Maund Emma, Guski Louise Schow, Gøtzsche Peter C
Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark
Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark.
CMAJ. 2017 Feb 6;189(5):E194-E203. doi: 10.1503/cmaj.151104. Epub 2016 Nov 14.
The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence.
We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]).
Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted.
Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.
欧洲药品管理局公开了临床研究报告，并公布了不批准上市许可申请的原因。度洛西汀在欧洲已被批准用于治疗女性压力性尿失禁。报道的度洛西汀不良反应包括心理健康问题和自杀倾向。我们从欧洲药品管理局获取了关于该药物用于压力性尿失禁的临床研究报告。
我们对提交给欧洲药品管理局用于女性压力性尿失禁适应症上市批准的4项度洛西汀随机安慰剂对照试验（共涉及1913例患者）进行了荟萃分析。我们使用临床研究报告中的数据（总计6870页，包括个体患者数据）来评估益处（包括尿失禁频率和生活质量评分变化，如患者总体改善印象评分）和危害（包括一般危害，如因不良事件停药，以及与自杀倾向、暴力行为及其潜在先兆相关的危害，如静坐不能和激越[如失眠、焦虑和躁动等刺激作用]）。
就每周尿失禁发作次数的百分比变化（平均差值-13.56%，95%置信区间[CI]-21.59%至-5.53%）和尿失禁生活质量总分变化（平均差值3.24，95%CI 2.00至4.48）而言，度洛西汀显著优于安慰剂。然而，效应量较小，一项敏感性分析（剔除一项试验）显示，患者总体改善印象评分为“好多了或非常好多了”时的治疗所需人数为8（95%CI 6至13）。因不良事件停药的危害所需人数为7（95%CI 6至8），经历激越事件的危害所需人数为7（95%CI 6至9）。未观察到自杀倾向、暴力或静坐不能事件。
尽管度洛西汀对女性压力性尿失禁有效，但在分析个体患者数据时，相关危害发生率较高，且危害超过了益处。
