Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
JAMA Cardiol. 2019 Jan 1;4(1):59-63. doi: 10.1001/jamacardio.2018.4178.
Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications.
To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab.
DESIGN, SETTING, AND PARTICIPANTS: We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018.
Interindividual variation in percent reduction in LDL-C with evolocumab.
There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10 325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups.
There appears to be a highly consistent robust reduction in LDL-C levels with evolocumab use.
ClinicalTrials.gov identifier: NCT01764633.
关于前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂药物降低低密度脂蛋白胆固醇（LDL-C）水平的异质性知之甚少。
评估 PCSK9 抑制剂依洛尤单抗降低 LDL-C 的个体间变异性。
设计、地点和参与者：我们研究了在进一步心血管结果研究中 PCSK9 抑制剂在高风险人群中的应用（FOURIER）试验中，接受他汀类药物治疗的稳定动脉粥样硬化性心血管疾病患者中，PCSK9 抑制剂依洛尤单抗治疗组与安慰剂对照组相比，LDL-C 水平从基线的百分比变化。在筛选期间 LDL-C 变异性高的患者（n=3524）、未接受研究药物的患者、改变了背景降脂治疗方案的患者或在第 4 周没有 LDL-C 水平样本的患者被排除在主要分析之外。对患者的分析按治疗组分层。数据于 2013 年至 2016 年采集，2018 年 1 月至 11 月进行数据分析。
依洛尤单抗降低 LDL-C 的个体间变异性。
队列中有 27564 人；排除基线变异性（n=3524）或背景脂质治疗和其他原因的改变（n=2272）后，21768 名患者被纳入。第 4 周时，与安慰剂相比，依洛尤单抗组 LDL-C 水平从基线降低了 66%（中位数[四分位数范围]，54%-76%；中位数[四分位数范围]基线值，90[79-105]mg/dL；变化后值，31[21-44]mg/dL）。在第一年中，依洛尤单抗组 10902 名患者中有 10325 名（94.7%）LDL-C 水平降低 50%或更多，10669 名（97.9%）降低 30%或更多，10849 名（99.5%）有任何 LDL-C 水平降低。53 名患者（0.5%）的 LDL-C 水平没有明显降低。在安慰剂组中，LDL-C 中位数降低 4%（四分位数范围为 6%增加到 13%降低；基线中位数[四分位数范围]值为 90[79-106]mg/dL；变化后值为 87[74-103]mg/dL）在第 4 周。瀑布图显示了依洛尤单抗和安慰剂组中前 5%和后 5%的患者都存在明显的变异性，安慰剂组的 LDL-C 水平有较大变化（增加≥25%，531 名患者[4.9%]；降低≥25%，985 名患者[9.1%]）。第 4 周时，与安慰剂相比，依洛尤单抗组 LDL-C 水平降低 50%或更多的患者为 10866 名患者中的 9839 名（90.5%），降低 30%或更多的患者为 10846 名患者中的 10846 名（99.8%）。结果在所有有临床意义的亚组中均一致。
似乎使用依洛尤单抗可显著降低 LDL-C 水平。
ClinicalTrials.gov 标识符：NCT01764633。
