Retrospective cohort study comparing the risk of severe hepatotoxicity in hospitalized patients treated with echinocandins for invasive candidiasis in the presence of confounding by indication

Francis Vekeman,M Rita Capparella,Lisa Weiss,Rachel H Bhak,Wendy Y Cheng,Mei Sheng Duh,Jalal Aram,Shahrzad Moosavi,Raluca Ionescu-Ittu,Philippe Montravers,Margaret Tawadrous,Yongling Xiao

doi:10.1186/s12879-018-3333-0

Abstract

BackgroundTo compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults.MethodsThis retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0).ResultsTreatments included anidulafungin (n = 1700), caspofungin (n = 4431), or micafungin (n = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% (p < 0.001) and micafungin 25.6% (p < 0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 (p = 0.002) and 1.19 (p = 0.183) overall, and 0.88 (P = 0.773) and 0.97 (P = 0.945) for normal baseline LFT, respectively.ConclusionsAccounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

Highlights

To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults
All measurements of liver function test (LFT) parameters pointed to a higher degree of abnormal liver function at baseline for the anidulafungin group relative to the caspofungin and micafungin groups
There were statistically significantly more patients with Aspartate transaminase (AST), Alanine aminotransferase (ALT), and total bilirubin tests of Grades 3–4 in the baseline period in the anidulafungin group than in the caspofungin and micafungin groups (AST: 26.6% versus 16.8% and 16.9%; ALT: 17.9% versus 9.8 and 10.9%; bilirubin: 27.7% versus 15.5 and 14.9%; all P-values < 0.001), which translated into more patients with an overall Grade 3 and 4 for the baseline LFTs in the anidulafungin group than in the caspofungin and micafungin groups (40.4% versus 25.9 and 25.6%, P < 0.001 for both comparisons)

Summary

Introduction

To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. Anidulafungin is the only echinocandin that undergoes elimination by chemical degradation and non-specific peptidases in the plasma, instead of being metabolized by the liver [6, 7]. It is, expected that anidulafungin may lead to a lower risk of liver injuries than the other echinocandins. One possible explanation may be a result of channeling bias in clinical practice; as anidulafungin is expected to have minimal impact on the liver, physicians may preferentially use anidulafungin in more severely ill patients including those with liver impairment [9]. The extent of this channeling bias in the real world is unknown

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Discussion

Conclusion