Janjua Sadia, Fortescue Rebecca, Poole Phillippa
Cochrane Airways, Population Health Research Institute, St George's, University of London, London, UK.
Department of Medicine, University of Auckland, Auckland, New Zealand.
Cochrane Database Syst Rev. 2020 May 1;5(5):CD002309. doi: 10.1002/14651858.CD002309.pub6.
Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE₄) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020.
To evaluate the efficacy and safety of oral PDE₄ inhibitors for management of stable COPD.
We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers.
We included RCTs if they compared oral PDE₄ inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy.
We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations).
We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE₄ inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV₁) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE₄ inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE₄ inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE₄ inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials.
AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE₄ inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE₄ inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE₄ inhibitors modify FEV₁ decline, hospitalisation, or mortality in COPD.
慢性阻塞性肺疾病（COPD）与咳嗽、咳痰或呼吸困难相关，会导致肺功能、生活质量和预期寿命下降。除戒烟外，尚无其他可减缓肺功能下降的治疗方法。罗氟司特和西洛司特是口服磷酸二酯酶-4（PDE₄）抑制剂，旨在减轻COPD患者的气道炎症和支气管收缩。本Cochrane系统评价首次发表于2011年，并于2017年和2020年进行了更新。
评估口服PDE₄抑制剂治疗稳定期COPD的疗效和安全性。
我们从Cochrane气道试验注册库（最后检索日期为2020年3月9日）中识别随机对照试验（RCT）。我们还在基于网络的临床试验注册库中查找了其他试验。
如果RCT将口服PDE₄抑制剂与COPD患者的安慰剂进行比较，我们将其纳入。我们允许联合使用标准的COPD治疗方法。
我们采用标准的Cochrane方法。两名独立的综述作者选择纳入试验、提取数据并评估偏倚风险。我们通过纳入第三位综述作者解决分歧。我们使用GRADE推荐评估对证据的信心。主要结局为肺功能变化（最小重要差异（MID）=100 mL）和生活质量（0至100分；分数越高表明受限越多）。
我们发现42项符合纳入标准的RCT，纳入罗氟司特分析的有28项试验（18,046名参与者）、西洛司特的有14项试验（6457名参与者）或替托司特的有1项试验（84名参与者），试验持续时间为六周至一年或更长。这些试验纳入了来自国际研究中心的中重度至极重度COPD患者（慢性阻塞性肺疾病全球倡议（GOLD）II至IV级），平均年龄为64岁。在39项已发表和未发表的试验中，我们总体判断选择偏倚、实施偏倚和失访偏倚风险较低。肺功能与安慰剂相比，PDE₄抑制剂治疗在40周内使一秒用力呼气容积（FEV₁）有小幅改善，但临床意义不大（平均差异（MD）49.33 mL，95%置信区间（CI）44.17至54.49；参与者=20,815；研究=29；中等确定性证据）。40周内用力肺活量（FVC）和呼气峰值流速（PEF）也有所改善（FVC：MD 86.98 mL，95%CI 74.65至99.31；参与者=22,108；研究=17；高确定性证据；PEF：MD 6.54 L/min，95%CI 3.95至9.13；参与者=42,45；研究=6；低确定性证据）。生活质量试验报告显示，在33周内生活质量有所改善（圣乔治呼吸问卷（SGRQ）MD -1.06分，95%CI -1.68至-0.4；参与者=7645；中等确定性证据）。急性加重发生率与安慰剂相比，PDE₄抑制剂治疗在40周内使COPD急性加重的可能性降低（比值比（OR）0.78，95%CI 0.73至0.84；参与者=20,382；研究=27；高确定性证据），即每100名接受PDE₄抑制剂治疗的患者中，在研究期间比接受安慰剂治疗的患者多5人无急性加重（额外有益结局的需治疗人数（NNTB）20，95%CI 16至27）。未发现COPD相关症状或运动耐量有变化。不良事件在39周内，治疗组比对照组有更多参与者出现不良事件（OR 1.30，95%CI 1.22至1.38；参与者=21,310；研究=30；低确定性证据）。参与者出现一系列胃肠道症状，如腹泻、恶心、呕吐或消化不良。腹泻在PDE₄抑制剂治疗中更常见（OR 3.20，95%CI 2.74至3.50；参与者=20,623；研究=29；高确定性证据），即每100名接受PDE₄抑制剂治疗的患者中，在研究期间比接受安慰剂治疗的患者多7人患腹泻（额外有害结局的需治疗人数（NNTH）15，95%CI 13至17）。500μg罗氟司特导致精神不良事件的可能性高于安慰剂（OR 2.13，95%CI 1.79至2.54；参与者=11,168；研究=15（COPD汇总数据）；中等确定性证据）。特别是罗氟司特在试验期间与体重减轻、失眠和抑郁情绪症状增加有关。接受PDE₄抑制剂治疗的参与者退出试验的可能性更大；平均而言，治疗组14%的参与者退出，而对照组为8%。死亡率未发现对死亡率有影响（OR 0.98，95%CI
