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:
CreatorsEmailORCIDORCID Put Code
Marr, Kieren A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlamm, Haran T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herbrecht, RaoulUNSPECIFIEDorcid.org/0000-0002-9381-4876UNSPECIFIED
Rottinghaus, Scott T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bow, Eric J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cornely, Oliver A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinz, Werner J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jagannatha, ShylaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koh, Liang PiuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kontoyiannis, Dimitrios P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Dong-GunUNSPECIFIEDorcid.org/0000-0003-4655-0641UNSPECIFIED
Nucci, MarcioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pappas, Peter G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slavin, Monica A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Queiroz-Telles, FlavioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selleslag, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walsh, Thomas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wingard, John R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maertens, Johan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
CELL TRANSPLANT RECIPIENTS; PULMONARY ASPERGILLOSIS; AMPHOTERICIN-B; GALACTOMANNAN INDEX; IN-VITRO; VORICONAZOLE; ANIDULAFUNGIN; PHARMACOKINETICS; MULTICENTER; MORTALITYMultiple languages
Medicine, General & InternalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41454

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