1. Combination antifungal therapy for invasive aspergillosis: a randomized trial.
- Author
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Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, and Maertens JA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anidulafungin, Antifungal Agents adverse effects, Aspergillosis complications, Aspergillosis diagnosis, Aspergillosis mortality, Double-Blind Method, Drug Therapy, Combination, Echinocandins adverse effects, Female, Galactose analogs & derivatives, Hematologic Neoplasms therapy, Humans, Karnofsky Performance Status, Male, Mannans blood, Middle Aged, Platelet Count, Treatment Outcome, Voriconazole adverse effects, Young Adult, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Echinocandins therapeutic use, Hematologic Neoplasms complications, Hematopoietic Stem Cell Transplantation, Voriconazole therapeutic use
- Abstract
Background: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy., Objective: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA., Design: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479)., Setting: 93 international sites., Patients: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed., Measurements: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures., Results: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different., Limitations: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability., Conclusion: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority., Primary Funding Source: Pfizer.
- Published
- 2015
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