Felson D T, Anderson J J, Lange M L, Wells G, LaValley M P
Boston University Arthritis Center and School of Public Health, Massachusetts, USA.
Arthritis Rheum. 1998 Sep;41(9):1564-70. doi: 10.1002/1529-0131(199809)41:9<1564::AID-ART6>3.0.CO;2-M.
To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials.
Data from 6 RA trials were reanalyzed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 201), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi-square value differentiating the active treatment group from the control group, with the corresponding P value.
With an increase in the threshold for improvement, the percentage of placebo-treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receiving active therapy (second-line drug, combination therapy, tumor necrosis factor p75-Fc fusion protein) who were classified as experiencing response. Generally, the drop in active treatment response rates was greater than the drop in placebo response rates, leaving the difference between the 2 groups less at the higher thresholds. Therefore, chi-square values fell as the threshold for response was raised. The ordinal definition of improvement yielded chi-square values similar to those obtained using ACR 20 alone.
Adopting a definition of efficacy in RA trials that requires 50% or 70% improvement in core set parameters would likely compromise statistical power and make it more difficult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.
确定在类风湿关节炎（RA）临床试验中，是否应要求核心指标参数改善超过20%才能判定患者病情改善。
对6项RA试验的数据进行重新分析，以评估4种提议的改善定义的判别效度（区分积极治疗与对照的能力）：当前美国风湿病学会（ACR）定义（核心指标参数20%的阈值[ACR 20]）、50%的阈值（ACR 50）、70%的阈值（ACR 70），以及一种序贯定义，即患者可被分类为3种类别中的任何一种（未改善、ACR 20或ACR 50）。为评估这4种改善定义的判别效度，我们根据每种定义将每项试验中的每位患者判定为病情改善或未改善，并计算区分积极治疗组与对照组的卡方值及相应的P值。
随着改善阈值的提高，在所有试验中，被判定有反应的接受安慰剂治疗患者的百分比大幅下降，接受积极治疗（二线药物、联合治疗、肿瘤坏死因子p75 - Fc融合蛋白）且被判定有反应的患者百分比也大幅下降。一般来说，积极治疗反应率的下降幅度大于安慰剂反应率的下降幅度，使得两组之间在较高阈值时的差异更小。因此，随着反应阈值的提高，卡方值下降。改善的序贯定义产生的卡方值与仅使用ACR 20时获得的卡方值相似。
在RA试验中采用要求核心指标参数改善50%或70%的疗效定义可能会损害统计效能，并使区分两种疗效不同的治疗更加困难。ACR 20应继续作为RA试验中疗效的主要衡量指标，更高的改善阈值应作为次要疗效指标来确定和报告。
