粘稠補充療法用於膝蓋骨關節炎:效益小、風險大


  【24drs.com】根據線上發表於6月12日內科醫學誌的一篇系統性回顧和統合分析,對膝蓋骨關節炎(OA)病患進行粘稠補充療法、關節腔內注射玻尿酸,在疼痛與功能性方面的效果有限甚至無效,而且會增加嚴重不良反應和局部不良反應的風險。
  
  瑞士柏恩大學社會與預防醫學研究中心Anne W.S. Rutjes博士等人,分析了針對成年膝蓋OA病患比較粘稠補充療法與安慰劑或其他非介入式控制方式的89篇隨機試驗,初級結果是疼痛強度,次級結果是物理性功能,預先設定之最小臨床重要性差異的效益大小為-0.37。
  
  研究者發現,對於有症狀的膝蓋OA病患,粘稠補充療法對疼痛和功能的效益分別是相當小(疼痛)與無效(功能性)。
  
  接受注射後24至72小時內,注射膝蓋症狀惡化是主要的安全性結果;次級安全性結果是嚴重副作用、因為副作用而停止或退出、整體的副作用、注射之膝蓋的滲出、注射之膝蓋的局部副作用,中止或退出(不論任何原因)。
  
  這89篇試驗包括了12,667名病患,其中68篇試驗有安慰劑對照組,40篇的追蹤期大於3個月。
  
  Rutjes博士寫道,整體而言,71篇試驗(9,617名病患)顯示粘稠補充療法可適度緩解疼痛(效益大小-0.37 [95%信心區間-0.46至-0.28])。各試驗之間有重要的異質性,且呈現不對稱漏斗圖:試驗大小、雙盲結果評估、出版狀態與相關效益大小。回顧者也發現5篇未發表的試驗(1,149名病患),顯示的效益大小為-0.03 (CI,-0.14至0.09)。
  
  作者們寫道,有關未發表試驗之資料,我們確認了6篇未發表的試驗,其中5篇有分析疼痛、共1,149名病患,總病患數的12%納入疼痛結果統合分析。我們無法揭露其中3篇的詳細結果,但是匯整這5篇未發表試驗之後可提出總結為:效益大小為-0.03且T2值為0.00。從倫理和科學的角度來看,這類發表偏差是令人不安、不可接受的。
  
  作者們寫道,探討18篇(5,094名病患)進行雙盲結果分析的大型試驗顯示,臨床無關的疼痛效益大小為-0.11 (CI,-0.18至-0.04)。
  
  回顧者也發現,粘稠補充療法和惡化風險增加有關,但未達統計上的顯著意義,嚴重副作用風險則是顯著增加(相關風險1.41;CI,1.02 - 1.97)。最常見的副作用是胃腸道、心血管、癌症、肌肉骨骼方面。
  
  作者們結論表示,因為嚴重副作用和局部副作用的風險增加,不鼓勵給予這些製劑。
  
  髖骨與膝蓋OA處置之2009年版OARSI建議的第一作者Weiya Zhang醫師表示,這是篇相當好的報告,總結了目前關節腔內注射玻尿酸(IAHA)治療膝蓋OA的研究證據,包括了一些未出版的資料;研究結果顯示,IAHA對於安慰劑或未治療的對照組有一些邊際效益,可能有害IAHA,可能會誘發急性關節惡化。希望讀者記住的是,IAHA不如我們所想的有效,安全性也尚未確認。
  
  不過,Zhang醫師指出,使用IAHA於OA治療依賴個別病患的特徵與治療反應,隨機控制試驗只探討治療的平均價值,通常無法一般化到每個病患。
  
  資料來源: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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