Ridker Paul M
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
J Thromb Haemost. 2009 Jul;7 Suppl 1:332-9. doi: 10.1111/j.1538-7836.2009.03404.x.
While inflammation is a crucial component of atherothrombosis and patients with elevated inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) are at increased vascular risk, it remains unknown whether inhibition of inflammation per se will lower vascular event rates. The recently completed JUPITER (N Engl J Med 2008, 359, 2195) trial demonstrates that statins reduce myocardial infarction, stroke, and all-cause mortality among healthy individuals with low cholesterol and elevated hsCRP. However, a direct test of the inflammatory hypothesis of atherothrombosis requires an agent that inhibits inflammation without impacting other components of the atherothrombotic process, and has an acceptable safety profile for a trial setting. On this basis, the cardiovascular inflammation reduction trial (CIRT) proposes to allocate 7000 stable coronary artery disease patients with persistent elevations of hsCRP to placebo or very-low-dose-methotrexate (VLDM, 10 mg weekly), a proven anti-inflammatory regimen that reduces TNFalpha, IL-6, and CRP levels and is in wide use among rheumatoid arthritis patients. If successful, CIRT would both confirm the inflammatory hypothesis of atherothrombosis and open novel approaches to the treatment and prevention of cardiovascular disorders.
虽然炎症是动脉粥样硬化血栓形成的关键组成部分，且炎症生物标志物升高的患者（如高敏C反应蛋白[hsCRP]升高）血管风险增加，但炎症本身的抑制是否会降低血管事件发生率仍不清楚。最近完成的JUPITER试验（《新英格兰医学杂志》2008年，第359卷，第2195页）表明，他汀类药物可降低胆固醇水平低且hsCRP升高的健康个体的心肌梗死、中风及全因死亡率。然而，对动脉粥样硬化血栓形成的炎症假说进行直接验证需要一种能抑制炎症而不影响动脉粥样硬化血栓形成过程其他成分的药物，且在试验环境中具有可接受的安全性。在此基础上，心血管炎症减少试验（CIRT）提议将7000例hsCRP持续升高的稳定型冠状动脉疾病患者随机分配至安慰剂组或极低剂量甲氨蝶呤（VLDM，每周10 mg）组，甲氨蝶呤是一种已证实的抗炎方案，可降低肿瘤坏死因子α、白细胞介素-6和CRP水平，且在类风湿关节炎患者中广泛使用。如果试验成功，CIRT将既证实动脉粥样硬化血栓形成的炎症假说，又为心血管疾病的治疗和预防开辟新途径。
