Combination antifungal therapy for invasive aspergillosis: a randomized trial

Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anidulafungin
  • Antifungal Agents / adverse effects
  • Antifungal Agents / therapeutic use*
  • Aspergillosis / complications
  • Aspergillosis / diagnosis
  • Aspergillosis / drug therapy*
  • Aspergillosis / mortality
  • Double-Blind Method
  • Drug Therapy, Combination
  • Echinocandins / adverse effects
  • Echinocandins / therapeutic use*
  • Female
  • Hematologic Neoplasms / complications*
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Karnofsky Performance Status
  • Male
  • Mannans / blood
  • Middle Aged
  • Platelet Count
  • Treatment Outcome
  • Voriconazole / adverse effects
  • Voriconazole / therapeutic use*
  • Young Adult

Substances

  • Antifungal Agents
  • Echinocandins
  • Mannans
  • galactomannan
  • Anidulafungin
  • Voriconazole

Associated data

  • ClinicalTrials.gov/NCT00531479