Lancet：Meta分析证实非甾体抗炎药物可增加心脏病发作风险

最新研究显示，较大剂量的常用非甾体抗炎药物（NSAIDs）增加主要血管不良事件的风险高达1/3左右，这些事件包括非致死性的心脏病发作、卒中和死亡，其中主要风险为心脏病发作风险。这项研究在线发表在Lancet官网上。

一直以来，NSAIDs是治疗炎症性疾病如风湿性关节炎所致疼痛症状的基石，并成为世界范围内应用最为广泛的药物。早先的一些研究提示，NSAIDs的使用可能导致严重胃肠道并发症的风险增加。为减少胃肠道副反应，开发了新一代的昔布类NSAIDs。目前研究者们正对新一代的NSAIDs是否增加心脏病发作及死亡进行严格审视。

新发表的这项Meta分析显示，较大剂量使用传统NSAIDs，如双氯芬酸每天150mg或布洛芬每天2400mg，以及新型NSAIDs均可导致心脏疾病风险的升高，且升高程度相似。也就是说，如服用一年较大剂量的双氯芬酸或布洛芬，每1000个中危心血管疾病患者，将有三人发生可避免的心脏病发作，其中一人为致命性心脏病发作。另外，所有的NSAIDs将使心力衰竭风险成倍上升，严重上消化道并发症如出血性溃疡的发生风险增加2至4倍。

CNT研究（昔布类和传统NSAIDs联合研究）通过收集35300名患者的预后数据，比较了使用某种NSAIDs或其他NSAIDs或安慰剂的效应。

这项Meta分析使用的数据来自于639项随机研究，分析结果表明NSAIDs造成的消化道疾病和心血管疾病风险增加的大小是可预测的，这种可预测性将帮助临床医生在决定给他的患者使用何种NSAIDs作为最佳治疗方案。

重要的是，使用NSAIDs是所致心脏病发作的风险增加与个体潜在的心脏病发作风险是成正比的。所以在那些既往有心脏病病史或那些已经具有心脏病危险因素如血压增高、胆固醇增高的患者，因NSAIDs所致的心脏病风险增加最明显。

据本项研究的主要研究者，英国牛津大学Colin Baigent教授称：“尽管NSAIDs或多或少都会增加血管及消化道疾病风险，但我们的分析显示，不同药物对于特定人群的不同效应是可预测的，这或许可以为临床医生选用NSAIDs提供辅助性决策。这可以帮助他们了解在不同的患者中哪种NSAIDs的最安全的。”

美国范德比尔特大学医学中心的Marie Griffin教授在一片相关述评中说，“这一Meta分析确认了最常处方的NSAIDs在较大剂量使用时与主要心血管事件之间的相关性，但对使用较低剂量NSAIDs方面、更长时程用药、停药后参与效应与心血管事件风险之间的关系仍是空白。”她还认为：“对慢性疼痛治疗的有效和安全策略亟需确认。同时，长期大剂量使用NSAIDs仍应作为使用NSAIDs后获得显著症状缓解患者的治疗策略。”

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials
Background
The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.
Methods
We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).
Findings
Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14—1·66; p=0·0009) or diclofenac (1·41, 1·12—1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31—2·37; p=0·0001; diclofenac 1·70, 1·19—2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10—4·48; p=0·0253), but not major vascular events (1·44, 0·89—2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69—1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00—2·49; p=0·0103) and diclofenac (1·65, 0·95—2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56—6·41; p=0·17), but not by naproxen (1·08, 0·48—2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17—2·81, p=0·0070; diclofenac 1·89, 1·16—3·09, p=0·0106; ibuprofen 3·97, 2·22—7·10, p<0·0001; and naproxen 4·22, 2·71—6·56, p<0·0001).
Interpretation
The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.