Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508.
Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy.
To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA.
Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479).
93 international sites.
454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed.
The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures.
Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different.
Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability.
Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority.
Pfizer.
侵袭性曲霉病（IA）与血液恶性肿瘤（HM）和造血细胞移植（HCT）患者的不良预后相关。一些小型研究表明联合抗真菌治疗具有一定作用。
评估伏立康唑和阿尼芬净联合治疗与伏立康唑单药治疗用于治疗 IA 的安全性和疗效。
随机、双盲、安慰剂对照的多中心试验。（ClinicalTrials.gov：NCT00531479）。
93 个国际地点。
454 名 HM 或 HCT 患者和疑似或确诊 IA 患者被随机分配接受伏立康唑和阿尼芬净联合治疗或安慰剂治疗。主要分析是在 277 名 IA 得到确认的改良意向治疗人群中进行的。
主要结局是 6 周死亡率；次要结局包括 12 周死亡率、主要亚组死亡率和安全性措施。
6 周时死亡率分别为联合治疗组 19.3%（26/135）和单药治疗组 27.5%（39/142）（差异，-8.2 个百分点[95%CI，-19.0 至 1.5]；P=0.087）。次要死亡率结局有利于联合治疗。多变量回归分析表明，最大半乳甘露聚糖值、卡诺夫斯基评分和基线血小板计数具有预后意义。大多数患者（277 例中的 218 例[78.7%]）通过影像学发现和最大半乳甘露聚糖阳性诊断为 IA。在该主要亚组的事后分析中，联合治疗组 6 周死亡率低于单药治疗组（15.7%[17/108] vs. 27.3%[30/110]；差异，-11.5 个百分点[CI，-22.7 至-0.4]；P=0.037）。安全性措施，包括肝毒性，无差异。
6 周死亡率高于预期，死亡率差异低于预期，这降低了检测治疗效果的能力。入组仅限于 HM 或 HCT 患者，这限制了其普遍性。
与伏立康唑单药治疗相比，阿尼芬净联合治疗在 IA 患者亚组中导致生存率提高。由于效力有限，无法确定优越性的结论。
辉瑞。
