2018 ACC/AHA Multi-Society Cholesterol Guideline Overview

Introduction

This section provides an overview of the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol, hereafter referred to as the 2018 multi-society (cholesterol) guideline. This guideline continues the cholesterol management paradigm of using the potential net atherosclerotic cardiovascular disease (ASCVD) risk-reduction benefit to guide therapy that was first introduced in the 2013 American Heart Association and American College of Cardiology (AHA/ACC) guideline. This approach focuses on assessing the patient’s risk of ASCVD, estimating the potential reduction in ASCVD risk from therapy and considering the potential for adverse events.

The key “take-home” recommendations from the 2018 multi-society guideline are summarized in Table 8-1. Evidence supporting the main recommendations is discussed in subsequent sections on primary and secondary prevention. The ACC/AHA classification of recommendations and levels of evidence are described in Figure 8-1.

Clinical Highlight I

• The 2018 multi-society cholesterol guideline provides robust evidence-based recommendations for cholesterol-lowering therapy to reduce ASCVD risk.
• A heart-healthy lifestyle should be emphasized in all patients, regardless of age or comorbidities.
• Statin intensity should be maximized in the four statin benefit groups.
• Patients outside the four statin benefit groups may also benefit from statin therapy, as discussed in subsequent sections.
• Regularly monitor therapeutic response and adherence to lifestyle and drug therapy.
• Nonstatins may be considered to further reduce risk in selected patients, generally those who are:
  • Unable to tolerate statin intensification, and
  • Unable to achieve a target LDL-C percent reduction or goal
• Because of favorable cost-effectiveness, ezetimibe is the preferred initial nonstatin.

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Treatment Groups and Patient Classification

The 2013 ACC/AHA guideline identified four groups of patients with strong evidence for a net ASCVD risk reduction benefit from statin therapy, based on randomized trials. This categorization is retained in the 2018 multi-society guideline, with the four statin treatment groups being:

• Clinical ASCVD
• Severe hypercholesterolemia (LDL-C ≥190 mg/dL)
• Diabetes (age 40-75 years)
• ≥7.5% 10-year ASCVD risk (age 40-75 years).

Like its 2013 predecessor, the 2018 multi-society guideline stresses the importance of a heart-healthy lifestyle, including diet and exercise, in all patients, regardless of the presence of ASCVD or other comorbidities.

For secondary prevention of ASCVD, the 2018 multi-society guideline makes a distinction between patients with very high-risk ASCVD (Table 8-2) and those without. Initiation of high-intensity statin therapy is recommended for all patients with very high-risk ASCVD. For patients who have ASCVD that is not very high-risk, there is an age-based cutoff: high-intensity statins should be started in those 75 years of age or younger; for patients older than 75, initiation of moderate- or high-intensity statin may be reasonable, following a risk discussion (Figure 8-2).

For primary prevention of ASCVD, the 2018 multi-society guideline recommends a high-intensity statin regimen for all patients with low-density lipoprotein cholesterol (LDL-C) levels of 190 mg/dL or above and at least a moderate-intensity statin regimen for patients with diabetes mellitus who are 40-75 years of age. For patients between the ages of 40 and 75 whose LDL-C levels are between 70 and 190 mg/dL, the 2018 multi-society guideline introduces four risk categories based on a 10-year ASCVD risk calculation: 1) low risk (<5%), for whom lifestyle changes are indicated to control risk; 2) borderline risk (5 to <7.5%) for whom the presence of ASCVD risk enhancers (Figure 8-3) may prompt discussion of initiating a moderate-intensity statin therapy; 3) intermediate risk (7.5% to <20%), for whom moderate-intensity statin therapy is indicated to reduce LDL-C levels by 30-49% (if risk enhancers and risk assessment favor statins); and 4) high risk (≥20%) for whom statins are indicated to reduce LDL-C levels by 50% or more. For younger adults (20 to 39 years of age), statin therapy may be considered in individuals with a family history of premature ASCVD and LDL-C levels ≥160 mg/dL. The focus for pediatric patients should be on lifestyle management, with statin therapy reasonable in patients with a clinical presentation consistent with familial hypercholesterolemia who fail to adequately respond after 3-6 months of lifestyle therapy. See Figure 8-3 for the algorithm on risk assessment and treatment recommendations.

Statin intensity is defined in Statins. High intensity statin regimens include atorvastatin 40-80 mg and rosuvastatin 20-40 mg; medium-intensity statin therapies include atorvastatin 10 mg, rosuvastatin 10 mg and simvastatin 20-40 mg. There appears to be no clear benefit from statin therapy in those with advanced heart failure or receiving maintenance hemodialysis.

There is little evidence from randomized trials to guide statin therapy in individuals outside the above-mentioned patient groups, although selected individuals could benefit from statin therapy (see Special Clinical Populations). Compared to its 2013 predecessor, the 2018 multi-society guideline introduced or expanded discussion around specific populations, including children and women. While the 2013 ACC/AHA guideline included a risk calculator specific to Black patients, the 2018 multi-society guideline includes a broader discussion of topics related to ethnicity as well as specific issues to consider for East and South Asian, Hispanic/Latino and Black patients. Suggested approaches to the assessment and management of patients not included in the four major statin benefit groups are provided in subsequent sections.

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Monitoring Therapeutic Response and Adherence

After initiating statin therapy, patients should have regular clinical and laboratory follow-up to assess their response to therapy and their adherence to drug therapy and healthy lifestyle habits (see Monitoring Therapeutic Response, Adherence, and Tolerability). The 2018 multi-society guideline recommends the first follow-up assessment at 4 to 12 weeks after initiation of therapy, followed by repeated assessments every 3 to 12 months (depending on need). A fasting lipid panel should be obtained at each visit to assess treatment response and adherence. As part of the ongoing therapeutic relationship with the patient, each visit should address lifestyle habits, adverse effects and control of other risk factors.

Anticipated therapeutic responses to statins:

• High-intensity statin: approximately ≥50% reduction in LDL-C from baseline
• Moderate-intensity statin: 30% to <50% LDL-C reduction from baseline
• For patients whose baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in the high-intensity statin trials.

The 2018 multi-society cholesterol guideline recommends specific LDL-C percent reduction goals for statin therapy in line with the anticipated therapeutic responses listed above (≥50% and 30-49% for high- and moderate-intensity regimens, respectively). Specific LDL-C thresholds may also provide a guide for adding nonstatin agents to the existing statin regimen.

To achieve the desired average LDL-C reduction observed in randomized trials in higher-risk patients, it is reasonable to intensify lifestyle changes, increase statin intensity, or add a nonstatin. In selected cases, evaluation for secondary causes of hypercholesterolemia may be needed (see Secondary Hyperlipidemia).

LDL-C Reduction Goals and Treatment Decision Thresholds

The 2013 ACC/AHA cholesterol guideline moved away from specific LDL-C or non-HDL-C treatment targets to focus on net ASCVD risk reduction benefit. This change from prior practice was driven by a lack of sufficient evidence from randomized trials to support specific lipid goals, and a number of other reasons (Table 8-3). Because many high-risk patients “at goal” would not be treated under the “treat to target” paradigm, it has been estimated that the 2013 removal of treatment goals would prevent 450,000 more ASCVD events over 10 years than the earlier ATP III approach (Figure 8-4).

Evidence has also emerged that an LDL-C treatment goal of 100 or 70 mg/dL may deny patients the full benefit of maximizing statin intensity. In a pooled individual level analysis of statin trials, greater relative risk reductions occur with progressively lower LDL-C levels on statin therapy, with the greatest reduction in CV risk observed when LDL-C levels are <50 mg/dL (Figure 8-5). In a pooled analysis of eight coronary intravascular ultrasound studies evaluating high-intensity statins, increasingly greater magnitudes of atheroma regression occurred down to LDL-C levels of 15 mg/dL (Figure 8-6). And, finally, in a pooled analysis of three high-intensity statin trials, in patients who achieved LDL-C levels <70 mg/dL, a greater reduction in CV risk occurred in those with a ≥50% LDL-C reduction than in those with a <50% LDL-C reduction (Figure 8-7).

While the 2018 multi-society guideline has maintained the paradigm of avoiding the use of absolute LDL-C levels as treatment targets, it has incorporated percent LDL-C reduction goals in several Class I recommendations, including those concerning primary prevention in patients with an intermediate and high risk of ASCVD. The 2018 multi-society guideline has also brought back the use of absolute LDL-C levels (typically 100 or 70 mg/dL) as thresholds to guide the addition of nonstatin agents, rather than as treatment targets.

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Nonstatin Agents

Another notable change in the 2018 multi-society cholesterol guideline is increased attention to nonstatin agents. These were not extensively covered by the 2013 ACC/AHA guideline because of a lack of good clinical efficacy data. The 2018 multi-society guideline considers three nonstatin medications potentially useful in combination with a statin regimen: ezetimibe (see Ezetimibe), PCSK9 inhibitors (see PCSK9) and bile acid sequestrants (Bile Acid Sequestrants).

Of the three nonstatin agents, the guideline suggests adding ezetimibe before the other agents. For example, for patients with very high-risk ASCVD who are on maximally-tolerated statin therapy and whose LDL-C levels are ≥70 mg/dL, ezetimibe is considered a reasonable add-on medication, while the addition of PCSK9 is specifically recommended only in cases where the LDL-C levels remain ≥70 mg/dL on maximally tolerated statins and ezetimibe. Similarly, for patients with severe hypercholesterolemia who are 20-75 years of age and who achieve <50% reduction in LDL-C levels or whose LDL-C levels remain ≥100 mg/dL on a maximally-tolerated statin regimen, the guideline considers ezetimibe reasonable; the addition of bile acids sequestrants or PCSK9 inhibitors should be considered only if specific targets are not reached after addition of ezetimibe.

Ezetimibe is suggested before PCSK9 inhibitors because of its generic availability, better safety profile and better value; the guideline considers PCSK9 inhibitors to be low value (costing >$150,000 per quality-adjusted life-year at mid-2018 prices), despite greater LDL-C lowering efficacy.

Several advances in nonstatin therapies have occurred since the 2018 multi-society guideline was published, including positive results from trials of ASCVD risk reduction with PCSK9 monoclonal antibodies and approvals of inclisiran (a small interfering RNA against PCSK9) and bempedoic acid for LDL-C lowering. Following these developments, the ACC released an Expert Consensus Decision Pathway (ECDP) in 2022 to provide interim guidance to clinicians and patients until a full set of new guidelines is prepared. For more information on the recommendations from the 2022 ACC ECDP.