TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Masschusetts.
Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway.
JAMA Cardiol. 2019 Jul 1;4(7):613-619. doi: 10.1001/jamacardio.2019.0886.
The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events.
To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists.
DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019.
The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms.
The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001).
The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events.
ClinicalTrials.gov identifier: NCT01764633.
在进一步心血管结局研究中，PCSK9 抑制剂依洛尤单抗降低了低密度脂蛋白胆固醇和首次心血管事件，该研究纳入了具有高风险的受试者（FOURIER 试验），但患者仍存在较高的心血管事件复发风险。
评估依洛尤单抗对全因心血管事件的影响，因为全因心血管事件对患者、临床医生和卫生经济学家都很重要。
设计、设置和参与者：这是一项随机、双盲临床试验的二次分析。FOURIER 试验比较了依洛尤单抗或匹配安慰剂，并对患者进行了中位数为 2.2 年的随访。该研究纳入了 27564 例稳定动脉粥样硬化疾病且正在接受他汀类药物治疗的患者。数据分析于 2017 年 5 月至 2019 年 2 月进行。
主要终点（PEP）是首次心血管死亡、心肌梗死、卒中和不稳定型心绞痛住院或冠状动脉血运重建的时间；关键次要终点是首次心血管死亡、心肌梗死或卒中的时间。在预先指定的分析中，评估了治疗组之间的全因心血管事件。
患者的平均年龄为 63 岁，69%的患者正在接受高强度他汀类药物治疗，基线时 LDL-C 中位数为 92 mg/dL（要转换为毫摩尔/升，请乘以 0.0259）。试验期间共发生 2907 例首次 PEP 事件和 4906 例全因 PEP 事件。依洛尤单抗使全因 PEP 事件减少 18%（发生率比[RR]，0.82；95%CI，0.75-0.90；P < .001），包括首次事件（风险比，0.85；95%CI，0.79-0.92；P < .001）和后续事件（RR，0.74；95%CI，0.65-0.85）。依洛尤单抗组有 2192 例全因原发性事件，安慰剂组有 2714 例全因事件。在接受 3 年治疗的每 1000 例患者中，依洛尤单抗预防了 22 例首次 PEP 事件和 52 例全因 PEP 事件。全因事件减少主要归因于心肌梗死（RR，0.74；95%CI，0.65-0.84；P < .001）、卒中和冠状动脉血运重建（RR，0.77；95%CI，0.64-0.93；P = .007）的减少。
在他汀类药物治疗的基础上加用 PCSK9 抑制剂依洛尤单抗改善了临床结局，全因 PEP 事件显著减少，这主要归因于心肌梗死、卒中和冠状动脉血运重建的减少。与仅分析首次事件相比，依洛尤单抗组比安慰剂组预防了更多的事件，增加了一倍以上。这些数据进一步支持了继续进行强化降脂治疗以预防心血管事件复发的益处。
ClinicalTrials.gov 标识符：NCT01764633。
