Discontinuing NSAIDs in Veterans with Knee Osteoarthritis

描述（由申请人提供）： 膝关节骨关节炎（OA）是退伍军人残疾的主要原因，也是VA膝关节置换术的主要适应症。非甾体类抗炎药（NSAID）是膝关节OA最常用的处方药。虽然短期研究表明NSAID比安慰剂和对乙酰氨基酚更有效，但没有长期数据支持其使用。这是值得关注的，因为长期使用NSAID与显著的发病率和死亡率相关。已经发布了指南以提高NSAID的安全使用;然而，VA对这些循证建议的依从性较低。因此，迫切需要确定长期使用非甾体抗炎药是否比更安全的替代品提供任何增量益处。对于退伍军人来说尤其如此， 非甾体类抗炎药诱发毒性的高风险。认知行为疗法（CBT）是OA的一种有效且安全的治疗选择。这种方式在VA中越来越多地用于治疗慢性疼痛以及其他慢性疾病，如抑郁症，创伤后应激障碍和失眠症。CBT可以通过电话成功管理，因此有利于生活在偏远地区的退伍军人，他们无法进入医院或社区门诊诊所。在这项研究中，我们计划进行一项2期随机退出试验（RWT）。该试验将重点招募使用NSAID至少3个月的膝关节OA退伍军人。在研究的第一阶段，544名患有膝关节OA的退伍军人将被随机分配继续接受NSAID或安慰剂治疗4周。这个双盲阶段将使我们能够推断安慰剂是否非劣效于持续使用NSAID。在第二阶段，NSAID组的受试者将继续使用NSAID，安慰剂组的受试者将停止服用安慰剂并参加为期12周的CBT计划。第二阶段是单盲阶段，将使我们能够推断CBT是否非劣于NSAID。所有研究数据将通过电话收集，从而使退伍军人谁有困难安排交通到VA参与。我们将在第4周和第16周使用经过充分验证的西安大略和麦克马斯特大学骨关节炎指数（主要结局）测量膝关节疼痛，以检验组间差异。我们还将检验下肢残疾、受试者对变化的总体印象和联合治疗的使用（次要结局）的组间差异。根据非劣效性试验的建议，我们将进行意向治疗和符合方案分析。最后，我们将评估CBT方案与持续使用NSAID相比的潜在成本效益。尽管随机分配至活性研究药物组的受试者继续接受当前NSAID治疗是理想的，但不可能让VA药房配制多种不同的活性药物并保持盲态。因此，我们将纳入2周导入期，研究受试者将用美洛昔康替代NSAID。选择美洛昔康作为研究药物，因为它是我们中心最常用的处方药，并且与其他NSAID相比具有良好的安全性。如果成功，该试验将提高因OA导致慢性膝关节疼痛的退伍军人的护理质量。拟议的策略特别有吸引力，因为它用更安全的替代品取代了广泛使用的NSAID，能够为获得有限服务的退伍军人提供护理，并且可能节省成本。

DESCRIPTION (provided by applicant): Knee osteoarthritis (OA) is a major cause of disability among Veterans and is the primary indication of knee replacement in the VA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for knee OA. Though short-term studies have demonstrated that NSAIDs are more effective than placebo and acetaminophen, there are no long-term data supporting their use. This is of concern, because long-term use of NSAIDs is associated with significant morbidity and mortality. Guidelines have been published to improve safe use of NSAIDs; however, adherence to these evidence-based recommendations is low in the VA. There is therefore an important need to determine if the long-term use of NSAIDs offers any incremental benefit over safer alternatives. This is especially true for Veterans, a population at high risk for NSAID-induced toxicity. Cognitive behavioral therapy (CBT) is an effective and safe treatment alternative for OA. This modality is becoming increasingly available in the VA for treatment of chronic pain as well as other chronic disorders such as depression, post-traumatic stress disorder and insomnia. CBT can be successfully administered over the telephone and thus stands to benefit Veterans living in more remote areas with limited access to hospital or community-based outpatient clinics. In this study, we propose to conduct a 2-phase randomized withdrawal trial (RWT). The trial will focus on recruiting Veterans with knee OA who have been using NSAIDs for at least 3 months. In the first phase of the study, 544 Veterans with knee OA will be randomized to continue NSAIDs or to placebo for 4 weeks. This double-blind phase will enable us to infer whether placebo is non-inferior to continued NSAID use. In the second phase, subjects in the NSAIDs group will continue NSAIDs and those on placebo will stop taking the placebo and participate in a 12-week CBT program. The second, single-blind, phase will allow us to infer whether CBT is non-inferior to NSAIDs. All study data will be collected over the telephone thus enabling Veterans who have difficulty arranging transportation to the VA to participate. We will test for between-group differences in knee pain measured using the well-validated Western Ontario and McMaster Universities Osteoarthritis Index (primary outcome) at 4 and 16 weeks. We will also test for between group differences in lower extremity disability, subjects' global impression of change and use of co- therapies (secondary outcomes). As recommended for non-inferiority trials, we will perform both an intent to treat and per protocol analysis. Lastly, we will estimate the potential cost-effectiveness of the CBT protocol compared with continued NSAID use. Though it would be ideal for subjects randomized to the active study drug to continue their current NSAID, having the VA pharmacy formulate multiple different active drugs and maintaining the blind is not possible. Therefore, we will include a 2-week run-in period where study subjects will replace their NSAID with meloxicam. Meloxicam was chosen as the study drug because it is the most commonly prescribed at our center and has a favorable safety profile compared to other NSAIDS. If successful, the trial will improve the quality of care delivered to Veterans with chronic knee pain due to OA. The proposed strategy is particularly appealing because it replaces the widespread use of NSAIDs with a safer alternative, enables delivery of care to Veterans with limited access, and is likely to be cost saving.