TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway.
Lancet. 2017 Oct 28;390(10106):1962-1971. doi: 10.1016/S0140-6736(17)32290-0. Epub 2017 Aug 28.
LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9).
In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633.
Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events.
There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.
Amgen.
LDL 胆固醇是动脉粥样硬化性心血管疾病的一个既定风险因素。一个人应该或安全地降低多少这个风险因素仍然存在争议。我们旨在探讨 FOURIER 试验中依洛尤单抗（一种针对前蛋白转化酶枯草溶菌素 9（PCSK9）的单克隆抗体）治疗 4 周时 LDL 胆固醇浓度逐渐降低与临床疗效和安全性之间的关系。
在这项对 25982 名随机 FOURIER 试验患者的预先设定的二次分析中，研究了在 4 周时达到的 LDL 胆固醇浓度与随后的心血管结局（主要终点是心血管死亡、心肌梗死、中风、冠状动脉血运重建或不稳定型心绞痛的复合终点；关键次要终点是心血管死亡、心肌梗死或中风的复合终点）和十个预先设定的感兴趣的安全性事件之间的关系，中位随访时间为 2.2 年。我们使用多变量模型调整了与达到的 LDL 胆固醇相关的基线因素。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01764633。
在 2013 年 2 月 8 日至 2015 年 6 月 5 日期间，27564 名患者被随机分配到 FOURIER 研究中的一种治疗方案。1025 名（4%）患者在 4 周时没有测量 LDL 胆固醇，557 名（2%）在第 4 周就诊前已经发生了主要终点事件或十个预先设定的安全事件之一。在其余的 25982 名患者（94%的随机分配患者）中，13013 名患者被分配接受依洛尤单抗治疗，12969 名患者被分配接受安慰剂治疗。25982 名患者中有 2669 名（10%）达到 LDL 胆固醇浓度低于 0.5mmol/L，8003 名（31%）患者达到浓度在 0.5mmol/L 至小于 1.3mmol/L 之间，3444 名（13%）患者达到浓度在 1.3mmol/L 至小于 1.8mmol/L 之间，7471 名（29%）患者达到浓度在 1.8mmol/L 至小于 2.6mmol/L 之间，4395 名（17%）患者达到 2.6mmol/L 或更高的浓度。在主要和次要疗效复合终点的低 LDL 胆固醇浓度和较低风险之间存在高度显著的单调关系，一直延伸到第一个百分位（LDL 胆固醇浓度小于 0.2mmol/L；主要终点的 p=0.0012，次要终点的 p=0.0001）。相反，在所有严重不良事件或其他九个预先设定的安全事件中，都没有观察到达到的 LDL 胆固醇与安全性结果之间存在显著关联。
在 LDL 胆固醇浓度达到小于 0.2mmol/L 时，达到的 LDL 胆固醇与主要心血管结局之间存在单调关系。相反，在中位数为 2.2 年的时间内，非常低的 LDL 胆固醇浓度没有安全性问题。这些数据支持在心血管疾病患者中进一步降低 LDL 胆固醇，以达到低于当前建议的水平。
在 FOURIER 试验中，依洛尤单抗治疗 4 周时 LDL 胆固醇浓度逐渐降低与临床疗效和安全性之间存在单调关系，直至 LDL 胆固醇浓度小于 0.2mmol/L。相反，在中位数为 2.2 年的时间内，非常低的 LDL 胆固醇浓度没有安全性问题。这些数据支持在心血管疾病患者中进一步降低 LDL 胆固醇，以达到低于当前建议的水平。
