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Table 5 Adjusted incidence rate ratios of severe hepatotoxicity – final model for main analysis

From: 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

  Patients treated with anidulafungin versus caspofungin (N = 6131) Patients treated with anidulafungin versus micafungin (N = 8247)
IRR (95% CI) P-value IRR (95% CI) P-value
Echinocandin exposure
 Anidulafungin versus caspofungin 1.43 (1.14, 1.79)* 0.0022*
 Anidulafungin versus micafungin 1.19 (0.92, 1.54) 0.1825
Demographics
 Age categories (ref: 18–49 years)
  50–64 years 1.06 (0.87, 1.30) 0.5517 1.06 (0.89, 1.25) 0.5101
  65+ years 1.10 (0.90, 1.35) 0.3317 1.14 (0.96, 1.36) 0.1245
 Female (ref: male) 0.91 (0.79, 1.07) 0.2511 0.97 (0.86, 1.11) 0.6880
 Cerner dataset (ref: Humedica) 0.76 (0.58, 1.00)* 0.0466* 0.82 (0.69, 0.99)* 0.0379*
 Admission through ER 0.80 (0.67, 0.96)* 0.0151* 0.77 (0.64, 0.92)* 0.0053*
Baseline liver function
 ALT grade (ref: 0)a
  1 1.13 (0.91, 1.41) 0.2746 1.13 (0.93, 1.37) 0.2236
  2 1.17 (0.85, 1.62) 0.3291 1.31 (1.00, 1.72)* 0.0484*
  3 1.91 (1.29, 2.82)* 0.0013* 1.71 (1.24, 2.37)* 0.0012*
  4 2.38 (1.40, 4.05)* 0.0014* 2.34 (1.53, 3.58)* < 0.0001*
 AST grade (ref: 0)a
  1 1.75 (1.40, 2.20)* < 0.0001* 1.96 (1.61, 2.39)* < 0.0001*
  2 2.24 (1.66, 3.02)* < 0.0001* 2.63 (2.02, 3.41)* < 0.0001*
  3 3.90 (2.73, 5.57)* < 0.0001* 4.67 (3.45, 6.33)* < 0.0001*
  4 4.62 (2.79, 7.63)* < 0.0001* 6.89 (4.56, 10.4)* < 0.0001*
 Bilirubin grade (ref: 0)a
  1 1.71 (1.33, 2.19)* < 0.0001* 1.63 (1.32, 2.01)* < 0.0001*
  2 2.84 (2.24, 3.60)* < 0.0001* 2.77 (2.28, 3.36)* < 0.0001*
  3 13.8 (10.9, 17.3)* < 0.0001* 12.1 (9.96, 14.7)* < 0.0001*
  4 25.9 (19.3, 34.7)* < 0.0001* 17.2 (13.3, 22.1)* < 0.0001*
Fungal infection
 Prior use of in-hospital echinocandin 1.31 (0.99, 1.74) 0.0567
 Number of fungal infection sites (ref: 1)
   ≥ 2 0.81 (0.54, 1.20) 0.2935 0.85 (0.61, 1.19) 0.3479
  No candidiasis ICD-9-CM codes 1.59 (1.29, 1.95)* < 0.0001* 1.36 (1.14, 1.61)* 0.0005*
Comorbidities
 Charlson Comorbidity Index (ref: 0)
  1 0.79 (0.59, 1.06) 0.1111 0.77 (0.60, 1.00) 0.0545
  2 0.80 (0.61, 1.04) 0.0990 0.99 (0.78, 1.25) 0.9042
  3 0.75 (0.56, 1.01) 0.0599 1.28 (1.00, 1.65)* 0.0496*
   ≥ 4 1.17 (0.90, 1.52) 0.2497 1.41 (1.12, 1.78)* 0.0036*
 Liver diseases
  Esophageal varices 1.83 (1.10, 3.05)* 0.0194* 1.65 (1.11, 2.46)* 0.0130*
  Liver disease secondary to biliary pathologies 1.15 (0.91, 1.45) 0.2427 1.18 (0.98, 1.42) 0.0768
  Other liver disease 1.96 (1.53, 2.51)* < 0.0001* 1.52 (1.26, 1.83)* < 0.0001*
 Other comorbidities
  Diabetes 0.67 (0.55, 0.83)* 0.0002* 0.90 (0.76, 1.06) 0.2073
  Endocarditis 0.59 (0.40, 0.87)* 0.0073*
  Gastroesophageal reflux disease 0.83 (0.62, 1.11) 0.2089 0.90 (0.72, 1.13) 0.3778
  Hypertension 0.72 (0.59, 0.89)* 0.0022* 0.78 (0.67, 0.92)* 0.0022*
  Neutropenia 1.26 (1.00, 1.59)* 0.0470*
  Organ failures 1.21 (0.99, 1.47) 0.0602 1.18 (0.98, 1.42) 0.0756
  Sepsis 1.46 (1.22, 1.75)* < 0.0001* 1.34 (1.15, 1.56)* 0.0001*
 Renal dysfunction (CKD stage) (ref: Stage 1 [GFR ≥ 90 mL/min/1.73 m])
  Stage 2 (GFR 60–89) 1.21 (0.91, 1.63) 0.1915
  Stage 3 (GFR 30–59) 1.24 (0.93, 1.64) 0.1378
  Stage 4 (GFR 15–29) 1.53 (1.14, 2.06)* 0.0047*
  Stage 5 (GFR < 15) 1.07 (0.79, 1.45) 0.6534
Risk factors for fungal infection
 Admission to ICU or CCU 1.32 (1.15, 1.53)* 0.0001*
 Use of central venous catheter 0.73 (0.62, 0.87)* 0.0003*
 Surgery 0.63 (0.53, 0.74)* < 0.0001* 0.66 (0.57, 0.76)* < 0.0001*
Hospital formulary proxy (ref: anidulafungin only covered)
 All three echinocandins covered 0.97 (0.71, 1.33) 0.8532 1.17 (0.85, 1.60) 0.3382
 Anidulafungin and caspofungin covered 0.95 (0.69, 1.29) 0.7249 0.93 (0.68, 1.27) 0.6426
 Anidulafungin and micafungin covered 1.22 (0.79, 1.87) 0.3701 1.12 (0.80, 1.58) 0.5090
 Caspofungin and micafungin covered 0.95 (0.59, 1.52) 0.8169 1.01 (0.71, 1.44) 0.9584
 Caspofungin only covered 1.11 (0.76, 1.62) 0.5756
 Micafungin only covered 1.00 (0.69, 1.44) 0.9910
Hepatotoxic drugs initiated in the baseline period
 Number of distinct hepatotoxic drugs (ref: 0–5)
  6–10 0.73 (0.57, 0.93)* 0.0095*
  11–25 0.58 (0.46, 0.73)* < 0.0001*
  26–48 0.42 (0.25, 0.69)* 0.0006*
 Acetaminophen 0.82 (0.70, 0.96)* 0.0135*
 Antibiotics 0.94 (0.83, 1.07) 0.3741
  1. *P-value < 0.05
  2. Abbreviations: ALT alanine aminotransferase, AST aspartate transaminase, CI confidence interval, CCU critical care unit, CKD chronic kidney disease, ER emergency room, GFR glomerular filtration rate, ICD-9-CM 9th International Classification of Disease, Clinical Modification, ICU intensive care unit, IRR incidence rate ratio
  3. aUnknown categories not shown