Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial
Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial
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DOI：
10.1016/s0140-6736(17)30981-9
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发表时间：
2017-06-17
期刊：
影响因子：
168.9
通讯作者：
Kyaw, Moe H.
中科院分区：
文献类型：
--
作者：
Chan, Francis K. L.;Ching, Jessica Y. L.;Kyaw, Moe H.
背景目前的指南对于心血管和胃肠道事件的高危患者来说是相互矛盾的，这些患者仍然需要非类固醇抗炎药(NSAIDs)。我们假设环氧合酶-2选择性非甾体抗炎药加质子泵抑制剂在预防伴随有溃疡出血的阿司匹林使用者复发性溃疡出血方面优于非选择性非选择性非甾体抗炎药加质子泵抑制剂。方法在香港一家学术医院进行的这项独立于行业的、双盲、双模拟、随机试验，我们筛查了出现上消化道出血、服用非类固醇抗炎药并需要联合阿司匹林的关节炎和心血栓疾病患者。溃疡愈合后，一名独立工作人员随机分配(1：1)幽门螺杆菌阴性的患者，并通过计算机生成的随机数字列表接受口服塞来昔布100毫克/天2次+埃索美拉唑20 mg/天或萘普生500 mg/天2次+埃索美拉唑20 mg/天，为期18个月。所有患者恢复服用阿司匹林80 mg，每天一次。患者和调查人员都对他们的治疗戴上了面具。主要终点是18个月内反复上消化道出血。对改良意向治疗人群中的主要终点和次要安全终点进行了分析。这项研究已在临床试验中注册。GOV，编号NCT00153660。2005年5月24日至2012年11月28日，我们招募了514名患者，将257名患者分配到每个研究组，所有患者都包括在意向治疗人群中。塞来昔布组上消化道再出血14例(胃溃疡9例，十二指肠溃疡5例)，萘普生组31例(胃溃疡25例，十二指肠溃疡3例，胃溃疡和十二指肠溃疡1例，出血糜烂2例)。18个月内塞来昔布组和萘普生组的累积再出血发生率分别为5.6%(95%CI3.3~9.2)和12.3%(8.8~17.1)(p=0.008；粗风险比0.44，95%CI0.23~0.82；p=0.010)。不包括到达研究终点的患者，塞来昔布组有21名患者(8%)和萘普生组的17名患者(7%)发生了导致停止治疗的不良事件。研究期间没有发生与治疗相关的死亡。对于心血管和胃肠道事件的高危患者，需要同时服用阿司匹林和非甾体抗炎药，塞来昔布加质子泵抑制剂是降低上消化道复发出血风险的首选治疗方法。尽管人们认为萘普生对心血管安全，但仍应避免使用。
Background Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding.Methods For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1: 1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials. gov, number NCT00153660.Findings Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5.6% (95% CI 3.3-9.2) in the celecoxib group and 12.3% (8.8-17.1) in the naproxen group (p=0.008; crude hazard ratio 0.44, 95% CI 0.23-0.82; p= 0.010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study.Interpretation In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety.Funding The Research Grant Council of Hong Kong.