Gabler Nicole B, French Benjamin, Strom Brian L, Palevsky Harold I, Taichman Darren B, Kawut Steven M, Halpern Scott D
Center for Clinical Epidemiology and Biostatistics, Philadelphia, PA, USA.
Circulation. 2012 Jul 17;126(3):349-56. doi: 10.1161/CIRCULATIONAHA.112.105890. Epub 2012 Jun 13.
Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials.
First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%- 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m.
Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.
几乎所有现有的肺动脉高压治疗方法都是基于6分钟步行距离的变化（Δ6MWD）作为临床重要终点获批的，但其作为替代终点的有效性从未得到证实。我们旨在验证肺动脉高压试验中Δ6MWD的差异与临床事件发生概率之间的关系。
首先，为了确定基线和12周时的Δ6MWD是否介导了治疗分配与临床事件发生之间的关系，我们对之前提交给美国食品药品监督管理局的10项随机安慰剂对照试验的患者水平数据进行了汇总分析（n = 2404例患者）。其次，为了确定表明临床事件有统计学显著减少的Δ6MWD阈值效应，我们在21种药物/剂量水平组合中进行了Meta回归分析。Δ6MWD占治疗效果的22.1%（95%置信区间，12.1% - 31.1%）（P < 0.001）。Meta分析显示，Δ6MWD的平均差异为22.4 m（95%置信区间，17.4 - 27.5 m），与安慰剂相比，活性治疗更具优势。活性治疗降低了临床事件的发生概率（汇总比值比，0.44；95%置信区间，0.33 - 0.57）。Meta回归分析显示有显著的41.8 m阈值效应。
我们的结果表明，Δ6MWD并不能解释很大一部分治疗效果，作为临床事件的替代终点，其有效性有限，可能不是一个充分的替代终点。有必要进一步研究41.8 m的阈值对于长期结局是否有效，或者在使用背景治疗或完全缺乏安慰剂对照的试验中该阈值是否不同。
