Itraconazole for Antifungal Prophylaxis in Neutropenic Patients: An Update of a Meta-Analysis with Now 3846 Patients.
Authors: Glasmacher Axel , Hahn Corinna , von Lilienfeld-Toal Marie , Orlopp Katjana , Schmidt-Wolf Ingo , Prentice Archie 
Published: April 2020

Invasive fungal infections, esp. from Aspergillus spp., still are a major cause of mortality and morbidity in neutropenic patients with haematological malignancies. We have published a meta-analysis on the use of itraconazole for antifungal prophylaxis (Glasmacher et al., JCO2003; 21: 4615) and now present updated results.

Methods: In a continuous search of electronic databases and abstracts we identified randomized clinical trials in neutropenic patients that compared itraconazole with either nothing, oral polyenes or fluconazole. Again, analysis was restricted to proven invasive fungal infections according to EORTC/MSG criteria. Statistical analyses were performed with the Cochrane Review Manager (Version 2.4.8), relative risk ratios (RR) with their 95% confidence intervals (95%CI) and appropriate P values were reported. Subgroups were defined by itraconazole preparation and the comparator. A RR below 1 indicates better results for itraconazole.

Results - New Trials: Two new trials with 54 and 195 evaluable patients (pts) were identified and the data of one unpublished trials was updated. Both studies used itraconazole solution (400 mg/d) and compared it to 400 mg/d fluconazole. One study applied intravenous solutions of both drugs if necessary. No study was powered to detect a significant difference in proven invasive fungal infections between the two drugs. One study reported a reduction of fungal-related mortality in the itraconazole arm (fluconazole 9/12, 75%, vs. itraconazole 5/11, 45%; P=0.154).

Results - Meta-Analysis: The incidence of proven invasive fungal infection from all studies and arms was 4.1% and 8.3% if suspected infections were included. The reduction in the incidence of proven breakthrough invasive mycosis was significant (Table 1). As in the original analysis, the relative risk is reduced only in the group provided with itraconazole solution and with a relative risk reduction of 46%.

Results - Itraconazole vs. Fluconazole: Table 2 reports a comparison of itraconazole solution vs. fluconazole for different relevant outcomes. There is a significant superiority of itraconazole for the reduction of all proven invasive fungal infections and for invasive Aspergillus infections and reductions are in the same range but not significant for the other outcomes.

Conclusions: Itraconazole is still and significantly superior to its comparators, including fluconazole, in reducing the rate of breakthrough invasive fungal infections. This effect is only seen with the itraconazole oral or intravenous solution (at least 400 mg/d) which also reduce the rate of proven invasive Aspergillus infections.

Table 1: Incidence of proven invasive fungal infections Subgroup No. Pts (Trials) Relative Risk 95%CI P All studies 3846 (15) 0.62 0.45–0.77 0.003 Itraconazole capsules 735 (5) 0.93 0.51–1.69 0.81 Itraconazole solution 3111 (10) 0.54 0.37–0.77 0.0008 Table 2: Comparison of itraconazole solution vs fluconazole (proven only) Outcome No. of trials Itraconazole (n/N) Fluconazole (n/N) Relative Risk 95%CI P Abbrev.: n= pts. with event; N=total pts. Invasive fungal infections 6 23/883 43/874 0.52 0.32–0.84 0.008 Invasive yeast infections 6 9/851 16//854 0.56 0.25–1.24 0.15 Invasive Aspergillus infections 5 12/850 24/853 0.50 0.26–0.98 0.04 Fungal-related Mortality 4 20/754 31/754 0.64 0.38–1.09 0.10