Systematic review and mixed treatment comparison meta-analysis of randomized clinical trials of primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.

Eric J Bow,Richard Chambers,Michal Kantecki,Carlos Solano,Sonja Sorensen,Catherine Cordonnier,David J Vanness,Haran Schlamm,David Weinstein,Monica Slavin,Lael Cragin,Antonio Pagliuca,Alissa J Shaul,Oliver A Cornely,David I Marks

doi:10.1186/s12879-015-0855-6

Abstract

BackgroundAntifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making.MethodsRandomized controlled trials (RCTs) of fluconazole, itraconazole, posaconazole, and voriconazole for primary antifungal prophylaxis were identified through a systematic literature review. Outcomes of interest (incidence of IFI/invasive aspergillosis/invasive candidiasis, all-cause mortality, and use of other antifungals) were extracted from eligible RCTs and incorporated into a Bayesian hierarchical random-effects MTC.ResultsFive eligible RCTs, randomizing 2147 patients in total, were included. Relative to fluconazole, prophylaxis with itraconazole (odds ratio [OR]: 0.52; interquartile range [IQR]: 0.35–0.76), posaconazole (OR: 0.56; IQR: 0.32–0.99), and voriconazole (OR: 0.46; IQR: 0.28–0.73) reduced incidence of overall proven/probable IFI. Posaconazole (OR: 0.31; IQR: 0.17–0.58) and voriconazole (OR: 0.33; IQR: 0.17–0.58) prophylaxis reduced proven/probable invasive aspergillosis more than itraconazole (OR: 0.68; IQR: 0.42–1.12). All-cause mortality was similar across all mould-active agents.ConclusionAs expected, mould-active azoles prevented IFIs, particularly invasive aspergillosis, more effectively than fluconazole in alloHCT recipients. The paucity of comparative efficacy data suggests that other factors such as long-term tolerability, availability of intravenous formulations, local IFI epidemiology, and drug costs may need to form the basis for selection among the mould-active azoles.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-0855-6) contains supplementary material, which is available to authorized users.

Highlights

Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant recipients, but the optimum prophylactic agent is unknown
Randomized controlled trials (RCTs) meeting the search criteria were included in the mixed treatment comparison (MTC) network analysis of fluconazole, itraconazole, posaconazole, and voriconazole if they included a comparator common to multiple RCTs
The 5 head-to-head studies [10,26,27,28,29] constituting the evidence network (Figure 2) for the MTC randomized a total of 2147 patients, with individual study sample sizes ranging from 140–600 patients

Summary

Introduction

Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making. To our knowledge no single head-to-head randomized clinical trial (RCT) has directly compared more than 2 of these options in alloHCT recipients. The paucity of such studies impedes the use of traditional pairwise meta-analysis to inform the clinical decisionmaking process. Our objective was to compare the efficacy of these agents for the prevention of documented IFI in alloHCT recipients based on several key outcomes, with the purpose of informing medical decisionmaking

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