2018 Cholesterol Clinical Practice Guidelines: Synopsis of the 2018 American Heart Association/American College of Cardiology/Multisociety Cholesterol Guideline*

Abstract

According to the Centers for Disease Control and Prevention, heart disease is the leading cause of death in the United States, including for African American, Hispanic, and white persons (1) and for both women and men. The leading cause of death attributable to cardiovascular disease (CVD) in the United States is coronary heart disease (43.8%), followed by stroke (16.8%)the 2 components of fatal atherosclerotic CVD (ASCVD) (2). The economic impact of ASCVD is large: It accounted for 14% of total health expenditures in 2013 to 2014, more than any major diagnostic group. The American Heart Association and American College of Cardiology (AHA/ACC), with the support of 10 collaborating organizations, have recently released their 2018 cholesterol guideline (3). In addition, they have released a companion special report on the use of risk assessment tools to guide decision making in primary prevention of ASCVD (4). Guideline Development Process The writing committees of both documents represented various areas of expertise, and all members were free of recent and relevant industry-related conflicts. New since the 2013 guideline are 3 randomized controlled trials (RCTs) that support the use of nonstatin lipid-modifying medications to reduce ASCVD events in patients at highest risk. The AHA/ACC commissioned an independent panel to systematically review evidence and assess the magnitude of benefits and harms from the addition of nonstatin medications to statin therapy in ASCVD (5). Their report was used by the guideline panel for the secondary prevention recommendations. An extensive evidence review covering May 1980 to July 2017 was also done initially. The writing committee considered additional relevant studies published through August 2018 during the guideline-writing process and added them to the evidence tables when appropriate. Synopsis of Recommendations 1. Healthy lifestyle over the lifespan. A healthy lifestyle reduces ASCVD risk at all ages. In younger persons, healthy lifestyle can reduce development of risk factors, can prevent the need for subsequent statin use, and is foundational therapy for ASCVD risk reduction. In young adults aged 20 to 39 years, an assessment of lifetime risk facilitates the clinicianpatient risk discussion and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome. 2. Use of maximally tolerated doses of statins in secondary prevention of ASCVD. In patients with clinical ASCVD, the guideline recommends reduction of low-density lipoprotein cholesterol (LDL-C) levels with high-intensity or maximally tolerated statin therapy. The more LDL-C is reduced during statin therapy, the greater the subsequent risk reduction will be. High-intensity statins typically reduce LDL-C levels by an average of at least 50%, which is an attainable goal in most patients with ASCVD. 3. Use of nonstatin medications in addition to statin therapy for patients at very high risk for ASCVD. Very high risk is defined as a history of multiple major ASCVD events, or 1 major ASCVD event and multiple other high-risk conditions. In very-high-risk ASCVD, the guideline recommends an LDL-C threshold of 1.8 mmol/L (70 mg/dL) as reasonable for adding a nonstatin medication (ezetimibe or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) to maximally tolerated statin therapy. In patients who had very high risk, had a baseline LDL-C level of approximately 1.8 mmol/L (70 mg/dL), and were receiving statin therapy, addition of ezetimibe reduced risk for major events by 2 percentage points (6). Two RCTs recruited patients at very high risk who were receiving maximally tolerated doses of statins, had LDL-C levels greater than 1.8 mmol/L (70 mg/dL) (average, about 2.3 mmol/L [90 mg/dL]), and were treated with PCSK9 inhibitors for approximately 3 years (7, 8). Addition of PCSK9 inhibitors reduced risk for subsequent ASCVD events by about 15%. On the basis of these RCTs, the guideline states that addition of ezetimibe to maximally tolerated statin therapy is reasonable when LDL-C levels are 1.8 mmol/L (70 mg/dL) or higher. In patients at very high risk whose LDL-C levels remain above this threshold while they receive maximally tolerated statin and ezetimibe therapy, the guideline suggests that a PCSK9 inhibitor is a reasonable addition, although long-term safety (>3 years) is uncertain and cost-effectiveness was low at mid-2018 list prices. Some prescription programs have recently been initiated to reduce the cost of PCSK9 inhibitors. As cost decreases, cost-effectiveness will increase (9). 4. Severe primary hypercholesterolemia, often starting in childhood. In patients with primary, severe hypercholesterolemia (LDL-C level 4.9 mmol/L [190 mg/dL]), calculating 10-year ASCVD risk is not necessary. Maximally tolerated statin therapy is required to reduce LDL-C levels toward a lower risk range. If the LDL-C level remains at or above 2.6 mmol/L (100 mg/dL), adding ezetimibe is reasonable. If the patient still has an LDL-C level above this threshold while receiving a statin plus ezetimibe and has multiple factors that increase subsequent risk for ASCVD events, a PCSK9 inhibitor may be considered, although long-term safety (>3 years) is uncertain and economic value is low based on list prices from mid-2018. 5. Adults aged 40 to 75 years with diabetes mellitus and an LDL-C level of 1.8 mmol/L (70 mg/dL) or higher. In these patients, the guidelines recommend starting moderate-intensity statin therapy without the need to calculate 10-year ASCVD risk. In patients with diabetes and higher risk, especially those who have multiple risk factors or are aged 50 to 75 years, use of a high-intensity statin is reasonable to reduce the LDL-C level by at least 50%. 6. Clinicianpatient risk discussion. In adults aged 40 to 75 years who are evaluated for primary ASCVD prevention, the guidelines continue to recommend a clinicianpatient risk discussion before statin therapy is started. Risk discussion should include review of major risk factors (such as cigarette smoking and elevated levels of blood pressure, LDL-C, hemoglobin A1c level [if indicated], or calculated 10-year risk for ASCVD), risk-enhancing factors (see recommendation 8), the potential benefits of lifestyle and statin therapies, the potential for adverse effects and drugdrug interactions, consideration of costs of statin therapy, and patient preferences and values in shared decision making. 7. Adults aged 40 to 75 years without diabetes mellitus who have LDL-C levels of at least 1.8 mmol/L (70 mg/dL), and a 10-year ASCVD risk of 7.5% or higher. In this population, the guidelines recommend moderate-intensity statin therapy if a discussion of treatment options favors statins. Patients without ASCVD are categorized and stratified for risk by age, coexisting conditions, and risk factors (Figure). When those with diabetes or LDL-C levels above 4.9 mmol/L (190 mg/dL) are excluded, RCT evidence for the benefit of statin therapy in persons aged 40 to 75 years continues to accumulate (10). Patients in this age range are triaged into 4 categories of 10-year risk for ASCVD: low (<5%), borderline (5% to 7.4%), intermediate (7.5% to 19.9%), and high (20%). In the latter category, the guideline recommends high-intensity statin therapy because of its proven benefit. Evidence from RCTs supports the efficacy of statin therapy for patients whose 10-year risk is 5% or higher. Nonetheless, in those with borderline or intermediate risk, clinical judgment is required to initiate statin treatment on the basis of riskbenefit considerations and patient preferences. Figure. Flow diagram for primary prevention of ASCVD. Color corresponds to class of recommendation: green = Class I (strong); yellow = Class IIa (moderate); orange = Class IIb (weak). apoB= apolipoprotein B; ASCVD= atherosclerotic cardiovascular disease; CAC= coronary artery calcium; CHD = coronary heart disease; hs-CRP= high-sensitivity C-reactive protein; LDL-C= low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a). (Reproduced from Grundy and colleagues [3] with permission of the American Heart Association/American College of Cardiology.). 8. Decision making in primary prevention in adults aged 40 to 75 years. The guideline endorses a 3-tiered decision process for treatment in adults aged 40 to 75 years with borderline (5% to 7.4%) or intermediate (7.5% to 19.9%) risk for ASCVD. The decision process begins with estimation of 10-year risk. As in prior guidelines, 10-year risk of 7.5% or higher does not result in automatic statin assignment. To personalize risk, the current guideline recommends evaluation of risk-enhancing factorsthat is, stable factors that associate with ASCVD beyond the major risk factors incorporated into the risk calculator. These include family history of premature ASCVD; LDL-C levels of 4.1 mmol/L (160 mg/dL) or higher; metabolic syndrome; chronic kidney disease; history of preeclampsia or premature menopause (in women); chronic inflammatory disorders; high-risk ethnicity, such as South Asian ancestry; triglyceride levels persistently elevated above 2.0 mmol/L (175 mg/dL); and, if measured, elevations in apolipoprotein B (may be especially useful if hypertriglyceridemia >2.3 mmol/L [>200 mg/dL] persists), high-sensitivity C-reactive protein levels of 19.0476 nmol/L (2.0 mg/L) or higher, lipoprotein(a) levels with elevations above 125 nmol/L (50 mg/dL) (especially useful in those with a family history of premature ASCVD), or reduced anklebrachial index. Presence of risk-enhancing factors in patients at intermediate risk favors statin therapy. In addition, if risk status remains uncertain, measurement of coronary artery calcium (CAC) can be considered. 9. CAC scoring to improve risk stratification. In adults who do not have diabetes, are aged 40 to 75 years, have LDL-C levels of 1.8 to 4.9 mmol/L (70 to 189 mg/dL), and have a 10-year risk of