Vardakas, K.Z., Michalopoulos, A., & Falagas, M.E. (2005). Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: A meta-analysis of randomised-controlled trials. British Journal of Haematology, 131, 22–28.

The study aim was to evaluate the comparative safety and effectiveness of fluconazole versus itraconazole as primary prophylaxis in neutropenic patients with cancer. The main outcomes of the study were withdrawals from the studies because of adverse effects, documented fungal infections, invasive fungal infections, differentiation between mold and yeast invasive infections, and overall mortality. Secondary outcomes were total fungal infections, suspected fungal infections, superficial fungal infections, and mortality attributed by the authors of each randomized, controlled trial (RCT) to fungal infections.

PubMed (until March 2005), Current Contents Connect, and the Cochrane Central Register for Controlled Trials databases were searched, as were the references from relevant articles, including review papers, to identify relevant RCTs. Two independent reviewers performed literature searches and examined the identified relevant RCTs for evaluation of data on toxicity and effectiveness.
   

Search terms included prophylaxis, prevention, antifungal, azoles, fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole, neutropenia, granulocytopenia, bone marrow transplantation (BMT) and stem cell transplantation (SCT)
   

A study was considered eligible if it was an RCT, it compared the effectiveness of prophylactic fluconazole with prophylactic itraconazole in neutropenic patients, and it assessed toxicity, effectiveness of azoles, or mortality. Concurrent use of topical antifungal agents, such as nystatin or amphotericin B, were permitted. The administration of IV amphotericin B was not permitted unless an invasive fungal infection was documented or suspected.

RCTs comparing the effectiveness of fluconazole or itraconazole with placebo or no treatment or polyenes were excluded. RCTs comparing other azoles also were excluded.

Seven refernece were retreived.

Statistical analyses were performed using meta-analyst software. The heterogeneity between RCTs was assessed by using a chi-square test; a p value lower than 0.1 was defined to note statistical significance in the analysis of heterogeneity. Publication bias was assessed by the funnel plot method using Egger’s test. Pooled odds ratios (OR) and 95% confidence intervals (CIs) for all primary and secondary outcomes were calculated, by using both the Mantel-Haenszel fixed effects and the DerSimonian-Laird random effects models. Results from the fixed effects model are presented only when no heterogeneity between RCTs was observed; otherwise, results from the random effects model are presented. A methodologic quality assessment of each trial was performed. Details of randomisation, the use of double blinding, handling of withdrawals, concealment of allocation, and generation of allocation sequences were awarded one point, for a maximum achievable score of five points. High-quality RCTs scored more than two points, while low-quality RCTs scored two or less points, according to the reported methodology.

• Five total studies were reviewed.
• Sample sizes per article ranged from 59–581.
• Key characteristics indluded neutropenic patients with cancer treated with fluconazole or itraconazole for the prevention of fungal infections.

Active treatment

No statistically significant differences were noted between prophylaxis with fluconazole and itraconazole regarding documented fungal infections (OR = 1.51, 95% CI [0.97, 2.35], five RCTs), invasive fungal infections (OR = 1.44, 95% CI [0.96, 2.17], four RCTs), development of mold infections (OR = 1.36, 95% CI [0.83, 2.24], four RCTs), development of yeast infections (OR = 2.28, 95% CI [0.92, 5.666], three RCTs), and all-cause mortality (OR = 0.89, 95% CI [0.63, 1.24], five RCTs).

Prophylactic use of fluconazole resulted in significantly more fungal infections (OR = 1.62, 95% CI [1.06, 2.48], four RCTs). However, no statistical difference was noted between fluconazole and itraconazole in the development of suspected fungal infections (OR = 1.23, 95% CI [0.74, 2.02], four RCTs), superficial fungal infections (OR = 1.49, 95% CI [0.67, 3.31], three RCTs), and mortality attributed by the authors to fungal infections (OR = 1.3, 95% CI [0.75, 2.25], five RCTs). Significantly fewer patients were withdrawn from the studies due to the development of adverse effects with fluconazole prophylaxis when compared with itraconazole (OR = 0.27, 95% CI [0.18, 0.41], five RCTs). Gastrointestinal complaints were the most common reason for withdrawal from the studies because of adverse effects. The main reason for withdrawal from the RCTs because of an adverse effect was hepatic or renal dysfunction.

Fluconazole was associated with slightly more fungal infections, but there was no difference in mortality between fluconazole and itraconazole, and fluconazole was associated with fewer adverse effects.

Fluconazole and itraconazole are both effective for primary antifungal prophylaxis.