Jevsevar David, Donnelly Patrick, Brown Gregory A, Cummins Deborah S
Department of Orthopaedics, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address:
Research and Scientific Affairs Department, American Academy of Orthopaedic Surgeons, 9400 West Higgins Road, Rosemont, IL 60018. E-mail address for P. Donnelly:
J Bone Joint Surg Am. 2015 Dec 16;97(24):2047-60. doi: 10.2106/JBJS.N.00743.
The purpose of this analysis was to determine the clinical significance of injectable hyaluronic acid (HA) in the treatment of knee osteoarthritis, and to assess which trial-level factors influence the overall treatment effect of HA on pain (as measured by a VAS [visual analog scale] or the WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index]) and the WOMAC function and WOMAC stiffness subscales.
A comprehensive literature search of PubMed, EMBASE, the Physiotherapy Evidence Database, and the Cochrane Central Register of Controlled Trials was done to locate randomized controlled trials that compared HA with control treatment and had a minimum of thirty patients per subgroup. To be considered for inclusion, each article had to include VAS or WOMAC pain, WOMAC function, and/or WOMAC stiffness as outcomes because the minimal important difference (MID) has been established for these instruments. A "best-evidence" systematic review and meta-analysis of nineteen trials was performed; because of high heterogeneity among the trials, meta-regression analyses were conducted to determine the influence of trial characteristics on overall HA treatment effects for pain, function, and stiffness.
The most consistent finding was that double-blinded, sham-controlled trials had much smaller treatment effects than trials that were not sufficiently blinded (p < 0.05). For double-blinded trials, the overall treatment effect was less than half of the MID for pain, function, and stiffness. Other significant associations were found for cross-linked HAs and follow-up duration. However, the effect sizes among double-blinded trials of cross-linked HAs were still less than half of the MIDs for pain and stiffness. The statistically significant effect of follow-up duration disappeared when the open-label trials were removed from the analysis.
Meta-analysis of only the double-blinded, sham-controlled trials with at least sixty patients did not show clinically important differences of HA treatment over placebo. When all literature was added to the analysis, the overall effect was greater but was biased toward stronger treatment effects because of the influence of nonblinded or improperly blinded trials.
本分析的目的是确定注射用透明质酸（HA）治疗膝关节骨关节炎的临床意义，并评估哪些试验水平的因素会影响HA对疼痛（通过视觉模拟量表[VAS]或西安大略和麦克马斯特大学骨关节炎指数[WOMAC]测量）、WOMAC功能以及WOMAC僵硬子量表的总体治疗效果。
对PubMed、EMBASE、物理治疗证据数据库和Cochrane对照试验中央注册库进行全面文献检索，以查找将HA与对照治疗进行比较且每个亚组至少有30名患者的随机对照试验。每篇文章要被纳入分析，必须将VAS或WOMAC疼痛、WOMAC功能和/或WOMAC僵硬作为结局指标，因为这些工具已确定了最小重要差异（MID）。对19项试验进行了“最佳证据”系统评价和荟萃分析；由于试验间存在高度异质性，进行了荟萃回归分析以确定试验特征对HA治疗疼痛、功能和僵硬的总体效果的影响。
最一致的发现是，双盲、假对照试验的治疗效果比未充分设盲的试验小得多（p<0.05）。对于双盲试验，疼痛、功能和僵硬的总体治疗效果小于MID的一半。还发现了交联HA和随访时间的其他显著关联。然而，交联HA双盲试验中的效应大小仍小于疼痛和僵硬MID的一半。当从分析中剔除开放标签试验时，随访时间的统计学显著效应消失。
仅对至少60名患者的双盲、假对照试验进行荟萃分析，未显示HA治疗与安慰剂相比有临床重要差异。当将所有文献纳入分析时，总体效果更大，但由于未设盲或设盲不当试验的影响，偏向于更强的治疗效果。
