Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis - The CLASS study: A randomized controlled trial
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis - The CLASS study: A randomized controlled trial
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DOI：
10.1001/jama.284.10.1247
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发表时间：
2000-09-13
影响因子：
120.7
通讯作者：
Geis, GS
中科院分区：
文献类型：
--
作者：
Silverstein, FE;Faich, G;Geis, GS
传统的非甾体抗炎药（NSAIDs）由于抑制环氧化酶(COX)-1而具有一系列毒性作用，特别是胃肠道（GI）效应。cox -2特异性抑制剂是否与较少的临床胃肠道毒性作用相关尚不清楚。目的探讨cox -2特异性抑制剂塞来昔布与常规非甾体抗炎药相比，是否具有较低的上消化道毒性反应和其他不良反应发生率。塞来昔布长期关节炎安全性研究（CLASS）是一项双盲、随机对照试验，于1998年9月至2000年3月进行。在美国和加拿大设立了386个临床站点。共有8059例（大于或等于18岁）骨关节炎（OA）或类风湿性关节炎（RA）患者入组研究，其中7968例接受了至少1剂量的研究药物。总共4573例（57%）患者接受了6个月的治疗。患者被随机分配接受塞来昔布，400mg，每天2次（分别是RA和OA最大剂量的2倍和4倍；n = 3987）；布洛芬，800毫克，每天3次（n = 1985）；或双氯芬酸，75毫克，每天两次（n = 1996）。阿司匹林用于心血管预防（小于或等于325毫克/天）是允许的。在6个月的治疗期间，前瞻性定义的症状性上消化道溃疡和溃疡并发症（出血、穿孔和梗阻）及其他不良反应的发生率。结果在所有患者中，塞来昔布与非甾体抗炎药单独治疗和合并症状性溃疡的年化上消化道溃疡并发症发生率分别为0.76%对1.45% （P = 0.09）和2.08%对3.54% （P = 0.02）。对于未服用阿司匹林的患者，塞来昔布与非甾体抗炎药单独和合并症状性溃疡的年化上消化道溃疡并发症发生率分别为0.44%对1.27% （P = 0.04）和1.40%对2.91% （P = 0.02）。对于服用阿司匹林的患者，塞来昔布与非甾体抗炎药单独使用和合并症状性溃疡的年化上消化道溃疡并发症发生率分别为2.01%对2.12% （P = 0.92）和4.70%对6.00% （P = 0.49）。塞来昔布治疗的患者比非甾体抗炎药治疗的患者更少出现慢性胃肠道出血、胃肠道不耐受、肝毒性或肾毒性。无论是否使用阿司匹林，塞来昔布和非甾体抗炎药的心血管事件发生率均无差异。在本研究中，与标准剂量的非甾体抗炎药相比，塞来昔布在大于临床指征剂量时，与较低的症状性溃疡和溃疡并发症发生率以及其他临床重要毒性作用相关。在未同时服用阿司匹林的患者中，上消化道毒性的降低最为明显。
Context Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown.Objective To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.Design The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.Setting Three hundred eighty-six clinical sites in the United States and Canada.Participants A total of 8059 patients (greater than or equal to 18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months.Interventions Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (less than or equal to 325 mg/d) was permitted.Main Outcome Measures Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period.Results For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P = .04) and 1.40% vs 2.91% (P = .02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use.Conclusions In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly.