Evaluating the Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs
Evaluating the Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs
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DOI：
10.1161/circulationaha.117.027288
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发表时间：
2017-05-23
期刊：
影响因子：
37.8
通讯作者：
Antman, Elliott M.
中科院分区：
文献类型：
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作者：
Antman, Elliott M.
一些用于治疗非心血管疾病的药物可能会对患有或不患有已知心血管疾病的个体的心血管状态产生不利影响。当美国食品药品监督管理局判断潜在的心血管安全性信号值得足够关注时，可能会要求相关药物的制药商进行上市后（4期）随机对照试验（RCT）。尽管历史上许多4期RCT关注疗效（使用优效性设计），但当代4期RCT通常关注安全性并使用非劣效性设计。研究者在专门用于评价心血管安全性的上市后4期RCT的计划阶段所做的选择可能会影响比较标准药物和试验药物的能力。反映针对一般医学状况开展IV期RCT的多个因素可能影响心血管安全性信号的解读。未能遵守方案和退出研究的比率越高，偏倚风险越大。评价非甾体抗炎药（NSAID）用于关节炎时心血管安全性的试验很难进行，甚至更难解释。关注点包括比较不能提供可比镇痛疗效的药物方案，以及遵守方案和保留在研究中的问题。根据迄今为止的NSAID 4期RCT，低风险受试者接受相对较低剂量的塞来昔布给药与环加氧酶-2抑制活性较低的NSAID的心血管风险大致相同，但代价是不能有效控制关节炎疼痛。
Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively.