Impact of Oral Voriconazole As Prophylaxis during Intensive Chemotherapy for Adult Patients with Acute Myeloid Leukemia: A Retrospective Cohort Study Using Japanese Administrative Database

Background

Prevention of invasive fungal infections (IFIs) during chemotherapy is an important issue for patients with hematologic malignancies. Although preventive effects of antifungal drugs on hematological stem cell transplantation (HSCT) has been reported, the appropriate approach for prophylaxis of IFIs during intensive chemotherapy for patients with acute myeloid leukemia (AML) has been still unclear. To solve this issue, we analyzed the Diagnosis Procedure Combination/Per-Diem Payment System (DPC/PDPS) database instituted by the Ministry of Health, Labour and Welfare of Japan as a payment system for medical services, which contains a large nationwide inpatient administrative data. The objective of this study is to investigate the effectiveness of oral voriconazole (VRCZ) as prophylaxis of IFIs in adult AML patients undergoing intensive chemotherapy.

Methods

This is a retrospective cohort study analyzing data of which were extracted from the DPC database collected from July 2010 to June 2015. The prophylactic usage of oral antifungal drugs is defined as administration of these drugs for more than 3 consecutive days prescribed within 3 days after the onset of chemotherapy. The selection criteria were as follows: patients diagnosed as AML, aged 18 years or older, conducted intensive chemotherapy under aseptic management, and administrated either of oral fluconazole (FLCZ), itraconazole (ITCZ) or VRCZ for the prophylactic usage defined as above. The data for HSCT were excluded. The main analyses were conducted in these 2 groups: the group of patients administrated oral VRCZ, and the other oral azoles (FLCZ or ITCZ). Primary outcome was the intravenous antifungal drug usage within 30 days after the onset of chemotherapy. Subgroup analyses were performed in the following categories: 1) VRCZ group vs FLCZ group/VRCZ group vs ITCZ group; 2) Age < 65/ Age ≥ 65. Secondary outcomes were 1) length of hospital stay, and 2) in-hospital mortality. The log-transformed values were used for analyses of length of hospital stay because its distribution was right-skewed. Panel instrumental variable (IV) method was carried out to address unobserved time-invariant characteristics of individuals, time-variant factors, and the endogeneity due to the unmeasured bias.

Results

A total of 63,197 inpatient data of 923 hospitals for AML patients aged 18 years or older were screened. Finally, 10,083 data of 413 hospitals, including 655 in VRCZ group, 4,445 in FLCZ group, and 4,983 in ITCZ group, were met to the selection criteria. The result of panel IV approach showed that prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage within 30 days after the onset of chemotherapy compared to the other azoles (RD −0.13, 95%CI −0.22 to −0.03, p = 0.012). It was also associated with the shortening the log-transformed value of length of hospital stay compared to the other oral azoles (RD −0.11, 95%CI −0.23 to −0.00, p = 0.043), but not with in-hospital mortality (RD 0.02, 95%CI −0.04 to 0.08, p = 0.513). In the subgroup analyses, prophylactic administration of oral VRCZ was significantly associated with the reduction of intravenous antifungal drug usage compared with FLCZ (RD −0.18, 95%CI −0.28 to −0.08, p < 0.001), but not with ITCZ (RD −0.07, 95%CI −0.16 to 0.34, p = 0.150). When the data was analyzed by age groups, it was significantly associated with the reduction of intravenous antifungal drug usage in patients under the age of 65 (RD −0.18, 95%CI −0.35 to −0.02, p = 0.033), but not in patients aged 65 years or older (RD −0.09, 95%CI −0.22 to 0.04, p = 0.196) compared to the other azoles.

Conclusions

By analyzing the large nationwide database, the present results revealed that the prophylactic administration of oral VRCZ would be effective for reducing the intravenous antifungal drug usage and shortening of hospital stay, which might contribute to reduction of IFIs and improvement of quality of life especially for young AML patients receiving the intensive chemotherapy.