Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.
Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.
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DOI：
10.1056/nejmoa1809798
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发表时间：
2019-02-21
期刊：
影响因子：
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通讯作者：
CIRT Investigators
中科院分区：
文献类型：
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作者：
Ridker PM;Everett BM;Pradhan A;MacFadyen JG;Solomon DH;Zaharris E;Mam V;Hasan A;Rosenberg Y;Iturriaga E;Gupta M;Tsigoulis M;Verma S;Clearfield M;Libby P;Goldhaber SZ;Seagle R;Ofori C;Saklayen M;Butman S;Singh N;Le May M;Bertrand O;Johnston J;Paynter NP;Glynn RJ;CIRT Investigators
炎症与动脉粥样硬化形成有因果关系。canakinumab是一种通过中和白细胞介素-1β来抑制炎症的单克隆抗体，在之前的随机试验中，使用canakinumab治疗比安慰剂的心血管事件发生率低。我们试图确定是否用低剂量甲氨蝶呤替代炎症抑制的方法可能提供类似的益处。我们进行了一项随机双盲试验，在4786例既往心肌梗死或多支冠状动脉疾病患者中进行了低剂量甲氨蝶呤（目标剂量为每周15 - 20mg）或匹配的安慰剂，这些患者同时患有2型糖尿病或代谢综合征。所有参与者每天服用1毫克叶酸。试验开始时的主要终点为非致死性心肌梗死、非致死性卒中或心血管死亡的复合终点。接近试验结束，但在解盲之前，因不稳定型心绞痛导致紧急血运重建术的住院被添加到主要终点。该试验在中位随访2.3年后停止。甲氨蝶呤并没有导致白细胞介素-1β、白细胞介素-6或c反应蛋白水平低于安慰剂。最终的主要终点出现在甲氨蝶呤组201例患者和安慰剂组207例患者（发病率，4.13 vs 4.31 / 100人-年；风险比，0.96；95%可信区间[CI]， 0.79 ~ 1.16）。最初的主要终点发生在甲氨蝶呤组的170名患者和安慰剂组的167名患者（发病率，3.46 vs 3.43 / 100人-年；风险比，1.01;95% CI, 0.82 - 1.25）。甲氨蝶呤与肝酶水平升高、白细胞计数和红细胞压积水平降低以及非基底细胞皮肤癌发生率高于安慰剂相关。在稳定的动脉粥样硬化患者中，低剂量甲氨蝶呤并没有降低白细胞介素-1β、白细胞介素-6或c反应蛋白的水平，也没有导致比安慰剂更少的心血管事件。（由国家心脏、肺和血液研究所资助；CIRT ClinicalTrials.gov号码，.）
Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, .)