Bonnet Jacques, McPherson R, Tedgui A, Simoneau D, Nozza A, Martineau P, Davignon Jean
Hôpital du Haut-Lévèque, Pessac, France.
Clin Ther. 2008 Dec;30(12):2298-313. doi: 10.1016/j.clinthera.2008.12.023.
The major beneficial effect of statins- reducing the risk for coronary events-has primarily been ascribed to reductions in low-density lipoprotein cholesterol (LDL-C) but may in part be related to a direct antiinflammatory action (ie, decreased high-sensitivity C-reactive protein [hs-CRP] concentration).
The objectives of this CAP (Comparative Atorvastatin Pleiotropic Effects) study were to compare the effects of low- versus high-dose atorvastatin on hs-CRP concentrations and to determine the relationship between changes in LDL-C and hs-CRP concentrations in patients with coronary artery disease (CAD), low-grade inflammation, and normal lipoprotein concentrations.
This multicenter, prospective, randomized, double-blind, double-dummy study was conducted at 65 centers across Canada and Europe. Patients with documented CAD, low-grade inflammation (hs-CRP concentration, 1.5-15.0 mg/L), and a normal-range lipid profile (LDL-C concentration, 1.29-3.87 mmol/L [50-150 mg/dL]; triglyceride [TG] concentration, <4.56 mmol/L [<400 mg/dL]) were randomly assigned to receive 26-week double-blind treatment with atorvastatin 10 or 80 mg QD. Investigators were to aim for the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C target of <2.59 mmol/L (<100 mg/dL). The primary end point was the percentage change from baseline in hs-CRP, as measured at baseline and weeks 5, 13, and 26 using high-sensitivity, latex microparticle-enhanced immunoturbidimetric assay. Changes from baseline in LDL-C, as measured directly in serum at the same time points, were also calculated. The secondary efficacy variables included the percentage changes from baseline in lipid parameters (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], TG, apolipoprotein B, non-HDL-C, and TC:HDL-C ratio) at 5, 13, and 26 weeks of treatment. Tolerability was assessed using physical examination, including vital sign measurement, and laboratory analyses.
A total of 339 patients were enrolled (283 men, 56 women; mean age, 62.5 years; weight, 81.3 kg; 10-mg/d group, 170 patients; 80-mg/d group, 169). No significant differences in baseline demographic or clinical data were found between the 2 treatment arms. In the 10-mg group, hs-CRP was decreased by 25.0% at 5 weeks and remained stable thereafter (%Delta at week 26, -24.3%; P < 0.01). In the 80-mg group, hs-CRP was decreased by 36.4% at 5 weeks and continued to be decreased over the study period (%Delta, -57.1% at week 26; P < 0.001 vs baseline). At 5 weeks, LDL-C was decreased by 35.9% in the 10-mg group and by 52.7% in the 80-mg group (P < 0.001 between groups) and remained stable thereafter (%Delta at week 26, -34.8% and -51.3%, respectively; P < 0.001 between groups). The NCEP ATP III LDL-C target of <2.59 mmol/L (<100 mg/dL) was reached in 77.1% of patients treated with atorvastatin 10 mg and 92.3% of those treated with 80 mg (P < 0.001). Dual targets of hs-CRP <2 mg/L and LDL-C <1.81 mmol/L (<70 mg/dL) were reached in a significantly greater proportion of patients in the 80-mg group compared with the 10-mg group (55.6% vs 13.5%; P < 0.001). The decrease in hs-CRP was largely independent of baseline LDL-C and change in LDL-C. Two serious adverse events were reported by the investigator as treatment related: acute hepatitis in the 10-mg group and intrahepatic cholestasis in the 80-mg group, in 2 patients with multiple comorbidities. Two deaths occurred during the study, both in the atorvastatin 80-mg group (1, myocardial infarction; 1, sudden death), neither of which was deemed treatment related by the investigator.
In these patients with documented CAD, evidence of low-grade inflammation, and normal range lipid profiles, the effects of atorvastatin on changes in hs-CRP were dose dependent, with the high dose (80 mg) being associated with significantly greater reductions in hs-CRP concentrations. Both doses were associated with a significant and progressive decline in hs-CRP largely independent of changes in LDL-C, HDL-C, and TG. Clinical Trials Identification Number: NCT00163202.
他汀类药物降低冠状动脉事件风险的主要有益作用主要归因于低密度脂蛋白胆固醇（LDL-C）的降低，但可能部分与直接抗炎作用有关（即高敏C反应蛋白[hs-CRP]浓度降低）。
本CAP（阿托伐他汀多效性比较）研究的目的是比较低剂量与高剂量阿托伐他汀对hs-CRP浓度的影响，并确定冠心病（CAD）、低度炎症和脂蛋白浓度正常的患者中LDL-C和hs-CRP浓度变化之间的关系。
这项多中心、前瞻性、随机、双盲、双模拟研究在加拿大和欧洲的65个中心进行。有记录的CAD、低度炎症（hs-CRP浓度为1.5 - 15.0 mg/L）且血脂谱正常（LDL-C浓度为1.29 - 3.87 mmol/L[50 - 150 mg/dL]；甘油三酯[TG]浓度<4.56 mmol/L[<400 mg/dL]）的患者被随机分配接受26周的双盲治疗，每日服用阿托伐他汀10或80 mg。研究者的目标是达到美国国家胆固醇教育计划成人治疗小组III（NCEP ATP III）的LDL-C目标<2.59 mmol/L（<100 mg/dL）。主要终点是使用高敏乳胶微粒增强免疫比浊法在基线以及第5、13和26周测量的hs-CRP相对于基线的百分比变化。同时还计算了在相同时间点直接在血清中测量的LDL-C相对于基线的变化。次要疗效变量包括治疗第5、13和26周时脂质参数（LDL-C；高密度脂蛋白胆固醇[HDL-C]；总胆固醇[TC]；TG；载脂蛋白B；非HDL-C以及TC:HDL-C比值）相对于基线的百分比变化。使用体格检查（包括生命体征测量）和实验室分析评估耐受性。
共纳入339例患者（283例男性，56例女性；平均年龄62.5岁；体重81.3 kg；10 mg/d组170例患者；80 mg/d组169例）。两个治疗组之间在基线人口统计学或临床数据方面未发现显著差异。在10 mg组中，hs-CRP在第5周时降低了25.（此处原文有误，应为25.0%），此后保持稳定（第26周时变化百分比为-24.3%；P<0.01）。在80 mg组中，hs-CRP在第5周时降低了36.4%，并且在研究期间持续降低（第26周时变化百分比为-57.1%；与基线相比P<0.001）。在10 mg阿托伐他汀治疗的患者中，77.1%达到了NCEP ATP III的LDL-C目标<2.59 mmol/L（<100 mg/dL），在80 mg治疗的患者中这一比例为92.3%（P<0.001）。与10 mg组相比，80 mg组中达到hs-CRP<2 mg/L和LDL-C<1.81 mmol/L（<70 mg/dL）双重目标的患者比例显著更高（55.6%对13.5%；P<0.001）。hs-CRP的降低在很大程度上独立于基线LDL-C和LDL-C的变化。研究者报告了两例与治疗相关的严重不良事件：10 mg组中的急性肝炎和80 mg组中的肝内胆汁淤积，这两名患者均有多种合并症。研究期间发生了两例死亡，均在阿托伐他汀80 mg组（1例心肌梗死；1例猝死），研究者认为这两例均与治疗无关。
在这些有记录的CAD、低度炎症证据且血脂谱正常的患者中，阿托伐他汀对hs-CRP变化的影响是剂量依赖性的，高剂量（80 mg）与hs-CRP浓度显著更大程度的降低相关。两种剂量均与hs-CRP显著且逐渐下降相关，这在很大程度上独立于LDL-C、HDL-C和TG的变化。临床试验识别号：NCT00163202。
