茶碱治疗慢性阻塞性肺疾病的随机双盲平行对照研究

Theophylline in the treatment of chronic obstructive pulmonary disease:a randomized,double-blind,placebo-controlled study

目的观察长期口服小剂量缓释茶碱治疗稳定期慢性阻塞性肺疾病(COPD)的疗效和安全性。方法采用随机双盲安慰剂平行对照研究方法,对2002至2003年广东韶关农村地区流行调查中筛选出符合入选标准的110例稳定期 COPD 患者进行简单随机分组,分别予缓释茶碱(每次100 mg,每天2次)和安慰剂口服治疗1年。评估肺功能、慢性阻塞性肺疾病急性发作(AECOPD)情况、生活质量、气促分数、治疗满意度和不良反应等。疗效比较采用优势检验。结果 85例(缓释茶碱组42例,对照组43例)完成1年随访。目标治疗(ITT)人群分析结果显示,缓释茶碱组 AECOPD总次数[(0.8±1.2)次/年]较安慰剂组[(1.7±2.6)次/年]减少(Z=-1.674,P=0.047),AECOPD总时间[(4.6±7.9)d]较安慰剂组[(12.5±22.8)d]减少(Z=-1.699,P=0.045);中度及以上AECOPD 次数[(0.4±1.0)次/年]较安慰剂组[(1.0±1.8)次/年]显著减少(Z=-2.136,P=0.017),扩张前的第一秒用力呼气容积(FEV_1)递减值[(0.006±0.180)L]较安慰剂组[(-0.503±0.169)L]显著减少(t=1.789,P=0.038),疗效总满意度(其中对疗效很满意的患者16例)较安慰剂组(对疗效很满意患者3例)高(Z=-2.198,P=0.014),首次 AECOPD 时间(中位数表示,365 d)较安慰剂组(276 d)延迟(X^2=3.880,P=0.049),但两组支气管扩张试验后的 FEV_1递减值(t=-0.012,P=0.495)和不良反应(P=0.076)比较差异均无统计学意义。符合方案(PP)人群分析结果显示类似的结果,缓释茶碱组的生活质量[(-28±20)分]较安慰剂组[(-20±23)分]显著改善(F=2.893,P=0.047)。结论小剂量缓释茶碱长期治疗稳定期 COPD 安全有效。

Objective To observe the benefits and safety of low-dose, slow-release oral theophylline for long-term treatment of stable chronic obstructive pulmonary disease （COPD）. Methods This was a randomized, parallel-group, double-blind, placebo-controlled trial. Slow-release theophylline （ 200 mg/d ） twice daily or placebo（matching theophylline） was randomly given to 110 patients with stable COPD in the rural area of Shaoguan, Guangdong Province, for one year. Efficacy measures were spirometry and exacerbations, quality of life, dyspnea scores, satisfaction with treatments and adverse effects. Comparison of benefits was performed using superiority test. Results Of 110 patients, 85 （42 subjects in theophylline group and 43 subjects in placebo group） completed the study. An analysis for intention-to-treat （ITT） individuals showed that individuals with the treatment of theophylline experienced statistically fewer numbers [ （0. 8 ± 1.2 ） times/year, （ 1.7 ± 2. 6 ） times/year, Z = - 1. 674, P = 0. 047 ] and days of exacerbations [ （4. 6 ± 7.9） d, （ 12. 5 ± 22. 8 ） d, Z = - 1. 699, P = 0. 045 ] in comparison to subjects receiving placebo, that patients receiving theophylline were less likely than the placebo group to experience moderate exacerbations [ （ 0. 4 ± 1.0） times/year, （ 1.0 ± 1.8 ） times/year, Z = - 2. 136, P = 0. 017 ], and that more individuals satisfied with treatments in the theophylline group than the placebo group （ n = 16,3, Z = -2. 198,P = 0.014）,and that statistically greater improvement in pre-bronchodilators FEV1 [ （0.006 ±0. 180）L, （ -0. 053 ± 0. 169）L ,t = 1. 789 ,P=0. 038 ] were found in the theophylline group in comparison to the placebo group. The similar results were observed in an analysis for per-protocol （PP） subjects. Statistical improvement on quality of life was observed in the PP subjects of theophylline group than in placebo group（ - 28 ± 20, - 20 ± 23, F = 2. 893, P = 0. 047 ）. Time to the first exacerbation in patients receiving theophylline was also delayed in comparison to placebo（ 365 d ,276 d, χ^2 = 3. 880, P = 0. 049 ）. But no statistical difference was found between the two groups in post-bronchodilators FEV1 in both ITT and PP subjects（ t = - 0. 012, P = 0. 495 and t = 0. 040, P = 0. 484 respectively）. Drug-related adverse events （8.8%） such as insomnia, palpitation, stomach discomforts or stomachache, and headache were observed in the theophylline group. Conclusion Slow-released oral theophylline（200 mg/d） may be beneficial and safe in long-term treatment of stable COPD in rural area.