The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Multisociety Guideline on the Management of Blood Cholesterol¹ divides patients with clinical atherosclerotic cardiovascular disease (ASCVD) into high-risk and very high-risk categories. The high-risk group includes those with stable ASCVD who are treated with high-intensity statins. Very high-risk patients are those with ASCVD plus other high-risk conditions; these patients are potential candidates for maximal statin therapy plus 2 nonstatins (ezetimibe and/or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors). This article compares and contrasts the AHA/ACC guideline with the dyslipidemia guidelines recently published by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)²; the latter offers a different definition of very high risk for the identification of patients deemed eligible for adding nonstatins to statin therapy (Table).

Table 1. Comparison of Major Treatment Recommendations of the 2018 AHA/ACC Multisociety Cholesterol Guideline and the 2019 ESC/EAS Guidelines for Secondary ASCVD Prevention

ACC indicates American College of Cardiology; AHA, American Heart Association; ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and PCSK9, proprotein convertase subtilisin kexin 9.

*By AHA/ACC, very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions. Major ASCVD events include recent acute coronary syndrome within the past 12 months, a history of myocardial infarction other than the recent acute coronary syndrome event, a history of ischemic stroke, and symptomatic peripheral arterial disease (defined as history of claudication with ankle-brachial index <0.85 or previous revascularization or amputation). High-risk conditions include age of ≥65 years, heterozygous familial hypercholesterolemia, prior percutaneous coronary intervention/coronary bypass surgery, diabetes mellitus, hypertension, chronic kidney disease, current, smoking, history of heart failure, and LDL-C level of 100 mg/dL (to convert to millimoles per liter, multiple by 0.0259) or higher while receiving maximal statin plus ezetimibe.

†By ESC/EAS, very high risk incudes documented ASCVD, either clinical or unequivocal on imaging. Also included are diabetes mellitus with complications, severe chronic kidney disease, 10-year risk for fatal CVD ≥10%, and familial hypercholesterolemia plus ASCVD or another major risk factor. Documented ASCVD includes previous acute coronary syndrome (myocardial infarction or unstable angina), stable angina, coronary revascularization procedures, stroke and transient ischemic attack, and peripheral arterial disease. Unequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events such as significant plaque on coronary angiography or computed tomography scan (multivessel coronary disease with 2 major epicardial arteries having >50% stenosis) or on carotid ultrasound.

Both guidelines highlight the causal role of low-density lipoprotein (LDL) in atherogenesis, and they identify LDL-cholesterol (LDL-C) as the primary target of therapy. Both guidelines recognize a heart-healthy lifestyle as the foundation for treatment. Both further recommend high-intensity statin therapy in patients with ASCVD on the basis of meta-analysis of secondary prevention randomized controlled trials of statin therapy.^1,2 High-intensity statins typically reduce LDL-C by ≥50%, which supports the primary goal of therapy being a ≥50% reduction in LDL-C. Periodic monitoring of the response to therapy is generally recommended. An important addition to both guidelines is the identification of very high-risk patients who may benefit with greater absolute risk reduction from the addition of nonstatins (ezetimibe±PCSK9 inhibitor) to maximal statin therapy.

Although the 2 guidelines share many similarities, notable differences must be recognized and considered. For the definition of documented ASCVD, both guidelines include acute coronary syndrome, stable angina, coronary revascularization, stroke, transient ischemic attack, and peripheral arterial disease. The most important distinction is the definition of very high risk. The AHA/ACC guideline defines very high risk as a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions (see footnote to the Table for details). According to the ESC/EAS, very high risk consists of documented ASCVD or various other higher-risk conditions in the absence of ASCVD (see footnote to the Table for details). These include subclinical atherosclerosis as detected by imaging and several other conditions, for example, diabetes mellitus with complications, severe chronic kidney disease, or 10-year risk of fatal CVD ≥10%. This may expand the number of patients who are candidates for nonstatin add-on therapy, especially patients without ASCVD who are classified as very high risk in the ESC/EAS guidelines. It is important to note that sufficient magnitude of benefit has not been demonstrated with randomized controlled trials, especially with nonstatin therapy in patients noted as very high risk without ASCVD.

The AHA/ACC guideline relegates subclinical atherosclerosis to primary prevention and moderate-intensity statin therapy; high-intensity statins are reserved for those also having multiple risk factors (10-year risk for ASCVD ≥20%). However, the AHA/ACC guideline does not consider subclinical atherosclerosis as an indication for nonstatin therapies. The same can be said for high-risk conditions (except familial hypercholesterolemia) without concomitant ASCVD, for example, diabetes mellitus, chronic kidney disease, or multiple risk factors. As per the AHA/ACC guideline, these conditions alone usually trigger statin therapy but do not warrant the addition of PCSK9 inhibitors.

Besides the LDL-C goal of 50% reduction in patients with ASCVD, both guidelines use numeric thresholds for enhancement of LDL-lowering therapy with nonstatins. In the AHA/ACC guideline, for very high-risk patients, when LDL-C exceeds 70 mg/dL (1.8 mmol/L) on maximal statin therapy, ezetimibe is recommended. If LDL-C remains ≥70 mg/dL or non–high-density lipoprotein cholesterol remains ≥100 mg/dL, consideration can be given to adding a PCSK9 inhibitor. ESC/EAS guidelines offer a similar recommendation for very high-risk patients except that the threshold for adding nonstatins is an LDL-C level ≥55 mg/dL (1.4 mmol/L).

Marginal gains in ASCVD risk reduction diminish as LDL-C levels fall to very low levels. The reason is the curvilinear (log-linear) relation between LDL-C and ASCVD risk. Moreover, a high percentage of patients with ASCVD will have LDL-C ≥55 mg/dL even on maximal statin plus ezetimibe; thus, efficacy and cost considerations may make greatly expanded use of PCSK9 inhibitors problematic. Even in clinical trials of high-intensity statin therapy, ≈75% of patients with acute coronary syndrome continue to have LDL-C levels ≥50 mg/dL, with ≈55% of the patients with LDL-C ≥60 mg/dL.³ Whether such a large number of patients should be prescribed ezetimibe or PCSK9 inhibitors to lower LDL-C levels to <55 mg/dL, at which point gains exist but in terms of net benefit are marginal, remains worthy of further study.

In summary, the AHA/ACC guideline focuses on strictly defined criteria in the clinical trials of statin and nonstatin therapy. That guideline uses the concept of LDL-C and non–high-density lipoprotein cholesterol thresholds. By defining a very high-risk patient with ASCVD subset using clinical criteria, this guideline attempts to identify patients with ASCVD who will derive a much larger absolute reduction in recurrent ASCVD risk compared with an average patient with ASCVD.⁴ The ESC/EAS guidelines recommend an alternative goal-based approach in all patients with either clinical or imaging-based ASCVD (moderate subclinical atherosclerosis). This approach can probably be justified on theoretical grounds and the general concept that lower is better for LDL-C. However, it lacks rigorous testing of efficacy by randomized controlled trials and cost-effectiveness analysis. We hope that further dialog and evidence will guide future iterations of both guidelines in this ever-growing field. Meanwhile, it is crucial to improve implementation of both guidelines to ensure that the maximum ASCVD events are prevented among patients with clinical ASCVD.

Dr Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service Investigator Initiated Grant (IIR 16-072), an American Heart Association Beginning Grant-in-Aid (14BGIA20460366), and a Houston Veterans Affairs Health Services Research and Development Center for Innovations grant (CIN13-413). The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs or the US government.

Dr Virani reports receiving honorarium from the American College of Cardiology (associate editor innovations, ACC.org). The other authors report no conflicts.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

https://www.ahajournals.org/journal/circ

2018年美国心脏协会（AHA）/美国心脏病学会（ACC）血液胆固醇管理多社会指南¹将临床动脉粥样硬化性心血管疾病（ASCVD）的患者分为高风险和极高风险类别。高危人群包括用高强度他汀类药物治疗的稳定ASCVD者。极高风险的患者是那些患有ASCVD加上其他高风险疾病的患者；这些患者可能是接受最大他汀类药物治疗和2种非他汀类药物（依泽替米贝和/或前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型[PCSK9]抑制剂）的潜在候选人。本文将AHA / ACC指南与欧洲心脏病学会（ESC）和欧洲动脉粥样硬化学会（EAS）最近发布的血脂异常指南进行了比较和对比² ; 后者为鉴定被认为有资格在他汀类药物中添加非他汀类药物的患者的识别提供了非常高风险的另一种定义（表）。

表1. 2018 AHA / ACC多社会胆固醇指南和2019 ESC / EAS二级ASCVD预防指南的主要治疗建议的比较

ACC表示美国心脏病学院；美国心脏协会AHA；ApoB，载脂蛋白B；ASCVD，动脉粥样硬化性心血管疾病；EAS，欧洲动脉粥样硬化学会；ESC，欧洲心脏病学会；HDL-C，高密度脂蛋白胆固醇；LDL-C，低密度脂蛋白胆固醇；和PCSK9，前蛋白转化酶枯草杆菌蛋白酶kexin 9。

*通过AHA / ACC，非常高的风险包括多个主要ASCVD事件的历史或1个主要ASCVD事件加上多个高风险条件。主要的ASCVD事件包括最近12个月内的近期急性冠状动脉综合征，除近期的急性冠状动脉综合征事件外的心肌梗塞史，局部缺血性中风史和有症状的外周动脉疾病（定义为足踝肱指数lau行史） <0.85或先前的血运重建或截肢）。高危疾病包括年龄≥65岁，杂合性家族性高胆固醇血症，事先经皮冠状动脉介入治疗/冠状动脉搭桥手术，糖尿病，高血压，慢性肾脏疾病，当前，吸烟，心力衰竭史以及LDL-C水平为100 mg / dL（转换为每升毫摩尔，乘以0。

†通过ESC / EAS，非常高的风险提示有临床或明确影像学表现的ASCVD。还包括具有并发症的糖尿病，严重的慢性肾脏疾病，致命性CVD≥10％的10年风险，家族性高胆固醇血症加ASCVD或其他主要危险因素。已记录的ASCVD包括先前的急性冠状动脉综合征（心肌梗塞或不稳定型心绞痛），稳定型心绞痛，冠状动脉血运重建手术，中风和短暂性脑缺血发作以及周围动脉疾病。影像学上明确记录的ASCVD包括已知可预测临床事件的那些发现，例如冠状动脉造影或计算机断层扫描（显着的斑块状病变，多发性冠状动脉疾病，其中2条主要心外膜动脉狭窄> 50％）或颈动脉超声。

两项指南均强调了低密度脂蛋白（LDL）在动脉粥样硬化中的起因作用，并且将LDL-胆固醇（LDL-C）确定为治疗的主要目标。两项准则都将健康的生活方式视为治疗的基础。两者均根据对他汀类药物治疗的二级预防随机对照试验的荟萃分析，建议对ASCVD患者使用高强度他汀类药物治疗。^1,2高强度他汀类药物通常可使LDL-C降低≥50％，这支持治疗的主要目标是将LDL-C降低≥50％。通常建议定期监测对治疗的反应。这两项指南的重要补充是确定非常高风险的患者，这些患者可能会因将非他汀类药物（依泽替米贝±PCSK9抑制剂）与最大他汀类药物疗法相结合而获得更大的绝对风险降低。

尽管这两个准则具有许多相似之处，但必须认识并考虑显着差异。对于已定义的ASCVD，两个指南均包括急性冠脉综合征，稳定型心绞痛，冠脉血运重建，中风，短暂性脑缺血发作和周围动脉疾病。最重要的区别是极高风险的定义。AHA / ACC指南将非常高的风险定义为具有多个主要ASCVD事件或1个主要ASCVD事件加上多个高风险条件的历史（有关详细信息，请参见表的脚注）。根据ESC / EAS的规定，极高的风险由记录在案的ASCVD或在没有ASCVD的情况下的其他各种较高风险的情况组成（有关详细信息，请参见表的脚注）。这些包括通过影像学检查和其他几种情况检测到的亚临床动脉粥样硬化，例如，具有并发症，严重的慢性肾脏疾病或致命CVD的10年风险≥10％的糖尿病。这可能会增加接受非他汀类药物联合治疗的患者人数，尤其是没有ASCVD且在ESC / EAS指南中被归类为极高风险的患者。重要的是要注意，随机对照试验未显示出足够的获益，尤其是对于非AS汀治疗非常高风险的非他汀类药物治疗。

AHA / ACC指南将亚临床动脉粥样硬化降级为一级预防和中度他汀类药物治疗；高强度他汀类药物是专为那些也具有多种风险因素（ASCVD的10年风险≥20％）的患者而保留的。但是，AHA / ACC指南并未将亚临床动脉粥样硬化视为非他汀类药物治疗的指征。对于没有伴随ASCVD的高危疾病（家族性高胆固醇血症除外），例如糖尿病，慢性肾脏病或多种危险因素，也可以说相同。根据AHA / ACC指南，这些情况通常单独触发他汀类药物治疗，但不保证需要添加PCSK9抑制剂。

除了将ASCVD患者的LDL-C降低50％的目标外，两个指南均使用数字阈值来增强非他汀类药物降低LDL的治疗效果。在AHA / ACC指南中，对于极高风险的患者，当最大他汀类药物疗法的LDL-C超过70 mg / dL（1.8 mmol / L）时，建议使用依泽替米贝。如果LDL-C保持≥70 mg / dL或非高密度脂蛋白胆固醇保持≥100 mg / dL，则可以考虑添加PCSK9抑制剂。ESC / EAS指南为高危患者提供了类似的建议，只是添加非他汀类药物的阈值是LDL-C水平≥55mg / dL（1.4 mmol / L）。

随着LDL-C水平降至非常低的水平，减少ASCVD风险的边际收益会减少。原因是LDL-C与ASCVD风险之间存在曲线（对数线性）关系。此外，即使使用最大的他汀类药物和依折麦布，也有很大一部分ASCVD患者的LDL-C≥55mg / dL。因此，出于功效和成本考虑，可能会使PCSK9抑制剂的使用范围大大扩大。即使在高强度他汀类药物治疗的临床试验中，约有75％的急性冠状动脉综合征患者的LDL-C水平仍≥50 mg / dL，而约有55％的LDL-C≥60mg / dL。³是否应向如此大量的患者开具依泽替米贝或PCSK9抑制剂以将LDL-C水平降低至<55 mg / dL，在这一点上存在获益，但净收益微不足道，仍有待进一步研究。

总之，AHA / ACC指南集中在他汀类和非他汀类药物治疗的临床试验中严格定义的标准。该指南使用LDL-C和非高密度脂蛋白胆固醇阈值的概念。通过使用临床标准定义一个非常高风险的ASCVD子集患者，本指南试图确定与普通ASCVD病人相比，将使ASCVD复发风险的绝对降低更大的ASCVD患者。⁴ESC / EAS指南建议所有基于临床或影像学的ASCVD（中度亚临床动脉粥样硬化）患者均采用基于目标的替代方法。这种方法可能可以从理论基础和低密度脂蛋白胆固醇更好的一般概念上证明。但是，它缺乏通过随机对照试验和成本效益分析进行严格的功效测试。我们希望在这个不断发展的领域中，进一步的对话和证据将指导这两种指南的未来迭代。同时，至关重要的是要改善两个指南的实施，以确保在临床ASCVD患者中最大程度地防止ASCVD事件的发生。

Virani博士得到了退伍军人事务卫生服务研究与发展服务研究人员发起的资助（IIR 16-072），美国心脏协会开始提供助学金（14BGIA20460366）和休斯顿退伍军人事务卫生服务研究与发展的支持创新中心资助（CIN13-413）。表达的观点反映了作者的观点，而不一定反映退伍军人事务部或美国政府的观点。

Virani博士报告说获得了美国心脏病学会的酬金（副主编创新，ACC.org）。其他作者报告没有冲突。

本文表达的观点不一定是编辑者或美国心脏协会的观点。

https://www.ahajournals.org/journal/circ