Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia

• Published in: PloS one Vol. 10; no. 11; p. e0140930
• Main Authors: Fung, Monica, Kim, Jane, Marty, Francisco M, Schwarzinger, Michaël, Koo, Sophia
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-11-2015; Public Library of Science (PLoS)
• Subjects: Antifungal agents; Antifungal Agents - administration & dosage; Antifungal Agents - economics; Antifungal Agents - therapeutic use; Aspergillus; Bias; Blood cancer; Bone marrow; Chemotherapy-Induced Febrile Neutropenia - complications; Chemotherapy-Induced Febrile Neutropenia - immunology; Clinical trials; Construction costs; Cost analysis; Cost-Benefit Analysis; Costs; Costs and Cost Analysis; Decision Trees; Diagnostic systems; Diagnostic tests; Diagnostic Tests, Routine - economics; Drug Administration Schedule; Drug Costs; Drugs; Early Diagnosis; Empirical analysis; Epidemiologic Studies; Estimates; Feasibility Studies; Fungal diseases; Fungal infections; Fungi; Fungicides; Health Care Costs; Health risks; Hematologic Neoplasms - complications; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - immunology; Hematology; Hospitals; Humans; Immunocompromised Host; Infectious diseases; Lung Diseases, Fungal - diagnosis; Lung Diseases, Fungal - drug therapy; Lung Diseases, Fungal - economics; Lung Diseases, Fungal - etiology; Malignancy; Management; Mannans - blood; Mathematical models; Medical diagnosis; Meta-analysis; Morbidity; Mortality; Mycoses; Mycoses - diagnosis; Mycoses - drug therapy; Mycoses - economics; Mycoses - etiology; Mycoses - prevention & control; Neutropenia; Opportunistic Infections - diagnosis; Opportunistic Infections - drug therapy; Opportunistic Infections - economics; Opportunistic Infections - etiology; Opportunistic Infections - prevention & control; Optimization; Parameter estimation; Parameter sensitivity; Parameter uncertainty; Patient outcomes; Patients; Physiological aspects; Polymerase chain reaction; Randomized Controlled Trials as Topic; Risk; Sensitivity analysis; Statistical analysis; Substance abuse treatment; Systematic review; Therapy; Tomography; Transplants & implants
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140930

Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients.
We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates.
Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing.
Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.