Table 5.
Adjusted incidence rate ratios of severe hepatotoxicity – final model for main analysis
| 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 |
*P-value < 0.05
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
aUnknown categories not shown