The American College of Cardiology/American Heart Association/Multisociety cholesterol guidelines recommend adding a nonstatin if the low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL in patients with high-risk atherosclerotic cardiovascular disease ASCVD,¹ effectively creating a target of <70 mg/dL. The 2019 European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines go further and recommend an LDL-C goal of <55 mg/dL for patients with very high-risk ASCVD and to consider an even lower goal of <40 mg/dL for patients with multiple cardiovascular events within 2 years despite optimal statin therapy.² The advent of PCSK9 inhibition allows many patients to achieve even lower LDL-C levels. For example, evolocumab lowered LDL-C by 59% when added to statin therapy in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), reducing LDL-C from a median of 93 mg/dL to 30 mg/dL.³ Nevertheless, a key question is whether there is evidence of continued clinical benefit with lowering LDL-C below 40 mg/dL.

An analysis from FOURIER showed no significant heterogeneity in clinical benefit of evolocumab between patients with a baseline LDL-C less than versus greater than or equal to 70 mg/dL, but this analysis did not address the fraction of LDL-C lowering below subsequently published targets.⁴ Another analysis demonstrated a strong relationship between achieved LDL-C at 1 month and adjusted risk of cardiovascular events.⁵ However, this was a postrandomization association analysis, which carries the risk of confounding. Therefore, in the current analysis, we aimed to determine whether there is continued cardiovascular benefit from lowering LDL-C to <40 mg/dL using comparisons of randomized groups and analyzing in the context of the magnitude of LDL-C lowering below the most recent recommended targets.

To achieve this aim, we performed an exploratory analysis in FOURIER, a cardiovascular outcomes trial comparing evolocumab with placebo in patients with stable ASCVD on optimized statin therapy.³ Major adverse cardiovascular events were defined as cardiovascular death, myocardial infarction, or stroke. Median follow-up was 2.2 years. We used a Cox proportional hazard regression model to determine the hazard ratio for major adverse cardiovascular events for evolocumab versus placebo (normalized per 39 mg/dL [1 mmol/L] reduction in LDL-C) across the range of baseline LDL-C. When LDL-C was <40 mg/dL, ultracentrifugation was performed. Nonetheless, we also performed analogous analyses using apolipoprotein B and non–high-density lipoprotein cholesterol given they are metrics of all atherogenic lipoproteins and there are no analytic concerns. Each site’s ethics committee approved the trial protocol, and all subjects provided informed consent. Data will not be made publicly available; however, interested parties can contact the corresponding authors.

Among 27 564 patients with ASCVD enrolled in FOURIER (mean age, 63 years; 75% men), 81% had previous myocardial infarction, 19% previous ischemic stroke, and 13% peripheral artery disease. A total of 80% had hypertension, 37% had diabetes, and 28% were smokers. The median baseline LDL-C was 93 mg/dL (interquartile range, 80–109 mg/dL) with 99% on a moderate- or high-intensity statin regimen. Of subjects randomized to evolocumab, 65% achieved an LDL-C <40 mg/dL.

In the Figure (A), top, the achieved LDL-C (y axis) is plotted as a function of baseline LDL-C (x-axis) in each treatment arm. The shaded area represents the amount of LDL-C lowering that occurred between the treatment arms at a given baseline LDL-C, with blue shading representing LDL-C lowering that occurred above 40 mg/dL and red shading representing LDL-C lowering that occurred below 40 mg/dL. As the baseline LDL-C level went below 93 mg/dL, the mean achieved LDL-C went below 40 mg/dL. Thus, the further baseline LDL-C levels were below 93 mg/dL, the greater the proportion of LDL-C lowering was below 40 mg/dL, ranging from, on average, 0% of the difference between treatment arms at 93 mg/dL, to 38% of the difference between treatment arms when the starting LDL-C was 58 mg/dL.

Figure. Cardiovascular benefit of continued LDL-C lowering below 40 mg/dl and equivalent thresholds of apoB and non-HDL-C. A, Top, Achieved low-density lipoprotein cholesterol (LDL-C) at 48 weeks as a function of baseline LDL-C.The shaded area represents the amount of LDL-C lowering that occurred between the treatment arms at a given baseline LDL-C, with blue shading representing LDL-C lowering that occurred above 40 mg/dL and red shading representing LDL-C lowering that occurred below 40 mg/dL. The further baseline LDL-C levels were below 93 mg/dL (black dashed line), the greater the proportion of LDL-C lowering that was below 40 mg/dL, ranging from, on average, 0% at 93 mg/dL to 38% at 58 mg/dL. Bottom, Hazard ratio for evolocumab (Evo) versus placebo for cardiovascular death, myocardial infarction (MI), or stroke per 39 mg/dL (1 mmol/L) reduction in LDL-C as a function of baseline LDL-C. As the proportion of LDL-C lowering below 40 mg/dL increased, there was no evidence of attenuation in treatment effect (P value for treatment interaction = 0.78). B, Hazard ratio for evolocumab versus placebo for cardiovascular death, MI, or stroke per 39 mg/dL (1 mmol/L) reduction in LDL-C as a function of baseline apolipoprotein B (apoB). The further baseline apoB levels were below 98 mg/dL (black dashed line), the greater the proportion of apoB lowering that was below 50 mg/dL. As the proportion of apoB lowering below 50 mg/dL increased, there was no evidence of attenuation in treatment effect (P value for treatment interaction = 0.62). C, Hazard ratio for evolocumab versus placebo for cardiovascular death, MI, or stroke per 39 mg/dL (1 mmol/L) reduction in LDL-C as a function of baseline non–high-density lipoprotein (non-HDL-C). The further baseline non-HDL-C levels were below 147 mg/dL (black dashed line), the greater the proportion of non-HDL-C that was below 70 mg/dL. As the proportion of non-HDL-C lowering below 70 mg/dL increased, there was no evidence of attenuation in treatment effect (P value for treatment interaction = 0.60). MACE indicates major adverse cardiovascular event.

If there were no benefit of lowering LDL-C below 40 mg/dL, then one would expect the hazard ratio to be progressively attenuated (ie, increase toward 1.0) the lower the baseline LDL-C was below 93 mg/dL (ie, toward the left side of the hazard ratio curve, Figure [A], bottom) because a progressively greater proportion of the LDL-C lowering with evolocumab would be below 40 mg/dL. However, in contrast, we observed a consistent benefit of LDL-C lowering regardless of how low the baseline LDL-C was. Specifically, despite more than one-third of LDL-C lowering occurring below 40 mg/dL in subjects with baseline LDL-C of 58 mg/dL, the clinical benefit of LDL-C lowering was not attenuated (P interaction=0.78), with robust reductions in the risk of major adverse cardiovascular events (Figure [A]). A similar pattern was seen for apolipoprotein B and non–high-density lipoprotein lowering (Figure [B and C]). There was also no attenuation in the absolute risk reduction at lower baseline LDL-C (–2.1% when baseline LDL-C was 70 to <90 mg/dL and –1.9% when it was 90–110 mg/dL).

Over the last 2 decades, we have seen the guidelines shift to lower and lower LDL-C goals on the basis of clinical trials demonstrating that lower is better. The European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines have selected an LDL-C goal of <40 mg/dL as the next step in this progression. Previous clinical trials have proven that such levels are safe,³ and we have demonstrated in this study that there is continued effectiveness even below 40 mg/dL in patients with high-risk ASCVD.

In conclusion, these data support the European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines recommendations and suggest that lowering LDL-C well below 40 mg/dL in a wider range of patients with ASCVD would further lower cardiovascular risk.

N.A.M. contributed to study design, literature search, statistical analysis, data interpretation, figures, and drafting of the article. R.P.G. and M.S.S. contributed to study design, statistical analysis, data interpretation, figures, and critical review of the article. J.-G.P. contributed to data preparation, study design, and statistical analysis. A.R., P.S.S., and A.C.K. contributed to data interpretation and critical review of the article. M.S.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The FOURIER trial was sponsored by Amgen.

Disclosures Dr Marston reports grant support from the National Institutes of Health and involvement in clinical trials with Amgen, Ionis, Pfizer, Novartis, and AstraZeneca without personal fees, payments, or increase in salary. Dr Guigliano reports grants from Amgen and Daiichi Sankyo during the conduct of the study; personal fees from Akcea, grants and personal fees from Amarin, personal fees from the American College of Cardiology, grants and personal fees from Amgen, personal fees from Bristol Myers Squibb, personal fees from CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Lexicon, grants and personal fees from Merck, personal fees from Pfizer, and personal fees from Servier, outside the submitted work; and an institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital for research he is not directly involved in from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr Park is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, The Medicines Company, and Zora Biosciences. Dr Ruzza is an Amgen employee and stockholder. Dr Sever reports research grants and honoraria for the speakers bureau from Amgen and Pfizer. Dr Keech reports grants and personal fees from Abbott, personal fees from Amgen, personal fees from AstraZeneca, grants and personal fees from Mylan, personal fees from Pfizer, grants from Sanofi, grants from Novartis, and personal fees from Bayer, outside the submitted work. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, IONIS, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; and consulting for Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, Fibrogen, IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, and Novo Nordisk. He is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences.

This work was presented as an abstract at the European Society of Cardiology Congress, August 27–30, 2021.

For Sources of Funding and Disclosures, see page 1733.

Circulation is available at www.ahajournals.org/journal/circ

美国心脏病学会/美国心脏协会/多社会胆固醇指南建议，如果高危动脉粥样硬化性心血管疾病 ASCVD 患者的低密度脂蛋白胆固醇 (LDL-C) 仍然≥70 mg/dL，则添加非他汀类药物¹ ，有效地创造一个<70 mg/dL 的目标。2019 年欧洲心脏病学会/欧洲动脉粥样硬化学会血脂异常指南更进一步，建议高危 ASCVD 患者的 LDL-C 目标为 <55 mg/dL，并考虑为患者制定更低的目标 <40 mg/dL尽管进行了最佳他汀类药物治疗，但在 2 年内发生多次心血管事件。^2个PCSK9 抑制的出现使许多患者能够达到更低的 LDL-C 水平。例如，在 FOURIER 试验（Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk）中，evolocumab 将 LDL-C 降低 59%，将 LDL-C 从中位数 93 mg/dL 降低至 30 mg /分升。³然而，一个关键问题是是否有证据表明将 LDL-C 降低至 40 mg/dL 以下会带来持续的临床益处。

FOURIER 的一项分析显示，在基线 LDL-C 低于 70 mg/dL 与高于或等于 70 mg/dL 的患者之间，evolocumab 的临床获益没有显着异质性，但该分析未解决 LDL-C 低于随后公布的比例目标。⁴另一项分析表明，1 个月时达到的 LDL-C 与调整后的心血管事件风险之间存在密切关系。^5个然而，这是一项随机化后的关联分析，存在混杂的风险。因此，在目前的分析中，我们的目的是通过比较随机分组并在 LDL-C 降低幅度低于最近的水平的背景下进行分析，以确定将 LDL-C 降低至 <40 mg/dL 是否会持续带来心血管益处推荐目标。

为实现这一目标，我们在 FOURIER 中进行了探索性分析，FOURIER 是一项心血管结果试验，比较依洛单抗与安慰剂在接受优化他汀类药物治疗的稳定 ASCVD 患者中的疗效。^3个主要不良心血管事件定义为心血管死亡、心肌梗死或中风。中位随访时间为 2.2 年。我们使用 Cox 比例风险回归模型来确定 evolocumab 与安慰剂相比在基线 LDL-C 范围内主要不良心血管事件的风险比（LDL-C 每减少 39 mg/dL [1 mmol/L] 标准化）。当 LDL-C <40 mg/dL 时，进行超速离心。尽管如此，我们还使用载脂蛋白 B 和非高密度脂蛋白胆固醇进行了类似的分析，因为它们是所有致动脉粥样硬化脂蛋白的指标，并且没有分析问题。每个站点的伦理委员会都批准了试验方案，并且所有受试者都提供了知情同意书。数据不会公开；然而，

在纳入 FOURIER 研究的 27 564 名 ASCVD 患者（平均年龄 63 岁；75% 为男性）中，81% 曾患过心肌梗死，19% 曾患过缺血性卒中，13% 患有外周动脉疾病。共有 80% 的人患有高血压，37% 的人患有糖尿病，28% 的人吸烟。中位基线 LDL-C 为 93 mg/dL（四分位间距，80-109 mg/dL），其中 99% 接受中等或高强度他汀类药物治疗。在随机化至 evolocumab 的受试者中，65% 达到 LDL-C <40 mg/dL。

在图 (A) 顶部，将实现的 LDL-C（y轴）绘制为每个治疗组中基线 LDL-C（x 轴）的函数。阴影区域表示在给定基线 LDL-C 下治疗组之间发生的 LDL-C 降低量，蓝色阴影表示发生在 40 mg/dL 以上的 LDL-C 降低，红色阴影表示发生的 LDL-C 降低低于 40 毫克/分升。当基线 LDL-C 水平低于 93 mg/dL 时，平均达到的 LDL-C 低于 40 mg/dL。因此，基线 LDL-C 水平进一步低于 93 mg/dL，LDL-C 降低低于 40 mg/dL 的比例越大，范围从 93 mg/dL 治疗组之间差异的平均 0% dL，当起始 LDL-C 为 58 mg/dL 时，治疗组之间差异的 38%。

数字。 持续降低 LDL-C 低于 40 mg/dl 以及 apoB 和非 HDL-C 的等效阈值的心血管益处。A，顶部，在 48 周时达到的低密度脂蛋白胆固醇 (LDL-C) 作为基线 LDL-C 的函数。阴影区域表示在给定基线 LDL- 下治疗组之间发生的 LDL-C 降低量C，蓝色阴影代表发生在 40 mg/dL 以上的 LDL-C 降低，红色阴影代表发生在 40 mg/dL 以下的 LDL-C 降低。进一步的基线 LDL-C 水平低于 93 mg/dL（黑色虚线），LDL-C 降低低于 40 mg/dL 的比例越大，范围从 93 mg/dL 的平均 0% 到58 毫克/分升时为 38%。底部，作为基线 LDL-C 函数的 LDL-C 每降低 39 mg/dL (1 mmol/L)，evolocumab (Evo) 与安慰剂相比，心血管死亡、心肌梗死 (MI) 或中风的风险比。随着 LDL-C 低于 40 mg/dL 的比例增加，没有证据表明治疗效果会减弱（治疗相互作用的P值 = 0.78）。乙，作为基线载脂蛋白 B (apoB) 函数的 LDL-C 每降低 39 mg/dL (1 mmol/L)，evolocumab 与安慰剂相比对心血管死亡、MI 或中风的风险比。进一步基线 apoB 水平低于 98 mg/dL（黑色虚线），低于 50 mg/dL 的 apoB 降低比例越大。随着低于 50 mg/dL 的 apoB 比例增加，没有证据表明治疗效果减弱（治疗相互作用的P值 = 0.62）。C，作为基线非高密度脂蛋白 (non-HDL-C) 函数的 LDL-C 每降低 39 mg/dL (1 mmol/L)，evolocumab 与安慰剂相比对心血管死亡、MI 或中风的风险比。基线非 HDL-C 水平进一步低于 147 mg/dL（黑色虚线），非 HDL-C 低于 70 mg/dL 的比例越大。随着非 HDL-C 低于 70 mg/dL 的比例增加，没有证据表明治疗效果会减弱（治疗相互作用的P值 = 0.60）。MACE 表示主要不良心血管事件。

如果将 LDL-C 降低到 40 mg/dL 以下没有任何好处，那么人们会预期风险比会逐渐减弱（即增加到 1.0），基线 LDL-C 越低到 93 mg/dL 以下（即，向风险比曲线的左侧，图 [A]，底部），因为随着 evolocumab 逐渐降低的 LDL-C 比例将低于 40 mg/dL。然而，相比之下，无论基线 LDL-C 有多低，我们都观察到 LDL-C 降低的一致益处。具体而言，尽管基线 LDL-C 为 58 mg/dL 的受试者中超过三分之一的 LDL-C 降低发生在 40 mg/dL 以下，但 LDL-C 降低的临床益处并未减弱（Pinteraction=0.78)，主要不良心血管事件的风险显着降低（图 [A]）。载脂蛋白 B 和非高密度脂蛋白降低也有类似的模式（图 [B 和 C]）。较低基线 LDL-C 的绝对风险降低也没有减弱（当基线 LDL-C 为 70 至 <90 mg/dL 时为–2.1%，当为 90–110 mg/dL 时为–1.9%）。

在过去的 20 年里，我们已经看到指南转向越来越低的 LDL-C 目标，因为临床试验表明越低越好。欧洲心脏病学会/欧洲动脉粥样硬化学会血脂异常指南选择了 <40 mg/dL 的 LDL-C 目标作为该进展的下一步。之前的临床试验已经证明，这样的水平是安全的，³而我们在本研究中证明，即使低于 40 mg/dL，对于高危 ASCVD 患者也有持续的有效性。

总之，这些数据支持欧洲心脏病学会/欧洲动脉粥样硬化学会血脂异常指南的建议，并表明在更广泛的 ASCVD 患者中将 LDL-C 降低至远低于 40 mg/dL 将进一步降低心血管风险。

NAM 为研究设计、文献检索、统计分析、数据解释、图表和文章起草做出了贡献。RPG 和 MSS 对研究设计、统计分析、数据解释、图表和文章的批判性审查做出了贡献。J.-GP 为数据准备、研究设计和统计分析做出了贡献。AR、PSS 和 ACK 对文章的数据解释和批判性审查做出了贡献。MSS 是这项工作的担保人，因此可以完全访问研究中的所有数据，并对数据的完整性和数据分析的准确性负责。

FOURIER 试验由 Amgen 赞助。

披露Marston 博士报告说，他获得了美国国立卫生研究院的资助支持，并参与了 Amgen、Ionis、Pfizer、Novartis 和 AstraZeneca 的临床试验，无需个人费用、付款或加薪。Guigliano 博士报告了在进行研究期间来自 Amgen 和 Daiichi Sankyo 的资助；Akcea 的个人费用、Amarin 的补助金和个人费用、美国心脏病学会的个人费用、Amgen 的补助金和个人费用、Bristol Myers Squibb 的个人费用、CVS Caremark 的个人费用、Daiichi Sankyo 的补助金和个人费用、个人费用GlaxoSmithKline 的费用、Janssen 的个人费用、Lexicon 的个人费用、Merck 的赠款和个人费用、Pfizer 的个人费用以及 Servier 的个人费用，在提交的作品之外；Brigham and Women's Hospital 的 TIMI Study Group 的机构研究资助，用于他未直接参与的研究、MedImmune、Merck、Novartis、Pfizer、Poxel、Quark Pharmaceuticals、Roche、Takeda、The Medicines Company 和 Zora Biosciences。Park 博士是 TIMI 研究小组的成员，该小组通过布莱根妇女医院获得了雅培、安进、Anthos Therapeutics、阿斯利康、第一三共、卫材、Intarcia、MedImmune、默克、诺华、辉瑞、再生元的机构研究资助支持Pharmaceuticals, Inc、Roche、The Medicines Company 和 Zora Biosciences。Ruzza 博士是安进公司的员工和股东。Sever 博士报告了来自 Amgen 和 Pfizer 的演讲机构的研究资助和酬金。Keech 博士报告了来自雅培的赠款和个人费用、来自安进的个人费用、来自阿斯利康的个人费用、来自迈兰的赠款和个人费用、来自辉瑞的个人费用、来自赛诺菲的赠款、来自诺华的赠款以及来自拜耳的个人费用，在提交的工作之外. Sabatine 博士报告了来自 Amgen、AstraZeneca、Bayer、Daiichi-Sankyo、Eisai、GlaxoSmithKline、Intarcia、IONIS、Janssen Research and Development、The Medicines Company、MedImmune、Merck、Novartis、Pfizer、Poxel、Quark 的布莱根妇女医院的研究资助支持制药和武田；为 Amgen、Anthos Therapeutics、AstraZeneca、Bristol-Myers Squibb、CVS Caremark、DalCor、Dynamix、Esperion、Fibrogen、IFM Therapeutics、Intarcia、Ionis、Janssen Research and Development、The Medicines Company、MedImmune、Merck、Novartis 和 Novo Nordisk。他是 TIMI 研究小组的成员，该小组还通过布莱根妇女医院从 Abbott、Aralez、Roche 和 Zora Biosciences 获得了机构研究资助支持。

这项工作在 2021 年 8 月 27 日至 30 日的欧洲心脏病学会大会上作为摘要提出。

有关资金来源和披露，请参阅第 1733 页。

流通可在 www.ahajournals.org/journal/circ