Trends in Implementation of Loading Dose of Voriconazole from 2010 to 2019 and Influencing Factors of Loading Dose Based on a Japanese Administrative Claim Database: A Retrospective Cohort Study

Abstract

A loading dose of voriconazole (VRCZ) is recommended to increase its blood concentration at an early stage. However, the trends in the implementation of the loading dose in VRCZ in Japan has not yet been clarified. In addition, although pharmacists play many important roles in antimicrobial stewardship, the effect of pharmacist intervention on the implementation of a loading dose of VRCZ has not yet been reported. Therefore, this study aimed to clarify the implementation of loading dose of VRCZ and the influencing factors of loading dose. This study used an administrative claims database that included patients who received injectable VRCZ between 2010 and 2019. The implementation of loading doses in the VRCZ was evaluated annually. Multivariate logistic regression analysis was performed to identify the factors influencing loading dose. Overall, 2197 patients were included. The implementation rate of the loading dose remained below 65% throughout the study period. Among medical fees that can be calculated through pharmacist intervention, only the infection prevention and control premium significantly increased the implementation of loading dose of VRCZ (odds ratio: 1.587, 95% confidence interval: 1.053-2.392). In conclusion, antifungal stewardship may have been promoted at medical institutions that established infection prevention and control. In the future, pharmacists will need to intervene more actively from the beginning of VRCZ administration.

INTRODUCTION

Voriconazole (VRCZ) is a broad-spectrum triazole antifungal agent. As VRCZ has a large volume of distribution,¹⁾ a loading dose is recommended to increase its blood concentration at an early stage.²⁾ A previous multicenter study in Japan reported that the proportion of implementation of the loading dose in the VRCZ was 65.8%.³⁾ However, this report focused on university hospitals and thus did not fully reflect the actual situation in Japan. The trends in the rate of implementation of the loading dose on the VRCZ has not been clarified. In addition, the influencing factors of loading dose of VRCZ remains unclear.

The concept of antimicrobial stewardship (AMS) has spread worldwide,⁴⁾ and thus, the appropriate use of antibiotics and antifungals should be promoted.⁵⁾ Although pharmacists play several important roles in AMS,⁴⁾ the effect of pharmacist intervention on the implementation of loading dose of VRCZ has not yet been reported.

Recent research has been increasingly using real-world data (RWD) that relate to patient health status and/or the delivery of healthcare routinely collected from various sources.⁶⁾ The administrative claims database, a source of RWD, contains information on patient background, prescribed drugs, and calculated reimbursements at multiple medical institutions collected over time. This study aimed to clarify the implementation rate of loading dose of VRCZ and the influencing factors of loading dose, using an administrative claims database.

MATERIALS AND METHODS

Data Source and Patient Selection

This study used the administrative claims database provided by Medical Data Vision Co., Ltd. Adults or children weighing over 50 kg who received injectable VRCZ for at least 4 consecutive days between 2010 and 2019 were identified. Oral VRCZ was excluded from this study. The date of the first VRCZ administration was defined as the index date. For patients who were also treated with VRCZ for another course of treatment, only data during the initial treatment period were included. The treatment and management fee for specific drugs was defined as the medical fee that can be paid when therapeutic drug monitoring (TDM) was implemented.⁷⁾ This was used as an alternative index for TDM implementation based on a previous report.⁸⁾ This fee is calculated in cases where drugs recommended for TDM are administered. Therefore, when several drugs requiring TDM were administered, it was impossible to identify the specific fee for each drug. Patients were excluded when they were treated with drugs for which TDM was recommended, except for VRCZ, within 7 d of the index date, based on a previous study.⁸⁾ Additionally, patients treated in the hematology department were excluded because they may have received VRCZ prophylactically and were confounded when evaluating the implementation of loading dose of VRCZ.

Ethics Approval and Consent to Participate

This study was approved by the Institutional Review Board of the Kyoto Pharmaceutical University (Approval Number: E-00026) and was conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived owing to the use of anonymized patient data.

Definition

This study used the drug management and guidance fee⁷⁾ and the inpatient pharmaceutical service premium⁷⁾ as medical fees related to pharmacist interventions. Treatment and management fee for specific drugs⁷⁾ and infection prevention and control premium⁷⁾ were also evaluated. The loading dose was defined as performed when the sum of the VRCZ doses on days 1 and 2 divided by the sum of the doses on days 3 and 4 was greater than 1.

Statistical Analysis

Linear regression analysis was performed to evaluate the changes over time in the proportion of implementation of loading doses in the administration of VRCZ from 2010 to 2019. In addition, multivariate logistic regression analysis was used to evaluate the influencing factors of loading dose of VRCZ. All statistical analyses were performed using Stata software (version 17.0; Stata Corp., College Station, TX, U.S.A.) and EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan).⁹⁾ A p-value of <0.05 was considered significant.

RESULTS

Among the 5892 patients who were administered VRCZ injections between 2010 and 2019. Finally, 2197 patients were included in the study. The patient selection flowchart is shown in Fig. 1.

Fig. 1. Patient Selection Flowchart

VRCZ, voriconazole.

The trends in the implementation of loading doses in VRCZ from 2010 to 2019 are shown in Fig. 2. Although the implementation rate of the loading dose increased significantly over time (r = 0.015, 95% confidence interval (CI): 0.006–0.024, P_{for trend} = 0.005), it remained below 65% throughout the study period.

Fig. 2. Trends in the Implementation of Voriconazole Loading Dose from 2010 to 2019

The implementation rate of the loading dose significantly increased over time (r = 0.015, 95% confidence interval: 0.006–0.024, P _{for trend} = 0.005).

Multivariate logistic regression analysis of the influencing factors of loading dose of VRCZ is shown in Table 1. The implementation rate of loading dose of VRCZ was significantly higher in claims for infection prevention and control premium (odds ratio: 1.587, 95%CI: 1.053–2.392). The implementation of loading dose of VRCZ was not significantly associated with the drug management and guidance fee and the inpatient pharmaceutical services premium.

Table 1. Influencing Factors of Loading Dose of Voriconazole

	Multivariate logistic regression analysis
	Odds ratio	95% CI	p-Value
Patient information
Age	0.993	0.986–1.000	0.040
Sex (ref. female patients)	1.470	1.217–1.777	<0.01
Number of beds
200–499 (ref. ≤199)	0.989	0.649–1.508	0.961
≥500 (ref. ≤199)	1.024	0.666–1.575	0.914
Charlson Comorbidity Index	0.988	0.962–1.014	0.352
Reimbursement
No. of drug management and guidance fee	1.132	0.949–1.351	0.167
No. of inpatient pharmaceutical service premium	1.130	0.944–1.353	0.183
No. of infection prevention and control premium	1.587	1.053–2.392	0.027
No. of treatment and management fee for specific drugs	1.096	0.877–1.371	0.421
Hospital department
Respiratory department (ref. Internal department)	0.882	0.711–1.094	0.253
Others (ref. Internal department)	1.036	0.843–1.272	0.738

CI, confidence interval.

DISCUSSION

The loading dose in the VRCZ increased significantly over time. In Japan, the first edition of the TDM guidelines was published in 2012 and revised in 2016. The loading doses of VRCZ are recommended in these guidelines and package inserts. A previous study has reported that the publication or revision of guidelines may have affected the antibiotic use.¹⁰⁾ Similarly, the publication and revision of the TDM guidelines made the importance of loading doses more widely known, which may have improved the implementation of the loading dose.

The implementation rate of the loading dose remained below 65% throughout the study period. A previous multicenter study in Japan reported a similar rate of 65.8%.³⁾ When VRCZ is used to prevent invasive mycosis, it is determined that there is no need to increase the blood concentration early, and the loading dose of VRCZ may not be implemented. Patients treated in the hematology department were excluded in this study because they were likely to have received VRCZ prophylactically. The implementation rate of the loading dose may have been low because prophylactic administration was also performed in other clinical departments. However, it was not possible to determine the purpose of VRCZ use in this study. Further research that considers the purpose of VRCZ use based on electronic medical record data is needed.

Drug management and guidance fee and inpatient pharmaceutical service premium were not associated with the implementation of the loading dose of VRCZ. Drug management and guidance fee can be claimed when pharmacological management is performed in individual patients.⁷⁾ Meanwhile, inpatient pharmaceutical service premium can be claimed when a system is established in which a pharmacist is stationed in the hospital ward.⁷⁾ Thus, these medical fees may not have affected the implementation of the loading dose at the beginning of administration. It is expected that pharmacists will actively intervene from the beginning of VRCZ administration to further improve the implementation rate of loading doses.

The implementation rate of the loading dose of VRCZ was significantly higher in claims for infection prevention and control premium. The promotion of AMS is important for the appropriate use of antimicrobials, including VRCZ.¹¹⁾ We speculated that AMS is more actively promoted in medical institutions that established infection prevention and control measures. More facilities should develop a system for acquiring infection prevention and control premium.

This study had some limitations. First, this study does not cover all patients in Japan. However, the database covers approximately 26% of all hospitals in Japan that have adopted a diagnosis procedure combination system. In addition, the number of medical institutions covered by Medical Data Vision Co., Ltd. has been increasing over time. As shown in Fig. 2, the annual number of patients administered VRCZ varies. Particularly, in years with a small number of patients, the results may have a large variability and should thus be interpreted with caution. Second, this study targeted only the initial treatment period and did not consider second and subsequent treatment histories with loading doses of VRCZ. Therefore, the implementation of the loading dose may have been underestimated. Despite these limitations, this study provides instrumental information regarding the implementation of the loading dose of VRCZ.

In conclusion, the implementation rate of loading dose of VRCZ was less than 65%. Antifungal stewardship may have been promoted at medical institutions that established infection prevention and control measures. In the future, pharmacists will need to intervene more actively from the beginning of VRCZ administration.

Author Contributions

R.I., M.S., and Y.M. conceptualized the study, analyzed the data, interpreted the results, and drafted the manuscript. R.I., M.S., and R.G. analyzed the data. All authors interpreted the results. N.O. reviewed and edited the manuscript.

Conflict of Interest

This work was supported by a research Grant from the Ministry of Health, Labor, and Welfare of Japan (23HA2002). The authors declare no conflict of interest.

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