Sixty four RCTs (n=13,015; 6,517 receiving treatment and 6,498 controls) were included in the review. Allocation generation and concealment was adequately reported in 16 studies. Twenty six studies were double blind.
Systemic antifungals versus placebo/no treatment/non systemic antifungals
All-cause mortality was reported in 31 studies. Mortality at the end of follow-up and 30-day mortality were significantly reduced when patients were treated with systemic antifungals: RR 0.84 (95% CI: 0.74, 0.95, p=0.007) at the end of follow-up and RR 0.79 (95% CI: 0.68, 0.92) for 30-day mortality. Subgroup analyses reported different outcomes. The authors reported that meta-regression showed only one significant association, which was between the percentage of patients with acute leukaemia (with or without HSCT) and RR for mortality at the end of follow-up (RR 1.006, p=0.29). Thirty three studies reported significant differences between fungal-related mortality, favouring systemic antifungals: RR 0.55 (95% CI: 0.41, 0.74, p<0.0001).
There was no evidence of heterogeneity or publication bias. Secondary outcomes were reported.
Comparison of two systemic antifungal agents (19 studies)
Seven studies comparing fluconazole with itraconazole reported significant increases in adverse events with itraconazole, resulting in the study being discontinued: RR 2.50 (95% CI: 1.89, 3.33). No other significant differences were reported. Subgroup analyses and indirect comparison of drugs versus placebo or no treatment, or two systemic antifungals were also reported.
Significant reductions in IFIs were reported with fluconazole versus amphotericin B (three studies): RR 0.49 (95% CI: 0.28, 0.86). More adverse events were reported in amphotericin B: RR 6.67 (95% CI: 2.6, 16.7).
Two studies compared posaconazole with fluconazole or itraconazole, reporting: borderline significant reductions in all-cause mortality (RR 0.77; 95% CI: 0.59, 1.01); a significant reduction in fungal-related mortality (RR 0.25; 95% CI: 0.11, 0.57); documented or probable IFIs (RR 0.47; 95% CI: 0.3, 0.74); and documented invasive Aspergillus infections (RR 0.22; 95% CI: 0.11, 0.42).
Outcomes for fluconazole versus antifungals with antimould activity and other trials were also reported in the review.