |
p-value |
| N |
586 |
2,566 |
|
| Sex |
Male |
380 (64.8) |
1,468 (57.2) |
0.00071) |
| Female |
206 (35.2) |
1,098 (42.8) |
|
| Age (years) |
n |
586 |
2,566 |
0.00382) |
| mean ± SD |
75.5 ± 11.8 |
74.4 ± 12.7 |
|
| BMI (kg/m2) |
n |
487 |
967 |
0.05932) |
| mean ± SD |
20.92 ± 3.76 |
20.46 ± 3.97 |
|
| Body weight (kg) |
n |
497 |
1,001 |
0.00272) |
| mean ± SD |
52.86 ± 12.04 |
50.87 ± 12.05 |
|
| SIADH treatment (Pre-prescription for Tolvaptan-treated group) |
Sodium chloride (oral) |
146 (24.9) |
538 (21.0) |
— |
| Sodium chloride (intravenous) |
195 (33.3) |
375 (14.6) |
— |
| Laboratory value at visit (minimum value of serum sodium concentration) |
| Serum sodium (mEq/L) |
n |
60 |
127 |
<0.00012) |
| mean ± SD |
121.0 ± 8.9 |
130.4 ± 7.9 |
|
| Serum potassium (mEq/L) |
n |
60 |
127 |
0.90302) |
| mean ± SD |
4.32 ± 0.57 |
4.33 ± 0.57 |
|
| Serum chloride (mEq/L) |
n |
58 |
120 |
<0.00012) |
| mean ± SD |
86.9 ± 9.1 |
94.9 ± 7.9 |
|
| eGFR (mL/min/1.73 m2) |
n |
57 |
123 |
0.00282) |
| mean ± SD |
89.642 ± 39.525 |
72.948 ± 31.810 |
|
| Serum creatinine (mg/dL) |
n |
57 |
123 |
0.40682) |
| mean ± SD |
0.782 ± 0.661 |
0.889 ± 0.858 |
|
| BUN (mg/dL) |
n |
57 |
121 |
0.96842) |
| mean ± SD |
16.64 ± 10.38 |
16.69 ± 7.47 |
|
| ALT (IU/L) |
n |
51 |
116 |
0.00013) |
| median |
25.0 |
16.0 |
|
| Q1–Q3 |
15.0–40.0 |
12.0–21.5 |
|
| AST (IU/L) |
n |
51 |
115 |
<0.00013) |
| median |
27.0 |
23.0 |
|
| Q1–Q3 |
23.0–48.0 |
18.0–28.0 |
|
| γ-GTP (IU/L) |
n |
44 |
93 |
0.00803) |
| median |
33.5 |
22.0 |
|
| Q1–Q3 |
17.5–81.5 |
15.0–34.0 |
|
| ALP(IU/L) |
n |
45 |
87 |
0.32613) |
| median |
84.0 |
78.0 |
|
| Q1–Q3 |
68.0–111.0 |
67.0–102.0 |
|
| Alb (g/dL) |
n |
45 |
97 |
0.04082) |
| mean ± SD |
3.51 ± 0.64 |
3.74 ± 0.60 |
|
| Uric acid (mg/dL) |
n |
33 |
75 |
0.00112) |
| mean ± SD |
3.18 ± 1.34 |
4.27 ± 1.64 |
|
Sex is expressed by the number of patients (%). ALT, AST, γ-GTP, and ALP are expressed by number (first line), median (second line) and Q1–Q3 (third line). Other variables are shown as number (upper) and mean ± SD (lower).
Q1, 1st quartile; Q3, 3rd quartile; SD, standard deviation.
BMI, body mass index; BUN, blood urea nitrogen; ALT, alanine transaminase; AST, aspartate aminotransferase; γ-GTP, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; and Alb, albumin.
1) Fisher’s exact test 2) two samples t-test 3) Wilcoxon rank sum test
Since most patients in the tolvaptan-treated group received 3.75 mg or 7.5 mg as the initial dose of tolvaptan, we compared clinical characteristics between patients with an initial dose of tolvaptan of 3.75 mg and 7.5 mg. Table 2 shows that patients in the 3.75 mg group were significantly older with lower BMI and lower body weight compared with the 7.5 mg group, while there was no significant difference in the distribution of sex between the groups. The levels of serum creatinine and BUN were significantly higher in the 3.75 mg group than in the 7.5 mg group, while there were no significant differences in other laboratory values between the groups. There were no significant differences between the 3.75 mg and 7.5 mg groups in the comorbidities that occurred during admission nor any great differences in the comorbidities that occurred during the previous 2 years, including those which could cause SIADH (Supplementary Table 3).
Table 2
Baseline characteristics of patients in whom 3.75 mg and 7.5 mg tolvaptan was administered as the initial dose
|
Initial dose of tolvaptan |
p-value |
| 3.75 mg |
7.5 mg |
| N |
290 |
250 |
|
| Sex |
Male |
190 (65.5) |
160 (64.0) |
0.06721) |
| Female |
100 (34.5) |
90 (36.0) |
|
| Age (years) |
n |
290 |
250 |
0.04082) |
| mean ± SD |
76.9 ± 10.5 |
74.9 ± 12.0 |
|
| BMI (kg/m2) |
n |
235 |
212 |
0.02182) |
| mean ± SD |
20.65 ± 3.53 |
21.27 ± 4.12 |
|
| Body weight (kg) |
n |
240 |
217 |
0.01332) |
| mean ± SD |
51.53 ± 10.69 |
54.39 ± 13.55 |
|
| Laboratory value at visit (minimum value of serum sodium concentration) |
| Serum sodium (mEq/L) |
n |
25 |
32 |
0.30102) |
| mean ± SD |
121.6 ± 9.0 |
119.3 ± 8.3 |
|
| Serum potassium (mEq/L) |
n |
25 |
32 |
0.91042) |
| mean ± SD |
4.32 ± 0.62 |
4.30 ± 0.50 |
|
| Serum chloride (mEq/L) |
n |
24 |
31 |
0.10582) |
| mean ± SD |
88.0 ± 8.5 |
84.3 ± 7.9 |
|
| eGFR (mL/min/1.73m2) |
n |
24 |
30 |
0.09912) |
| mean ± SD |
82.924 ± 36.841 |
99.967 ± 37.237 |
|
| Serum creatinine (mg/dL) |
n |
24 |
30 |
0.03322) |
| mean ± SD |
0.793 ± 0.413 |
0.597 ± 0.237 |
|
| BUN (mg/dL) |
n |
24 |
30 |
0.02252) |
| mean ± SD |
18.70 ± 10.34 |
13.08 ± 5.68 |
|
| ALT (IU/L) |
n |
20 |
29 |
0.91083) |
| median |
26.0 |
23.0 |
|
| Q1–Q3 |
16.5–39.5 |
16.0–40.0 |
|
| AST (IU/L) |
n |
20 |
29 |
0.70653) |
| median |
28.5 |
27.0 |
|
| Q1–Q3 |
23.5–43.5 |
21.0–51.0 |
|
| γ-GTP (IU/L) |
n |
19 |
23 |
0.28263) |
| median |
42.0 |
24.0 |
|
| Q1–Q3 |
18.0–91.0 |
16.0–71.0 |
|
| ALP (IU/L) |
n |
18 |
26 |
0.34573) |
| median |
86.5 |
83.5 |
|
| Q1–Q3 |
71.0–127.0 |
65.0–108.0 |
|
| Alb (g/dL) |
n |
18 |
25 |
0.74212) |
| mean ± SD |
3.48 ± 0.67 |
3.57 ± 0.63 |
|
| Uric acid (mg/dL) |
n |
11 |
20 |
0.14132) |
| mean ± SD |
3.56 ± 1.47 |
2.83 ± 1.19 |
|
Sex is expressed by the number of patients (%). ALT, AST, γ-GTP, ALP are expressed by number (first line), median (second line) and Q1–Q3 (third line). Other variables are shown as number (upper) and mean ± SD (lower).
Q1, 1st quartile; Q3, 3rd quartile; SD, standard deviation.
BMI, body mass index; BUN, blood urea nitrogen; ALT, alanine transaminase; AST, aspartate aminotransferase; γ-GTP, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; and Alb, albumin.
1) Fisher’s exact test 2) two samples t-test 3) Wilcoxon rank sum test
Table 3 shows tolvaptan treatment in patients with the initial dose of 3.75 mg and 7.5 mg during the follow-up period. The percentages of patients in whom the tolvaptan dose was increased were significantly higher in the 3.75 mg group than in the 7.5 mg group. In contrast, the percentages of patients in whom the tolvaptan dose was decreased were significantly higher in the 7.5 mg group than in the 3.75 mg. The median of the maximum tolvaptan doses were 7.5 mg and 15 mg, and that of the minimum doses were 1.88 mg and 3.75 mg in the 3.75 mg and 7.5 mg groups, respectively. There was no significant difference in the duration of tolvaptan prescription between the 3.75 mg and 7.5 mg groups. Tolvaptan was re-administered in 131 (45.2%) and 108 (43.2%) patients with an initial dose of 3.75 mg and 7.5 mg, showing no significant difference.
Table 3
Details of treatment in patients in whom 3.75 mg and 7.5 mg tolvaptan was administered as the initial dose
|
Initial dose of tolvaptan |
p-value |
| 3.75 mg |
7.5 mg |
| N |
290 |
250 |
|
| Increase in tolvaptan dose |
112 (38.6) |
71 (28.4) |
<0.00011) |
| Decrease in tolvaptan dose |
8 (2.8) |
46 (18.4) |
<0.00011) |
| Maximum dose in patients with increase in tolvaptan dose (mg) |
n |
112 |
71 |
— |
| median |
7.50 |
15.00 |
|
| Q1–Q3 |
7.50–11.25 |
15.00–15.00 |
|
| min–max |
4.88–30.00 |
11.25–90.00 |
|
| Minimum dose in patients with decrease in tolvaptan dose (mg) |
n |
8 |
46 |
— |
| median |
1.88 |
3.75 |
|
| Q1–Q3 |
1.88–1.88 |
3.75–3.75 |
|
| min–max |
1.875–2.00 |
1.875–3.75 |
|
| Length of tolvaptan prescription (days) |
<3 |
21 (7.2) |
14 (5.6) |
0.89042) |
| ≥3, <7 |
44 (15.2) |
36 (14.4) |
|
| ≥7, <14 |
52 (17.9) |
36 (14.4) |
|
| ≥14, <21 |
30 (10.3) |
36 (14.4) |
|
| ≥21, <28 |
25 (8.6) |
22 (8.8) |
|
| ≥28, <60 |
53 (18.3) |
53 (21.2) |
|
| ≥60, <90 |
14 (4.8) |
17 (6.8) |
|
| 90 |
51 (17.6) |
36 (14.4) |
|
| n |
290 |
250 |
|
| mean ± SD |
32.7 ± 31.8 |
33.1 ± 30.6 |
|
| median |
20.0 |
21.0 |
|
| Q1–Q3 |
7.0–50.0 |
8.0–51.0 |
|
| min–max |
1–90 |
1–90 |
|
| Re-administration of tolvaptan |
131 (45.2) |
108 (43.2) |
0.66471) |
Increase/decrease in tolvaptan dose is expressed by the number of patients (%). Maximum and minimum dose are expressed by number (first line), median (second line), Q1–Q3 (third line), and range (fourth line). Length of tolvaptan prescription is expressed by distribution, number, mean ± SD, median, Q1–Q3, and range.
Re-administered patients were defined as those who received tolvaptan after more than 1 day of a temporary discontinuation are expressed by number (%).
Q1, 1st quartile; Q3, 3rd quartile; min, minimum value; max, maximum value.
1) Fisher’s exact test 2) two samples t-test
We examined changes in the serum sodium concentrations before and after the administration of 3.75 mg and 7.5 mg tolvaptan (Fig. 2). There was no difference in the increases in serum sodium concentrations after the tolvaptan treatment between the 3.75 mg and 7.5 mg groups. In both treatment groups, the mean serum sodium concentrations began to increase on the second day of administration, reached 135 mEq/L on the fourth day, and were maintained for 2 weeks. There was no rapid correction of hyponatremia in 16 patients with the initial dose of 3.75 mg, whereas that occurred in 4 out of 15 patients with the initial dose of 7.5 mg. Four out of 9 measurements on the second day and 1 out of 10 measurements on the third day met the definition of rapid correction with an initial dose of 7.5 mg, while none of the 22 measurements met the definition of rapid correction with an initial dose of 3.75 mg (Table 4).
Table 4
The frequency of the rapid correction of hyponatremia in patients after administration of 3.75 mg and 7.5 mg tolvaptan as the initial dose
|
Initial dose of tolvaptan |
| 3.75 mg |
7.5mg |
Number of patient: the rapid correction of hyponatremia
(based on the first time point of the two points that provided the largest difference in the serum sodium concentration) |
0/16 (0.0) |
4/15 (26.7) |
| Incidence of rapid correction of hyponatremia (rise from onset) |
Total number of times checked |
22 |
19 |
| number of times meeting the criteria for rapid correction, (%) |
0 (0.0) |
5 (26.3) |
| Total number of times checked on the second day |
7 |
9 |
| number of times meeting the criteria for rapid correction, (%) (increase of more than 10 mEq/L in a day) |
0 (0.0) |
4 (44.4) |
| Total number of times checked on the third day |
15 |
10 |
| number of times meeting the criteria for rapid correction, (%) (increase of more than 18 mEq/L in 2 days) |
0 (0.0) |
1 (10.0) |
The upper row shows the patient number of the rapid correction of hyponatremia, total patient number (%). Only patients with available data were included.
Rapid correction of hyponatremia was defined as more than 10 mEq/L increases in serum sodium concentrations in 1 day or more than 18 mEq/L increases in 2 days during the treatment.
The lower row shows subgroup analysis. Basing on the above definition of rapid correction of hyponatremia, the patients that meet this definition are counted separately on the second day and third day.
Discussion
This study is the first survey of real-world practice in Japan after tolvaptan was approved for the treatment of SIADH indication. In the current study, we surveyed the actual use status of tolvaptan for SIADH in routine clinical practice and investigated the clinical data before and after the tolvaptan treatment using a Japanese medical database.
From the MDV database between July 1, 2020, and June 30, 2021, a total of 3,152 patients aged ≥18 years were extracted as SIADH patients, among whom tolvaptan was administered to 586 patients. Our data showed that a difference in body weight was found between tolvaptan-treated and non-tolvaptan-treated groups. Since the proportion of male patients was higher in the tolvaptan-treated group, it is possible that the patients in the tolvaptan-treated group also weighed more. Treatment with sodium chloride was administered to 46.8% of the patients in the tolvaptan-treated group prior to tolvaptan administration. The same treatment was administered to 29.6% of patients in the non-tolvaptan-treated group within 90 days from the diagnosis of SIADH. Regarding the initial dose of tolvaptan, approximately 50% and 40% of patients were administered 3.75 mg and 7.5 mg tolvaptan as the initial dose, respectively. As for patient characteristics, Table 2 shows that the age was higher and BMI and body weight were lower in patients with an initial dose of 3.75 mg than those in patients with an initial dose of 7.5 mg, suggesting that the lower dose (3.75 mg) was selected as the initial dose in these patients, probably in consideration of the risk of rapid increase of serum sodium concentration. In addition, tolvaptan dose was increased during the follow-up period in approximately 40% of patients with initial dose of 3.75 mg and in approximately 30% of patients with initial dose of 7.5 mg, in order to reach an optimal level of sodium concentrations. While duration of treatment was within 60 days for most patients, more than 10% in both the groups with initial dose of 3.75 mg and 7.5 mg were being administered tolvaptan for more than 90 days. Thus, the course of treatment for hyponatremia due to SIADH varies greatly among patients. It is also worth noting that re-administration of tolvaptan occurred in approximately 45% of the patients during the follow-up, which includes cases of one-time temporary drug discontinuation for various reasons. Although the detailed reasons for withdrawal from tolvaptan treatment or re-administration are unclear, it is reported that the serum sodium concentration decreased in almost all patients after the discontinuation of tolvaptan treatment [4].
It seems from Fig. 2 that increasing effects of tolvaptan on serum sodium concentrations were similar between 3.75 mg and 7.5 mg groups. The initial dose was also 7.5 mg in a clinical trial conducted in Japan [4] and there have not been any reports of use of tolvaptan in patients with SIADH at an initial dose of 3.75 mg. In this study, differences were found between the treatment groups in some of the patient characteristics such as age, body weight, and BMI, but the serum sodium concentrations over time were similar between the treatment groups. By selecting the initial dose in accordance with the patient’s individual condition, it might be possible to adequately increase the serum sodium concentration in a personalized manner. However, if a change in serum sodium concentrations was observed in each patient, there was a difference: while no rapid and excessive correction (≥10 mEq/L in 24 h or ≥18 mEq/L in 48 h) of serum sodium concentrations occurred in patients treated with 3.75 mg tolvaptan, rapid and excessive correction was observed in 26.7% of patients treated with 7.5 mg tolvaptan. In the four patients in whom rapid correction of serum sodium concentration was observed, the mean ± standard deviation (SD) of serum sodium concentration measured before tolvaptan treatment was 119.25 ± 8.92 mEq/L. The rapid and excessive correction of chronic hyponatremia possibly induces ODS [5], which is a neurological disorder caused by damage to the myelin sheath of brain cells [6] and presents dysarthria, dysphagia, oculomotor dysfunction, and quadriparesis. It was reported that, whereas half of cases fully recovered, variable degree of sequela remained in 25% and death in another 25% [7]. Low serum sodium concentration before the initiation of tolvaptan treatment is considered a potential risk for rapid correction, and possibly for the development of ODS. For the prevention of ODS during the treatment of hyponatremia, <8–10 mEq/L of correction of serum sodium concentration in 24 h is recommended [8]. It is thus suggested that 3.75 mg was safer as an initial dose of tolvaptan for the treatment of SIADH than 7.5 mg.
Previous studies in Korea and Italy demonstrated that, while 7.5 mg tolvaptan did not induce the overcorrection of hyponatremia in patients with non-hypovolemic hyponatremia, the overcorrection occurred in considerable cases treated with 15 mg tolvaptan [9, 10]. While the safe initial dose of tolvaptan could differ between race, taken together with our study, it is suggested that the lower dose of tolvaptan should be considered, especially in patients with risk factors of ODS such as hypokalemia, alcohol abuse, and liver disorder.
In summary, we investigated the details of tolvaptan prescription in routine clinical practice in Japanese patients with SIADH using a medical database. Our data demonstrated that serum sodium concentrations in patients with SIADH can increase rapidly in response to 3.75 mg tolvaptan without overcorrection of hyponatremia, suggesting that 3.75 mg may be more appropriate than 7.5 mg as the initial dose of tolvaptan, at least for some people.
Limitations
First, we could not validate the diagnosis of SIADH in patients selected with the DPC code. Second, the limited number of institutions providing laboratory data to MDV restricted the number of patients for investigation of changes in the serum sodium concentrations before and after the tolvaptan administration. In addition, laboratory data were only obtained for a portion of patients (approximately 10% of patients from hospitals using the DPC/PDPS). Third, medical practices performed in institutions other than those involved in this study were not available in the database used for the present study. Therefore, information on treatment before and even during the observation period could be missing.
Acknowledgement
Data was provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Statistical support was provided by EPS Corporation. Medical writing support was provided by Makoto Ueno at EPS Corporation. The authors thank Takahiro Hirano (Otsuka Pharmaceutical Co., Ltd.) for his support of the study design.
Funding
The study was funded by Otsuka Pharmaceutical Co., Ltd.
Author Contribution
D.H and H.A provided advice regarding the study design. M.M, Y.N, and J.T designed the study, wrote the protocol, and analyzed the data. All authors contributed to interpretation of the data, drafting the manuscript, and have approved the final manuscript for submission.
Disclosure
Daisuke Hagiwara and Hiroshi Arima received speaker honoraria from Otsuka Pharmaceutical Co., Ltd. Miyuki Matsukawa, Yumiko Nakamura, and Junko Tasaki are employees of Otsuka Pharmaceutical Co., Ltd.
Supplementary Table 1
Data digits of baseline laboratory test data
| Laboratory value at visit |
Data Digits (Baseline) |
| Significant digits |
n |
% |
| Serum sodium |
Integer |
164 |
(87.7) |
| 1 decimal place |
23 |
(12.3) |
| Serum potassium |
Integer |
9 |
(4.8) |
| 1 decimal place |
153 |
(81.8) |
| 2 decimal places |
25 |
(13.4) |
| Serum chloride |
Integer |
160 |
(87.4) |
| 1 decimal place |
23 |
(12.6) |
| eGFR |
Rounded to 2 decimal places as it includes the calculated values. |
| Serum creatinine |
Integer |
3 |
(1.6) |
| 1 decimal place |
21 |
(11.2) |
| 2 decimal places |
164 |
(87.2) |
| BUN |
Integer |
50 |
(26.6) |
| 1 decimal place |
138 |
(73.4) |
| ALT |
Integer |
186 |
(100.0) |
| AST |
Integer |
186 |
(100.0) |
| γ-GTP |
Integer |
163 |
(100.0) |
| ALP |
Integer |
165 |
(100.0) |
| Alb |
Integer |
15 |
(8.9) |
| 1 decimal place |
145 |
(86.3) |
| 2 decimal places |
8 |
(4.8) |
| Uric acid |
Integer |
14 |
(10.2) |
| 1 decimal place |
123 |
(89.8) |
The number and percentage of patients with available data for each significant digit in the baseline laboratory test results.
Supplementary Table 2
Baseline comorbidity of patients in the tolvaptan-treated and non-tolvaptan treated groups
|
Tolvaptan-treated group |
Non-tolvaptan-treated group |
p-value |
| N |
586 |
2,566 |
|
| Comorbidity during admission |
Liver disorder |
82 (14.0) |
319 (12.4) |
0.30331) |
| Hypokalemia |
27 (4.6) |
158 (6.2) |
0.17241) |
| Alcohol abuse |
0 (0.0) |
1 (0.0) |
1.00001) |
| Comorbidity during the past 2 years |
| Disease of central nervous system |
Meningitis |
5 (0.9) |
29 (1.1) |
— |
| Encephalitis |
7 (1.2) |
28 (1.1) |
— |
| Head injury |
3 (0.5) |
5 (0.2) |
— |
| Subarachnoid hemorrhage |
13 (2.2) |
33 (1.3) |
— |
| Cerebral infarction/hemorrhage |
79 (13.5) |
242 (9.4) |
— |
| Brain tumor |
36 (6.1) |
67 (2.6) |
— |
| Guillain-Barre syndrome |
1 (0.2) |
9 (0.4) |
— |
| Lung disease |
Lung tumor |
12 (2.0) |
17 (0.7) |
— |
| Pneumonia |
160 (27.3) |
553 (21.6) |
— |
| Pulmonary tuberculosis |
4 (0.7) |
20 (0.8) |
— |
| Pulmonary aspergillosis |
6 (1.0) |
20 (0.8) |
— |
| Bronchial asthma |
31 (5.3) |
125 (4.9) |
— |
| Positive-pressure breathing |
32 (5.5) |
90 (3.5) |
— |
| Ectopic vasopressin-producing tumor |
Small cell lung cancer |
58 (9.9) |
75 (2.9) |
— |
| Pancreatic cancer |
8 (1.4) |
18 (0.7) |
— |
Qualitative variables are expressed by the number of patients (%).
1) Fisher’s exact test
Supplementary Table 3
Baseline comorbidity of patients in whom 3.75 mg and 7.5 mg tolvaptan was administered as the initial dose
|
Initial dose of tolvaptan |
p-value |
| 3.75 mg |
7.5 mg |
| N |
290 |
250 |
|
| Comorbidity during admission |
Liver disorder |
38 (13.1) |
35 (14.0) |
0.80131) |
| Hypokalemia |
14 (4.8) |
13 (5.2) |
0.84601) |
| Alcohol abuse |
0 (0.0) |
0 (0.0) |
— |
| Comorbidity during the past 2 years |
| Disease of central nervous system |
Meningitis |
0 (0.0) |
4 (1.6) |
— |
| Encephalitis |
4 (1.4) |
3 (1.2) |
— |
| Head injury |
1 (0.3) |
1 (0.4) |
— |
| Subarachnoid hemorrhage |
6 (2.1) |
5 (2.0) |
— |
| Cerebral infarction/hemorrhage |
36 (12.4) |
36 (14.4) |
— |
| Brain tumor |
15 (5.2) |
19 (7.6) |
— |
| Guillain-Barre syndrome |
1 (0.3) |
0 (0.0) |
— |
| Lung disease |
Lung tumor |
9 (3.1) |
2 (0.8) |
— |
| Pneumonia |
76 (26.2) |
70 (28.0) |
— |
| Pulmonary tuberculosis |
1 (0.3) |
3 (1.2) |
— |
| Pulmonary aspergillosis |
0 (0.0) |
5 (2.0) |
— |
| Bronchial asthma |
13 (4.5) |
16 (6.4) |
— |
| Positive-pressure breathing |
16 (5.5) |
13 (5.2) |
— |
| Ectopic vasopressin-producing tumor |
Small cell lung cancer |
26 (9.0) |
28 (11.2) |
— |
| Pancreatic cancer |
2 (0.7) |
5 (2.0) |
— |
Qualitative variables are expressed by the number of patients (%).
1) Fisher’s exact test
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