低密度脂蛋白胆固醇（LDL-C）水平是动脉粥样硬化心血管疾病的公认危险因素。然而，在长期内实现的最佳LDL-C水平，涉及疗效和安全性仍然未知。在FOURIER（亚洲和太平洋地区稳定的动脉粥样硬化心血管病人科学研究）中，27,564名患有稳定动脉粥样硬化心血管疾病的患者被随机分配到使用evolocumab或安慰剂组，随访中位数为2.2年。在FOURIER-OLE（FOURIER开放标签扩展）中，这些患者中的6635人无论最初的治疗分配如何，都转变为使用evolocumab的开放标签，并进行了额外的中位随访5年。在这个预先规定的分析中，我们检查了FOURIER-OLE中实现的LDL-C水平（前两个LDL-C水平的平均值，在6559名患者中可获得），以及后继心血管和安全结果的发生率之间的关系。我们还对整个FOURIER和FOURIER-OLE患者人群进行了敏感性分析，评估心血管和安全结果。多变量建模被用来调整与实现的LDL-C水平相关的基线因素。在FOURIER-OLE中，1604名（24％），2627名（40％），1031名（16％），486名（7％）和811名（12％）患者分别实现了<20、20到<40、40到<55、55到<70和≥70mg/dL的LDL-C水平。实现更低的LDL-C水平-甚至是低于20mg/dL的非常低水平-与试验的主要疗效终点（心血管死亡，心肌梗死，中风或因不稳定心绞痛或冠状动脉重建而住院）和关键次要疗效终点（心血管死亡，心肌梗死或中风）之间存在单调关系，这种关系在多变量调整后仍然存在（调整Ptrend<0.0001）。在主要分析中，没有统计学显著性的关联存在于实现更低的LDL-C水平和安全结果（严重不良事件，新发或复发癌症，与白内障相关的不良事件，出血性中风，新发糖尿病，神经认知不良事件，肌肉相关事件或非心血管死亡）之间。在整个FOURIER和FOURIER-OLE队列中，类似的结果被观察到，最长随访时间为8.6年。在患有动脉粥样硬化心血管疾病的患者中，实现更低的LDL-C水平-甚至是<20mg/dL（<0.5mmol/L）的水平，与心血管结局的风险降低且没有明显的安全问题相关。URL：https://www.gov；唯一标识符：NCT01764633。

Low-density lipoprotein cholesterol (LDL-C) level is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown.In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed up with for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels.In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the trial's primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, or hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for both end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years.In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns.URL: https://www.gov; Unique identifier: NCT01764633.