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依维莫司和高危血管疾病的心血管结局。

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease.

机构信息

From the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland (A.M.L., V.M., E.M., K.W., D.M., S.E.N.); South Australian Heart and Medical Research Institute, University of Adelaide, Adelaide (S.J.N.), and School of Medical Sciences, University of New South Wales, Sydney (P.J.B.) - both in Australia; Eli Lilly, Indianapolis (J.S.R., G.R., B.V., G.W.); Washington Cardiovascular Associates, Medstar Research Institute, Washington, DC (H.B.B.); Centre for Cardiovascular Science, University of Edinburgh, Edinburgh (K.A.A.F.); Beth Israel Deaconess Medical Center, Boston (C.M.G.); Duke University Medical Center, Durham, NC (C.G.); Université Sorbonne Paris 6, ACTION Study Group, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Institut de Cardiologie, Paris (G.M.); Penn Heart and Vascular Center, Philadelphia (D.R.); Columbia University, New York (A.R.T.), and Saratoga Cardiology Associates, Saratoga Springs (D.K.) - both in New York; St. Michael's Hospital, Toronto (S.G.), Recherche Médicale Saint-Jérôme, Saint-Jérôme, QC (Y.P.), and Centre de Santé et de Services Sociaux du Nord de Lanaudière-Centre Hospitalier Régional de Lanaud, Saint-Charles-Borromée, QC (S.K.) - all in Canada; Instituto Cardiovascular de Buenos Aires, Buenos Aires (D.C.); University of Texas Southwestern Medical Center, Dallas (D.K.M.); Heart Institute (InCor)-University of São Paulo Medical School, São Paulo (J.C.N.); Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosi, Mexico (J.L.L.-P.); the First Affiliated Hospital of Harbin Medical University, Harbin, China (W.L.); and South Oklahoma Heart Research, Oklahoma City (N.T.).

出版信息

N Engl J Med. 2017 May 18;376(20):1933-1942. doi: 10.1056/NEJMoa1609581.

DOI:10.1056/NEJMoa1609581

PMID:28514624

Abstract

BACKGROUND

The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.

METHODS

In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

RESULTS

At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).

CONCLUSIONS

Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).

摘要

背景

胆固醇酯转移蛋白抑制剂依维莫司可显著提高高密度脂蛋白（HDL）胆固醇水平，降低低密度脂蛋白（LDL）胆固醇水平，并增强细胞胆固醇外排能力。我们旨在确定依维莫司对高危血管疾病患者主要不良心血管结局的影响。

方法

在一项多中心、随机、双盲、安慰剂对照的 3 期临床试验中，我们招募了 12092 名患者，他们至少存在以下一种情况：在过去 30 至 365 天内发生急性冠状动脉综合征、脑血管粥样硬化疾病、外周血管动脉疾病或合并冠心病的糖尿病。患者随机分为接受依维莫司 130mg 或匹配安慰剂治疗组，每日一次，同时接受标准的医学治疗。主要疗效终点是心血管原因死亡、心肌梗死、卒中等复合终点的首次发生。

结果

在 3 个月时，与安慰剂相比，依维莫司使 LDL 胆固醇水平平均降低 31.1%，而安慰剂组则升高 6.0%；依维莫司使 HDL 胆固醇水平平均升高 133.2%，而安慰剂组则升高 1.6%。在计划的 1670 例主要终点事件中的 1363 例发生后，数据和安全监测委员会建议提前终止试验，因为缺乏疗效。在中位数为 26 个月的依维莫司或安慰剂治疗后，依维莫司组有 12.9%的患者发生主要终点事件，安慰剂组有 12.8%的患者发生主要终点事件（风险比，1.01；95%置信区间，0.91 至 1.11；P=0.91）。