title: Combination antifungal therapy for invasive aspergillosis: a randomized trial.
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.
  
  
  METHODS
  Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479).
  
  
  METHODS
  93 international sites.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Pfizer.
authors.forename: Kieren A
authors.initials: KA
authors.lastname: Marr
authors.forename: Haran T
authors.initials: HT
authors.lastname: Schlamm
authors.forename: Raoul
authors.initials: R
authors.lastname: Herbrecht
authors.forename: Scott T
authors.initials: ST
authors.lastname: Rottinghaus
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bow
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Heinz
authors.forename: Shyla
authors.initials: S
authors.lastname: Jagannatha
authors.forename: Liang Piu
authors.initials: LP
authors.lastname: Koh
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.forename: Marcio
authors.initials: M
authors.lastname: Nucci
authors.forename: Peter G
authors.initials: PG
authors.lastname: Pappas
authors.forename: Monica A
authors.initials: MA
authors.lastname: Slavin
authors.forename: Flavio
authors.initials: F
authors.lastname: Queiroz-Telles
authors.forename: Dominik
authors.initials: D
authors.lastname: Selleslag
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: John R
authors.initials: JR
authors.lastname: Wingard
authors.forename: Johan A
authors.initials: JA
authors.lastname: Maertens
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001228:Aspergillosis / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D019337:Hematologic Neoplasms / Q000150:complications* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D008351:Mannans / Q000097:blood; D008875:Middle Aged; D010976:Platelet Count; D016896:Treatment Outcome; D065819:Voriconazole / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D008351:Mannans; C012990:galactomannan; D000077612:Anidulafungin; D065819:Voriconazole; D005690:Galactose