在严重哮喘治疗的试验中，对维持药物的依从性评估不足会导致效能损失和成本增加，系统的文献回顾和模型研究的结果
2019/04/19
摘要
背景：严重哮喘患者对吸入维持疗法的依从性很少得到充分评估，其对试验结果的影响尚不清楚。我们系统地确定了在重症哮喘“附加”治疗的临床试验中如何评价维持治疗的依从性。我们模拟了通过准确评估依从性可以实现试验效能的改进。
方法：对6个主要数据库进行系统搜索，确定了重症哮喘附加治疗的随机试验。评估依从性测量与研究结果之间的关系。利用数字记录的依从性试验数据，估计统计效能和样本量的潜在改善。
研究结果：包括87个随机对照试验，其中22173名参与者。67个试验未报告依从性评估（n=13 931，63%）。报告依从性的研究使用了一系列自我报告和主观方法。所有的研究都没有采用客观的依从性评估。与未评估依从性的研究相比，报告依从性的研究显著降低了FEV1的总方差：S2=0.144l2 vs S2=0.168I2，P<0.0001。在报告了依从性评估的试验中，检验临床相关FEV1变化的效能显著较高（平均效能达到59%:49%）。模型表明，高达50%的FEV1结果差异归因于研究未检测依从性变化。控制这些变化可能会使所需样本量减半。
解释：很少有重症哮喘附加治疗的试验评估患者对维持性吸入治疗的依从性，从而导致试验结果的更大差异和确定疗效的效能不足。
Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy. Results from a systematic literature review and modelling study.
Mokoka MC, McDonnell MJ, MacHale E, Cushen B, Boland F, Cormican S, Doherty C, Doyle F, Costello RW, Greene G.
Abstract
BACKGROUND: Adherence to inhaled maintenance therapy in severe asthma is rarely adequately assessed, and its influence on trial outcomes is unknown. We systematically determined how adherence to maintenance therapy is assessed in clinical trials of "add-on" therapy for severe asthma. We model the improvement in trial power which could be achieved by accurately assessing adherence.
METHODS: A systematic search of six major databases identified randomised trials of add-on therapy for severe asthma. The relationship between measuring adherence and study outcomes was assessed. An estimate of potential improvements in statistical power and sample size was derived using digitally recorded adherence trial data.
FINDINGS: 87 RCTs enrolling 22 173 participants were included. Adherence assessment was not reported in 67 (n=13 931, 63%). Studies which reported adherence used a range of self-report and subjective methods. None of the studies employed an objective assessment of adherence. Studies which reported adherence had a significantly reduced pooled variance in FEV1 compared to those which did not assess adherence: S2= 0·144L2 versus S2= 0·168L2, p<0·0001. Power to detect clinically relevant changes in FEV1 was significantly higher in trials which reported adherence assessment (mean power achieved 59% compared to 49%). Modelling suggests that up to 50% of variance in FEV1 outcomes is attributable to undetected variations in adherence. Controlling for such variations could potentially halve the required sample size.
INTERPRETATION: Few trials of add-on therapy monitor adherence to maintenance inhaled therapy, resulting in a greater variance in trial outcomes and inadequate power for determining efficacy.
背景：严重哮喘患者对吸入维持疗法的依从性很少得到充分评估，其对试验结果的影响尚不清楚。我们系统地确定了在重症哮喘“附加”治疗的临床试验中如何评价维持治疗的依从性。我们模拟了通过准确评估依从性可以实现试验效能的改进。
方法：对6个主要数据库进行系统搜索，确定了重症哮喘附加治疗的随机试验。评估依从性测量与研究结果之间的关系。利用数字记录的依从性试验数据，估计统计效能和样本量的潜在改善。
研究结果：包括87个随机对照试验，其中22173名参与者。67个试验未报告依从性评估（n=13 931，63%）。报告依从性的研究使用了一系列自我报告和主观方法。所有的研究都没有采用客观的依从性评估。与未评估依从性的研究相比，报告依从性的研究显著降低了FEV1的总方差：S2=0.144l2 vs S2=0.168I2，P<0.0001。在报告了依从性评估的试验中，检验临床相关FEV1变化的效能显著较高（平均效能达到59%:49%）。模型表明，高达50%的FEV1结果差异归因于研究未检测依从性变化。控制这些变化可能会使所需样本量减半。
解释：很少有重症哮喘附加治疗的试验评估患者对维持性吸入治疗的依从性，从而导致试验结果的更大差异和确定疗效的效能不足。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Eur Respir J. 2019 Mar 7. pii: 1802161. doi: 10.1183/13993003.02161-2018.)
(Eur Respir J. 2019 Mar 7. pii: 1802161. doi: 10.1183/13993003.02161-2018.)
Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy. Results from a systematic literature review and modelling study.
Mokoka MC, McDonnell MJ, MacHale E, Cushen B, Boland F, Cormican S, Doherty C, Doyle F, Costello RW, Greene G.
Abstract
BACKGROUND: Adherence to inhaled maintenance therapy in severe asthma is rarely adequately assessed, and its influence on trial outcomes is unknown. We systematically determined how adherence to maintenance therapy is assessed in clinical trials of "add-on" therapy for severe asthma. We model the improvement in trial power which could be achieved by accurately assessing adherence.
METHODS: A systematic search of six major databases identified randomised trials of add-on therapy for severe asthma. The relationship between measuring adherence and study outcomes was assessed. An estimate of potential improvements in statistical power and sample size was derived using digitally recorded adherence trial data.
FINDINGS: 87 RCTs enrolling 22 173 participants were included. Adherence assessment was not reported in 67 (n=13 931, 63%). Studies which reported adherence used a range of self-report and subjective methods. None of the studies employed an objective assessment of adherence. Studies which reported adherence had a significantly reduced pooled variance in FEV1 compared to those which did not assess adherence: S2= 0·144L2 versus S2= 0·168L2, p<0·0001. Power to detect clinically relevant changes in FEV1 was significantly higher in trials which reported adherence assessment (mean power achieved 59% compared to 49%). Modelling suggests that up to 50% of variance in FEV1 outcomes is attributable to undetected variations in adherence. Controlling for such variations could potentially halve the required sample size.
INTERPRETATION: Few trials of add-on therapy monitor adherence to maintenance inhaled therapy, resulting in a greater variance in trial outcomes and inadequate power for determining efficacy.
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