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降低心血管疾病患者的脂蛋白(a)
Lipoprotein(a) Reduction in Persons with Cardiovascular Disease


Sotirios Tsimikas ... 心脑血管疾病 • 2020.01.16
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摘要


背景

脂蛋白(a)水平由基因决定,而脂蛋白(a)水平升高是心血管疾病和主动脉瓣狭窄的危险因素。目前尚未批准任何用于降低脂蛋白(a)水平的药物疗法。

 

方法

我们开展了一项随机、双盲、安慰剂对照的剂量范围探索试验,本试验纳入了286例已确诊为心血管疾病,并且筛选时的脂蛋白(a)水平至少为60 mg/dL(150 nmol/L)的患者。患者接受了靶向肝细胞的反义寡核苷酸AKCEA-APO(a)-LRx(本文称为APO(a)-LRx)(每4周一次,每次20、40或60 mg;每2周一次,每次20 mg;或每周一次,每次20 mg)或盐水安慰剂皮下给药治疗,为期6~12个月。本试验采用不受亚型影响的测定法测定脂蛋白(a)水平。主要终点是暴露6个月(每月给药一次的组是在第25周,以更高频率给药的组是在第27周)时,脂蛋白(a)水平相对于基线的变化百分比。

 

结果

各组的基线脂蛋白(a)中位水平为204.5~246.6 nmol/L。APO(a)-LRx给药使脂蛋白(a)水平出现了剂量依赖性降低,每4周20 mg剂量、每4周40 mg剂量、每2周20 mg剂量、每4周60 mg剂量和每周20 mg剂量的平均降低百分比分别为35%、56%、58%、72%和80%,而采用安慰剂时为6%(与安慰剂组比较的P值范围为0.003到<0.001)。在血小板计数、肝和肾指标及流感样症状方面,任何APO(a)-LRx剂量与安慰剂之间均无显著差异。最常见的不良事件是注射部位反应。

 

结论

在脂蛋白(a)水平升高且已确诊为心血管疾病的患者中,APO(a)-LRx以剂量依赖性方式降低了脂蛋白(a)水平(由Akcea Therapeutics资助,在ClinicalTrials.gov注册号为NCT03070782)。





作者信息

Sotirios Tsimikas, M.D., Ewa Karwatowska-Prokopczuk, M.D., Ph.D., Ioanna Gouni-Berthold, M.D., Jean-Claude Tardif, M.D., Seth J. Baum, M.D., Elizabeth Steinhagen-Thiessen, M.D., Michael D. Shapiro, D.O., Erik S. Stroes, M.D., Patrick M. Moriarty, M.D., Børge G. Nordestgaard, M.D., D.M.Sc., Shuting Xia, M.S., Jonathan Guerriero, M.B.A., Nicholas J. Viney, B.Sc., Louis O’Dea, M.B., B.Ch., B.A.O., and Joseph L. Witztum, M.D. for the AKCEA-APO(a)-LRx Study Investigators*
From the Divisions of Cardiovascular Medicine (S.T.) and Endocrinology and Metabolism (J.L.W.), University of California, San Diego, La Jolla, and Ionis Pharmaceuticals, Carlsbad (S.T., S.X., N.J.V.) — both in California; Akcea Therapeutics, Boston (E.K.-P., J.G., L.O.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany (I.G.-B.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Excel Medical Clinical Trials, Boca Raton, FL (S.J.B.); the Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Berlin, Berlin Institute of Health, Berlin (E.S.-T.), and the Division of Geriatrics, University Medicine Greifswald, Greifswald (E.S.-T.) — both in Germany; the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (M.D.S.); the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.S.); the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); and the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev (B.G.N.), and the Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (B.G.N.) — all in Denmark. Address reprint requests to Dr. Tsimikas at the Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093, or at stsimikas@health.ucsd.edu. *A list of the AKCEA-APO(a)-LRx Study Investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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