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[Lancet Respir Med发表论文]:嗜酸粒细胞指导激素治疗AECOPD住院患者
2019年09月10日 时讯速递, 进展交流 暂无评论

ARTICLES| VOLUME 7, ISSUE 8, P699-709, AUGUST 01, 2019

Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial

Pradeesh Sivapalan, Therese S Lapperre, Julie Janner, et al.

Lancet Respir Med 2019; 7: 699-709 DOI:https://doi.org/10.1016/S2213-2600(19)30176-6

Summary

Background 背景

Treatment with systemic corticosteroids in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) is associated with debilitating adverse effects. Therefore, strategies to reduce systemic corticosteroid exposure are urgently required and might be offered by a personalised biomarker-guided approach to treatment. The aim of this study was to determine whether an algorithm based on blood eosinophil counts could safely reduce systemic corticosteroid exposure in patients admitted to hospital with acute exacerbations of COPD.

全身激素治疗AECOPD伴随副作用。因此,迫切需要减少全身皮质激素暴露的策略,且应当采取生物标志物指导的个体化治疗。本研究的目的在于确定,对于因AECOPD住院的患者,基于嗜酸粒细胞计数的治疗方案能否安全地减少全身性皮质激素暴露。

Methods 方法

We did a multicentre, randomised, controlled, open-label, non-inferiority trial at the respiratory departments of three different university-affiliated hospitals in Denmark. Eligible participants were patients included within 24h of admission to the participating sites, aged at least 40 years, with known airflow limitation (defined as a post-bronchodilator FEV 1/forced vital capacity [FVC] ratio ≤0·70) and a specialist-verified diagnosis of COPD, who were designated to start on systemic corticosteroids by the respiratory medicine physician on duty. We randomly assigned patients (1:1) to either eosinophil-guided therapy or standard therapy with systemic corticosteroids. Both investigators and patients were aware of the group assignment. All patients received 80 mg of intravenous methylprednisolone on the first day. The eosinophil-guided group were from the second day given 37·5 mg of prednisolone oral tablet daily (for a maximum of up to 4 days) on days when their blood eosinophil count was at least 0·3 × 10 9 cells per L. On days when the eosinophil count was lower, prednisolone was not administered. If a patient was discharged during the treatment period, a treatment based on the last measured eosinophil count was prescribed for the remaining days within the 5-day period (last observation carried forward). The control group received 37·5 mg of prednisolone tablets daily from the second day for 4 days. The primary outcome was the number of days alive and out of hospital within 14 days after recruitment, assessed by intention to treat (ITT). Secondary outcomes included treatment failure at day 30 (ie, recurrence of acute exacerbation of COPD resulting in emergency room visits, admission to hospital, or need to intensify pharmacological treatment), number of deaths on day 30, and duration of treatment with systemic corticosteroids. The non-inferiority margin was 1·2 days (SD 3·8). This trial is registered at ClinicalTrials.gov, number NCT02857842, and was completed in January, 2019.

我们在丹麦3个不同大学附属医院的呼吸科进行了一项多中心、随机、开放标签、非劣效研究。患者入选标准包括入院24小时内,年龄至少40岁,已知气流受限(定义为支气管扩张剂后FEV 1/FVC比值 ≤ 0·70)且专科医生诊断为COPD,根据值班的呼吸科医生决定开始使用全身皮质激素。我们将患者按照1:1的比例分组,分别接受嗜酸粒细胞指导治疗或标准治疗。研究者和患者均了解分组情况。所有患者第一天均使用静脉甲基强的松龙80 mg。从第二天起,嗜酸粒细胞指导组患者若嗜酸粒细胞计数至少为0·3 × 10 9 /L,则口服强的松龙37·5 mg(最多不超过4天)。如果嗜酸粒细胞计数低于上述阈值,则不使用强的松龙。如果患者在治疗期间出院,则在5天疗程的剩余时间内,根据最后一次嗜酸粒细胞计数结果给予强的松龙。对照组从第二天起开始,每日服用强的松龙37·5 mg,疗程4天。主要预后指标为入选后14天内非住院存活天数,采用意向治疗分析(ITT)。次要预后指标包括30天时治疗失败(即AECOPD复发导致急诊就诊,住院,或需要加强药物治疗),30天内死亡,以及全身皮质激素疗程。非劣效界值为1·2天 (SD 3·8)。试验在ClinicalTrials.gov注册,注册号 NCT02857842,于2019年1月结束。

Findings 结果

Between Aug 3, 2016, and Sept 30, 2018, 159 patients in the eosinophil-guided group and 159 patients in the control group were included in the ITT analyses. There was no between-group difference for days alive and out of hospital within 14 days after recruitment: mean 8·9 days (95% CI 8·3–9·6) in the eosinophil-guided group versus 9·3 days (8·7–9·9) in the control group (absolute difference –0·4, 95% CI −1·3 to 0·5; p=0·34). Treatment failure at 30 days occurred in 42 (26%) of 159 patients in the eosinophil-guided group and 41 (26%) of 159 in the control group (difference 0·6%, 95% CI −9·0 to 10·3; p=0·90). At 30 days nine patients (6%) of 159 in the eosinophil-guided group and six (4%) of 159 in the control group had died (difference 1·9%, 95% CI −2·8 to 6·5; p=0·43). Median duration of systemic corticosteroid therapy was lower in the eosinophil-guided group: 2 days (IQR 1·0 to 3·0) compared with 5 days (5·0 to 5·0) in the control group, p<0·0001.

2016年8月3日至2018年9月30日间,嗜酸粒细胞指导组159名患者以及对照组159名患者纳入ITT分析。两组间入选后14天内非住院存活日没有差异:嗜酸粒细胞指导组 8·9 天 (95% CI 8·3–9·6),对照组 9·3 天 (8·7–9·9) (绝对差异 –0·4, 95% CI −1·3 to 0·5; p=0·34)。30天时嗜酸粒细胞组159名患者中42名 (26%) 及对照组159名患者中 41 名 (26%) 出现治疗失败(差异 0·6%, 95% CI −9·0 to 10·3; p=0·90)。至第30天时,嗜酸粒细胞指导组159名患者中9名 (6%) 以及对照组159名患者中6名 (4%) 死亡(差异1·9%, 95% CI −2·8 to 6·5; p=0·43)。嗜酸粒细胞指导组全身皮质激素治疗疗程中位数为 2 天 (IQR 1·0 to 3·0),显著低于对照组的 5 天 (5·0 to 5·0),p<0·0001。

Interpretation 结论

Eosinophil-guided therapy was non-inferior compared with standard care for the number of days alive and out of hospital, and reduced the duration of systemic corticosteroid exposure, although we could not entirely exclude harm on some secondary outcome measures. Larger studies will help to determine the full safety profile of this strategy and its role in the management of COPD exacerbations.

嗜酸粒细胞指导治疗患者的非住院存活天数不劣于标准治疗组,且全身皮质激素暴露时间缩短,尽管我们不能完全排除部分次要预后指标的恶化。更大样本的研究将有助于确定这一策略的安全性及其在AECOPD治疗中的作用。

Funding

The Danish Regions Medical Fund and the Danish Council for Independent Research.

评论[仅代表个人意见]

  • 似乎无论对什么专科而言,生物标志物指导的治疗都是研究热点
  • 在全盘接受研究的阳性结果前,需要多问几个为什么,尤其是针对对照组而言。
  • 最重要的问题就是,为什么疗程是5天而不是2天?这个问题如果没有很好的答案,其实研究结果并没有太多价值

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