Discontinuing NSAIDs in Veterans with Knee Osteoarthritis

描述(由申请人提供)： 膝关节骨关节炎是退伍军人致残的主要原因，也是退伍军人膝关节置换术的主要适应症。非类固醇抗炎药(NSAIDs)是膝骨性关节炎最常用的处方药。尽管短期研究表明非甾体抗炎药比安慰剂和对乙酰氨基酚更有效，但没有长期数据支持它们的使用。这一点令人担忧，因为长期使用非类固醇抗炎药与显著的发病率和死亡率有关。已经公布了改善非类固醇抗炎药安全使用的指南；然而，退伍军人管理局对这些循证建议的遵守程度很低。因此，有必要确定长期使用非类固醇抗炎药是否比更安全的替代品提供任何递增的益处。对于退伍军人来说尤其如此，这是一个人口 具有非甾体抗炎药引起的毒性的高风险。认知行为疗法(CBT)是治疗骨性关节炎的一种安全有效的治疗方法。在退伍军人管理局，这种模式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。CBT可以通过电话成功实施，因此将使生活在更偏远地区的退伍军人受益，他们去医院或社区门诊的机会有限。在这项研究中，我们建议进行两阶段随机戒断试验(RWT)。这项试验的重点将是招募患有膝骨性关节炎的退伍军人，他们已经使用非类固醇抗炎药至少3个月。在研究的第一阶段，544名患有膝骨性关节炎的退伍军人将被随机分为继续服用非类固醇抗炎药或服用安慰剂4周。这一双盲阶段将使我们能够推断安慰剂是否不逊于继续使用非甾体抗炎药。在第二阶段，NSAIDs组的受试者将继续服用NSAIDs，而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，单盲，将使我们能够推断CBT是否不逊于非类固醇抗炎药。所有研究数据将通过电话收集，从而使难以安排交通工具前往退伍军人管理局的退伍军人能够参加。我们将在第4周和第16周使用经过充分验证的安大略省西部大学和麦克马斯特大学骨关节炎指数(主要结果)来测试膝关节疼痛的组间差异。我们还将测试两组之间在下肢残疾方面的差异、受试者对变化的总体印象以及联合治疗的使用(次要结果)。按照非自卑试验的建议，我们将进行意向治疗分析和按方案分析。最后，我们将评估CBT方案与继续使用非甾体抗炎药相比的潜在成本效益。尽管对于被随机分配到活性研究药物的受试者来说，继续他们目前的非甾体抗炎药是理想的，但让退伍军人管理局药房开发多种不同的活性药物并保持盲人是不可能的。因此，我们将包括两周的磨合期，研究对象将用美洛昔康取代他们的非甾体抗炎药。美洛昔康被选为研究药物是因为它是我们中心最常用的处方药，与其他非甾体抗炎药相比具有良好的安全性。如果成功，这项试验将提高为退伍军人提供的护理质量，这些退伍军人因膝盖骨关节炎而慢性膝盖疼痛。拟议的战略特别有吸引力，因为它用一种更安全的替代方案取代了非类固醇抗炎药的广泛使用，使有限机会的退伍军人能够获得护理，并可能节省成本。

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.