Impact of new lipid management guidelines on the treatment of extreme and very high-risk patients: AACE/ACE and AHA/ACC guidelines

In February 2017, the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) published an update of their Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. While several topics were updated in the AACE/ACE Guideline, including strategies to assess cardiovascular disease (CVD) risk and treat dyslipidemia in type 1 diabetes, the most substantial changes pertained to atherosclerotic cardiovascular disease (ASCVD) risk categories and low-density lipoprotein cholesterol (LDL-C) goal categorization. For the first time, an “Extreme Risk” category was established, along with the most aggressive LDL-C-lowering goals recognized by any scientific organization to that date.1 The evidence for and treatment implications related to this change, both in general and in context with the recently published American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Management of Blood Cholesterol,2 are discussed below.

1 EXTREME RISK

Individuals who fall into the AACE/ACE “Extreme Risk” category include patients: (a) who experience progressive ASCVD, including unstable angina, after achieving LDL-C < 70 mg/dL; (b) with established clinical CVD and diabetes mellitus (DM), stage 3 or 4 chronic kidney disease (CKD), or heterozygous familial hypercholesterolemia (HeFH); and/or (c) with a history of premature ASCVD (aged <55 years for males and <65 years for females) (Table 1).1 Clinical ASCVD, a component of the new AACE/ACE extreme-risk category, is defined by the ACC/AHA as coronary heart disease (CHD) (acute coronary syndrome [ACS], history of myocardial infarction [MI], stable or unstable angina, coronary or other arterial revascularization), stroke or transient ischemic attack (TIA), or peripheral arterial disease.3

CKD, another component of the extreme-risk category, is a well-recognized major risk factor for ASCVD and increased all-cause mortality.4-6 In a large population-based cohort study (>1 million participants; median follow-up 48 months), unadjusted all-cause mortality in patients with CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m²) was similar to that of patients with a previous MI and greater than in patients with diabetes alone. Patients with diabetes and CKD had the highest all-cause mortality.4 In a systematic review, all-cause and CVD mortality rates were increased by 6- and 16-fold, respectively, in patients with proteinuria at baseline compared to those without.6 Likewise, a meta-analysis of general population cohort studies (N = 105 872) found that albuminuria, whether measured by albumin/creatinine ratio or urine protein dipstick, was associated with elevated all-cause and CV mortality.5

HeFH is another component of the extreme-risk category. Individuals with HeFH who are untreated are 20 times more likely to develop coronary artery disease (CAD) than those without.7 By age 50, untreated men with familial hypercholesterolemia (FH) have a 50% risk for a fatal or nonfatal coronary event; for untreated women, this rate is 30% by age 60.8 A long-term (8.5 years) cohort study of patients with FH (N = 2146) demonstrated that statin treatment in patients with FH substantially improved cumulative CHD-free survival; compared with untreated patients, statin patients had a 76% reduction in CHD risk (hazard ratio: 0.24 [95% CI: 0.18-0.30]; P <.001).9

2 LDL-C GOAL

The AACE/ACE LDL-C goal for patients at extreme risk is <55 mg/dL, with a non-high-density lipoprotein cholesterol (HDL-C) goal of <80 mg/dL and an apolipoprotein B (ApoB) goal of <70 mg/dL. The LDL-C goal of <55 mg/dL was derived from a number of evidence lines clearly indicating that “lower is better.”1, 10-12 In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; N = 18 144), patients at very high/extreme CVD risk who achieved an average LDL-C of 53.2 mg/dL with statin and ezetimibe experienced a significantly lower risk of CVD events than patients treated with statin alone (average LDL-C: 69.9 mg/dL). The prespecified diabetes subgroup benefited the most from achieving lower LDL-C with combination therapy.11

Additionally, the 2010 Cholesterol Treatment Trialists' (CTT) Collaboration meta-analysis of 26 clinical trials (N = 169 138 patients with ACS or stable ASCVD) studied the benefits of statin therapy for LDL-C reduction. Results of this trial showed that each 39 mg/dL reduction in LDL-C corresponded with an approximate 29% or 37% reduction in major vascular events for participants with baseline LDL-C < 77 mg/dL or LDL-C < 70 mg/dL, respectively.1, 12 When CHD events are plotted against achieved LDL-C in secondary prevention trials, there is a direct relationship between lower LDL-C levels and reduced CHD events; this relationship existed continuously to LDL-C levels well below 70 mg/dL.10

3 CALCULATING RISK

The AACE/ACE guidelines recommend four risk calculators to help assess patient risk for a coronary event: the Framingham Risk Assessment Tool, the Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD Risk with Coronary Artery Calcification Calculator, Reynolds Risk Score, and the United Kingdom Prospective Diabetes Study risk engine to calculate ASCVD risk in individuals with type 2 diabetes.1 The lipid guidelines highlight the MESA calculator in particular, which utilizes coronary artery calcification (CAC) scoring, in conjunction with traditional risk factors, as a useful tool to improve risk prediction, especially in low-risk patients.13, 14 The presence of CAC greatly amplifies CVD risk, independent of traditional risk factors,15, 16 and CAC scoring has the same risk stratification utility in patients both with and without diabetes,17 in contrast to the long-held belief that diabetes is a CAD equivalent.

4 PCSK9 INHIBITION

The recently introduced proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide substantial additive LDL-C lowering, and evidence for the efficacy of these drugs18-20 further validates the benefit of very aggressive LDL-C reductions in patients at extreme risk.1 The Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV; N = 968) was a double-blind, placebo-controlled, randomized clinical trial to determine the effects of evolocumab added to statins on the progression of coronary atherosclerosis. As LDL-C was lowered to 20 mg/dL, linear and continuous plaque regression was demonstrated, with no threshold.18

Two randomized, double-blind, placebo-controlled cardiovascular outcome trials of evolocumab and alirocumab (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk [FOURIER; N = 27 564]19 and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab [ODYSSEY Outcomes; N = 18 924])20 validated “lower is better” in patients at extreme CVD risk. In the FOURIER trial, a clear CVD benefit resulted when LDL-C was lowered by 60 mg/dL to very low levels (30 mg/dL) with statin + evolocumab compared to an LDL-C of 90 mg/dL in the statin-only group. A prespecified post hoc analysis of achieved LDL-C levels in FOURIER showed a progressive decrease in CVD death, MI, and stroke as LDL-C was lowered to <10 mg/dL.21 Last, the ODYSSEY Outcomes trial, targeting LDL-C levels as low as 15 mg/dL with alirocumab, reduced major adverse cardiovascular events by 15%, MI by 14%, ischemic stroke by 27%, and unstable angina by 39% vs controls.20

5 DIFFERENCES BETWEEN AACE/ACE AND ACC/AHA GUIDELINES

The ACC/AHA guidelines establish a secondary prevention “Very High Risk” ASCVD category. This is the only ACC/AHA category with an LDL-C threshold (≥70 mg/dL) triggering consideration of PCSK9 inhibitor therapy for maximum LDL-C lowering. The very high-risk category comprises either multiple major ASCVD events or one major ASCVD event and ≥2 high-risk condition (Table 2). The major ASCVD events category does not include prior coronary artery bypass graft (CABG) or percutaneous coronary intervention; these are listed only as high-risk conditions. There is also no recognition in the ACC/AHA guidelines of TIA as a major ASCVD event or high-risk condition.2 Compared to the general population, patients with CABG have increased cumulative mortality for up to three decades following surgery.22 Both CABG and TIA are well-established risk factors, are components of the ACC/AHA definition of clinical ASCVD, and are used to classify patient risk in the AACE/ACE lipid guidelines.1, 23

In the absence of multiple major ASCVD events, ≥2 high-risk conditions, along with one major ASCVD event are required for the ACC/AHA very high-risk category. There are many scenarios in which individuals would fall into the AACE/ACE extreme-risk category, but not the ACC/AHA very high-risk category (Table 3).2 For example, a patient with a history of MI and a single high-risk condition (ie, DM, CKD, HeFH, hypertension, prior CABG, or history of MI after achieving LDL-C ≤ 70 mg/dL) but who lacks a second high-risk condition, would not be at very high risk according to the ACC/AHA. Other examples include TIA or stroke in patients with DM, CKD, hypertension or past CABG, and recent ACS with prior CABG, all without a second high-risk condition. According to the ACC/AHA treatment algorithm, none of these patients would be candidates for maximal LDL-C lowering with PCSK9 inhibitor therapy.

In many (perhaps most) instances, individuals who have a major ASCVD event will manifest >1 high-risk condition and will qualify under both sets of guidelines for maximal LDL-C lowering using PCSK9 inhibitor therapy. However, if risk stratification is limited to the ACC/AHA guidelines, clinicians should be aware that patients who would be classified by AACE/ACE as “Extreme Risk,” with an LDL-C goal of <55 mg/dL, may not be classified as “Very High Risk,” and as a result, may not be treated as aggressively as is supported by current evidence.

DISCLOSURE OF INTERESTS

Speaker's Bureau: Amgen, Regeneron/Sanofi.

2017年2月，美国临床内分泌学家协会(American Association of Clinical Endocrinologists，AACE)与美国内分泌学协会(American College of Endocrinology，ACE)发布公告对血脂异常管理和心血管疾病预防指南进行了更新。在AACE/ACE指南中更新了几个主题，包括评估1型糖尿病患者心血管疾病(cardiovascular disease CVD)风险以及治疗血脂异常的策略，最重要的变化是与动脉粥样硬化性心血管疾病(ASCVD)风险分类和低密度脂蛋白胆固醇(LDL-C)控制目标分类相关。首次确立了“极高危”类别，并且沿用了迄今为止任何科学组织公认的最积极的LDL-C控制目标¹。无论是在一般情况下，还是在最近美国心脏病学协会/美国心脏协会(ACC/AHA)出版的血胆固醇管理指南的背景下²，下面将要讨论的是这种变化的相关证据以及治疗意义。

1 极高危

属于AACE/ACE“极高危”类别的患者包括:(a)达到 LDL-C < 70 mg/dL 后出现累进性 ASCVD，包括不稳定型心绞痛；(b)确诊的临床CVD和糖尿病(diabetes mellitus，DM)、3期或4期慢性肾脏病(chronic kidney disease，CKD)或杂合子型家族性高胆固醇血症(heterozygous familial hypercholesterolemia，HeFH)；(c)有早发性ASCVD病史(男性<55岁，女性<65岁)的患者(表1)。临床ASCVD是新的AACE/ACE极高危类别的组成部分，ACC/AHA将其定义为冠心病(coronary heart disease，CHD)[急性冠状动脉综合征(acute coronary syndrome，ACS)、心肌梗死(myocardial infarction，MI)病史、稳定性或者不稳定性心绞痛、冠状动脉或者其他动脉血运重建术)、卒中或短暂性脑缺血发作(TIA)或外周动脉疾病³。

CKD是极高危类别的另一个组成部分，是公认的ASCVD和全因死亡率增加的主要危险因素^4-6。在一项大规模的基于人群的队列研究中(>100万参与者；中位数随访时间为48个月)，合并CKD患者(估算的肾小球滤过率<60 ml/min/1.73 m²)未校正的全因死亡率与既往MI患者相似，但高于单纯糖尿病患者。糖尿病合并CKD患者的全因死亡率最高⁴。在一篇系统综述中，基线有蛋白尿患者的全因死亡率和CVD死亡率分别是无蛋白尿患者的6倍和16倍⁶。同样，一项针对普通人群队列研究的meta分析(N=105 872)发现，无论是用白蛋白/肌酐比值还是用尿蛋白试纸检测来诊断白蛋白尿，白蛋白尿均与全因死亡率和CV死亡率升高相关⁵。

HeFH是极高危类别的另一个组成部分。患有HeFH但未接受治疗的个体发生冠状动脉疾病(coronary artery disease，CAD)的可能性是未患有HeFH个体的20倍⁷。到50岁时，未经治疗的家族性高胆固醇血症(familial hypercholesterolemia，FH)男性患者有50%的可能性会发生致命性或者非致命性冠状动脉事件；对于未治疗的女性来说，60岁时发生这些事件的可能性为30%⁸。一项针对FH患者(N=2146)的长期(8.5年)队列研究表明，FH患者接受他汀类药物治疗后可显著改善累积的无CHD生存率；与未治疗的患者相比，他汀类药物治疗患者的CHD风险降低76%(风险比:0.24[95% CI:0.18-0.30]；P<001)⁹。

2 LDL-C控制目标

AACE/ACE制定的极高危类别患者的LDL-C控制目标为<55mg/dL，非高密度脂蛋白胆固醇(high-density lipoprotein cholesterol，HDL-C)控制目标为<80 mg/dL，载脂蛋白B(apolipoprotein B，ApoB)控制目标<70mg/dL。之所以将LDL-C的控制目标制定为<55mg/dL是由于大量证据表明LDL-C“越低越好”^10-12。在进一步减少终点事件:Vytorin疗效国际试验(IMPROVE-IT；N=18 144)中，与单纯使用他汀类药物治疗的患者(平均LDL-C:69.9 mg/dL)相比，使用他汀类联合依折麦布治疗的高危/极高危CVD风险患者(平均LDL-C达到53.2 mg/dL)发生CVD事件的风险显著降低。预先定义的糖尿病亚组患者从联合治疗降低LDL-C中获益最多¹¹。

此外，2010年胆固醇治疗试验(Cholesterol Treatment Trialists'，CTT)对26项研究他汀类药物治疗后LDL-C下降获益的临床试验(N=169 138，合并ACS或稳定性ASCVD的患者)进行了联合meta分析。这项试验结果显示，LDL-C每降低39 mg/dL，基线LDL-C < 77 mg/dL或LDL-C < 70 mg/dL的受试者的主要血管事件分别减少约29%或37%。在二级预防试验中，将发生的CHD事件与达到的LDL-C水平进行绘图，发现较低的LDL-C水平与更少的CHD事件之间具有直接相关性；当LDL-C水平低于70 mg/dL时，这种相关性持续存在¹⁰。

3 预测风险

AACE/ACE指南推荐了4种可用于评估冠状动脉事件风险的计算方法:使用Framingham风险评估工具、动脉粥样硬化多种族研究(the Multi-Ethnic Study of Atherosclerosis，MESA)10年ASCVD风险与冠状动脉钙化计算器、Reynolds风险评分和英国前瞻性糖尿病研究风险引擎来计算2型糖尿病患者的ASCVD风险¹。在血脂指南中特别强调了MESA计算器，这种方法使用冠状动脉钙化(coronary artery calcification，CAC)评分结合传统危险因素来评估患者，是一种有用的可改善风险预测结果的方法，尤其是在低风险患者中^13,14。存在CAC大大增加了CVD风险，这种相关性独立于传统的危险因素^15,16，并且CAC评分在糖尿病和非糖尿病患者中具有相同的危险分层效用¹⁷，这与长期以来公认的糖尿病是CAD等位症的观点相反。

4 PCSK9抑制剂

最近推出的前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/ kexin type 9，PCSK9)抑制剂可使LDL-C进一步显著下降，并且这些药物的疗效证据^18-20进一步证实了极高危患者积极降低LDL-C的获益¹。血管内超声测量PCSK9抗体对斑块消退的整体评估试验(GLAGOV；N=968)是一项双盲、安慰剂对照、随机临床试验，旨在确定evolocumab 联合他汀类药物对冠状动脉粥样硬化进展的影响。结果发现随着LDL-C降低至20mg/dL，LDL-C下降与斑块消退之间呈持续线性相关，无阈值¹⁸。

在具有极高危CVD风险的患者中进行的两项分别使用evolocumab与alirocumab治疗的随机、双盲、安慰剂对照心血管结局试验(评估高危受试者使用PCSK9抑制剂治疗后的进一步心血管结局研究[FOURIER；N=27 564]¹⁹与评估急性冠状动脉综合征后使用alirocumab治疗的心血管结局研究[ODYSSEY结局；N=18 924])²⁰均证实了LDL-C“越低越好”。在FOURIER试验中，与单纯使用他汀类药物治疗后LDL-C降低至90 mg/dL相比，联合使用他汀类药物和evolocumab治疗后LDL-C进一步降低60 mg/dL至极低水平(30 mg/dL)具有明显的CVD获益。对FOURIER试验中达到的LDL-C水平进行预先设定的事后分析发现，随着LDL-C降至<10 mg/dL²¹，CVD死亡、MI和卒中风险逐渐降低。最后，在旨在加用alirocumab使LDL-C水平降低至15 mg/dL的ODYSSEY结局试验中，与对照组相比，alirocumab治疗组的主要不良心血管事件减少15%，MI减少14%，缺血性卒中减少27%，不稳定型心绞痛减少39%²⁰。

5 AACE/ACE与ACC/AHA指南的差异

ACC/AHA指南确立了二级预防“非常高危”ASCVD类别。在这个仅在ACC/AHA中存在的类别中，LDL-C阈值达到≥70mg/dL就要考虑加用PCSK9抑制剂治疗以最大程度降低LDL-C。非常高危类别包括多个主要ASCVD事件或者一个主要ASCVD事件加≥2个高危因素(表2)。主要ASCVD事件类别不包括既往冠状动脉旁路移植术(CABG)与经皮冠状动脉介入治疗；这些仅被列为高危因素。ACC/AHA指南中也未将TIA确认为主要ASCVD事件或高危因素。与普通人群相比较，CABG患者术后30年的累积死亡率明显上升²²。CABG与TIA是公认的危险因素，均是ACC/AHA定义的临床ASCVD的组成部分，在AACE/ACE血脂指南中用于对患者风险进行分类^1,23。

在无多个主要ASCVD事件的情况下，ACC/AHA定义的非常高危类别需要≥2个高危因素加1个主要ASCVD事件。在许多情况下，患者可能属于AACE/ACE定义的极高危类别，但却不属于ACC/AHA定义的非常高危类别(表3)²。例如，根据ACC/AHA指南，有MI病史并且只有1个高危因素(亦即合并DM、CKD、HeFH、高血压、既往CABG或达到LDL-C≤70 mg/dL后有MI病史)，但无第二种高危因素的患者不属于非常高危类别。其他例子包括合并DM、CKD、高血压或既往CABG史以及既往CABG伴近期ACS，但均无第2种高危因素的患者中发生TIA或卒中。根据ACC/AHA治疗策略，这些患者均不适合使用PCSK9抑制剂治疗以最大程度降低LDL-C。

在很多(很可能是大多数)情况下，发生ASCVD事件的患者会合并1种以上的高危因素，根据这两个指南患者将需要使用PCSK9抑制剂治疗以最大程度降低LDL-C。然而，如果只限于使用ACC/AHA指南进行风险分层，临床医生应注意，那些被AACE/ACE归类为“极高危”类别，LDL-C控制目标为<55mg/dL的患者，根据ACC/AHA指南可能并不会被归类为“非常高危”类别，因此不会像当前证据支持的那样接受积极治疗。

缩略语:AACE，美国临床内分泌学家协会；ACE，美国内分泌学协会；ACS，急性冠脉综合征；ApoB，载脂蛋白B；ASCVD，动脉粥样硬化性心血管疾病；CKD，慢性肾脏病；CVD，心血管疾病；DM，糖尿病；HDL-C，高密度脂蛋白胆固醇；HeFH，杂合子型家族性高胆固醇血症；LDL-C，低密度脂蛋白胆固醇；NR，不推荐。

缩略语:ACC，美国心脏病学协会；ACS，急性冠状动脉综合征；AHA，美国心脏协会；ASCVD，动脉粥样硬化性心血管疾病；CKD，慢性肾脏病；DM，糖尿病；eGFR，估算的肾小球滤过率；HeFH，杂合子型家族性高胆固醇血症；LDL-C，低密度脂蛋白胆固醇；MI，心肌梗死；PCI，经皮冠状动脉介入治疗。

缩略语:AACE，美国临床内分泌学家协会；ACC，美国心脏病学协会；ACE，美国内分泌学协会；ACS，急性冠状动脉综合征；ASCVD，动脉粥样硬化性心血管疾病；AHA，美国心脏协会；CABG，冠状动脉搭桥术；CKD，慢性肾脏病；CVD，心血管疾病；DM，糖尿病；HeFH，杂合子型家族性高胆固醇血症；HTN，高血压；LDL-C，低密度脂蛋白胆固醇；MI，心肌梗死；PAD，外周动脉疾病；TIA，短暂性脑缺血发作。