Chêne G, Morlat P, Leport C, Hafner R, Dequae L, Charreau I, Aboulker J P, Luft B, Aubertin J, Vildé J L, Salamon R
INSERM U330, Département d'Informatique Médicale, Université Victor Segalen Bordeaux 2, France.
Control Clin Trials. 1998 Jun;19(3):233-48. doi: 10.1016/s0197-2456(97)00145-1.
Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.
采用意向性分析方法进行分析的随机临床试验能在各治疗组间提供无偏倚的比较。为避免治疗效果被稀释，许多人也会按实际接受的治疗进行分析，尽管这种方法可能会给结果带来偏倚。本文介绍了用于分析近期一项试验数据的几种方法以及解读每种方法结果时遇到的困难。ANRS 005/ACTG 154研究是一项双盲、安慰剂对照、随机、国际性（法国、美国和西班牙）多中心试验，旨在评估乙胺嘧啶对晚期免疫缺陷的HIV感染患者预防脑弓形虫病（CT）的有效性。在意向性分析中，乙胺嘧啶组（11.9%）和安慰剂组（13.1%）在1年时CT的累积概率无显著差异，风险比（HR）=0.94（95%置信区间（CI）=0.62 - 1.42），而实际治疗分析则显示出显著差异：乙胺嘧啶组为4.2%，安慰剂组为12.4%，HR = 0.44（95%CI = 0.24 - 0.80）。数据显示依从性与治疗结果之间存在显著交互作用；在乙胺嘧啶组，副作用更常被列为违反依从性的原因。几种不同的分析方法（仅在患者因特定原因停止研究用药时对数据进行删失）未能解释意向性分析和实际治疗分析对乙胺嘧啶疗效估计之间的差异。这一经验使我们相信，比较两种分析的结果是让临床医生相信意向性分析是唯一可解释分析的最佳方法。我们担心，即使乙胺嘧啶有有益效果，除非能在治疗分配时预测每位患者停用研究药物的情况，否则很难（1）进行量化以及（2）应用于临床实践。尽管探索性分析可能会在治疗评估中产生临床相关信息和有用的阐释，但意向性分析仍然是临床试验唯一可解释的分析方法。
