Ping, B., Zhu, Y., Gao, Y., Yue, C., & Wu, B. (2013). Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: A systematic review and meta-analysis. Annals of Hematology, 92, 831–839.

STUDY PURPOSE: To compare second-generation azoles with first-generation azoles in patients with hematologic malignancies by comparing rates of proven or probable invasive fungal infections (IFIs), invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from studies related to development of adverse effects

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: MEDLINE, EMBASE, and Cochrane Registry of Controlled Trials databases; conference proceedings from the American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, and European Group for Blood and Marrow Transplantation from 2002–2012

KEYWORDS: voriconazole or posaconazole and prophylaxis or prevention

INCLUSION CRITERIA: Studies written in English; prospective and randomized controlled trials comparing second-generation and first-generation azole antifungal agents with regards to antifungal prophylaxis in patients with hematologic malignancies who were neutropenic following cytotoxic chemotherapy or hematopoietic stem cell transplantation, or receiving immunosuppressive therapy

EXCLUSION CRITERIA: IV administration of azole antifungal agents, unless the IFI was proven or suspected; prospective studies in which the control arm used a historical cohort; ongoing trials

TOTAL REFERENCES RETRIEVED = 168 reviewed (Of these, 18 were identified as potentially relevant; of these, 14 were screened out.)

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two reviewers independently screened the literature for eligibility for inclusion, and two other reviewers independently extracted the data from included studies and assessed for quality parameters.

• FINAL NUMBER STUDIES INCLUDED = 4
• SAMPLE RANGE ACROSS STUDIES = 465–602
• TOTAL PATIENTS INCLUDED IN REVIEW: 2,267 patients (Although elsewhere in the article, the authors note 2,165 patients.)
• KEY SAMPLE CHARACTERISTICS: Multi-center, two-arm, parallel, prospective, randomized controlled trials. Three of the four studies included patients who received allogeneic stem cell transplantation. The fourth study included patients experiencing prolonged neutropenia following induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.

PHASE OF CARE: Transition phase after active treatment

Prophylaxis using second-generation azole antifungal agents significantly reduced IFIs as compared to first-generation agents (OR = 0.47, 95% CI 0.32–0.69, I² = 0%, p = 0.0001; four trials, 2,267 patients) and also significantly reduced invasive aspergillosis (OR = 0.28, 95% CI 0.17–0.48, I² = 28%, p < 0.00001; four trials, 2,267 patients). Additionally, posaconazole significantly reduced the incidence of fungal infection (OR = 0.40, 95% CI 0.19–0.87, I² = 52%, p = 0.02; two trials, 1,202 patients), but voriconazole did not (OR = 0.56, 95% CI 0.30–1.04, I² = 0%, p = 0.06; two trials, 1,065 patients). Second-generation azoles significantly reduced IFIs (OR = 0.47, 95% CI 0.31–0.71, I² = 0%, p = 0.0003; three trials, 1,744 patients) and invasive aspergillosis (OR = 0.31, 95% CI 0.13–0.52, I² = 44%, p < 0.0001; three trials, 1,744 patients) when compared to fluconazole. When compared to itraconazole, second-generation azoles resulted in significantly fewer IFIs (OR = 0.35, 95% CI 0.14–0.87, I² = 35%, p = 0.02; two trials, 827 patients) and cases of invasive aspergillosis (OR = 0.11, 95% CI 0.03–0.40, I² = 0%, p = 0.0008; two trials, 827 patients).

Significantly fewer patients receiving prophylaxis with second-generation azoles required empirical antifungal therapy (OR = 0.62, 95% CI 0.50–0.77, I² = 0%, p < 0.0001; three trials, 1,667 patients). Despite these findings, no difference was noted in overall mortality in patients receiving antifungal prophylaxis with second-generation or first-generation azoles (OR = 0.81, 95% CI 0.64–1.01, I² = 0%, p = 0.06; three trials, 1,802 patients).

Patients with hematologic malignancies are at increased risk of IFIs, with invasive aspergillosis being particularly worrisome. Second-generation azoles appear to be superior to first-generation azoles in regards to prevention of IFIs, including invasive aspergillosis, without increased risk of adverse events. Second-generation agents also have better bioavailability and fewer drug-drug interactions than first-generation agents.

• Small number of studies (four)
• Variation between studies regarding duration of administration of antifungal agents
• No subgroup analysis of specific study populations
• The risk of heterogeneity is moderate to low, as significant heterogeneity appeared in only a portion of subgroup analyses.

This meta-analysis suggests that antifungal prophylaxis with second-generation azoles is more effective than first-generation azoles in prevention of IFIs, and without increase in adverse events. Interestingly, no difference was observed in overall mortality.