达拉匹林对稳定型冠心病或冠心病风险等同患者血浆脂蛋白相关磷脂酶A2活性及心血管生物标志物的影响：一项多中心、随机、双盲、安慰剂对照研究的结果

The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study.

作者信息

Mohler Emile R, Ballantyne Christie M, Davidson Michael H, Hanefeld Markolf, Ruilope Luis M, Johnson Joel L, Zalewski Andrew

机构信息

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

出版信息

J Am Coll Cardiol. 2008 Apr 29;51(17):1632-41. doi: 10.1016/j.jacc.2007.11.079.

DOI:10.1016/j.jacc.2007.11.079

PMID:18436114

Abstract

OBJECTIVES

This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk.

BACKGROUND

Elevated Lp-PLA(2) levels are associated with an increased risk of CV events.

METHODS

Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers.

RESULTS

Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted.

CONCLUSIONS

Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

摘要

目的

本研究探讨选择性脂蛋白相关磷脂酶A2（Lp-PLA2）抑制剂达拉匹林对心血管（CV）风险生物标志物的影响。

背景

Lp-PLA2水平升高与CV事件风险增加相关。

方法

将接受阿托伐他汀（20或80mg）治疗的冠心病（CHD）和CHD风险等同患者（n = 959）随机分为每日口服40mg、80mg、160mg达拉匹林或安慰剂，共12周。对血样进行Lp-PLA2活性及其他生物标志物分析。

结果

基线低密度脂蛋白胆固醇（LDL-C）为67±22mg/dl。老年患者（≥75岁）、男性、服用20mg阿托伐他汀者、LDL-C≥70mg/dl或高密度脂蛋白胆固醇（HDL-C）<40mg/dl者或有血管疾病记录者的血浆Lp-PLA2水平较高（多变量回归；p<0.01）。与安慰剂相比，40mg、80mg和160mg达拉匹林分别使Lp-PLA2活性抑制约43%、55%和66%（第4周和第12周时p<0.001）。在阿托伐他汀两个治疗组以及不同基线LDL-C（≥70mg/dl与<70mg/dl）和HDL-C（<40mg/dl与≥40mg/dl）水平总体均观察到持续的剂量依赖性抑制。在第12周时，与安慰剂相比，160mg达拉匹林使白细胞介素（IL）-6降低12.3%（95%置信区间[CI]-22%至-1%；p = 0.028），使高敏C反应蛋白（hs-CRP）降低13.0%（95%CI -28%至+5%；p = 0.15）。Lp-PLA2抑制对血小板生物标志物（P-选择素、CD40配体、尿11-脱氢血栓烷B2）无有害影响。未观察到重大安全问题。