Nevitt Sarah J, Thornton Judith, Murray Clare S, Dwyer Tiffany
Department of Biostatistics, University of Liverpool, Block F, Waterhouse Building, 1-5 Brownlow Hill, Liverpool, UK, L69 3GL.
Cochrane Database Syst Rev. 2018 Feb 9;2(2):CD008649. doi: 10.1002/14651858.CD008649.pub3.
Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 28 September 2017.
All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
Six studies (reported in 50 publications) were included with a total of 784 participants.Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population.Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole.While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies.Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality.For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF.For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations.In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS: There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.
有几种药物可用于清除囊性纤维化患者气道中的分泌物。甘露醇可增加黏液纤毛清除功能，但其确切作用机制尚不清楚。与需要通过雾化器给药的现有药物相比，甘露醇干粉制剂可能更方便、更易于使用。吸入性甘露醇干粉治疗囊性纤维化的III期试验已经完成，目前已在澳大利亚和欧洲一些国家上市。这是对之前一篇综述的更新。
评估吸入性甘露醇干粉是否耐受性良好，是否能改善囊性纤维化患者的生活质量和呼吸功能，以及与该治疗相关的不良事件有哪些。
我们检索了Cochrane囊性纤维化和遗传疾病研究组试验注册库，该注册库包括从全面的电子数据库、手工检索相关期刊以及会议摘要中识别出的参考文献。最后一次检索日期：2017年9月28日。
所有比较甘露醇与安慰剂、吸入性活性对照药物（如高渗盐水或 Dornase alfa）或不治疗的随机对照研究。
作者独立评估纳入研究，进行数据提取，并评估纳入研究的偏倚风险。使用GRADE评估证据质量。
纳入6项研究（发表于50篇出版物），共784名参与者。纳入研究的治疗持续时间为12天至6个月，其中2项研究有为期6个月的开放标签治疗。5项研究将甘露醇与对照（极低剂量的甘露醇或不可吸入的甘露醇）进行比较，最后1项研究将甘露醇分别与单独使用的Dornase alfa以及甘露醇加Dornase alfa进行比较。2项大型研究采用了相似的平行设计，为600名参与者提供了数据，在有特定结局和时间点数据的情况下可以进行合并分析。其余研究样本量小得多（从22到95不等），由于设计、干预措施和人群不同，数据无法合并。来自2项大型平行研究的合并证据质量被判定为低到中等质量，来自较小研究的证据质量被判定为低到非常低质量。在所有研究中，都有一个初始测试来查看参与者是否能耐受甘露醇，只有能耐受该药物的参与者才会被随机分组；因此，研究结果并不适用于整个囊性纤维化人群。虽然已发表的论文未提供我们分析所需的所有数据，但药物制造商和其中一项研究的作者提供了额外的未发表数据。合并比较甘露醇与对照的大型平行研究，在长达6个月（包括6个月）的时间里，与对照组相比，甘露醇组以毫升和预测值百分比衡量的肺功能（一秒用力呼气量）显著改善（中等质量证据）。在这些研究中的成年人以及同时使用Dornase alfa者和未使用者中均观察到有益结果。在较小的研究中，与不可吸入的甘露醇组相比，甘露醇组的肺功能也有统计学上的显著改善；然而，我们判定该证据质量为低到非常低质量。对于甘露醇与对照的比较，除治疗负担外，我们发现在任何领域与健康相关的生活质量均无一致差异，在两项设计相似的合并研究中，甘露醇在长达4个月时的治疗负担较轻；这种差异在6个月时未持续存在。应注意，用于测量与健康相关生活质量的工具并非设计用于评估黏液溶解剂，合并适用年龄的工具（如部分纳入研究中所做的那样）可能无效，因此结果被判定为质量低到非常低，应谨慎解读。咳嗽、咯血、支气管痉挛、咽喉疼痛和咳嗽后呕吐是两个治疗组中最常报告的副作用。在可以比较不良事件发生率的情况下，甘露醇组和对照组之间未发现统计学上的显著差异；尽管其中一些事件可能对囊性纤维化患者具有临床相关性。对于甘露醇分别与单独使用的Dornase alfa以及甘露醇加Dornase alfa的比较，一项对28名参与者进行的为期12周的交叉研究提供的极低质量证据表明，在记录的与健康相关生活质量领域或肺功能测量方面无统计学上的显著差异。咳嗽是单独使用甘露醇组中最常见的副作用，但单独使用Dornase alfa组未出现咳嗽，从甘露醇加Dornase alfa组退出的最常见原因是肺部病情加重。就本综述的次要结局（肺部病情加重、住院、症状、痰液微生物学）而言，纳入研究提供的证据更为有限。对于所有比较，在甘露醇与对照治疗（包括Dornase alfa）之间未观察到一致的统计学上显著且具有临床意义的差异。
有中等质量证据表明，与对照相比，为期6个月的甘露醇治疗与囊性纤维化患者某些肺功能指标的改善相关。有低到非常低质量的证据表明，与对照相比，服用甘露醇的参与者在生活质量方面无差异。本综述提供的极低质量证据表明，在肺功能或生活质量方面，甘露醇与单独使用的Dornase alfa以及甘露醇加Dornase alfa相比无差异。本综述的临床意义表明，甘露醇可被视为囊性纤维化的一种治疗方法；但需要进一步研究以确定谁可能最受益以及这种益处是否能长期维持。此外，在将其考虑用于主流治疗之前，需要开展比较其与其他（现有）黏液溶解疗法疗效的研究。
