Universität zu Köln

Marr, Kieren A., Schlamm, Haran T., Herbrecht, Raoul ORCID: 0000-0002-9381-4876, Rottinghaus, Scott T., Bow, Eric J., Cornely, Oliver A., Heinz, Werner J., Jagannatha, Shyla, Koh, Liang Piu, Kontoyiannis, Dimitrios P., Lee, Dong-Gun ORCID: 0000-0003-4655-0641, Nucci, Marcio, Pappas, Peter G., Slavin, Monica A., Queiroz-Telles, Flavio, Selleslag, Dominik, Walsh, Thomas J., Wingard, John R. and Maertens, Johan A. (2015). Combination Antifungal Therapy for Invasive Aspergillosis A Randomized Trial. Ann. Intern. Med., 162 (2). S. 81 - 90. PHILADELPHIA: AMER COLL PHYSICIANS. ISSN 1539-3704

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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 multi-center 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Marr, Kieren A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlamm, Haran T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herbrecht, Raoul UNSPECIFIED orcid.org/0000-0002-9381-4876 UNSPECIFIED Rottinghaus, Scott T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bow, Eric J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cornely, Oliver A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinz, Werner J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jagannatha, Shyla UNSPECIFIED UNSPECIFIED UNSPECIFIED Koh, Liang Piu UNSPECIFIED UNSPECIFIED UNSPECIFIED Kontoyiannis, Dimitrios P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Dong-Gun UNSPECIFIED orcid.org/0000-0003-4655-0641 UNSPECIFIED Nucci, Marcio UNSPECIFIED UNSPECIFIED UNSPECIFIED Pappas, Peter G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Slavin, Monica A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Queiroz-Telles, Flavio UNSPECIFIED UNSPECIFIED UNSPECIFIED Selleslag, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Walsh, Thomas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wingard, John R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Maertens, Johan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-414542
DOI:	10.7326/M13-2508
Journal or Publication Title:	Ann. Intern. Med.
Volume:	162
Number:	2
Page Range:	S. 81 - 90
Date:	2015
Publisher:	AMER COLL PHYSICIANS
Place of Publication:	PHILADELPHIA
ISSN:	1539-3704
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL TRANSPLANT RECIPIENTS; PULMONARY ASPERGILLOSIS; AMPHOTERICIN-B; GALACTOMANNAN INDEX; IN-VITRO; VORICONAZOLE; ANIDULAFUNGIN; PHARMACOKINETICS; MULTICENTER; MORTALITY Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41454