| Objective: Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. The early diagnosis of IFD, such as lung high resolution computed tomography(CT), β-d- glucan, galactomannan antigenemia assay for Aspergillus infection, PCR, are widely used in clinic,make it possible to more precise starting point for the diagnosis and treatment. Reserving antifungals for this stage may achieve similar survival rates and reduce antifungal drug toxicity and antifungal drug costs,compared with empirical antifungal therapy.In this doublecenter, prospective, randomized, controlled, open-label, noninferiority trial,we compared an empirical antifungal strategy with a diagnosis-driven one.Methods: Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Diagnosis-driven treatment was defined as treatment of patients who have clinical, imaging, β-d-glucan,or galactomannan-antigen-assay evidence suggesting fungal disease. 2 weeks after recovery from neutropenia was the end point.First-line antifungal treatment was Voriconazole injection(load dosage 6 mg/kg twice a day,then 4 mg/kg twice a day).The primary efficacy outcome was the survival rate of patients at 2 weeks after recovery from neutropenia.The secondary efficacy outcome were to compare the incidence of IFD antifungal therapy days,adverse events, and antifungal drug consumption and costs.Results:1 The median duration of neutropenia(neutrophil count, <500 cells/mm3) for the 268 patients enrolled was 13 days(range, 4–56 days). By completer analysis, survival was 97.1% with empirical treatment and 94.6% with diagnosis-driven treatment. The mortality was 2.9% and 5.4% respectively. The lower 95% confidence limit for the difference in mortality was-6.5%, which was within the noninferiority margin of-8%. Probable or proven invasive fungal infections were more common among patients who received diagnosis-driven treatment than among patients who received empirical treatment,occurrence rate 9.2% to 2.2% respectively.The incidence of the similar between the two groups there is statistical significance(?2=6.309 P=0.012).IFD related mortality was 0.7% with empirical treatment and 2.3% with diagnosis-driven treatment,the 95% CI for the difference was-1.9% to-1.3%,no statistically significant mortality in both groups(?2=0.318 P=0.573).2 Diagnosis-driven treatment did not reduce the antifungal drug adverse reactions, but the cost of antifungal drugs was reduced by 30.8%.3 For the induction therapy subgroup, survival was 94.5% in the empirical treatment group and 92.5% in the diagnosis-driven treatment group. The mortality was 5.5% and 7.5% respectively.The lower 95% confidence limit for the difference in mortality was-8.78% to 4.78%, which included the noninferiority margin(-8%), so inferiority could not be ruled out.Most infections occurred during induction therapy.15 IFD cases, 13 cases occurred in the induction therapy subgroups, 2 cases occurred in consolidation therapy subgroups,incidence of 9.3% to 1.6% respectively.The incidence between the two groups there is statistical significance(?2=7.548 P=0.006).Conclusions: Diagnosis-driven treatment is noninferiority compared with empirical treatment.Diagnosis-driven treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased antifungal therapy days,antifungal drug consumption and costs.But did not reduce the patient’s hospital stay, and no lower antifungal drug adverse reaction of voriconazole and improve the effectiveness of voriconazole.In the induction chemotherapy group, diagnosis-driven treatment of noninferiority has not been ruled out.Empirical treatment may provide better survival rates for patients receiving induction chemotherapy. |
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