Puljak Livia, Marin Ana, Vrdoljak Davorka, Markotic Filipa, Utrobicic Ana, Tugwell Peter
Cochrane Croatia, University of Split School of Medicine, Soltanska 2, Split, Croatia, 21000.
Cochrane Croatia, Split, Croatia.
Cochrane Database Syst Rev. 2017 May 22;5(5):CD009865. doi: 10.1002/14651858.CD009865.pub2.
Osteoarthritis (OA) is the most common form of arthritis and is caused by degeneration of the joint cartilage and growth of new bone, cartilage and connective tissue. It is often associated with major disability and impaired quality of life. There is currently no consensus on the best treatment to improve OA symptoms. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID).
To assess the clinical benefits (pain, function, quality of life) and safety (withdrawals due to adverse effects, serious adverse effects, overall discontinuation rates) of celecoxib in osteoarthritis (OA).
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trials registers up to April 11, 2017, as well as reference and citation lists of included studies. Pharmaceutical companies and authors of published articles were contacted.
We included published studies (full reports in a peer reviewed journal) of prospective randomized controlled trials (RCTs) that compared oral celecoxib versus no intervention, placebo or another traditional NSAID (tNSAID) in participants with clinically- or radiologically-confirmed primary OA of the knee or hip, or both knee and hip.
Two authors independently performed data extraction, quality assessment, and compared results. Main analyses for patient-reported outcomes of pain and physical function were conducted on studies with low risk of bias for sequence generation, allocation concealment and blinding of participants and personnel.
We included 36 trials that provided data for 17,206 adults: 9402 participants received celecoxib 200 mg/day, and 7804 were assigned to receive either tNSAIDs (N = 1869) or placebo (N = 5935). Celecoxib was compared with placebo (32 trials), naproxen (6 trials) and diclofenac (3 trials). Studies were published between 1999 and 2014. Studies included participants with knee, hip or both knee and hip OA; mean OA duration was 7.9 years. Most studies included predominantly white participants whose mean age was 62 (± 10) years; most participants were women. There were no concerns about risk of bias for performance and detection bias, but selection bias was poorly reported in most trials. Most trials had high attrition bias, and there was evidence of selective reporting in a third of the studies. Celecoxib versus placeboCompared with placebo celecoxib slightly reduced pain on a 500-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale, accounting for 3% absolute improvement (95% CI 2% to 5% improvement) or 12% relative improvement (95% CI 7% to 18% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).Compared with placebo celecoxib slightly improved physical function on a 1700-point WOMAC scale, accounting for 4% absolute improvement (95% CI 2% to 6% improvement), 12% relative improvement (95% CI 5% to 19% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).There was no evidence of an important difference for withdrawals due to adverse events (Peto OR 0.99, 95% CI 0.85 to 1.15) (moderate quality evidence due to study limitations).Results were inconclusive for numbers of participants experiencing any serious AEs (SAEs) (Peto OR 0.95, 95% CI 0.66 to 1.36), gastro-intestinal events (Peto OR 1.91, 95% CI 0.24 to 14.90) and cardiovascular events (Peto OR 3.40, 95% CI 0.73 to 15.88) (very low quality evidence due to serious imprecision and study limitations). However, regulatory agencies have warned of increased cardiovascular events for celecoxib. Celecoxib versus tNSAIDsThere were inconclusive results regarding the effect on pain between celecoxib and tNSAIDs on a 100-point visual analogue scale (VAS), showing 5% absolute improvement (95% CI 11% improvement to 2% worse), 11% relative improvement (95% CI 26% improvement to 4% worse) (2 studies, 1180 participants, moderate quality evidence due to publication bias).Compared to a tNSAID celecoxib slightly improved physical function on a 100-point WOMAC scale, showing 6% absolute improvement (95% CI 6% to 11% improvement) and 16% relative improvement (95% CI 2% to 30% improvement). This improvement may not be clinically significant (low quality evidence due to missing data and few participants) (1 study, 264 participants).Based on low or very low quality evidence (downgraded due to missing data, high risk of bias, few events and wide confidence intervals) results were inconclusive for withdrawals due to AEs (Peto OR 0.97, 95% CI 0.74 to 1.27), number of participants experiencing SAEs (Peto OR 0.92, 95% CI 0.66 to 1.28), gastro-intestinal events (Peto OR 0.61, 0.15 to 2.43) and cardiovascular events (Peto OR 0.47, 95% CI 0.17 to 1.25).In comparisons of celecoxib and placebo there were no differences in pooled analyses between our main analysis with low risk of bias and all eligible studies. In comparisons of celecoxib and tNSAIDs, only one outcome showed a difference between studies at low risk of bias and all eligible studies: physical function (6% absolute improvement in low risk of bias, no difference in all eligible studies).No studies included in the main comparisons measured quality of life. Of 36 studies, 34 reported funding by drug manufacturers and in 34 studies one or more study authors were employees of the sponsor.
AUTHORS' CONCLUSIONS: We are highly reserved about results due to pharmaceutical industry involvement and limited data. We were unable to obtain data from three studies, which included 15,539 participants, and classified as awaiting assessment. Current evidence indicates that celecoxib is slightly better than placebo and some tNSAIDs in reducing pain and improving physical function. We are uncertain if harms differ among celecoxib and placebo or tNSAIDs due to risk of bias, low quality evidence for many outcomes, and that some study authors and Pfizer declined to provide data from completed studies with large numbers of participants. To fill the evidence gap, we need to access existing data and new, independent clinical trials to investigate benefits and harms of celecoxib versus tNSAIDs for people with osteoarthritis, with longer follow-up and more direct head-to-head comparisons with other tNSAIDs.
骨关节炎（OA）是最常见的关节炎形式，由关节软骨退变以及新骨、软骨和结缔组织生长所致。它常导致严重残疾和生活质量受损。目前对于改善OA症状的最佳治疗方法尚无共识。塞来昔布是一种选择性非甾体抗炎药（NSAID）。
评估塞来昔布治疗骨关节炎（OA）的临床益处（疼痛、功能、生活质量）和安全性（因不良反应停药、严重不良反应、总体停药率）。
我们检索了截至2017年4月11日的Cochrane对照试验中央登记库（CENTRAL）、MEDLINE、Embase及临床试验注册库，以及纳入研究的参考文献和引用列表。我们还联系了制药公司和已发表文章的作者。
我们纳入已发表的前瞻性随机对照试验（RCT）研究（同行评审期刊中的完整报告），这些研究比较了口服塞来昔布与未干预、安慰剂或另一种传统NSAID（tNSAID），参与者为临床或放射学确诊的膝关节或髋关节原发性OA，或膝关节和髋关节均受累。
两位作者独立进行数据提取、质量评估并比较结果。对疼痛和身体功能等患者报告结局的主要分析是在序列生成、分配隐藏以及参与者和研究人员设盲方面偏倚风险较低的研究中进行的。
我们纳入了36项试验，为17206名成年人提供了数据：9402名参与者接受每日200mg塞来昔布治疗，7804名被分配接受tNSAIDs（n = 1869）或安慰剂（n = 5935）治疗。塞来昔布与安慰剂（32项试验）、萘普生（6项试验）和双氯芬酸（3项试验）进行了比较。研究发表于1999年至2014年之间。研究纳入了膝关节、髋关节或膝关节和髋关节均受累的OA患者；平均OA病程为7.9年。大多数研究主要纳入白人参与者，平均年龄为62（±10）岁；大多数参与者为女性。对于实施和检测偏倚的风险没有担忧，但大多数试验中选择偏倚的报告较差。大多数试验存在较高的失访偏倚，并且有三分之一的研究存在选择性报告的证据。
与安慰剂相比，塞来昔布在500分的西安大略和麦克马斯特大学关节炎指数（WOMAC）疼痛量表上使疼痛略有减轻，绝对改善率为3%（95%CI 2%至5%改善）或相对改善率为12%（95%CI 7%至18%改善）（4项研究，1622名参与者）。这种改善可能无临床意义（高质量证据）。与安慰剂相比，塞来昔布在1700分的WOMAC量表上使身体功能略有改善，绝对改善率为4%（95%CI 2%至6%改善），相对改善率为12%（95%CI 5%至19%改善）（4项研究，1622名参与者）。这种改善可能无临床意义（高质量证据）。没有证据表明因不良事件导致的停药存在重要差异（Peto比值比0.99，95%CI 0.85至1.15）（由于研究局限性，为中等质量证据）。对于发生任何严重不良事件（SAEs）的参与者数量（Peto比值比0.95，95%CI 0.66至1.36）、胃肠道事件（Peto比值比1.91，95%CI 0.24至14.90）和心血管事件（Peto比值比3.40，95%CI 0.73至15.88），结果尚无定论（由于严重不精确性和研究局限性，为极低质量证据）。然而，监管机构已就塞来昔布心血管事件增加发出警告。
塞来昔布与tNSAIDs比较：在100分的视觉模拟量表（VAS）上，塞来昔布与tNSAIDs对疼痛的影响结果尚无定论，绝对改善率为5%（95%CI改善11%至恶化2%），相对改善率为11%（95%CI改善26%至恶化4%）（2项研究，1180名参与者，由于发表偏倚，为中等质量证据）。与tNSAIDs相比，塞来昔布在100分的WOMAC量表上使身体功能略有改善，绝对改善率为6%（95%CI 6%至11%改善），相对改善率为16%（95%CI 2%至30%改善）。这种改善可能无临床意义（由于数据缺失和参与者较少，为低质量证据）（1项研究，264名参与者）。基于低质量或极低质量证据（因数据缺失、偏倚风险高、事件数量少和置信区间宽而降级），因不良事件导致的停药（Peto比值比0.97，95%CI 0.74至1.27）、发生SAEs的参与者数量（Peto比值比0.92，95%CI 0.66至1.28）、胃肠道事件（Peto比值比0.61，0.15至2.43）和心血管事件（Peto比值比0.47，95%CI 0.17至1.25）的结果尚无定论。在塞来昔布与安慰剂的比较中，我们主要分析（偏倚风险低）与所有符合条件的研究的汇总分析之间没有差异。在塞来昔布与tNSAIDs的比较中，只有一个结局在偏倚风险低的研究与所有符合条件的研究之间存在差异：身体功能（偏倚风险低时绝对改善率为6%，所有符合条件的研究中无差异）。主要比较中没有研究测量生活质量。在36项研究中，34项报告了药物制造商的资助，在34项研究中，一名或多名研究作者是赞助商的员工。
由于制药行业的参与和数据有限，我们对结果持高度保留态度。我们无法从三项研究中获取数据，这三项研究包括15539名参与者，被归类为等待评估。当前证据表明，塞来昔布在减轻疼痛和改善身体功能方面略优于安慰剂和一些tNSAIDs。由于偏倚风险、许多结局的低质量证据，以及一些研究作者和辉瑞公司拒绝提供大量参与者的完整研究数据，我们不确定塞来昔布与安慰剂或tNSAIDs之间的危害是否存在差异。为填补证据空白，我们需要获取现有数据并开展新的独立临床试验，以研究塞来昔布与tNSAIDs对骨关节炎患者的益处和危害，进行更长时间的随访，并与其他tNSAIDs进行更直接的头对头比较。
