粘稠补充疗法用于膝盖骨关节炎:效益小、风险大


  【24drs.com】根据在线发表于6月12日内科医学志的一篇系统性回顾和统合分析,对膝盖骨关节炎(OA)病患进行粘稠补充疗法、关节腔内注射玻尿酸,在疼痛与功能性方面的效果有限甚至无效,而且会增加严重不良反应和局部不良反应的风险。
  
  瑞士柏恩大学社会与预防医学研究中心Anne W.S. Rutjes博士等人,分析了针对成年膝盖OA病患比较粘稠补充疗法与安慰剂或其它非介入式控制方式的89篇随机试验,初级结果是疼痛强度,次级结果是物理性功能,预先设定之最小临床重要性差异的效益大小为-0.37。
  
  研究者发现,对于有症状的膝盖OA病患,粘稠补充疗法对疼痛和功能的效益分别是相当小(疼痛)与无效(功能性)。
  
  接受注射后24至72小时内,注射膝盖症状恶化是主要的安全性结果;次级安全性结果是严重副作用、因为副作用而停止或退出、整体的副作用、注射之膝盖的渗出、注射之膝盖的局部副作用,中止或退出(不论任何原因)。
  
  这89篇试验包括了12,667名病患,其中68篇试验有安慰剂对照组,40篇的追踪期大于3个月。
  
  Rutjes博士写道,整体而言,71篇试验(9,617名病患)显示粘稠补充疗法可适度缓解疼痛(效益大小-0.37 [95%信心区间-0.46至-0.28])。各试验之间有重要的异质性,且呈现不对称漏斗图:试验大小、双盲结果评估、出版状态与相关效益大小。回顾者也发现5篇未发表的试验(1,149名病患),显示的效益大小为-0.03 (CI,-0.14至0.09)。
  
  作者们写道,有关未发表试验之资料,我们确认了6篇未发表的试验,其中5篇有分析疼痛、共1,149名病患,总病患数的12%纳入疼痛结果统合分析。我们无法揭露其中3篇的详细结果,但是汇整这5篇未发表试验之后可提出总结为:效益大小为-0.03且T2值为0.00。从伦理和科学的角度来看,这类发表偏差是令人不安、不可接受的。
  
  作者们写道,探讨18篇(5,094名病患)进行双盲结果分析的大型试验显示,临床无关的疼痛效益大小为-0.11 (CI,-0.18至-0.04)。
  
  回顾者也发现,粘稠补充疗法和恶化风险增加有关,但未达统计上的显著意义,严重副作用风险则是显著增加(相关风险1.41;CI,1.02 - 1.97)。最常见的副作用是胃肠道、心血管、癌症、肌肉骨骼方面。
  
  作者们结论表示,因为严重副作用和局部副作用的风险增加,不鼓励给予这些制剂。
  
  髋骨与膝盖OA处置之2009年版OARSI建议的第一作者Weiya Zhang医师表示,这是篇相当好的报告,总结了目前关节腔内注射玻尿酸(IAHA)治疗膝盖OA的研究证据,包括了一些未出版的资料;研究结果显示,IAHA对于安慰剂或未治疗的对照组有一些边际效益,可能有害IAHA,可能会诱发急性关节恶化。希望读者记住的是,IAHA不如我们所想的有效,安全性也尚未确认。
  
  不过,Zhang医师指出,使用IAHA于OA治疗依赖个别病患的特征与治疗反应,随机控制试验只探讨治疗的平均价值,通常无法一般化到每个病患。
  
  资料来源:http://www.24drs.com/professional/list/content.asp?x_idno=6852&x_classno=0&x_chkdelpoint=Y
  

Viscosupplementation for Knee OA: Little Gain, Big Risks

By Janis C. Kelly
Medscape Medical News

June 11, 2012 — Viscosupplementation, the intra-articular injection of hyaluronic acid, produced "minimal or nonexistent" effects on pain and function in patients with knee osteoarthritis (OA) but did increase the risks for serious adverse events and local adverse reactions, according to a systematic review and meta-analysis published online June 12 in the Annals of Internal Medicine.

Anne W.S. Rutjes, PhD, and colleagues from the Institute of Social and Preventive Medicine at the University of Bern, Switzerland, analyzed 89 randomized trials comparing viscosupplementation (with hyaluronic acid or a derivative) to sham or to nonintervention control in adults with knee OA. The primary outcome measure was pain intensity. The secondary effectiveness outcome measure was physical function. The prespecified minimal clinically important difference was an effect size of ?0.37.

The researchers found that the benefit of viscosupplementation on pain and function in patients with symptomatic OA of the knee was minimal (pain) or nonexistent (function).

Flare-up in the injected knee within 24 to 72 hours of injection was the primary safety outcome. Secondary safety outcomes were serious adverse events, withdrawals or dropouts because of adverse events, adverse events overall, effusions at the injected knee, any local adverse event in the injected knee, and dropouts and withdrawals overall (regardless of reason).

The 89 trials included 12,667 patients. Sixty-eight of 89 trials had a sham control, and 40 of 89 had follow-up longer than 3 months.

Unpublished Trials Reveal Publication Bias

Dr. Rutjes writes, "Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, ?0.37 [95% (confidence interval [CI]), ?0.46 to ?0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size." The reviewers also found 5 unpublished trials (1149 patients) that showed an effect size of ?0.03 (CI, ?0.14 to 0.09).

Regarding the data from unpublished trials, the authors write, "We identified 6 unpublished trials, of which 5 contributed to the analysis of pain, with 1149 patients, or 12% of the total number of patients included in the meta-analysis of pain outcomes. We could not disclose detailed results of 3 of them, but could report summary estimates after pooling all 5 unpublished trials: an effect size of ?0.03 and a T2 of 0.00. Such publication bias is disconcerting and unacceptable from an ethical and scientific point of view."

An analysis of the 18 large trials with blinded outcome assessment (5094 patients) "showed a clinically irrelevant [pain] effect size of ?0.11 (CI, ?0.18 to ?0.04)," the authors write.

The reviewers also found that viscosupplementation was associated with an increase in risk for flare-ups that was not statistically significant, as well as with a significantly increased risk for serious adverse events (relative risk, 1.41; CI, 1.02 - 1.97). The most common adverse events were related to the gastrointestinal system, cardiovascular system, cancer, and musculoskeletal system.

The authors conclude, "Because of increased risks for serious adverse events and local adverse events, the administration of these preparations should be discouraged."

Weiya Zhang, MD, lead author on the 2009 OARSI recommendations for management of hip and knee OA, reviewed the study for Medscape Medical News. Dr. Zhang is associate professor and reader in musculoskeletal epidemiology, faculty of medicine and health sciences at the University of Nottingham, United Kingdom. He was not involved in the study.

Dr. Zhang said, "This is a very good paper which summarizes the current research evidence for intra-articular hyaluronic acid (IAHA) for knee OA, including some unpublished data. The results showed that the IAHA has some marginal effects over placebo or untreated control and is potentially harmful (IAHA may trigger acute joint flare). The message to take home is that IAHA is not as effective as we thought, and its safety profile has yet to be confirmed."

However, Dr. Zhang noted that the use of IAHA in OA therapy depends on individual patient features and response to the treatment, as randomized controlled trials give only the mean value for therapy, which is often not generalizable to every patient.

The study was funded by the Arco Foundation, Zurich Switzerland. Dr. Rutjes and Dr. Zhang have disclosed no relevant financial relationships. Complete conflict of interest information for the article can be found on the journal's Web site .

Ann Intern Med. Published online June 12, 2012.

    
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