COPD急性加重：激素治疗5天足矣

《美国医学会杂志》5月21日在线发表的一项研究显示，对于慢性阻塞性肺病(COPD)急性加重患者而言，5天全身性糖皮质激素治疗与常规的14天治疗在预防再次加重方面具有同等效果(JAMA 2013 May 21 [doi:10.1001/jama.2013.5023])。

瑞士巴塞尔大学医院的Jōrg D. Leuppi医生及其同事报告称，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的6个月COPD急性加重复发率为35.9%，不劣于接受常规2周治疗者的36.8%。这一研究结果同期在美国胸科学会(ATS)2013年会上发表。

研究者称，短程激素治疗方案的主要优势在于可显著减少患者的糖皮质激素暴露，从而很有可能减少高血糖、体重增加、血压升高和失眠等短期不良反应。短程方案还可避免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。

研究者之所以开展这项名为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，是因为尚无高质量的随机临床试验直接比较长、短两种激素治疗方案的结局，同时“已经有很多医生在缺乏证据支持的情况下对COPD急性加重患者采取较短疗程的糖皮质激素治疗”。

本项研究从5家瑞士教学医院连续招募了5年间311例COPD急性加重的急诊患者。所有患者的年龄均超过40岁，均目前吸烟或曾经吸烟，吸烟史≥20包/年。所有患者均在第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。经过随机分组，在第6~14天有155例患者继续口服强的松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、看护者和研究者均不了解组别。

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。此外还按照指南建议接受理疗、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。

经过180天随访，56例(35.9%)短程治疗组患者和57例(36.8%)常规治疗组患者达到了主要终点(复发COPD急性加重)。两组在至复发时间方面没有显著差异。不仅如此，不论是在意向治疗分析中还是在完成治疗分析中，两组患者出现复发的危险比(HR)均相同，“达到了我们预设的非劣效性标准”。

在校正年龄、性别等变量的敏感性分析中，上述结果仍然具有鲁棒性。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，也得出了一致的结果。

两组患者在总生存率方面不存在显著差异。短程治疗组患者在住院期间对机械通气的需求也并未增加。第6天时，两组患者的第1秒用力呼气量(FEV1)均显著改善，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。

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。研究者称：“我们猜测，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，因为糖皮质激素不良反应并不会在开始治疗后很快出现。”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。

令人意外的是，短程治疗组患者的住院时间明显短于常规治疗组患者(中位时间：8天 vs. 9天)。由于没有观察到在糖皮质激素相关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种现象。

这项研究获得了巴塞尔大学医院、比安医院中心、Freiwilligen Akademische Gesellschaft、Fonds für Lehre und Forschung、阿斯利康、Viollier实验室和Gottfried und Julia Bangerter-Rhyner-Stiftung für Medizinische Forschung的支持。Leuppi医生报告称与上述组织以及勃林格殷格翰、Chibret、Merck Sharp & Dohme、诺华、奈科明和Pharmaxis等有关联。其合作者报告称与多家公司存在联系。

随刊述评：支持5天方案的严谨研究

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Don D. Sin医生和Hye Yun Park医生评论指出，这项严密、优质的临床试验明确地告诉我们：5天糖皮质激素方案足以应付多数COPD急性加重，并且可使激素累积暴露减少65%(JAMA 2013 May 21 [doi:10.1001/jama.2013.5644])。

“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。”

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。

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By: MARY ANN MOON, Internal Medicine News Digital Network

In patients with acute COPD exacerbations, 5-day systemic glucocorticoid therapy was as effective as a conventional 14-day course of the drugs at preventing further exacerbations, according to a report published online May 21 in JAMA.

In a multicenter, randomized clinical trial, the 6-month rate of recurrent COPD exacerbation was 35.9% among patients who received the short course of systemic glucocorticoids, which was noninferior to the 36.8% rate among those who received the usual 2-week course, said Dr. Jōrg D. Leuppi of the University Hospital of Basel (Switzerland) and his associates (JAMA 2013 May 21 [doi:10.1001/jama.2013.5023]).

The short-term approach’s main advantage is its significant reduction of patients’ exposure to glucocorticoids, which in turn will likely decrease short-term adverse effects such as hyperglycemia, weight gain, increased blood pressure, and insomnia, the investigators said. The short course also should prevent or delay longer-term steroid toxicities such as diabetes, osteoporosis, bone fractures, adrenal suppression, and ocular complications.

The investigators performed the noninferiority trial, known as the REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) study, because no adequately powered, randomized clinical trial has compared directly the outcomes of these two treatment durations. Despite that, "it has become quite common clinical practice to administer glucocorticoids in COPD exacerbations for shorter periods," the study authors noted.

The REDUCE trial’s results were published online and simultaneously reported at the annual meeting of the American Thoracic Society.

The study included 311 consecutive patients who presented with COPD exacerbations to emergency departments at five Swiss teaching hospitals during a 5-year period. All patients were older than 40 years, were current or past smokers, and had a smoking history of 20 or more pack-years.

All the study subjects received 40 mg of IV methylprednisolone on day 1, followed by 40 mg of oral prednisone on days 2-5. On days 6-14, 155 patients were randomly assigned to continue receiving oral prednisone (conventional therapy) and 156 to receive a matching placebo (short-course therapy). Patients, caregivers, and researchers were blinded to group assignment.

All the patients also received a broad-spectrum antibiotic for 7 days to prevent pneumonia; nebulized short-acting bronchodilators as needed while hospitalized; inhaled glucocorticoids combined with an inhaled beta-agonist twice daily; and inhaled tiotropium once daily. They all also received physiotherapy, supplemental oxygen, and ventilatory support according to accepted guidelines.

Patients who received short-course glucocorticoid therapy had a median cumulative prednisone dose of 200 mg and a mean cumulative dose of 379 mg. In contrast, those who received a longer duration of treatment had a median cumulative prednisone dose of 560 mg and a mean cumulative dose of 793 mg.

After 180 days of follow-up, 56 (35.9%) of patients in the short-course therapy group and 57 (36.8%) in the conventional therapy group reached the primary endpoint of a recurrent COPD exacerbation. The time to recurrence did not differ between the two groups.

In addition, the hazard ratios for experiencing a recurrence were nearly identical between the two study groups in both an intention-to-treat analysis and a per-protocol analysis, "meeting our noninferiority criterion," Dr. Leuppi and his colleagues said.

The findings remained robust in sensitivity analyses that adjusted for variables such as patient age and sex. They also persisted in subgroup analyses that compared patients who had different severities of underlying COPD and different past histories of glucocorticoid use.

Overall survival was not significantly different between patients who received 5 days and those who received 14 days of systemic glucocorticoids. The short-course therapy group also showed no increase in the need for mechanical ventilation during hospitalization.

Measures of forced expiratory volume in 1 second improved significantly in both groups by day 6 and remained stable thereafter, with "almost no differences" between groups. Patients in both groups reported significantly ameliorated dyspnea, as well as similarly improved bronchitis-related quality of life and overall performance.

Regarding short-term adverse effects of exposure to glucocorticoids, rates of new or worsening hypertension and new or worsening hyperglycemia were comparable between the two study groups. "We surmise that the length of hospital stay was insufficient to detect significant differences in blood pressure and blood glucose levels between groups, because these glucocorticoid adverse effects do not develop immediately after initiation of treatment," the researchers said.

There also were no differences in longer-term toxicities such as rates of infection, gastrointestinal bleeding, insomnia, fractures, psychiatric symptoms, or heart failure.

A surprising finding was that patients who received short-term glucocorticoids had a significantly shorter hospital stay (median, 8 days) than did those who received conventional glucocorticoids (median, 9 days). "Because we did not observe significant differences in glucocorticoid-related, short-term adverse effects, we cannot readily explain this observation, which might be a chance finding," Dr. Leuppi and his associates said.

This study was supported by the University Hospital Basel, the Hospital Center of Biel-Bienne, Freiwilligen Akademische Gesellschaft, Fonds für Lehre und Forschung, AstraZeneca, Viollier Laboratory, and Gottfried und Julia Bangerter-Rhyner-Stiftung für Medizinische Forschung. Dr. Leuppi reported ties to these groups and Boehringer-Ingelheim, Chibret, Merck Sharp & Dohme, Novartis, Nycomed, and Pharmaxis, and his associates reported ties to numerous industry sources.

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Rigorous study supports 5-day regimen

This rigorous, high-quality clinical trial by Leuppi et al. makes it clear that a 5-day regimen of glucocorticoids is sufficient for most COPD exacerbations, and it reduced the cumulative exposure to steroids by 65%, noted Dr. Don D. Sin and Dr. Hye Yun Park.

"This is welcome news for patients with COPD who experience multiple exacerbations annually and are exposed to repeated courses of systemic corticosteroids. These findings will enable clinicians to minimize steroid exposure and reduce the risk of steroid-related toxicity in these patients," they wrote.

Dr. Sin and Dr. Park are at the University of British Columbia James Hogg Research Centre and the Institute for Heart and Lung Health at St. Paul’s Hospital, both in Vancouver. Dr. Park also is in the division of pulmonary and critical care medicine at Samsung Medical Center, Seoul (South Korea). Dr. Park reported no financial conflicts of interest. Dr. Sin reported ties to Merck Frosst, Novartis Canada, AstraZeneca, Grifols, Boehinger Ingelheim, and GlaxoSmithKline. These remarks were taken from their editorial accompanying Dr. Leuppi’s report (JAMA 2013 May 21 [doi:10.1001/jama.2013.5644]).