Rationale, Criteria, and Impact of Identifying Extreme Risk in Patients with Atherosclerotic Cardiovascular Disease

Abstract

Assessment of the overall risk of atherosclerotic cardiovascular disease (ASCVD) is the first step in managing dyslipidemia and is an important reference for the target and intensity of treatment. Recently, different guidelines and consensuses on the management of this condition have successively recommended further risk stratification among patients with ASCVD, and a new “extreme risk” category has been proposed to identify patients who may obtain greater benefit from more intensive lipid-lowering therapy. The definition and terminology of extreme risk varies among different guidelines and consensuses; however, they all recommended an aggressive lipid-lowering therapeutic approach and/or a more stringent low-density lipoprotein cholesterol target for patients at extreme risk. Regardless of the definitions, this general approach may have a remarkable effect on the treatment of this condition in clinical practice. To help clinicians and patients to better understand the new strategy for the secondary prevention of ASCVD, this review provides a summary highlighting the necessity of further risk stratification among ASCVD patients, how patients at extreme risk can be identified, and the potential impact of applying the new “extreme risk” category in clinical practice.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in China and globally, and has an increasing disease burden.^[1–3] Evidence from genetic, epidemiologic, and clinical studies have consistently demonstrated that low-density lipoprotein cholesterol (LDL-C) is a causal factor for ASCVD.^[4] Lowering LDL-C levels can significantly reduce the risk of morbidity and mortality associated with this condition.^[5,6]

While the relationship between lower LDL-C levels and lower ASCVD risk in all individuals, from those at low risk to those at very high risk, has been confirmed, it is more cost-effective to use LDL-C lowering drugs only in patients at high or very high risk of ASCVD. Furthermore, different LDL-C targets have been recommended for people according to their level of ASCVD risk, based on available evidence from research.^[7–9] The strategy of lower LDL-C targets for those at higher risk of ASCVD has been broadly accepted in clinical practice. Therefore, ASCVD risk classification is the first step in the management of dyslipidemia, providing important guidance for clinical decisions on the target and intensity of treatment.^[7–9] For a long time, patients with ASCVD have all been considered to be at very high risk. The same intensity of lipid lowering treatment and the same LDL-C target were therefore recommended for all individuals with ASCVD.^[9–12] However, an increasing number of studies have found that the risk of recurrent cardiovascular events varied greatly among patients with ASCVD.^[13–15] Those with a higher risk obtained a greater benefit from lowering their LDL-C levels to a greater extent with more intensive lipid-lowering treatments, such as the combination of ezetimibe with maximally-tolerated statin therapy, or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), compared with their lower risk counterparts.^[14,16–19] Thus, further risk stratification among patients with ASCVD became necessary to identify those at even higher risk, who thus require more intensive treatment to lower their LDL-C below the previous target (<70 mg/dL).

Since 2017, different guidelines and consensuses on the management of dyslipidemia have successively proposed a new “extreme risk” category, and recommended that patients at extreme risk should be given more aggressive lipid-lowering therapy, and/or a more stringent LDL-C target should be used.^[8,20–22] The definition and terminology of extreme risk varies among guidelines and consensuses. However, regardless of the specific definition, applying stringent lipid-lowering strategies to those at extreme risk is likely to have a remarkable impact on clinical practice because it will substantially increase the number of individuals requiring combined lipid-lowering therapy to further lower their risk of recurrent ASCVD and death.

This review aims to summarize the literature regarding key issues associated with this new risk assessment strategy for ASCVD patients, focusing on why further risk stratification among ASCVD patients is required, how patients at extreme risk can be identified, and the potential impact of applying the new “extreme risk” category in clinical practice. This review thus provides a basis to help clinicians and patients better understand the new strategy for secondary prevention of ASCVD.

The rationale for risk stratification among ASCVD patients

Varied recurrent cardiovascular disease (CVD) risk among ASCVD patients

Based on the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events−TIMI 50 trial, Bohula et al^[13] found that the recurrent CVD risk varied among patients with a history of myocardial infarction (MI). They identified 9 risk factors associated with the risk of recurrent CVD events in this group, as follows: age ≥75 years, diabetes mellitus (DM), hypertension, smoking, peripheral arterial disease (PAD), previous stroke, previous coronary artery bypass grafting, heart failure (HF), and renal dysfunction (estimated glomerular filtration rate (eGFR) <60 mL/(min·1.73 m²)). Patients with a greater number of risk factors had greater risks of recurrent CVD events over a period of 3 years. This research established the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS 2°P) to evaluate the risk of recurrent cardiovascular events in patients with ASCVD.^[13] The positive association between TRS 2°P score and risk of recurrent CVD events has also been demonstrated in Chinese individuals with non-ST-elevated MI.^[23]

Further studies in China and other countries have also reported similar findings that among ASCVD patients, the risk of recurrent cardiovascular events varies considerably.^[15,24–27]

Higher residual ASCVD risk among higher-risk individuals with ASCVD

The main strategies for secondary prevention of ASCVD are well-established. Treatment strategies include lifestyle modifications, anti-hypertensive treatment, lipid-lowering therapy, the use of antiplatelet agents, and coronary artery revascularization in selected individuals.^[28] However, despite the use of these evidence-based therapies and attainment of all guideline-recommended targets for risk factor control, substantial residual risk for recurrent CVD events remains.^[28–30] For example, Kaasenbrood et al^[29] found substantial variation in the estimated 10-year risk of recurrent CVD among patients with ASCVD. If all known modifiable risk factors were at the guideline-recommended targets, half of patients would have a 10-year cardiovascular risk of more than 10%, and 9% of patients would have a 10-year cardiovascular risk of more than 30%.^[29] Thus, as ASCVD patients with higher risk have greater residual risk of ASCVD, approaches for reducing the residual risk for ASCVD remains an important issue in the secondary prevention of ASCVD.

Lowering LDL-C to a greater extent lowers residual risk in people with ASCVD

Among the risk factors for ASCVD, LDL-C is recognized as a causal factor for atherosclerosis, and represents a key target for primary and secondary prevention of ASCVD.^[4,7–9,20] Studies have consistently reported a continuous log-linear association between the absolute magnitude of exposure to plasma LDL-C and risk of ASCVD.^[4–6] A meta-analysis suggested that a 1-mmol/L reduction in the level of LDL-C in the plasma is associated with an approximately 21% reduction in the incidence of major vascular events among people with coronary heart disease (CHD).^[5] In those with ASCVD, studies have shown that lowering LDL-C levels to as low as 1.0 mmol/L does not increase the risk of severe adverse events.^[7,31,32] Using statins to lower LDL-C is an important cornerstone in the prevention and treatment of ASCVD. However, the extent to which statins can reduce LDL-C levels is relatively limited: doubling the statin dose can achieve a further reduction in LDL-C of approximately 6%. In addition, Chinese guidelines for cholesterol management recommend moderate-intensity statin therapy, owing to the relatively low tolerance to high-intensity statin treatment in Chinese population.^[9] Thus, to achieve lower LDL-C levels to further reduce residual ASCVD risk, maximally-tolerated statin therapy combined with ezetimibe, or even PCSK9i, is necessary.^[8,22]

Three large randomized controlled trials (RCTs) of non-statin drugs have demonstrated that further reduction of LDL-C in patients with ASCVD can reduce the residual risk of CVD events without increasing the risk of other adverse outcomes [Table 1].^[31–33] The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) indicated that, compared with results in a simvastatin monotherapy group, statins combined with ezetimibe achieved lower LDL-C levels (53.7 mg/dL vs. 69.5 mg/dL in the simvastatin monotherapy group). This combined treatment reduced the absolute and relative risks of cardiovascular events in acute coronary syndromes (ACS) patients with LDL-C levels within the guideline recommendations by 2% and 6.4%, respectively.^[33] The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study indicated that, adding PSCK9i (evolocumab) to statin therapy reduced LDL-C levels from 92 mg/dL to a median of 30 mg/dL; the absolute and relative risk of adverse cardiovascular events were also reduced by 2% and 15%, respectively, relative to the placebo group.^[32] Another RCT of a PCSK9i, ODYSSEY OUTCOMES, suggested that treatment with alirocumab reduced LDL-C levels from (92 ± 31) mg/dL at baseline to a median of 66 mg/dL at 48 weeks (intention-to-treat analysis), resulting in a lower risk of recurrent ischemic cardiovascular events compared with a placebo group (hazard ratio, 0.85; 95% confidence interval (CI), 0.78–0.93; P < 0.001).^[31]

Table 1 - Three well-known large randomized controlled trials of non-statin drugs

Study	Sample size	Study population	Intervention	Control	Follow-up	Outcomes	LDL-C levels	Results
IMPROVE-IT, 2015[33]	18,144	(1) People with ACS aged ≥50 years(2) LDL-C: 50–100 mg/dL (on LLT), 50–125 mg/dL (not on LLT)	Ezetimibe 10 mg + Simvastatin 40 mg	Placebo + Simvastatin 40 mg	2.5–7.0 years	CV death, nonfatal Ml, hospitalization for unstable angina, coronary revascularization, nonfatal stroke	Baseline, 93.8 mg/dL After 1 year, Control: 69.9 mg/dL; Intervention: 53.2 mg/dL, further reduction of 24%	At 7 years, Control: 34.7%; Intervention: 32.7%HR: 0.94 (0.89–0.99)
FOURIER, 2017[32]	27,564	(1) Aged 40–85 years(2) People with ASCVD or greater cardiovascular risk(3) LDL-C≥70 mg/dL or non-HDL-C≥100 mg/dL (on LLT)	Evolocumab	Placebo	Median 2.2 years	CV death, Ml, stroke, hospitalization for unstable angina, or coronary revascularization	Baseline, 92 mg/dL At 48 weeks, Intervention: 30 mg/dL, further reduction of 59%	At 3 years, Control: 14.6%; Intervention: 12.6% HR: 0.85 (0.79–0.92)
ODYSSEY OUTCOMES, 2018[31]	18,924	(1) Age≥40 years(2) ACS within the preceding 1–12 months(3) LDL-C≥70 mg/dL or non-HDL ≥100 mg/dL or apollpoproteln B ≥80 mg/dL (on LLT)	Alirocumab	Placebo	Median 2.8 years	CHD-related death, nonfatal Ml, fatal or nonfatal Ischemic stroke, unstable angina requiring hospitalization	Baseline, 92 mg/dL Placebo, 4 months: 93 mg/dL; 6 months: 96 mg/dL; 48 months:103 mg/dLIntervention, 4 months: 40 mg/dL; 6 months: 48 mg/dL; 48 months: 66 mg/dL	At 48 months, Placebo: 14.5%; Intervention: 12.5% HR: 0.85 (0.78–0.93)

ACS: Acute coronary syndrome; ASCVD: Atherosclerotic cardiovascular disease; CHD: Coronary heart disease; CV: Cardiovascular; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition In Subjects with Elevated Risk; HDL-C: High-density lipoprotein cholesterol; HR: Hazard ratio; IMPROVE-IT: Improved Reduction of Outcomes: Vytorln Efficacy International Trial; LDL-C: Low-density lipoprotein cholesterol; LLT: Lowerlng-llpld therapy; Ml: Myocardial Infarction.

All 3 large RCTs indicated that further reduction of LDL-C levels in ASCVD patients results in a lower risk of CVD events. However, it is not feasible to give all ASCVD patients intensive therapy to further lower their LDL-C levels owing to its economic cost, so a means of subdividing this group according to their potential to benefit from treatment is required.

Individuals with ASCVD at higher risk receive greater benefits from lipid-lowering treatment

Bohula et al^[14] demonstrated that the TRS 2°P can effectively identify patients at higher risk of recurrent cardiovascular events among post-ACS individuals, who have the greatest potential to benefit from the addition of ezetimibe to statin therapy according to the IMPROVE-IT trial. A strong graded relationship between TRS 2°P and the composite rate of cardiovascular-related death, MI, or ischemic stroke during a 7-year period was observed, ranging from 8.6% for patients with no risk indicators to 68.4% for patients with ≥5 risk indicators in the control group, who received placebo and simvastatin. The patients were stratified according to their risk of cardiovascular death, MI, or ischemic stroke, into low-risk (<2%/year), moderate-risk (2%–5%/year), and high-risk (>5%/year) categories, which aligned with the presence of 0 to 1, 2, and ≥3 risk indicators, respectively. Compared with the placebo and simvastatin treatment, ezetimibe combined with simvastatin reduced the absolute and relative risks of cardiovascular events by 6.3% and 19%, respectively, in patients at high risk, and by 2.2% and 11%, respectively, in patients at moderate risk. However, no risk reduction was observed among people with ASCVD at low risk. Other post hoc and subgroup analyses in the IMPROVE-IT, FOURIER, and ODYSSEY OUTCOMES trials suggested that several high-risk subgroups may benefit from more intensive lipid lowering therapy, including those with diabetes, multivessel disease, and those with a prior history of ≥2 MIs [Table 2].^[16–19]

Table 2 - Characteristics of 5 studies on the benefit of more intensive lowering-lipid therapy in ASCVD patients with different coexisting high-risk conditions.

References	Study	Sample size	Study population	Treatment/control	Follow-up	Outcomes	Results
Bohula, 2017[14]	IMPROVE-IT	17,717	(1) ACS patients aged >65 years(2) LDL-C: 50–100 mg/dL (on LIT), 50–125 mg/dL (not on LLT)	Treatment: simvastatin 40 mg+ezetimibe 10 mgControl: simvastatin 40 mg+ placebo	2.5–7.0 years	CV-related death, MI, or ischemic stroke at 7 years	Low risk (0–1 risk indicators): Treatment vs. control: 14.0% vs. 13.1%; ARR: −0.9% (−2.5%, 0.7%), HR: 1.05 (0.92, 1.19)Intermediate risk (2 risk indicators): Treatment vs. control: 19.3% vs. 21.5%; ARR: 2.2% (−0.3%, 4.6%), NNT: 45, HR: 0.89 (0.78, 1.01)High risk (>3 risk indicators): Treatment vs. control: 33.9% vs. 40.2%; ARR: 6.3% (2.9%, 9.7%), NNT: 16, HR: 0.81 (0.73, 0.90)
Giugliano, 2018[16]	IMPROVE-IT	18,144	(1) ACS patients aged >65 years(2) LDL-C: 50–100 mg/dL (on LLT), 50–125 mg/dL (not on LLT)	Treatment: simvastatin 40 mg+ezetimibe 10 mg Control: simvastatin 40 mg+placebo	2.5–7.0 years	CV-related death, major coronary event (eg, MI, unstable angina requiring hospital admission, coronary revascularization occurring ≥30 days after randomization), or stroke at 7 years	DM: Treatment vs. control: 40.0% vs. 45.5%; NNT: 18, HR: 0.85 (0.78, 0.94)No DM: Treatment vs. control: 30.2% vs. 30.8%; HR: 0.98 (0.91, 1.04)
Sabatine, 2017[17]	FOURIER	27,564	Patients with atherosclerotic disease who received statin therapy (11,031 with DM; 16,533 without DM)	Treatment: evolocumab Control: placebo	Median 2.2 years	CV-related death, MI, stroke, coronary revascularization, or hospital admission for unstable angina at 3 years	DM: Treatment vs. control: 14.4% vs. 17.1%; ARR: 2.7% (0.7%, 4.8%), NNT: 37, HR: 0.83 (0.75, 0.93)No DM: Treatment vs. control: 11.4% vs. 13.0%; ARR: 1.6% (0.1%, 3.2%), NNT: 62, HR: 0.87 (0.79, 0.96)
Sabatine, 2018[18]	FOURIER	22,351	Patients with prior MI	Treatment: evolocumab Control: placebo	Median 2.2 years	CV-related death, MI, stroke, coronary revascularization, or hospital admission for unstable angina at 3 years	MI within 2 years: Treatment vs. control: 13.5% vs. 16.9%; ARR: 3.4% (1.4%, 5.3%), HR: 0.80 (0.71, 0.91)Remote MI: Treatment vs. control: 13.3% vs. 14.0%; ARR: 0.8% (−1.1%, 2.7%), HR: 0.95 (0.85, 1.05)≥2 prior MIs: Treatment vs. control: 18.7% vs. 22.4%; ARR: 3.7% (0.8%, 6.6%), HR: 0.82 (0.72, 0.93)Without multiple MIs: Treatment vs. control: 11.5% vs. 12.8%; ARR: 1.3% (−0.2%, 2.7%), HR: 0.92 (0.84, 1.02)With multivessel disease: Treatment vs. control: 15.8% vs. 19.4%; ARR: 3.6% (0.7%, 6.4%), HR: 0.79 (0.69, 0.91)Without multivessel disease: Treatment vs. control: 12.4% vs. 13.6%; ARR: 1.2% (−0.3%, 2.7%), HR: 0.93 (0.85, 1.02)
Jukema, 2019[19]	ODYSSEY OUTCOMES	18,924	ACS patients: 17,370 monovascular (coronary) disease, 1405 polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), 149 with polyvascular disease in 3 beds	Treatment: alirocumab Control: placebo	Median 2.8 years	CHD-related death, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization at 3 years	Monovascular disease: Treatment vs. control: 8.5% vs. 10.0%; ARR: 1.4% (0.6%, 2.3%), HR: 0.85 (0.77, 0.93)Polyvascular disease in 2 beds: Treatment vs. control: 20.3% vs. 22.2%; ARR: 1.9% (−2.4%, 6.2%)CAD and PAD: Treatment vs. control: 22.8% vs. 23.7%; ARR: 0.9% (−5.9%, 7.6%), HR: 0.93 (0.67, 1.30)CAD and CeVD: Treatment vs. control: 18.5% vs. 21.1%; ARR: 2.6% (−2.9%, 8.2%), HR: 0.87 (0.63, 1.19)Polyvascular disease in 3 beds: Treatment vs. control: 26.8% vs. 39.7%; ARR: 13.0% (−2.0%, 28.0%), HR: 0.64 (0.35, 1.12)

ACS: Acute coronary syndrome; ARR: Absolute risk reduction; ASCVD: Atherosclerotic cardiovascular disease; CAD: Coronary artery disease; CeVD: Cerebrovascular disease; CHD: Coronary heart disease; CV: Cardiovascular; DM: Diabetes mellitus; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; HR: Hazard ratio; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C: Low-density lipoprotein cholesterol; LLT: Lowering-lipid therapy; MI: Myocardial infarction; NNT: Number needed to treat; PAD: Peripheral arterial disease.

Patients at higher risk can benefit significantly from further intensive lipid-lowering therapy. Therefore, the identification of subgroups of patients who are likely to benefit the most from the newer therapies is warranted to achieve more personalized and cost-efficient approaches.

Identifying individuals with ASCVD at extreme risk

Several definitions of extreme risk among those who were previously considered at very high risk of ASCVD have been issued by various professional organizations.^[8,20–22] There are some differences in the definition and terminology of extreme risk among these guidelines [Table 3].^[8,20–22]

Table 3 - Criteria for extreme risk/very high risk among ASCVD patients according to different guidelines/consensuses

CSC expert consensuses[22]	CCEP expert advice[21]	AHA/ACC cholesterol guidelines[8]	AACE/ACE cholesterol guidelines[20]
Extreme risk is defined as having multiple major ASCVD events or having 1 major ASCVD event and multiple very high-risk conditions.Major ASCVD events(1) Recent ACS (within the past 12 months)(2) History of MI (over 12 months)(3) History of ischemic stroke(4) Symptomatic PVD, previous revascularization or amputationVery high-risk conditions(1) Multi-vascular diseases (2 or 3 ischemic lesions in the coronary, cerebral, and peripheral arteries)(2) Premature CHD (male: aged <55 years, female: aged <65 years)(3) FH or baseline LDL-C > 4.9 mmol/L(4) History of CABG or PCI(5) DM(6) Hypertension(7) CKD (3/4)(8) Smoking(9) Persistently elevated LDL-C (≥2.6 mmol/L), despite maximally-tolerated statin therapy	ASCVD with one of the following conditions are classified as extreme risk:(1) Recurrent ASCVD events (the following events occurred at least 2 times within 2 years: ACS, ischemic stroke/transient ischemic attack, acute limb ischemia)(2) Multi-vascular disease(3) DM(4) Recent ACS (within 1 year)(5) LDL-C ≥4.9 mmol/L (190 mg/dL)(6) Multivessel CAD (≥50% stenosis in ≥2 major vessels)	Very high risk is defined as having a history of multiple major ASCVD events or 1 major ASCVD event and multiple very high-risk conditions.Major ASCVD events:(1) Recent ACS (within the past 12 months)(2) History of MI (other than the recent ACS event listed above)(3) History of ischemic stroke(4) Symptomatic PAD (history of claudication with ankle brachial index <0.85, or previous revascularization or amputation)Very high-risk conditions:(1) Aged ≥65 years(2) HeFH(3) Prior CABG or PCI outside of the major ASCVD events(4) DM(5) Hypertension(6) CKD (eGFR: 15–59 mL/(min·1.73 m2))(7) Smoking(8) Persistently elevated LDL-C (≥100 mg/dL (≥2.6 mmol/L)) despite maximally-tolerated statin therapy and ezetimibe(9) History of congestive HF	The extreme risk is defined as:(1) progressive ASCVD including unstable angina in patients after achieving an LDL-C <70 mg/dL(2) established clinical CVD in patients with DM, CKD 3/4, or HeFH(3) history of premature ASCVD (male: aged <55 years, female: aged <65 years)

AACE: American Association of Clinical Endocrinologists; ACC: American College of Cardiology; ACE: American College of Endocrinology; ACS: Acute coronary syndrome; AHA: American Heart Association; ASCVD: Atherosclerotic cardiovascular disease; CABG: Coronary artery bypass grafting; CAD: Coronary artery disease; CCEP: China Cholesterol Education Program; CHD: Coronary heart disease; CKD: Chronic kidney disease; CSC: Chinese Society of Cardiology; DM: Diabetes mellitus; eGFR: Estimated glomerular filtration rate; FH: Familial hypercholesterolemia; HeFH: Heterozygous familial hypercholesterolemia; HF: Heart failure; LDL-C: Low-density lipoprotein cholesterol; MI: Myocardial infarction; PAD: Peripheral arterial disease; PCI: Percutaneous coronary intervention; PVD: Peripheral vascular disease.

Extreme risk was first reported as a new category in the updated American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) Guidelines for the Management of Dyslipidemia and Prevention of Cardiovascular Disease in 2017.^[20] In these guidelines, a more stringent LDL-C target of <55 mg/dL (1.4 mmol/L) is recommended for individuals classified as being at extreme risk. The updated American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines on the Management of Blood Cholesterol issued in 2018 recommended the stratification of people with ASCVD into “very high risk” and “not very high risk”.^[8] Patients at very high risk were defined as those with a history of multiple major ASCVD events, or 1 major ASCVD event with multiple high-risk conditions. While the ACC/AHA guidelines did not recommend a fixed LDL-C treatment target, they recommended adding a non-statin therapy for patients at very high risk if the LDL-C level was ≥70 mg/dL, despite maximally-tolerated LDL-C lowering therapy. More recently, 2 expert consensuses, the China Cholesterol Education Program (CCEP) expert recommendations for the management of dyslipidemias to reduce cardiovascular risk (2019) and the Chinese expert consensus on lipid management of ultra-high-risk ASCVD patients from the Chinese Society of Cardiology (CSC), also issued new criteria to define extreme risk among individuals with ASCVD.^[15,16]

A comparison of the definitions of extreme risk, as recommended by the 4 guidelines or consensuses, is shown in Table 3.^[8,20–22] The criteria issued in the AACE/ACE cholesterol guidelines and the CCEP expert recommendations were relatively simple^[20,21]; both recommend that patients at extreme risk should aim to achieve an LDL-C level of <1.4 mmol/L, and the CCEP recommended an alternative target of reducing LDL-C levels by at least 50% from baseline.^[21] The criteria for extreme risk issued by the AHA/ACC cholesterol guidelines and CSC consensus share greater similarity.^[8,22] Both criteria adopted the “ASCVD events + very high-risk conditions” model, which states that individuals with 2 major ASCVD events or 1 major ASCVD event with 2 or more very high-risk factors should be classified as extreme risk or very high risk. The difference between the CSC expert consensus and 2018 AHA/ACC cholesterol management guidelines is that the CSC expert consensus did not include age ≥65 years or history of congestive HF as very high-risk factors, but added multi-vascular disease, premature CHD (age <55 years in men, <65 years in women), and baseline LDL-C >4.9 mmol/L as very high-risk factors. In addition, the dual targets of reducing LDL-C levels by at least 50% from baseline and <1.4 mmol/L were recommended by the CSC expert consensus for patients at extreme risk.^[22] The criteria for extreme risk/very high risk in the AHA/ACC cholesterol guidelines and CSC consensus classify a greater number of patients as being extreme risk or very high risk than the other 2 guidelines/consensuses as a greater number of high risk factors or conditions are included. Although the 4 guidelines and consensuses have different criteria for extreme risk or very high risk, they all share the same purpose of identifying subsets of individuals with ASCVD with a higher risk, who are thus likely to obtain a greater reduction in the risk of recurrent events through combination therapy than their lower risk counterparts.

In addition, the 2017 Taiwan lipid guidelines for high risk patients suggested a lower LDL-C target of <55 mg/dL could be considered in people with ACS and DM based on data from the IMPROVE-IT study.^[34] Furthermore, the 2019 European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidemias recognized all people with ASCVD as very high risk, with common LDL-C targets. For secondary prevention in very high-risk patients, a reduction in LDL-C of ≥50% from baseline and an overall target of LDL-C <1.4 mmol/L (<55 mg/dL) are recommended by these guidelines.^[7] An even lower target of LDL-C <1.0 mmol/L (<40 mg/dL) is recommended for patients with ASCVD who experience a second vascular event within 2 years while receiving maximally-tolerated statin therapy. Although these 2 guidelines did not propose further risk stratification in individuals with ASCVD, they also emphasized lower LDL-C targets for a subset of these individuals who are at higher risk.

Therefore, regardless of the criteria used to identify ASCVD patients at extremely high risk, it is vital to use combined lipid-lowering therapy to further lower LDL-C levels and improve cardiovascular outcomes. However, as different guidelines and consensuses included different very high-risk conditions in their definitions of extreme risk, more research is warranted to compare their rationales and impacts.

Clinical impacts of identifying patients at extreme risk

Since the concept of extreme risk was proposed, several studies have evaluated the proportion of patients at extreme risk, and the attainment of target LDL-C levels among those with ASCVD, classified using the different definitions [Table 4].^[35–41] Three studies found that between 42.8% and 63.1% individuals with ASCVD met the definition of extreme risk, according to the AHA/ ACC cholesterol guidelines.^[35–37] In addition, another 3 studies found that between 48.4% and 75.3% of those with ASCVD met the definition of extreme risk according to the AACE/ACE cholesterol guidelines.^[38–40] Our previous study enrolled 104,516 ACS inpatients in China, and found that 75.1% met the criteria for extreme risk according to the CSC expert consensus.^[41]

Table 4 - Proportion of ASCVD patients at extreme risk and the attainment of target LDL-C levels

References	Country/study design and data collection	Study population	Criteria	Proportion of individuals at extreme risk	Attainment of LDL-C levels	Rate of receipt of LLT
Rallidis, 2018[39]	Greece (LAERTES)	1629 patients ≤80 years with stable CAD	AACE/ACE guidelines	55%	Among extreme risk patients on LLT: 20.3% LDL-C <1.8 mmol/L, 5.3% LDL-C <1.4 mmol/L	LLT: 87.0%Statin monotherapy: 76.6%Statin and ezetimibe: 9.1%PCSK9i on maximum statin dose plus ezetimibe: 1.3%
Barkas, 2018[40]	Greece (retrospective study)	224 patients with CVD	AACE/ACE guidelines	48.4%	37% LDL-C <1.8 mmol/L, 16% LDL-C <1.4 mmol/L	Statins: 81.4%High-intensity statins: 28.8%Moderate-intensity statins: 50.8%Statins plus ezetimibe: 28.0%
Xing, 2019[38]	China (CCC project)	6523 ACS patients with history of MI, PCI or CABG	AACE/ACE guidelines	75.3%	18.2% LDL-C <1.4 mmol/L	Not available
Virani, 2019[35]	America (the entire Veterans Affairs health care system)	1,038,903 patients with ASCVD	AHA/ACC guidelines	42.8%≥2 major ASCVD events: 7.4%, 1 major ASCVD event + ≥2 very high-risk conditions: 35.4%	33.0% LDL-C <1.8 mmol/L	Statins: 82%High-intensity statins: 35%Ezetimibe: 2%
Colantonio, 2019[36]	America (MarketScan database)	27,775 patients with ASCVD	AHA/ACC guidelines	55.3% ≥2 major ASCVD events: 14.4%, 1 major ASCVD event + ≥2 very high-risk conditions: 40.9%	Not available	Not available
Roe, 2019[37]	ODYSSEY OUTCOMES	18,924 patients with ACS	AHA/ACC guidelines	63.1% ≥2 major ASCVD events: 23.5%, 1 major ASCVD event + ≥2 very high-risk conditions: 39.6%	Not available	Not available
Zeng, 2020[41]	China (CCC project)	104,516 patients with ACS	CSC expert consensus	75.1% ≥2 severe ASCVD events: 15.9%, 1 severe ASCVD event + ≥2 very high-risk conditions: 59.2%	6.6% LDL-C <1.4 mmol/L at admission	Prehospital LLT: 19.2%Stain monotherapy: 18.8%Combined LLT: 0.3%

AACE: American Association of Clinical Endocrinologists; ACC: American College of Cardiology; ACE: American College of Endocrinology; ACS: Acute coronary syndrome; AHA: American Heart Association; ASCVD: Atherosclerotic cardiovascular disease; CABG: Coronary artery bypass grafting; CAD: Coronary artery disease; CCC: Improving Care for Cardiovascular Disease in China; CSC: Chinese Society of Cardiology; CVD: Cardiovascular disease; LAERTES: Lipoprotein-Associated Phospholipase A2 in Stable Coronary Artery Disease Study; LDL-C: Low-density lipoprotein cholesterol; LLT: Lipid-lowering therapy; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PCSK9i: Proprotein convertase subtilisin/kexin type 9 inhibitors.

Of these 7 studies, 5 evaluated the attainment of LDL-C targets in those with extreme risk. Virani et al^[35] found that among these individuals, 82% received statins (35% on high-intensity treatment) and 2% received ezetimibe; 67% of patients with extreme risk had an LDL-C ≥1.8 mmol/L. Assuming a 6% LDL-C reduction with every doubling of the statin dose, it is estimated that approximately 37% of those in the extreme risk group would continue to have LDL-C levels ≥1.8 mmol/L after titration to high-intensity statins, and ezetimibe therapy should be added. Furthermore, assuming an 18% LDL-C reduction with the addition of ezetimibe to high-intensity statins, 24% of extreme risk patients would then be candidates for a PCSK9i. Rallidis et al^[39] found that among patients at extreme cardiovascular risk, 87% received lipid-lowering therapy (with 9.1% receiving a combination of statin and ezetimibe, and 1.3% receiving PCSK9i combined with a maximum dose of statins and ezetimibe), of whom 20.3% had LDL-C <1.8 mmol/L, and only 5.3% had LDL-C <1.4 mmol/L. In addition, Barkas et al^[40] found that among patients at extreme cardiovascular risk, 37% had LDL-C <1.8 mmol/L and 16% had LDL-C <1.4 mmol/L. Two studies evaluated the proportion of patients with ACS who qualified as being at extreme risk, and measured the gap between current LDL-C levels and the new LDL-C target in China.^[38,41] One study found that among patients identified as being at extreme risk using the AACE/ACE cholesterol guidelines, 18.2% had achieved an LDL-C target of <1.4 mmol/L at admission.^[38] The median difference from the target was 0.9 mmol/L among those at extreme risk who did not achieve the LDL-C target. Another study found that the prevalence of an LDL-C level <1.4 mmol/L was only 6.6% among ACS inpatients identified as being at extreme risk according to the CSC expert consensus.^[41] The median difference between the LDL-C level at admission and the target of 1.4 mmol/L was 1.3 mmol/L. If LDL-C could be further reduced to 50% of the admission level, it was estimated that 55.6% of extreme risk patients would achieve the dual LDL-C goal (reducing LDL-C levels by at least 50% from baseline and below 1.4 mmol/L). Moreover, the study also found that 93.5% of those at extreme risk were prescribed statins at discharge; among them, only 4.9% received combined lipid-lowering therapy.

Among ASCVD patients, 40%–75% are considered at extreme risk based on the different guidelines/consensuses; this group should thus have a much lower LDL-C target. However, for patient at extreme cardiovascular risk, the intensity of lipid-lowering therapy has been shown to be insufficient in clinical practice, with very few individuals achieving LDL-C levels <1.4 mmol/L. The new recommendations for patients at extreme risk expand the need for more intensive lipid-lowering therapies, especially combination treatments. Undoubtedly, the new risk-driven LDL-C lowering strategy in individuals with ASCVD will bring great challenges not only for current models of clinical practice, but also for the cost-effectiveness of secondary prevention of ASCVD.

Conclusions

High LDL-C is an important pathogenic factor in ASCVD, and effective control of LDL-C levels can significantly reduce the occurrence and development of ASCVD. Guidelines and expert consensuses issued by different professional organizations have consistently recommended the identification of patients at extreme risk among patients with ASCVD, in order to lower their LDL-C levels to a much lower target than those proposed in previous guidelines. To help clinicians and patients better understand this new strategy for the secondary prevention of ASCVD, this review provides a summary of currently available evidence for the need to further stratify individuals with ASCVD according to risk, how those at extreme risk can be identified, and the potential impact of applying a new “extreme risk” category in clinical practice. A solid understanding of this evidence among researchers, clinicians, and patients will contribute to the development of effective and feasible means of implementing this new strategy in clinical practice in China and worldwide.

Acknowledgments

We thank John Holmes, MSc, from Liwen Bianji (Edanz) (www.liwenbianji.cn/), for editing the English in the draft manuscript.

Funding

None.

Author Contributions

Dong Zhao and Yuhong Zeng conceived the study and participated in the study design. Yuhong Zeng contributed to literature searches and drafted the manuscript. Dong Zhao contributed to the critical revision of the manuscript. The final manuscript was read and approved by both authors.

Conflicts of Interest

None.