JAMA：全身性糖皮质激素治疗5天方案足以预防COPD急性加重

5月21日在线发表于《美国医学会杂志》的一项研究显示，对于慢性阻塞性肺病(COPD)急性加重患者如何预防再次加重方面，5天全身性糖皮质激素治疗与14天常规治疗具有同样的效果 (JAMA 2013 May 21 [doi:10.1001/jama.2013.5023])。

在这项多中心随机临床试验中，接受短程全身性糖皮质激素治疗者其6个月内COPD急性加重复发率为35.9%，不劣于常规2周治疗组的36.8%，瑞士巴塞尔大学医院的Jōrg D. Leuppi医生及其同事报告说。

研究者表示，短程激素治疗方案的主要优势表现在显著减少患者的糖皮质激素暴露，进而或可减少患者的短期不良反应如高血糖、体重增加、血压升高和失眠等。短程方案还可预防或延迟长期激素毒性的发生，如糖尿病、骨质疏松、骨折、肾上腺抑制和眼科并发症等。

研究者开展这项被称为REDUCE(减少COPD急性加重患者对皮质激素的使用)的非劣效性试验主旨，是由于尚无高质量的随机临床试验对长、短程两种激素治疗方案的结局予以直接比较，研究作者同时指出，虽然如此，“已经有很多医生对COPD急性加重患者采取较短疗程的糖皮质激素治疗了”。REDUCE研究结果在线发表的同时也在美国胸科学会(ATS)2013年会上予以公布。

该研究在5年间连续招募了来自5家瑞士教学医院的311例COPD急性加重的急诊患者。所有患者的年龄均超过40岁，均吸烟或有吸烟经历，吸烟史不低于20包/年。所有研究受试者均在第1天接受40 mg甲基强的松龙静脉注射，第2~5天口服强的松40 mg/d。然后经过随机分组，有155例患者在第6~14天继续口服强的松40 mg/d(常规治疗组)，其余156例患者服用安慰剂(短程治疗组)。患者、护理者和研究者均不清楚分组状况。所有患者还接受了7天的广谱抗生素治疗以预防肺炎，在住院期间按需使用雾化的短效支气管扩张剂，每日2次吸入糖皮质激素和β受体激动剂，每日1次吸入噻托溴铵。此外还根据指南建议接受理疗、补氧和通气支持。

接受短程糖皮质激素治疗组患者的强的松中位累计用量为200 mg，平均累计用量为379 mg，而接受较长疗程激素治疗者的中位和平均累计用量分别为560 mg和793 mg。随访期180天，发现短程治疗组有56例(35.9%)患者，常规治疗组有57例(36.8%)患者达到了定义为复发COPD急性加重的主要终点。复发时间无显著性组间差异。

此外，意向治疗分析和按方案分析都显示，两组患者出现复发的危险比(HR)相同，“符合我们预设的非劣效性标准”。当校正年龄、性别等变量后再行敏感性分析，发现上述结果仍然具有显著性。在针对不同COPD严重程度和不同糖皮质激素使用史的亚组分析中也得出了一致的结果。总生存率无显著性组间差异。在住院期间，短程治疗组患者对机械通气的需求也并未增加。

研究发现，在第6天时，两组患者的第1秒用力呼气量(FEV1)均有显著改善，并且在此后保持稳定，“几乎不存在组间差异”。两组患者均报告称呼吸困难得到明显缓解，支气管炎相关生活质量和总体体能的改善程度也相似。至于在糖皮质激素的短期不良反应方面，两组患者的新发/加重高血压和新发/加重高血糖发生率具有可比性。研究者表示：“考虑到糖皮质激素不良反应并不会在开始治疗后很快出现，我们推断住院期间并不能充分观察到两组在血压和血糖方面的差异。”两组患者在长期毒性如感染、消化道出血、失眠、骨折、精神症状或心力衰竭等方面也没有差异。

一项意外发现是，短程治疗组患者的住院时间显著性短于常规治疗组患者(中位时间：8天vs. 9天)。Leuppi医生和他的同事说，“因为没有观察到在糖皮质激素相关性短期不良反应方面存在组间差异，因此研究者尚不能解释这一发现，它也可能是偶然性发生的。”

随刊述评：研究支持5天治疗方案

Don D. Sin医生和Hye Yun Park医生评论道，这项严谨优秀的临床试验得出一个明显的结论：5天糖皮质激素方案足以治疗多数COPD急性加重，并且可减少激素累积暴露65%(JAMA 2013 May 21 [doi:10.1001/jama.2013.5644])。他们写道，“这对于每年多次出现急性加重、反复接受全身性皮质激素治疗的COPD患者而言无疑是个好消息。这一发现将使临床医生得以尽可能减少此类患者的激素暴露和激素相关毒性风险。”

加拿大不列颠哥伦比亚大学James Hogg研究中心、圣保罗医院心肺健康研究所的Park医生报告称无相关利益冲突。Sin医生报告称与Merck Frosst、诺华、阿斯利康、Grifols、勃林格殷格翰和葛兰素史克有利益关系。

Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease:
The REDUCE Randomized Clinical Trial
Importance 
International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.
Objective 
To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.
Design, Setting, and Patients 
REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.
Interventions 
Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.
Main Outcome and Measure 
Time to next exacerbation within 180 days.
Results 
Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of −1.2% (95% CI, −12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.
Conclusions and Relevance 
In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.