以整合分析探討退化性膝關節炎施打玻尿酸關節注射製劑與 傳統口服消炎止痛藥的成本效果分析

The cost-effectiveness analysis of hyaluronic acid and traditional oral anti-inflammatory drugs to osteoarthritis knee-use Meta-analysis method

韋有升(Yeou-Sheng Wei)

指導教授 ： 馬可容

高雄醫學大學/健康科學院/醫務管理學研究所碩士在職專班/碩士(2009年)

摘要

退化性關節炎是關節炎中盛行率最高且是人類疾病及失能最常見之原因，
在美國退化性關節炎是僅次於缺血性心臟病造成五十歲以上男性工作失能之原因。以玻尿酸關節注射製劑治療退化性關節炎，這一項新的或有爭議的治療方式， 醫療照護提供者，常會提出治療方式的適當性、有效性、及安全性予以評估。同樣的，臨床醫師，也必須考慮如上之問題，才能提供患者一適當、有效、及安全的治療方式。
研究目的：一 、探討玻尿酸關節注射製劑對膝退化性關節炎治療之療效(成效值)與安全性。二 、與傳統口服止痛消炎藥比較，玻尿酸關節注射劑之療效(成效值)與安全性是否較佳。三 、玻尿酸關節注射製劑在療效、 安全性、 費用三者考量下，是否能列入傳統膝退化性關節炎治療的標準治療指引。四 、依據上述目的結果，對現行給付治療規則，提出適宜的建議。
研究方法：透過電腦網路搜尋國內外相關文獻網站，依布林邏輯，將關鍵字分為兩組，分開搜尋： 第一組是：Hyaluronic acid AND Osteoarthritis knee AND Randomized controlled trial (RCT)。第二組是：Naproxen AND Osteoarthritis knee AND RCT。文獻納入標準：1 、針對人類所做之研究、且以英文發表者。2 、採取隨機分配、雙盲測試者。3 、有與安慰劑比較、及前後測者。4 、有足夠資料、可做成效值計算者。選擇以Visual Analogue Scale (VAS)及 Western Ontario and McMaster Universities(WOMAC) Osteoarthritis Index所得之結果，分別將治療組、與控制組之人數、 平均值、 及 標準差等變項，輸入NCSS軟體， 以進行統計分析，結果包括平均值的整合分析 、成效值計算、 異質性測試及森林圖的顯示。

研究結果：一、 納入標準之樣本： HA組11篇，N組6篇，總共17篇。另一方面要說明:HA組有9篇，N組有7篇，是因結果以趨勢圖呈現， 缺乏足夠數據納入分析，而遭排除， 非因文獻品質因素。二、玻尿酸關節注射製劑對退化性膝關節炎治療三個月追蹤：成效值平均為成效值平均為-14.0393，範圍自 -14.4776 至 -13.6011 之間，顯示玻尿酸製劑對退化性膝關節炎治療在三個月追蹤時有療效，且有明顯療效結果之一致性。三、玻尿酸關節注射劑製劑對退化性膝關節炎治療六個月追蹤：成效值平均為 -1.8856 ， 範圍自 -2.9893 至 -0.7819 之間，顯示玻尿酸關節注射劑製劑對退化性膝關節炎治療在六個月追蹤時仍有療效， 且有療效結果之一致性。而與三個月追蹤之平均成效值-14.0393 比較， 六個月追蹤之療效，明顯降低許多， 顯示玻尿酸關節注射劑製劑對退化性膝關節炎治療療效， 可能無法維持六個月之久。 四、非類固醇消炎止痛藥(Naproxen)對退化性膝關節炎治療二週時： 成效值平均為-4.1732， 範圍自 -4.6399 至 -3.7065之間， 顯示非類固醇消炎止痛藥對退化性膝關節炎治療，在二週追蹤時有療效， 且有療效結果之一致性。五、非類固醇消炎止痛藥對退化性膝關節炎治療十二週時：成效值平均為-4.3998， 範圍自 -4.8883 至 -3.9113 之間， 顯示非類固醇消炎止痛藥對退化性膝關節炎治療在十二週追蹤時有療效， 且有療效結果之一致性。而與二週追蹤時之平均成效值-4.1732比較，十二週追蹤之療效，是相當且稍微高的。六、安全性：在HA組， 顯示極少副作用， 安全性極高， 僅有少數局部注射部位疼痛感， 疼痛程度輕， 多數不必治療且無後遺症。至於N組， 副作用多為腸胃道之問題， 比率佔副作用發生率之20%至45% 之間， 這亦是退出研究的主要原因。
結論和建議：一、目前健保局對玻尿酸關節注射製劑，治療膝退化性關節炎的使用適應症，在兼顧病人安全與醫療品質的前提下，若要提昇玻尿酸關節注射製劑治療膝退化性關節炎的有效率，是否應考慮定訂明確疾病等級。二、以玻尿酸關節注射製劑治療膝退化性關節炎之療效，在各別研究報告雖然有被高估之現象。但在療效與安全性雙重考量下，在某些選擇性患者長期使用時，較傳統非類固醇消炎藥有優勢，若費用再有誘因，應更具有競爭力。三、對目前使用玻尿酸關節注射製劑之療程，每年僅有兩個療程，且要間隔半年，一般療效結果要持續至半年之療效結果較不穩定，以目前使用方式，似乎應搜集更多臨床證據予以適當調整，方能維持玻尿酸關節注射製劑治療膝退化性關節炎的適當療效。四、臨床醫師在治療膝退化性關節炎患者時，建議以美國廔痲學院之治療指引為基準，依據不同患者不同狀況(適應症) ，適當選擇適宜之治療方式。 五、臨床醫師看整合分析之結果，要依據利益(benefits)高於危害(risk)及費用(cost)之比重， 同時也要決定如何用、及何時用玻尿酸關節注射製劑，做為整體退化性關節炎醫療中的治療替代方案。

關鍵字

玻尿酸關節注射劑製劑 ； 退化性膝關節炎 ； 非類固醇消炎止痛藥 ； 隨機控制試驗 ； 整合分析 ； 視覺類比量表 ； 加拿大西安大略和麥克馬斯特大學關節炎量表

並列摘要

osteoarthritis arthritis is the highest prevalence of arthritis and in human disease and disability of the most common reasons. osteoarthritis arthritis in the United States is second only to ischemic heart disease caused more than 50-year-old male of the reasons for work disability. Intra-articular injection of hyaluronic acid preparations in the treatment of osteoarthritis knee, which a new or controversial treatments. Medical care providers often raise the appropriateness of treatment, effectiveness, and safety be assessed. Similarly, clinicians must also consider the above issues, can provide patients with an appropriate, effective, and safe treatment.
Purposes: 1), to explore intra-articular hyaluronic acid preparation on the treatment of knee osteoarthritis efficacy (effect size) and safety. 2), with the traditional anti-inflammatory drugs oral analgesics compared with intra-articular hyaluronic acid efficacy and safety is better. 3), intra-articular hyaluronic acid preparation in the efficacy, safety, cost of the three issues under consideration, whether the inclusion of the traditional treatment of knee osteoarthritis of the standard treatment guidelines. 4), based on the results of the above-mentioned purposes, the treatment of the existing benefit rules, make appropriate recommendations.
Methods: through the computer network abroad literature search sites, according to Boolean logic, keywords Hyaluronic acid, Naproxen, Osteoarthritis knee and RCT were divided into two groups, separated from the search: the first group is: Hyaluronic acid AND Osteoarthritis knee AND RCT. The second group is: Naproxen AND Osteoarthritis knee AND RCT. Literature inclusion criteria: 1), the research done for human beings, and those published in English. 2), taken randomly assigned, double-blind design. 3), compared with placebo, and those before and after the test. 4), there is sufficient information on the effectiveness of value can be calculated. VAS and WOMAC osteoarthritis index choose from the results of the treatment group, respectively, with the number of the control group-Treatment N Variables & Control N Variables, average-Treatment Mean Variables & Control Mean Variables, and standard deviation -Treatment SD Variables & Control SD Variables and other variables, enter the NCSS software for statistical analysis, the results of the meta-analysis including the average of Meta-Analysis of Means, the value of Treatment Effects, the Effect-Equality (Heterogeneity) Test and the Forest Plot display.

Results: 1), the inclusion samples: HA Group 11, N group 6, a total of 17. On the other hand must make it clear: HA Group 9, N group 7, is the result of a trend showing a lack of sufficient data into the analysis, were excluded, non-quality factors from the literature. 2), HA Group (3-months ): the average value of the effect size is -14.0393, ranging from -14.4776 to -13.6011, indicating the prominent effect of hyaluronic acid on the treatment of knee osteoarthritis , and there is clear consistency of efficacy results. 3), HA Group (6-months ): the average value of the effect size is -1.8856, ranging from -2.9893 to -0.7819 ,showed minimal treatment effect in six months interval. With an average of three months to track the effectiveness of the value of -14.0393 comparison, the six-month follow-up of efficacy, significantly reduced much, it’s mean that treatment effect of hyaluronic acid on osteoarthritis knee, may not be able to maintain as long as six months. 4), N group for the treatment of osteoarthritis knee at two weeks: the average value of effect size is -4.1732, ranging from -4.6399 to -3.7065 , show non-steroidal anti-inflammatory drugs for osteoarthritis knee treatment, follow-up two weeks in effect from time to time, and the consistency of efficacy results. 5), N group for the treatment of osteoarthritis knee at 12 weeks: the average value of effect size is -4.3998, ranging from -4.8883 to -3.9113 , show non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis knee in 12 weeks follow-up effect from time to time, and the consistency of efficacy results. compared with 2 weeks follow-up of efficacy , 12 weeks follow-up of efficacy is a little high. 6), security: In the HA group showed very few side effects, only a small number of local injection site pain, most do not have treatment and without sequelae. As regards the N group, mostly gastrointestinal side effects of the problem, the ratio of the incidence of side effects accounted for 20-45% between, and this is the main reason to withdraw from the study.
Conclusions and recommendations: 1), National Health Insurance Bureau set criteria of intra-articular hyaluronic acid preparations to treatment of knee osteoarthritis in the use of indications, in both patient safety and quality of medical care under the premise of intra-articular hyaluronic acid to enhance the preparation knee osteoarthritis treatment efficient, should the Government consider setting out a clear hierarchy of disease. 2), intra-articular hyaluronic acid preparations in treatment of knee osteoarthritis efficacy, although in individual studies of the phenomenon have been overestimated. However, the efficacy and safety considerations, in some patients with long-term use of selective than the traditional non-steroidal anti-inflammatory drugs have an advantage, if the cost of further incentives should be more competitive. 3),the use of hyaluronic acid on articular injection of treatment agents, only two courses each year, and the interval to six months, the general effect of the results of six months to continue to effect the outcome of the more volatile, with the present use, it seems to be gathering more appropriate clinical evidence adjustment can only be sustained if agents treatment of hyaluronic acid injections knee joint osteoarthritis of appropriate efficacy. 4), physicians in the treatment of patients with knee osteoarthritis, it is recommended to the United States Institute of ACR treatment guidelines based on different patients according to different conditions (indications), the appropriate choice of appropriate treatment. 5), physicians look at the results of meta-analysis, it is necessary to hyaluronic acid how agents can be used in patients, may be based on benefits higher than the risk and cost of the proportion, but also to decide how to use and when joint injections with hyaluronic acid preparations, the overall knee osteoarthritis as a medical treatment alternatives.

並列關鍵字

hyaluroinc acid ； non-steroidal anti-inflammatory drugs(NSAID) ； osteoarthritis knee ； randomized controlled trial (RCT) ； meta-analysis ； VAS ； WOMAC

參考文獻

一、納入整合分析之文獻

1. Dougados M, Nguyen M, Listrat V, Amor B. High molecular weight sodium hyaluronate(hyalectin)in osteoarthritis of the knee :a 1 year placebo-controlled trial. Osteoarthritis Cartilage.1993 Apr;1(2):97-103.

2. Henderson EB, Smith EC, Pegley F, Blake DR. Intra-articular injection of 750kD hyaluronan in the treatment of osteoarthritis:a randomized single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy. Ann Rheum Dis.1994 Aug;53(8):529-34.

3. Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford).1999 Jul;38(7):602-7.

4. Karlsson J, Sjogren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patient with knee osteoarthritis. A controlled,randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford). 2002 Nov;41(11):1240-8.