摘要目的 评价长期口服黏液调节/抗氧化剂预防慢性阻塞性肺疾病(慢阻肺)急性加重的有效性及安全性,并探讨药物剂量及合并使用吸入糖皮质激素(ICS)对疗效的影响.方法 对慢阻肺患者规律口服黏液调节/抗氧化剂超过3个月的临床随机对照试验(RCT)进行系统检索,检索Medline和Google Scholar数据库中已发表的文献,对纳入文献逐个进行质量评价和资料提取.进行统计学分析时,计数资料采用相对危险度(RR);计量资料采用加权均数差(WMD)或标准均数差(SMD).采用Stata 11.0软件对数据进行合并统计分析.结果 共纳入10篇文献,共3 434例患者,平均研究时长11.3个月.口服黏液调节/抗氧化剂组急性加重次数较对照组降低0.36次/人年(WMD=-0.36,95％ CI为-0.47～-0.26,z=6.97,P＜0.001).未合用ICS的亚组分析显示治疗组急性加重次数较对照组下降0.58次/人年(WMD=-0.58,95％ CI为-0.89～-0.27,z=3.62,P＜0.001).对不同剂量N-乙酰半胱胺酸(NAC)的疗效分析显示,高剂量时治疗组急性加重次数较对照组减低0.39次/人年(WMD=-0.39,95％ CI为-0.61 ～-0.16,z=3.33,P=0.001);低剂量NAC仅在合用ICS比例较低时才显示出降低慢阻肺急性加重的作用(WMD=-1.25,95％ CI为-1.99～-0.51,z=3.32,P=0.001),当合用ICS比例较高时,两组之间无统计学差异(WMD=-0.06,95％ CI为-0.29～-0.17,z=0.5,P=0.617).研究期间黏液调节/抗氧化剂组FEV1较对照组无明显改善(SMD=0.03,95％ CI为-0.09 ～0.15,z=0.49,P=0.626),而用力呼出气量为25％ ～75％肺活量时的平均流量(FEF 25％～75％)改善有统计学意义(SMD=0.41,95％ CI为0.13 ～0.68,z=2.90,P=0.004).与对照组相比,黏液调节/抗氧化剂组的副作用发生率未见明显增加(RR=1.08,95％ CI为0.92 ～ 1.27,z=0.92,P=0.356).结论 长期口服黏液调节/抗氧化剂可以在不增加副作用的前提下降低稳定期慢阻肺患者的急性加重频次,这一作用可能在未合用ICS患者中更为明显.高剂量NAC预防慢阻肺急性加重的作用较低剂量明确,低剂量仅在合用ICS比例较低时显示出相应的作用.

abstractsObjective To assess the effects and safety of long-term oral mucolytic and antioxidant agents for exacerbations in patients with stable chronic obstructive pulmonary disease.And to further discuss the drug dose and concomitant ICS on the effects.Methods Systematic searches were performed in Medline and Google Scholar databases.Randomized controlled trials which compared regular oral mucolytic and antioxidant agents with placebo and reported exacerbations over a treatment period more than 3 months were selected.Stata version 11 was used for data analysis.Results Ten RCTs involving 3 434 patients were identified.Compared with placebo,the use of mucolytic and antioxidant agents was associated with a reduction of 0.36 exacerbations per patient per year (95％ CI 0.47 to 0.26).The subgroup analysis restricting to studies without concomitant ICS indicated that there was a larger decrease between the two groups (WMD =-0.58,95％ CI-0.89--0.27).The analysis of NAC dose on the effect indicated that high-dose NAC treatment could significantly reduce the exacerbations (WMD =-0.39,95％ CI-0.61--0.16,z =3.33,P =0.001).While in the low-dose NAC group,only those studies with low rate of concomitant ICS showed the effects (WMD =-1.25,95％ CI-1.99--0.51,z =3.32,P =0.001),the difference was not significant in studies with high rate of concomitant ICS (WMD =-0.06,95％ CI -0.29--0.17,z =0.5,P =0.617).There was no difference in FEV1 improvement (SMD =0.03,95％ CI-0.09 ～ 0.15,z =0.49,P =0.626),but FEF 25％-75％ showed a significant improvement (SMD=0.41,95％CI0.13-0.68,z=2.90,P=0.004).Conclusion The use of mucolytic and antioxidant agents is associated with a reduction in the number of exacerbations.The effects may be larger in those patients without concomitant ICS.High-dose NAC treatment may be more effective than low-dose group,while the latter may be effective only when the rate of concomitant ICS was low.