N. J. Stone

Note from the National Guideline Clearinghouse (NGC): National Heart, Lung and Blood Institute (NHLBI) Evidence Statements are also included for each recommendation. See Appendix 4 in the original guideline document.

Each recommendation has been mapped from the NHLBI grading format to the American College of Cardiology/American Heart Association Class of Recommendation/Level of Evidence (ACC/AHA COR/LOE) construct and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. Definitions for the NHLBI strength of recommendation (A-E, N) and quality of evidence (High, Moderate, Low) and the ACC/AHA levels of the evidence (LOE: A-C) and classes of recommendations (COR: I-III) are provided at the end of the "Major Recommendations" field.

What's New in the Guideline?

Focus on Atherosclerotic Cardiovascular Disease (ASCVD Risk) Reduction: 4 Statin Benefit Groups

1. This guideline is based on a comprehensive set of data from randomized control trials (RCTs) from which 4 statin benefit groups were identified that focus efforts to reduce ASCVD events in secondary and primary prevention.

2. This guideline identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention.

A New Perspective on Low-density Lipoprotein Cholesterol (LDL-C) and/or Non–High-density Lipoprotein Cholesterol (HDL-C) Treatment Goals

1. The Expert Panel was unable to find RCT evidence to support continued use of specific LDL-C or non–HDL-C treatment targets.

2. The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit.

3. Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD.

Global Risk Assessment for Primary Prevention

1. This guideline recommends use of the new Pooled Cohort Equations to estimate 10-year ASCVD risk in both white and black men and women.

2. By more accurately identifying higher-risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit.

3. It also indicates, on the basis of RCT data, those high-risk groups that might not benefit.

4. This guideline recommends a discussion between clinicians and patients before initiation of statin therapy.

Safety Recommendations

1. This guideline used RCTs to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk.

2. Using RCTs to determine statin adverse effects facilitates understanding of the net benefit from statin therapy.

3. This guideline provides expert guidance on management of statin-associated adverse effects, including muscle symptoms.

Role of Biomarkers and Noninvasive Tests

1. Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment Work Group and Blood Cholesterol Expert Panel.

Future Updates to the Blood Cholesterol Guideline

1. This is a comprehensive guideline for the evidence-based treatment of blood cholesterol to reduce ASCVD risk.

2. Future updates will build on this foundation to provide expert guidance on the management of complex lipid disorders and incorporate refinements in risk stratification based on critical review of emerging data.

3. RCTs comparing alternative treatment strategies are needed in order to inform future evidence-based guidelines for the optimum ASCVD risk-reduction approach.

Note: See Appendix 5 in the original guideline document for an expanded discussion of what's new in the guideline.

Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults—Statin Treatment

Treatment Targets

1. The Expert Panel makes no recommendations for or against specific LDL-C or non–HDL-C targets for the primary or secondary prevention of ASCVD. NHLBI Grade: N (No recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

Secondary Prevention

1. High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤75 years of age who have clinical ASCVD*, unless contraindicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. In individuals with clinical ASCVD* in whom high-intensity statin therapy would otherwise be used, when high-intensity statin therapy is contraindicated† or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option if tolerated (see "Safety of Statins," below). NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Heart Protection Study Collaborative Group, 2002; Cholesterol Treatment Trialists' [CTT] Collaboration et al., 2010; Tikkanen et al., 2009; Holmes et al., 2006; Akushevich et al., 2012; Wolff, Starfield &, Anderson, 2002; Fried et al., "Effects," 2011; Robinson et al., 2007; Porock et al., 2005; Stineman et al., 2012; Schonberg et al., 2011; Fried et al., "Health outcome," 2011; Barry & Edgman-Levitan, 2012; Man-Son-Hing, Gage, & Montgomery, 2005; Fried et al., 2002; Ditto et al., 1996; Rosenfeld, Wenger, & Kagawa-Singer, 2000; Nease et al., 1995; Glynn et al., 2010; Shepherd et al., 2002; Trompet et al., 2010; Gray et al., 2011; LaCroix et al., 2008; Hippisley-Cox et al., 2005; Forman et al., 2011)

Primary Prevention in Individuals ≥21 Years of Age with LDL-C ≥190 mg/dL

1. Individuals with LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia (see Table 6 in the original guideline document). NHLBI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B (Berglund et al., 2012; Miller et al., 2011)

2. Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be treated with statin therapy (10-year ASCVD risk estimation is not required) NHLBI Grade: B (Moderate); ACC/AHA COR: I§; ACC/AHA LOE: B:

• Use high-intensity statin therapy unless contraindicated.
• For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity.

3. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at least a 50% LDL-C reduction. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (CTT Collaboration et al., 2010; LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Ridker et al, 2008; Baigent et al., 2005)

4. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, after the maximum intensity of statin therapy has been achieved, addition of a nonstatin drug may be considered to further lower LDL-C. Evaluate the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, and consider patient preferences. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Thompson, Packard, & Stone, 2004)

Primary Prevention in Individuals with Diabetes and LDL-C 70–189 mg/dL

1. Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Ridker et al., 2008; Ridker et al., 2012)

3. In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Roffi, Angiolillo, & Kappetein, 2011; Nathan et al., 2005; Rhodes et al., 2012; Paynter et al., 2011; Elley et al., 2010; Stevens et al., 2004; Bibbins-Domingo et al., 2007; Daniels et al., 2009; Jacob & Cho, 2010; Bainey & Jugdutt, 2009)

Primary Prevention in Individuals without Diabetes and with LDL-C 70–189 mg/dL

1. The Pooled Cohort Equations should be used to estimate 10-year ASCVD‖ risk for individuals with LDL-C 70–189 mg/dL without clinical ASCVD* to guide initiation of statin therapy for the primary prevention of ASCVD. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (Goff et al., 2014)

2. Adults 40 to 75 years of age with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk ≥7.5% should be treated with moderate- to high-intensity statin therapy. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. It is reasonable to offer treatment with a moderate-intensity statin to adults 40 to 75 years of age, with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk of 5% to <7.5%. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

4. Before initiation of statin therapy for the primary prevention of ASCVD in adults with LDL-C 70–189 mg/dL without clinical ASCVD* or diabetes, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions, as well as patient preferences for treatment. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Yu et al., 2013)

5. In adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk-based treatment decision is uncertain, additional factors¶ may be considered to inform treatment decision making. In these individuals, statin therapy for primary prevention may be considered after evaluation of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions and consider patient preferences. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Goff et al., 2014; CTT Collaborators et al., 2012)

Heart Failure and Hemodialysis

1. The Expert Panel makes no recommendations regarding the initiation or discontinuation of statins in patients with NYHA class II–IV ischemic systolic heart failure or in patients on maintenance hemodialysis. NHBLI Grade: N (No Recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

*Clinical ASCVD includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischaemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin.

†Contraindications, warnings, and precautions are defined for each statin according to the manufacturer's prescribing information ("Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013).

‡Individuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A triglyceride level ≥500 mg/dL was an exclusion criterion for almost all RCTs. Therefore, ruling out secondary causes is necessary to avoid inappropriate statin therapy.

§No RCTs included only individuals with LDL-C ≥190 mg/dL. However, many trials did include individuals with LDL-C ≥190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD events by 22%, and the relative reductions in ASCVD events were consistent across the range of LDL-C levels. Therefore, individuals with primary LDL-C ≥190 mg/dL should be treated with statin therapy.

ǁEstimated 10-year or "hard" ASCVD risk includes first occurrence of nonfatal MI, coronary heart disease death, and nonfatal and fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort Equations.

¶These factors may include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L; coronary artery calcium (CAC) score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx 

); ankle-brachial index (ABI) <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

See Table 5 in the original guideline document for high-, moderate-, and low-intensity statin therapies used in the RCTs reviewed by the Expert Panel.

Statin Safety Recommendations

Safety

1. To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD* risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present. Characteristics predisposing individuals to statin adverse effects include but are not limited to: NHBLI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: B

• Multiple or serious comorbidities, including impaired renal or hepatic function
• History of previous statin intolerance or muscle disorders
• Unexplained alanine aminotransferase (ALT) elevations ≥3 times the upper limit of normal (ULN)
• Patient characteristics or concomitant use of drugs affecting statin metabolism
• Age >75 years

Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to:

• History of hemorrhagic stroke
• Asian ancestry

2a. Creatine kinase (CK) should not be routinely measured in individuals receiving statin therapy. NHBLI Grade: A (Strong); ACC/AHA COR: III: No Benefit; ACC/AHA LOE: A

2b. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

2c. During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

3a. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiation of statin therapy. NHBLI Grade: B (Moderate); ACC/AHA COR: I†; ACC/AHA LOE: B

3b. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera). NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (U.S. Food and Drug Administration, 2012)

4. Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL. NHBLI Grade: C (Weak); ACC/AHA COR: IIb; ACC/AHA LOE: C

5. It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily. NHBLI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: A ("Zocor," 2012; U.S. Food and Drug Administration, 2010)

6. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (American Diabetes Association, 2013). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. NHBLI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B

7. For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for human immunodeficiency virus [HIV]). A review of the manufacturer's prescribing information may be useful before initiation of any cholesterol-lowering drug. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Heart Protection Study Collaborative Group, 2002; "Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013; U.S. Food and Drug Administration, 2012; Rawlins, 2008; Schwartz et al., 2001; Shepherd et al., 2006)

8. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm: NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Taylor et al., 2011; Eckel, 2010; Baigent et al., 2010; Mills et al., 2008; Dale et al., 2007)

• To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy.
• If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK and creatinine and performing urinalysis for myoglobinuria.
• If mild to moderate muscle symptoms develop during statin therapy:
  • Discontinue the statin until the symptoms can be evaluated.
  • Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
  • If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
  • If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
  • Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
  • If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above.
  • If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.

9. For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Shepherd et al., 2002; U.S. Food and Drug Administration, 2012; Collins et al., 2004; Roberts, 2009)

*Based on the presence of clinical ASCVD, diabetes, LDL-C ≥190 mg/dL, or level of estimated 10-year ASCVD risk.

†Individuals with elevated ALT levels (usually >1.5 or 2 times ULN) were excluded from RCT participation. Unexplained ALT ≥3 times ULN is a contraindication to statin therapy as listed in manufacturer's prescribing information.

‡Statin use is associated with a very modest excess risk of new-onset diabetes in RCTs and meta-analyses of RCTs (i.e., ∼0.1 excess cases per 100 individuals treated for 1 year with moderate-intensity statin therapy and ∼0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy. The increased risk of new-onset diabetes appears to be confined to those with risk factors for diabetes. These individuals are also at higher risk of ASCVD because of these risk factors. Therefore, if a statin-treated individual develops diabetes as detected by current diabetes screening guidelines, he or she should be counseled to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD events.

Nonstatin Safety Recommendations

Safety of Niacin

1. Baseline hepatic transaminases, fasting blood glucose or hemoglobin A1c, and uric acid should be obtained before initiation of niacin, and again during up-titration to a maintenance dose and every 6 months thereafter. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

2. Niacin should not be used if:

• Hepatic transaminase elevations are higher than 2 to 3 times ULN. NHLBI Grade: A (Strong); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• Persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or unexplained abdominal pain or gastrointestinal symptoms occur. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• New-onset atrial fibrillation or weight loss occurs. NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

3. In individuals with adverse effects from niacin, the potential for ASCVD benefits and the potential for adverse effects should be reconsidered before reinitiation of niacin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

4. To reduce the frequency and severity of adverse cutaneous symptoms, it is reasonable to: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

• Start niacin at a low dose and titrate to a higher dose over a period of weeks as tolerated.
• Take niacin with food or premedicate with aspirin 325 mg 30 minutes before niacin dosing to alleviate flushing symptoms.
• If an extended-release preparation is used, increase the dose of extended-release niacin from 500 mg to a maximum of 2,000 mg/day over 4 to 8 weeks, with the dose of extended-release niacin increasing not more than weekly.
• If immediate-release niacin is chosen, start at a dose of 100 mg 3 times daily and up-titrate to 3 g/day, divided into 2 or 3 doses.

Safety of Bile Acid Sequestrants (BAS)

1. BAS should not be used in individuals with baseline fasting triglyceride levels ≥300 mg/dL or type III hyperlipoproteinemia, because severe triglyceride elevations might occur. (A fasting lipid panel should be obtained before BAS is initiated, 3 months after initiation, and every 6 to 12 months thereafter.) NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. It is reasonable to use BAS with caution if baseline triglyceride levels are 250 to 299 mg/dL, and evaluate a fasting lipid panel in 4 to 6 weeks after initiation. Discontinue the BAS if triglycerides exceed 400 mg/dL. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Crouse, 1987)

Safety of Cholesterol-Absorption Inhibitors

1. It is reasonable to obtain baseline hepatic transaminases before initiation of ezetimibe. When ezetimibe is coadministered with a statin, monitor transaminase levels as clinically indicated, and discontinue ezetimibe if persistent ALT elevations ≥3 times ULN occur. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Safety of Fibrates

1. Gemfibrozil should not be initiated in patients on statin therapy because of an increased risk for muscle symptoms and rhabdomyolysis. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (ACCORD Study Group et al., 2010)

3. Renal status should be evaluated before fenofibrate initiation, within 3 months after initiation, and every 6 months thereafter. Assess renal safety with both a serum creatinine level and an estimated glomerular filtration rate (eGFR) based on creatinine. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

• Fenofibrate should not be used if moderate or severe renal impairment, defined as eGFR <30 mL/min per 1.73 m², is present. ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• If eGFR is between 30 and 59 mL/min per 1.73 m², the dose of fenofibrate should not exceed 54 mg/day.*
• If, during follow-up, the eGFR decreases persistently to ≤30 mL/min per 1.73 m², fenofibrate should be discontinued.

*Consult the manufacturer's prescribing information as there are several forms of fenofibrate available.

Safety of Omega-3 Fatty Acids

1. If eicosapentaenoic acid (EPA) and/or docosahexanoic acid (DHA) are used for the management of severe hypertriglyceridemia, defined as triglycerides ≥500 mg/dL, it is reasonable to evaluate the patient for gastrointestinal disturbances, skin changes, and bleeding. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Recommendations for Monitoring, Optimizing, and Addressing Insufficient Response to Statin Therapy

Monitoring Statin Therapy

1. Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4–12 weeks after initiation or dose adjustment, and every 3–12 months thereafter. Other safety measurements should be measured as clinically indicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

Optimizing Statin Therapy

1. The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended but not tolerated. NHLBI Grade: B (Moderate); ACC/AHA COR: I*; ACC/AHA LOE: B

Insufficient Response to Statin Therapy

1. In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: NHLBI Grade A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

• Reinforce medication adherence.
• Reinforce adherence to intensive lifestyle changes.
• Exclude secondary causes of hyperlipidemia.

2. It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Amarenco et al., 2006; Thompson & HEART-UK LDL Apheresis Working Group, 2008; Schwertz & Badellino, 2008)

• High-intensity statin therapy† generally results in an average LDL-C reduction of ≥50% from the untreated baseline.
• Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.
• LDL-C levels and percents reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.

3. In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. Higher-risk individuals include: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb: ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; ACCORD Study Group et al., 2010; Rossebo et al., 2007; Sharp Collaborative Group, 2010; Yokoyama, Origasa, & JELIS Investigators, 2003)

• Individuals with clinical ASCVD‡ <75 years of age.
• Individuals with baseline LDL-C ≥190 mg/dL.
• Individuals 40 to 75 years of age with diabetes.

Preference should be given to nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs.

4. In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Eckel, 2010; "Clofibrate and niacin in coronary heart disease," 1975; Frick et al., 1987; Lipid Research Clinics Program, 1984; "The Lipid Research Clinics Coronary Primary Prevention Trial results. II.," 1984; Rubins et al., 1999; Keech et al., 2005; HPS2-THRIVE Collaborative Group, 2013)

*Several RCTs found that low-intensity and low-moderate–intensity statin therapy reduced ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses found that each 39-mg/dL reduction in LDL-C reduces ASCVD risk by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-intensity statin therapy.

†In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C level <100 mg/dL was observed in most individuals receiving high-intensity statin therapy.

‡Clinical ASCVD includes acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.

Definitions:

NHLBI Grading of the Strength of Recommendations

Grade	Strength of Recommendation*
A	Strong recommendation There is high certainty based on evidence that the net benefit† is substantial.
B	Moderate recommendation There is moderate certainty based on evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate.
C	Weak recommendation There is at least moderate certainty based on evidence that there is a small net benefit.
D	Recommendation against There is at least moderate certainty based on evidence that there is no net benefit or that risks/harms outweigh benefits.
E	Expert opinion ("There is insufficient evidence or evidence is unclear or conflicting, but this is what the Work Group recommends.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Work Group thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area.
N	No recommendation for or against ("There is insufficient evidence or evidence is unclear or conflicting.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Work Group thought no recommendation should be made. Further research is recommended in this area.

*In most cases, the strength of the recommendation should be closely aligned with the quality of the evidence; however, under some circumstances, there may be valid reasons for making recommendations that are not closely aligned with the quality of the evidence (e.g., strong recommendation when the evidence quality is moderate, such as smoking cessation to reduce cardiovascular disease [CVD] risk or ordering an electrocardiogram [ECG] as part of the initial diagnostic work-up for a patient presenting with possible myocardial infarction [MI]). Those situations should be limited and the rationale explained clearly by the Work Group.

†Net benefit is defined as benefits minus risks/harms of the service/intervention.

NHLBI Quality Rating of the Strength of Evidence

Type of Evidence	Quality Rating*
Well-designed, well-executed† randomized controlled trials (RCTs) that adequately represent populations to which the results are applied and directly assess effects on health outcomes. Meta-analyses of such studies. Highly certain about the estimate of effect. Further research is unlikely to change confidence in the estimate of effect.	High
RCTs with minor limitations‡ affecting confidence in, or applicability of, the results. Well-designed, well-executed nonrandomized controlled studies§ and well-designed, well-executed observational studies¶. Meta-analyses of such studies. Moderately certain about the estimate of effect. Further research may have an impact on confidence in the estimate of effect and may change the estimate.	Moderate
RCTs with major limitations. Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results. Uncontrolled clinical observations without an appropriate comparison group (e.g., case series, case reports). Physiological studies in humans. Meta-analyses of such studies. Low certainty about the estimate of effect. Further research is likely to have an impact on confidence in the estimate of effect and is likely to change the estimate.	Low

*In some cases, other evidence, such as large all-or-none case series (e.g., jumping from airplanes or tall structures), can represent high- or moderate-quality evidence. In such cases, the rationale for the evidence rating exception should be explained by the Work Group and clearly justified.

†"Well-designed, well-executed" refers to studies that directly address the question; use adequate randomization, blinding, and allocation concealment; are adequately powered; use intention-to-treat analyses; and have high follow-up rates.

‡Limitations include concerns with the design and execution of a study that result in decreased confidence in the true estimate of the effect. Examples of such limitations include but are not limited to: inadequate randomization, lack of blinding of study participants or outcome assessors, inadequate power, outcomes of interest that are not prespecified for the primary outcomes, low follow-up rates, and findings based on subgroup analyses. Whether the limitations are considered minor or major is based on the number and severity of flaws in design or execution. Rules for determining whether the limitations are considered minor or major and how they will affect rating of the individual studies will be developed collaboratively with the methodology team.

§Nonrandomized controlled studies refer to intervention studies where assignment to intervention and comparison groups is not random (e.g., quasi-experimental study design).

¶Observational studies include prospective and retrospective cohort, case-control, and cross-sectional studies.

Applying Classification of Recommendations and Level of Evidence

		Size of Treatment Effect
		CLASS I Benefit >>> Risk Procedure/Treatment SHOULD be performed/ administered	CLASS IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment	CLASS IIb Benefit ≥ Risk Additional studies with broad objectives needed; additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED	CLASS III No Benefit or Class III Harm
						Procedure/Test	Treatment
					COR III: No Benefit	Not helpful	No proven benefit
					COR III: Harm	Excess cost without benefit or harmful	Harmful to patients
Estimate of Certainty (Precision) of Treatment Effect	LEVEL A Multiple populations evaluated* Data derived from multiple randomized clinical trials or meta-analyses	Recommendation that procedure or treatment is useful/effective Sufficient evidence from multiple randomized trials or meta-analyses	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from multiple randomized trials or meta-analyses	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from multiple randomized trials or meta-analyses	Recommendation that procedure or treatment is not useful/effective and may be harmful Sufficient evidence from multiple randomized trials or meta-analyses
	LEVEL B Limited populations evaluated* Data derived from a single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is useful/effective Evidence from single randomized trial or nonrandomized studies	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from single randomized trial or nonrandomized studies	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is not useful/effective and may be harmful Evidence from single randomized trial or nonrandomized studies
	LEVEL C Very limited populations evaluated* Only consensus opinion of experts, case studies, or standard of care	Recommendation that procedure or treatment is useful/effective Only expert opinion, case studies, or standard of care	Recommendation in favor of treatment or procedure being useful/effective Only diverging expert opinion, case studies, or standard of care	Recommendation's usefulness/efficacy less well established Only diverging expert opinion, case studies, or standard of care	Recommendation that procedure or treatment is not useful/effective and may be harmful Only expert opinion, case studies, or standard of care

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.

*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use.

†For comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

The following algorithms are provided in the original guideline document:

• Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults
• Initiating Statin Therapy in Individuals with Clinical ASCVD
• Initiating Statin Therapy in Individuals without Clinical ASCVD
• Statin Therapy: Monitoring Therapeutic Response and Adherence

Note from the National Guideline Clearinghouse (NGC): National Heart, Lung and Blood Institute (NHLBI) Evidence Statements are also included for each recommendation. See Appendix 4 in the original guideline document.

Each recommendation has been mapped from the NHLBI grading format to the American College of Cardiology/American Heart Association Class of Recommendation/Level of Evidence (ACC/AHA COR/LOE) construct and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. Definitions for the NHLBI strength of recommendation (A-E, N) and quality of evidence (High, Moderate, Low) and the ACC/AHA levels of the evidence (LOE: A-C) and classes of recommendations (COR: I-III) are provided at the end of the "Major Recommendations" field.

What's New in the Guideline?

Focus on Atherosclerotic Cardiovascular Disease (ASCVD Risk) Reduction: 4 Statin Benefit Groups

1. This guideline is based on a comprehensive set of data from randomized control trials (RCTs) from which 4 statin benefit groups were identified that focus efforts to reduce ASCVD events in secondary and primary prevention.

2. This guideline identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention.

A New Perspective on Low-density Lipoprotein Cholesterol (LDL-C) and/or Non–High-density Lipoprotein Cholesterol (HDL-C) Treatment Goals

1. The Expert Panel was unable to find RCT evidence to support continued use of specific LDL-C or non–HDL-C treatment targets.

2. The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit.

3. Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD.

Global Risk Assessment for Primary Prevention

1. This guideline recommends use of the new Pooled Cohort Equations to estimate 10-year ASCVD risk in both white and black men and women.

2. By more accurately identifying higher-risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit.

3. It also indicates, on the basis of RCT data, those high-risk groups that might not benefit.

4. This guideline recommends a discussion between clinicians and patients before initiation of statin therapy.

Safety Recommendations

1. This guideline used RCTs to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk.

2. Using RCTs to determine statin adverse effects facilitates understanding of the net benefit from statin therapy.

3. This guideline provides expert guidance on management of statin-associated adverse effects, including muscle symptoms.

Role of Biomarkers and Noninvasive Tests

1. Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment Work Group and Blood Cholesterol Expert Panel.

Future Updates to the Blood Cholesterol Guideline

1. This is a comprehensive guideline for the evidence-based treatment of blood cholesterol to reduce ASCVD risk.

2. Future updates will build on this foundation to provide expert guidance on the management of complex lipid disorders and incorporate refinements in risk stratification based on critical review of emerging data.

3. RCTs comparing alternative treatment strategies are needed in order to inform future evidence-based guidelines for the optimum ASCVD risk-reduction approach.

Note: See Appendix 5 in the original guideline document for an expanded discussion of what's new in the guideline.

Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults—Statin Treatment

Treatment Targets

1. The Expert Panel makes no recommendations for or against specific LDL-C or non–HDL-C targets for the primary or secondary prevention of ASCVD. NHLBI Grade: N (No recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

Secondary Prevention

1. High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤75 years of age who have clinical ASCVD*, unless contraindicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. In individuals with clinical ASCVD* in whom high-intensity statin therapy would otherwise be used, when high-intensity statin therapy is contraindicated† or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option if tolerated (see "Safety of Statins," below). NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Heart Protection Study Collaborative Group, 2002; Cholesterol Treatment Trialists' [CTT] Collaboration et al., 2010; Tikkanen et al., 2009; Holmes et al., 2006; Akushevich et al., 2012; Wolff, Starfield &, Anderson, 2002; Fried et al., "Effects," 2011; Robinson et al., 2007; Porock et al., 2005; Stineman et al., 2012; Schonberg et al., 2011; Fried et al., "Health outcome," 2011; Barry & Edgman-Levitan, 2012; Man-Son-Hing, Gage, & Montgomery, 2005; Fried et al., 2002; Ditto et al., 1996; Rosenfeld, Wenger, & Kagawa-Singer, 2000; Nease et al., 1995; Glynn et al., 2010; Shepherd et al., 2002; Trompet et al., 2010; Gray et al., 2011; LaCroix et al., 2008; Hippisley-Cox et al., 2005; Forman et al., 2011)

Primary Prevention in Individuals ≥21 Years of Age with LDL-C ≥190 mg/dL

1. Individuals with LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia (see Table 6 in the original guideline document). NHLBI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B (Berglund et al., 2012; Miller et al., 2011)

2. Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be treated with statin therapy (10-year ASCVD risk estimation is not required) NHLBI Grade: B (Moderate); ACC/AHA COR: I§; ACC/AHA LOE: B:

• Use high-intensity statin therapy unless contraindicated.
• For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity.

3. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at least a 50% LDL-C reduction. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (CTT Collaboration et al., 2010; LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Ridker et al, 2008; Baigent et al., 2005)

4. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, after the maximum intensity of statin therapy has been achieved, addition of a nonstatin drug may be considered to further lower LDL-C. Evaluate the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, and consider patient preferences. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Thompson, Packard, & Stone, 2004)

Primary Prevention in Individuals with Diabetes and LDL-C 70–189 mg/dL

1. Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Ridker et al., 2008; Ridker et al., 2012)

3. In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Roffi, Angiolillo, & Kappetein, 2011; Nathan et al., 2005; Rhodes et al., 2012; Paynter et al., 2011; Elley et al., 2010; Stevens et al., 2004; Bibbins-Domingo et al., 2007; Daniels et al., 2009; Jacob & Cho, 2010; Bainey & Jugdutt, 2009)

Primary Prevention in Individuals without Diabetes and with LDL-C 70–189 mg/dL

1. The Pooled Cohort Equations should be used to estimate 10-year ASCVD‖ risk for individuals with LDL-C 70–189 mg/dL without clinical ASCVD* to guide initiation of statin therapy for the primary prevention of ASCVD. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (Goff et al., 2014)

2. Adults 40 to 75 years of age with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk ≥7.5% should be treated with moderate- to high-intensity statin therapy. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. It is reasonable to offer treatment with a moderate-intensity statin to adults 40 to 75 years of age, with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk of 5% to <7.5%. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

4. Before initiation of statin therapy for the primary prevention of ASCVD in adults with LDL-C 70–189 mg/dL without clinical ASCVD* or diabetes, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions, as well as patient preferences for treatment. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Yu et al., 2013)

5. In adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk-based treatment decision is uncertain, additional factors¶ may be considered to inform treatment decision making. In these individuals, statin therapy for primary prevention may be considered after evaluation of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions and consider patient preferences. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Goff et al., 2014; CTT Collaborators et al., 2012)

Heart Failure and Hemodialysis

1. The Expert Panel makes no recommendations regarding the initiation or discontinuation of statins in patients with NYHA class II–IV ischemic systolic heart failure or in patients on maintenance hemodialysis. NHBLI Grade: N (No Recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

*Clinical ASCVD includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischaemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin.

†Contraindications, warnings, and precautions are defined for each statin according to the manufacturer's prescribing information ("Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013).

‡Individuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A triglyceride level ≥500 mg/dL was an exclusion criterion for almost all RCTs. Therefore, ruling out secondary causes is necessary to avoid inappropriate statin therapy.

§No RCTs included only individuals with LDL-C ≥190 mg/dL. However, many trials did include individuals with LDL-C ≥190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD events by 22%, and the relative reductions in ASCVD events were consistent across the range of LDL-C levels. Therefore, individuals with primary LDL-C ≥190 mg/dL should be treated with statin therapy.

ǁEstimated 10-year or "hard" ASCVD risk includes first occurrence of nonfatal MI, coronary heart disease death, and nonfatal and fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort Equations.

¶These factors may include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L; coronary artery calcium (CAC) score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx 

); ankle-brachial index (ABI) <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

See Table 5 in the original guideline document for high-, moderate-, and low-intensity statin therapies used in the RCTs reviewed by the Expert Panel.

Statin Safety Recommendations

Safety

1. To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD* risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present. Characteristics predisposing individuals to statin adverse effects include but are not limited to: NHBLI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: B

• Multiple or serious comorbidities, including impaired renal or hepatic function
• History of previous statin intolerance or muscle disorders
• Unexplained alanine aminotransferase (ALT) elevations ≥3 times the upper limit of normal (ULN)
• Patient characteristics or concomitant use of drugs affecting statin metabolism
• Age >75 years

Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to:

• History of hemorrhagic stroke
• Asian ancestry

2a. Creatine kinase (CK) should not be routinely measured in individuals receiving statin therapy. NHBLI Grade: A (Strong); ACC/AHA COR: III: No Benefit; ACC/AHA LOE: A

2b. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

2c. During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

3a. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiation of statin therapy. NHBLI Grade: B (Moderate); ACC/AHA COR: I†; ACC/AHA LOE: B

3b. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera). NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (U.S. Food and Drug Administration, 2012)

4. Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL. NHBLI Grade: C (Weak); ACC/AHA COR: IIb; ACC/AHA LOE: C

5. It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily. NHBLI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: A ("Zocor," 2012; U.S. Food and Drug Administration, 2010)

6. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (American Diabetes Association, 2013). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. NHBLI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B

7. For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for human immunodeficiency virus [HIV]). A review of the manufacturer's prescribing information may be useful before initiation of any cholesterol-lowering drug. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Heart Protection Study Collaborative Group, 2002; "Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013; U.S. Food and Drug Administration, 2012; Rawlins, 2008; Schwartz et al., 2001; Shepherd et al., 2006)

8. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm: NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Taylor et al., 2011; Eckel, 2010; Baigent et al., 2010; Mills et al., 2008; Dale et al., 2007)

• To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy.
• If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK and creatinine and performing urinalysis for myoglobinuria.
• If mild to moderate muscle symptoms develop during statin therapy:
  • Discontinue the statin until the symptoms can be evaluated.
  • Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
  • If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
  • If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
  • Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
  • If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above.
  • If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.

9. For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Shepherd et al., 2002; U.S. Food and Drug Administration, 2012; Collins et al., 2004; Roberts, 2009)

*Based on the presence of clinical ASCVD, diabetes, LDL-C ≥190 mg/dL, or level of estimated 10-year ASCVD risk.

†Individuals with elevated ALT levels (usually >1.5 or 2 times ULN) were excluded from RCT participation. Unexplained ALT ≥3 times ULN is a contraindication to statin therapy as listed in manufacturer's prescribing information.

‡Statin use is associated with a very modest excess risk of new-onset diabetes in RCTs and meta-analyses of RCTs (i.e., ∼0.1 excess cases per 100 individuals treated for 1 year with moderate-intensity statin therapy and ∼0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy. The increased risk of new-onset diabetes appears to be confined to those with risk factors for diabetes. These individuals are also at higher risk of ASCVD because of these risk factors. Therefore, if a statin-treated individual develops diabetes as detected by current diabetes screening guidelines, he or she should be counseled to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD events.

Nonstatin Safety Recommendations

Safety of Niacin

1. Baseline hepatic transaminases, fasting blood glucose or hemoglobin A1c, and uric acid should be obtained before initiation of niacin, and again during up-titration to a maintenance dose and every 6 months thereafter. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

2. Niacin should not be used if:

• Hepatic transaminase elevations are higher than 2 to 3 times ULN. NHLBI Grade: A (Strong); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• Persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or unexplained abdominal pain or gastrointestinal symptoms occur. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• New-onset atrial fibrillation or weight loss occurs. NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

3. In individuals with adverse effects from niacin, the potential for ASCVD benefits and the potential for adverse effects should be reconsidered before reinitiation of niacin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

4. To reduce the frequency and severity of adverse cutaneous symptoms, it is reasonable to: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

• Start niacin at a low dose and titrate to a higher dose over a period of weeks as tolerated.
• Take niacin with food or premedicate with aspirin 325 mg 30 minutes before niacin dosing to alleviate flushing symptoms.
• If an extended-release preparation is used, increase the dose of extended-release niacin from 500 mg to a maximum of 2,000 mg/day over 4 to 8 weeks, with the dose of extended-release niacin increasing not more than weekly.
• If immediate-release niacin is chosen, start at a dose of 100 mg 3 times daily and up-titrate to 3 g/day, divided into 2 or 3 doses.

Safety of Bile Acid Sequestrants (BAS)

1. BAS should not be used in individuals with baseline fasting triglyceride levels ≥300 mg/dL or type III hyperlipoproteinemia, because severe triglyceride elevations might occur. (A fasting lipid panel should be obtained before BAS is initiated, 3 months after initiation, and every 6 to 12 months thereafter.) NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. It is reasonable to use BAS with caution if baseline triglyceride levels are 250 to 299 mg/dL, and evaluate a fasting lipid panel in 4 to 6 weeks after initiation. Discontinue the BAS if triglycerides exceed 400 mg/dL. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Crouse, 1987)

Safety of Cholesterol-Absorption Inhibitors

1. It is reasonable to obtain baseline hepatic transaminases before initiation of ezetimibe. When ezetimibe is coadministered with a statin, monitor transaminase levels as clinically indicated, and discontinue ezetimibe if persistent ALT elevations ≥3 times ULN occur. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Safety of Fibrates

1. Gemfibrozil should not be initiated in patients on statin therapy because of an increased risk for muscle symptoms and rhabdomyolysis. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (ACCORD Study Group et al., 2010)

3. Renal status should be evaluated before fenofibrate initiation, within 3 months after initiation, and every 6 months thereafter. Assess renal safety with both a serum creatinine level and an estimated glomerular filtration rate (eGFR) based on creatinine. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

• Fenofibrate should not be used if moderate or severe renal impairment, defined as eGFR <30 mL/min per 1.73 m², is present. ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• If eGFR is between 30 and 59 mL/min per 1.73 m², the dose of fenofibrate should not exceed 54 mg/day.*
• If, during follow-up, the eGFR decreases persistently to ≤30 mL/min per 1.73 m², fenofibrate should be discontinued.

*Consult the manufacturer's prescribing information as there are several forms of fenofibrate available.

Safety of Omega-3 Fatty Acids

1. If eicosapentaenoic acid (EPA) and/or docosahexanoic acid (DHA) are used for the management of severe hypertriglyceridemia, defined as triglycerides ≥500 mg/dL, it is reasonable to evaluate the patient for gastrointestinal disturbances, skin changes, and bleeding. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Recommendations for Monitoring, Optimizing, and Addressing Insufficient Response to Statin Therapy

Monitoring Statin Therapy

1. Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4–12 weeks after initiation or dose adjustment, and every 3–12 months thereafter. Other safety measurements should be measured as clinically indicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

Optimizing Statin Therapy

1. The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended but not tolerated. NHLBI Grade: B (Moderate); ACC/AHA COR: I*; ACC/AHA LOE: B

Insufficient Response to Statin Therapy

1. In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: NHLBI Grade A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

• Reinforce medication adherence.
• Reinforce adherence to intensive lifestyle changes.
• Exclude secondary causes of hyperlipidemia.

2. It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Amarenco et al., 2006; Thompson & HEART-UK LDL Apheresis Working Group, 2008; Schwertz & Badellino, 2008)

• High-intensity statin therapy† generally results in an average LDL-C reduction of ≥50% from the untreated baseline.
• Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.
• LDL-C levels and percents reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.

3. In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. Higher-risk individuals include: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb: ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; ACCORD Study Group et al., 2010; Rossebo et al., 2007; Sharp Collaborative Group, 2010; Yokoyama, Origasa, & JELIS Investigators, 2003)

• Individuals with clinical ASCVD‡ <75 years of age.
• Individuals with baseline LDL-C ≥190 mg/dL.
• Individuals 40 to 75 years of age with diabetes.

Preference should be given to nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs.

4. In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Eckel, 2010; "Clofibrate and niacin in coronary heart disease," 1975; Frick et al., 1987; Lipid Research Clinics Program, 1984; "The Lipid Research Clinics Coronary Primary Prevention Trial results. II.," 1984; Rubins et al., 1999; Keech et al., 2005; HPS2-THRIVE Collaborative Group, 2013)

*Several RCTs found that low-intensity and low-moderate–intensity statin therapy reduced ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses found that each 39-mg/dL reduction in LDL-C reduces ASCVD risk by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-intensity statin therapy.

†In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C level <100 mg/dL was observed in most individuals receiving high-intensity statin therapy.

‡Clinical ASCVD includes acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.

Definitions:

NHLBI Grading of the Strength of Recommendations

Grade	Strength of Recommendation*
A	Strong recommendation There is high certainty based on evidence that the net benefit† is substantial.
B	Moderate recommendation There is moderate certainty based on evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate.
C	Weak recommendation There is at least moderate certainty based on evidence that there is a small net benefit.
D	Recommendation against There is at least moderate certainty based on evidence that there is no net benefit or that risks/harms outweigh benefits.
E	Expert opinion ("There is insufficient evidence or evidence is unclear or conflicting, but this is what the Work Group recommends.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Work Group thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area.
N	No recommendation for or against ("There is insufficient evidence or evidence is unclear or conflicting.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Work Group thought no recommendation should be made. Further research is recommended in this area.

*In most cases, the strength of the recommendation should be closely aligned with the quality of the evidence; however, under some circumstances, there may be valid reasons for making recommendations that are not closely aligned with the quality of the evidence (e.g., strong recommendation when the evidence quality is moderate, such as smoking cessation to reduce cardiovascular disease [CVD] risk or ordering an electrocardiogram [ECG] as part of the initial diagnostic work-up for a patient presenting with possible myocardial infarction [MI]). Those situations should be limited and the rationale explained clearly by the Work Group.

†Net benefit is defined as benefits minus risks/harms of the service/intervention.

NHLBI Quality Rating of the Strength of Evidence

Type of Evidence	Quality Rating*
Well-designed, well-executed† randomized controlled trials (RCTs) that adequately represent populations to which the results are applied and directly assess effects on health outcomes. Meta-analyses of such studies. Highly certain about the estimate of effect. Further research is unlikely to change confidence in the estimate of effect.	High
RCTs with minor limitations‡ affecting confidence in, or applicability of, the results. Well-designed, well-executed nonrandomized controlled studies§ and well-designed, well-executed observational studies¶. Meta-analyses of such studies. Moderately certain about the estimate of effect. Further research may have an impact on confidence in the estimate of effect and may change the estimate.	Moderate
RCTs with major limitations. Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results. Uncontrolled clinical observations without an appropriate comparison group (e.g., case series, case reports). Physiological studies in humans. Meta-analyses of such studies. Low certainty about the estimate of effect. Further research is likely to have an impact on confidence in the estimate of effect and is likely to change the estimate.	Low

*In some cases, other evidence, such as large all-or-none case series (e.g., jumping from airplanes or tall structures), can represent high- or moderate-quality evidence. In such cases, the rationale for the evidence rating exception should be explained by the Work Group and clearly justified.

†"Well-designed, well-executed" refers to studies that directly address the question; use adequate randomization, blinding, and allocation concealment; are adequately powered; use intention-to-treat analyses; and have high follow-up rates.

‡Limitations include concerns with the design and execution of a study that result in decreased confidence in the true estimate of the effect. Examples of such limitations include but are not limited to: inadequate randomization, lack of blinding of study participants or outcome assessors, inadequate power, outcomes of interest that are not prespecified for the primary outcomes, low follow-up rates, and findings based on subgroup analyses. Whether the limitations are considered minor or major is based on the number and severity of flaws in design or execution. Rules for determining whether the limitations are considered minor or major and how they will affect rating of the individual studies will be developed collaboratively with the methodology team.

§Nonrandomized controlled studies refer to intervention studies where assignment to intervention and comparison groups is not random (e.g., quasi-experimental study design).

¶Observational studies include prospective and retrospective cohort, case-control, and cross-sectional studies.

Applying Classification of Recommendations and Level of Evidence

		Size of Treatment Effect
		CLASS I Benefit >>> Risk Procedure/Treatment SHOULD be performed/ administered	CLASS IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment	CLASS IIb Benefit ≥ Risk Additional studies with broad objectives needed; additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED	CLASS III No Benefit or Class III Harm
						Procedure/Test	Treatment
					COR III: No Benefit	Not helpful	No proven benefit
					COR III: Harm	Excess cost without benefit or harmful	Harmful to patients
Estimate of Certainty (Precision) of Treatment Effect	LEVEL A Multiple populations evaluated* Data derived from multiple randomized clinical trials or meta-analyses	Recommendation that procedure or treatment is useful/effective Sufficient evidence from multiple randomized trials or meta-analyses	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from multiple randomized trials or meta-analyses	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from multiple randomized trials or meta-analyses	Recommendation that procedure or treatment is not useful/effective and may be harmful Sufficient evidence from multiple randomized trials or meta-analyses
	LEVEL B Limited populations evaluated* Data derived from a single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is useful/effective Evidence from single randomized trial or nonrandomized studies	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from single randomized trial or nonrandomized studies	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is not useful/effective and may be harmful Evidence from single randomized trial or nonrandomized studies
	LEVEL C Very limited populations evaluated* Only consensus opinion of experts, case studies, or standard of care	Recommendation that procedure or treatment is useful/effective Only expert opinion, case studies, or standard of care	Recommendation in favor of treatment or procedure being useful/effective Only diverging expert opinion, case studies, or standard of care	Recommendation's usefulness/efficacy less well established Only diverging expert opinion, case studies, or standard of care	Recommendation that procedure or treatment is not useful/effective and may be harmful Only expert opinion, case studies, or standard of care

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.

*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use.

†For comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

The following algorithms are provided in the original guideline document:

• Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults
• Initiating Statin Therapy in Individuals with Clinical ASCVD
• Initiating Statin Therapy in Individuals without Clinical ASCVD
• Statin Therapy: Monitoring Therapeutic Response and Adherence

Note from the National Guideline Clearinghouse (NGC): National Heart, Lung and Blood Institute (NHLBI) Evidence Statements are also included for each recommendation. See Appendix 4 in the original guideline document.

Each recommendation has been mapped from the NHLBI grading format to the American College of Cardiology/American Heart Association Class of Recommendation/Level of Evidence (ACC/AHA COR/LOE) construct and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. Definitions for the NHLBI strength of recommendation (A-E, N) and quality of evidence (High, Moderate, Low) and the ACC/AHA levels of the evidence (LOE: A-C) and classes of recommendations (COR: I-III) are provided at the end of the "Major Recommendations" field.

What's New in the Guideline?

Focus on Atherosclerotic Cardiovascular Disease (ASCVD Risk) Reduction: 4 Statin Benefit Groups

1. This guideline is based on a comprehensive set of data from randomized control trials (RCTs) from which 4 statin benefit groups were identified that focus efforts to reduce ASCVD events in secondary and primary prevention.

2. This guideline identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention.

A New Perspective on Low-density Lipoprotein Cholesterol (LDL-C) and/or Non–High-density Lipoprotein Cholesterol (HDL-C) Treatment Goals

1. The Expert Panel was unable to find RCT evidence to support continued use of specific LDL-C or non–HDL-C treatment targets.

2. The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit.

3. Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD.

Global Risk Assessment for Primary Prevention

1. This guideline recommends use of the new Pooled Cohort Equations to estimate 10-year ASCVD risk in both white and black men and women.

2. By more accurately identifying higher-risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit.

3. It also indicates, on the basis of RCT data, those high-risk groups that might not benefit.

4. This guideline recommends a discussion between clinicians and patients before initiation of statin therapy.

Safety Recommendations

1. This guideline used RCTs to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk.

2. Using RCTs to determine statin adverse effects facilitates understanding of the net benefit from statin therapy.

3. This guideline provides expert guidance on management of statin-associated adverse effects, including muscle symptoms.

Role of Biomarkers and Noninvasive Tests

1. Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment Work Group and Blood Cholesterol Expert Panel.

Future Updates to the Blood Cholesterol Guideline

1. This is a comprehensive guideline for the evidence-based treatment of blood cholesterol to reduce ASCVD risk.

2. Future updates will build on this foundation to provide expert guidance on the management of complex lipid disorders and incorporate refinements in risk stratification based on critical review of emerging data.

3. RCTs comparing alternative treatment strategies are needed in order to inform future evidence-based guidelines for the optimum ASCVD risk-reduction approach.

Note: See Appendix 5 in the original guideline document for an expanded discussion of what's new in the guideline.

Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults—Statin Treatment

Treatment Targets

1. The Expert Panel makes no recommendations for or against specific LDL-C or non–HDL-C targets for the primary or secondary prevention of ASCVD. NHLBI Grade: N (No recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

Secondary Prevention

1. High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤75 years of age who have clinical ASCVD*, unless contraindicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. In individuals with clinical ASCVD* in whom high-intensity statin therapy would otherwise be used, when high-intensity statin therapy is contraindicated† or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option if tolerated (see "Safety of Statins," below). NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Heart Protection Study Collaborative Group, 2002; Cholesterol Treatment Trialists' [CTT] Collaboration et al., 2010; Tikkanen et al., 2009; Holmes et al., 2006; Akushevich et al., 2012; Wolff, Starfield &, Anderson, 2002; Fried et al., "Effects," 2011; Robinson et al., 2007; Porock et al., 2005; Stineman et al., 2012; Schonberg et al., 2011; Fried et al., "Health outcome," 2011; Barry & Edgman-Levitan, 2012; Man-Son-Hing, Gage, & Montgomery, 2005; Fried et al., 2002; Ditto et al., 1996; Rosenfeld, Wenger, & Kagawa-Singer, 2000; Nease et al., 1995; Glynn et al., 2010; Shepherd et al., 2002; Trompet et al., 2010; Gray et al., 2011; LaCroix et al., 2008; Hippisley-Cox et al., 2005; Forman et al., 2011)

Primary Prevention in Individuals ≥21 Years of Age with LDL-C ≥190 mg/dL

1. Individuals with LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia (see Table 6 in the original guideline document). NHLBI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B (Berglund et al., 2012; Miller et al., 2011)

2. Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be treated with statin therapy (10-year ASCVD risk estimation is not required) NHLBI Grade: B (Moderate); ACC/AHA COR: I§; ACC/AHA LOE: B:

• Use high-intensity statin therapy unless contraindicated.
• For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity.

3. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at least a 50% LDL-C reduction. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (CTT Collaboration et al., 2010; LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Ridker et al, 2008; Baigent et al., 2005)

4. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, after the maximum intensity of statin therapy has been achieved, addition of a nonstatin drug may be considered to further lower LDL-C. Evaluate the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, and consider patient preferences. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Thompson, Packard, & Stone, 2004)

Primary Prevention in Individuals with Diabetes and LDL-C 70–189 mg/dL

1. Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

2. High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Ridker et al., 2008; Ridker et al., 2012)

3. In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Roffi, Angiolillo, & Kappetein, 2011; Nathan et al., 2005; Rhodes et al., 2012; Paynter et al., 2011; Elley et al., 2010; Stevens et al., 2004; Bibbins-Domingo et al., 2007; Daniels et al., 2009; Jacob & Cho, 2010; Bainey & Jugdutt, 2009)

Primary Prevention in Individuals without Diabetes and with LDL-C 70–189 mg/dL

1. The Pooled Cohort Equations should be used to estimate 10-year ASCVD‖ risk for individuals with LDL-C 70–189 mg/dL without clinical ASCVD* to guide initiation of statin therapy for the primary prevention of ASCVD. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (Goff et al., 2014)

2. Adults 40 to 75 years of age with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk ≥7.5% should be treated with moderate- to high-intensity statin therapy. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

3. It is reasonable to offer treatment with a moderate-intensity statin to adults 40 to 75 years of age, with LDL-C 70–189 mg/dL, without clinical ASCVD* or diabetes, and with an estimated 10-year ASCVD‖ risk of 5% to <7.5%. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

4. Before initiation of statin therapy for the primary prevention of ASCVD in adults with LDL-C 70–189 mg/dL without clinical ASCVD* or diabetes, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions, as well as patient preferences for treatment. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Yu et al., 2013)

5. In adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk-based treatment decision is uncertain, additional factors¶ may be considered to inform treatment decision making. In these individuals, statin therapy for primary prevention may be considered after evaluation of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions and consider patient preferences. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Goff et al., 2014; CTT Collaborators et al., 2012)

Heart Failure and Hemodialysis

1. The Expert Panel makes no recommendations regarding the initiation or discontinuation of statins in patients with NYHA class II–IV ischemic systolic heart failure or in patients on maintenance hemodialysis. NHBLI Grade: N (No Recommendation); ACC/AHA COR: n/a; ACC/AHA LOE: n/a

*Clinical ASCVD includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischaemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin.

†Contraindications, warnings, and precautions are defined for each statin according to the manufacturer's prescribing information ("Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013).

‡Individuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A triglyceride level ≥500 mg/dL was an exclusion criterion for almost all RCTs. Therefore, ruling out secondary causes is necessary to avoid inappropriate statin therapy.

§No RCTs included only individuals with LDL-C ≥190 mg/dL. However, many trials did include individuals with LDL-C ≥190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD events by 22%, and the relative reductions in ASCVD events were consistent across the range of LDL-C levels. Therefore, individuals with primary LDL-C ≥190 mg/dL should be treated with statin therapy.

ǁEstimated 10-year or "hard" ASCVD risk includes first occurrence of nonfatal MI, coronary heart disease death, and nonfatal and fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort Equations.

¶These factors may include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L; coronary artery calcium (CAC) score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx 

); ankle-brachial index (ABI) <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

See Table 5 in the original guideline document for high-, moderate-, and low-intensity statin therapies used in the RCTs reviewed by the Expert Panel.

Statin Safety Recommendations

Safety

1. To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD* risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present. Characteristics predisposing individuals to statin adverse effects include but are not limited to: NHBLI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: B

• Multiple or serious comorbidities, including impaired renal or hepatic function
• History of previous statin intolerance or muscle disorders
• Unexplained alanine aminotransferase (ALT) elevations ≥3 times the upper limit of normal (ULN)
• Patient characteristics or concomitant use of drugs affecting statin metabolism
• Age >75 years

Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to:

• History of hemorrhagic stroke
• Asian ancestry

2a. Creatine kinase (CK) should not be routinely measured in individuals receiving statin therapy. NHBLI Grade: A (Strong); ACC/AHA COR: III: No Benefit; ACC/AHA LOE: A

2b. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

2c. During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Eckel, 2010)

3a. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiation of statin therapy. NHBLI Grade: B (Moderate); ACC/AHA COR: I†; ACC/AHA LOE: B

3b. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera). NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (U.S. Food and Drug Administration, 2012)

4. Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL. NHBLI Grade: C (Weak); ACC/AHA COR: IIb; ACC/AHA LOE: C

5. It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily. NHBLI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: A ("Zocor," 2012; U.S. Food and Drug Administration, 2010)

6. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (American Diabetes Association, 2013). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. NHBLI Grade: B (Moderate); ACC/AHA COR: I‡; ACC/AHA LOE: B

7. For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for human immunodeficiency virus [HIV]). A review of the manufacturer's prescribing information may be useful before initiation of any cholesterol-lowering drug. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Heart Protection Study Collaborative Group, 2002; "Lescol," 2012; "Pravachol," 2012; "Livalo," 2012; "Zocor," 2012; "Mevacor," 2012; "Lipitor," 2012; "Crestor," 2013; U.S. Food and Drug Administration, 2012; Rawlins, 2008; Schwartz et al., 2001; Shepherd et al., 2006)

8. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm: NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Taylor et al., 2011; Eckel, 2010; Baigent et al., 2010; Mills et al., 2008; Dale et al., 2007)

• To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy.
• If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK and creatinine and performing urinalysis for myoglobinuria.
• If mild to moderate muscle symptoms develop during statin therapy:
  • Discontinue the statin until the symptoms can be evaluated.
  • Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases).
  • If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy.
  • If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin.
  • Once a low dose of a statin is tolerated, gradually increase the dose as tolerated.
  • If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above.
  • If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.

9. For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. NHBLI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (Shepherd et al., 2002; U.S. Food and Drug Administration, 2012; Collins et al., 2004; Roberts, 2009)

*Based on the presence of clinical ASCVD, diabetes, LDL-C ≥190 mg/dL, or level of estimated 10-year ASCVD risk.

†Individuals with elevated ALT levels (usually >1.5 or 2 times ULN) were excluded from RCT participation. Unexplained ALT ≥3 times ULN is a contraindication to statin therapy as listed in manufacturer's prescribing information.

‡Statin use is associated with a very modest excess risk of new-onset diabetes in RCTs and meta-analyses of RCTs (i.e., ∼0.1 excess cases per 100 individuals treated for 1 year with moderate-intensity statin therapy and ∼0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy. The increased risk of new-onset diabetes appears to be confined to those with risk factors for diabetes. These individuals are also at higher risk of ASCVD because of these risk factors. Therefore, if a statin-treated individual develops diabetes as detected by current diabetes screening guidelines, he or she should be counseled to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD events.

Nonstatin Safety Recommendations

Safety of Niacin

1. Baseline hepatic transaminases, fasting blood glucose or hemoglobin A1c, and uric acid should be obtained before initiation of niacin, and again during up-titration to a maintenance dose and every 6 months thereafter. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

2. Niacin should not be used if:

• Hepatic transaminase elevations are higher than 2 to 3 times ULN. NHLBI Grade: A (Strong); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• Persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or unexplained abdominal pain or gastrointestinal symptoms occur. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• New-onset atrial fibrillation or weight loss occurs. NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

3. In individuals with adverse effects from niacin, the potential for ASCVD benefits and the potential for adverse effects should be reconsidered before reinitiation of niacin therapy. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: I; ACC/AHA LOE: B (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

4. To reduce the frequency and severity of adverse cutaneous symptoms, it is reasonable to: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; "Clofibrate and niacin in coronary heart disease," 1975; Guyton & Bays, 2007; Brown & Zhao, 2008; Grundy et al., 2002)

• Start niacin at a low dose and titrate to a higher dose over a period of weeks as tolerated.
• Take niacin with food or premedicate with aspirin 325 mg 30 minutes before niacin dosing to alleviate flushing symptoms.
• If an extended-release preparation is used, increase the dose of extended-release niacin from 500 mg to a maximum of 2,000 mg/day over 4 to 8 weeks, with the dose of extended-release niacin increasing not more than weekly.
• If immediate-release niacin is chosen, start at a dose of 100 mg 3 times daily and up-titrate to 3 g/day, divided into 2 or 3 doses.

Safety of Bile Acid Sequestrants (BAS)

1. BAS should not be used in individuals with baseline fasting triglyceride levels ≥300 mg/dL or type III hyperlipoproteinemia, because severe triglyceride elevations might occur. (A fasting lipid panel should be obtained before BAS is initiated, 3 months after initiation, and every 6 to 12 months thereafter.) NHLBI Grade: C (Weak); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. It is reasonable to use BAS with caution if baseline triglyceride levels are 250 to 299 mg/dL, and evaluate a fasting lipid panel in 4 to 6 weeks after initiation. Discontinue the BAS if triglycerides exceed 400 mg/dL. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: C (Crouse, 1987)

Safety of Cholesterol-Absorption Inhibitors

1. It is reasonable to obtain baseline hepatic transaminases before initiation of ezetimibe. When ezetimibe is coadministered with a statin, monitor transaminase levels as clinically indicated, and discontinue ezetimibe if persistent ALT elevations ≥3 times ULN occur. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Safety of Fibrates

1. Gemfibrozil should not be initiated in patients on statin therapy because of an increased risk for muscle symptoms and rhabdomyolysis. NHLBI Grade: B (Moderate); ACC/AHA COR: III: Harm; ACC/AHA LOE: B

2. Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb; ACC/AHA LOE: C (ACCORD Study Group et al., 2010)

3. Renal status should be evaluated before fenofibrate initiation, within 3 months after initiation, and every 6 months thereafter. Assess renal safety with both a serum creatinine level and an estimated glomerular filtration rate (eGFR) based on creatinine. NHLBI Grade: B (Moderate); ACC/AHA COR: I; ACC/AHA LOE: B

• Fenofibrate should not be used if moderate or severe renal impairment, defined as eGFR <30 mL/min per 1.73 m², is present. ACC/AHA COR: III: Harm; ACC/AHA LOE: B
• If eGFR is between 30 and 59 mL/min per 1.73 m², the dose of fenofibrate should not exceed 54 mg/day.*
• If, during follow-up, the eGFR decreases persistently to ≤30 mL/min per 1.73 m², fenofibrate should be discontinued.

*Consult the manufacturer's prescribing information as there are several forms of fenofibrate available.

Safety of Omega-3 Fatty Acids

1. If eicosapentaenoic acid (EPA) and/or docosahexanoic acid (DHA) are used for the management of severe hypertriglyceridemia, defined as triglycerides ≥500 mg/dL, it is reasonable to evaluate the patient for gastrointestinal disturbances, skin changes, and bleeding. NHLBI Grade: C (Weak); ACC/AHA COR: IIa; ACC/AHA LOE: B

Recommendations for Monitoring, Optimizing, and Addressing Insufficient Response to Statin Therapy

Monitoring Statin Therapy

1. Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4–12 weeks after initiation or dose adjustment, and every 3–12 months thereafter. Other safety measurements should be measured as clinically indicated. NHLBI Grade: A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

Optimizing Statin Therapy

1. The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended but not tolerated. NHLBI Grade: B (Moderate); ACC/AHA COR: I*; ACC/AHA LOE: B

Insufficient Response to Statin Therapy

1. In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: NHLBI Grade A (Strong); ACC/AHA COR: I; ACC/AHA LOE: A

• Reinforce medication adherence.
• Reinforce adherence to intensive lifestyle changes.
• Exclude secondary causes of hyperlipidemia.

2. It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (LaRosa et al., 2005; Pedersen et al., 2005; Cannon et al., 2004; Amarenco et al., 2006; Thompson & HEART-UK LDL Apheresis Working Group, 2008; Schwertz & Badellino, 2008)

• High-intensity statin therapy† generally results in an average LDL-C reduction of ≥50% from the untreated baseline.
• Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.
• LDL-C levels and percents reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.

3. In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. Higher-risk individuals include: NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIb: ACC/AHA LOE: C (AIM-HIGH Investigators et al., 2011; ACCORD Study Group et al., 2010; Rossebo et al., 2007; Sharp Collaborative Group, 2010; Yokoyama, Origasa, & JELIS Investigators, 2003)

• Individuals with clinical ASCVD‡ <75 years of age.
• Individuals with baseline LDL-C ≥190 mg/dL.
• Individuals 40 to 75 years of age with diabetes.

Preference should be given to nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs.

4. In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. NHLBI Grade: E (Expert Opinion); ACC/AHA COR: IIa; ACC/AHA LOE: B (Eckel, 2010; "Clofibrate and niacin in coronary heart disease," 1975; Frick et al., 1987; Lipid Research Clinics Program, 1984; "The Lipid Research Clinics Coronary Primary Prevention Trial results. II.," 1984; Rubins et al., 1999; Keech et al., 2005; HPS2-THRIVE Collaborative Group, 2013)

*Several RCTs found that low-intensity and low-moderate–intensity statin therapy reduced ASCVD events. In addition, the Cholesterol Treatment Trialists meta-analyses found that each 39-mg/dL reduction in LDL-C reduces ASCVD risk by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-intensity statin therapy.

†In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C level <100 mg/dL was observed in most individuals receiving high-intensity statin therapy.

‡Clinical ASCVD includes acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.

Definitions:

NHLBI Grading of the Strength of Recommendations

Grade	Strength of Recommendation*
A	Strong recommendation There is high certainty based on evidence that the net benefit† is substantial.
B	Moderate recommendation There is moderate certainty based on evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate.
C	Weak recommendation There is at least moderate certainty based on evidence that there is a small net benefit.
D	Recommendation against There is at least moderate certainty based on evidence that there is no net benefit or that risks/harms outweigh benefits.
E	Expert opinion ("There is insufficient evidence or evidence is unclear or conflicting, but this is what the Work Group recommends.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Work Group thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area.
N	No recommendation for or against ("There is insufficient evidence or evidence is unclear or conflicting.") Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Work Group thought no recommendation should be made. Further research is recommended in this area.

*In most cases, the strength of the recommendation should be closely aligned with the quality of the evidence; however, under some circumstances, there may be valid reasons for making recommendations that are not closely aligned with the quality of the evidence (e.g., strong recommendation when the evidence quality is moderate, such as smoking cessation to reduce cardiovascular disease [CVD] risk or ordering an electrocardiogram [ECG] as part of the initial diagnostic work-up for a patient presenting with possible myocardial infarction [MI]). Those situations should be limited and the rationale explained clearly by the Work Group.

†Net benefit is defined as benefits minus risks/harms of the service/intervention.

NHLBI Quality Rating of the Strength of Evidence

Type of Evidence	Quality Rating*
Well-designed, well-executed† randomized controlled trials (RCTs) that adequately represent populations to which the results are applied and directly assess effects on health outcomes. Meta-analyses of such studies. Highly certain about the estimate of effect. Further research is unlikely to change confidence in the estimate of effect.	High
RCTs with minor limitations‡ affecting confidence in, or applicability of, the results. Well-designed, well-executed nonrandomized controlled studies§ and well-designed, well-executed observational studies¶. Meta-analyses of such studies. Moderately certain about the estimate of effect. Further research may have an impact on confidence in the estimate of effect and may change the estimate.	Moderate
RCTs with major limitations. Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results. Uncontrolled clinical observations without an appropriate comparison group (e.g., case series, case reports). Physiological studies in humans. Meta-analyses of such studies. Low certainty about the estimate of effect. Further research is likely to have an impact on confidence in the estimate of effect and is likely to change the estimate.	Low

*In some cases, other evidence, such as large all-or-none case series (e.g., jumping from airplanes or tall structures), can represent high- or moderate-quality evidence. In such cases, the rationale for the evidence rating exception should be explained by the Work Group and clearly justified.

†"Well-designed, well-executed" refers to studies that directly address the question; use adequate randomization, blinding, and allocation concealment; are adequately powered; use intention-to-treat analyses; and have high follow-up rates.

‡Limitations include concerns with the design and execution of a study that result in decreased confidence in the true estimate of the effect. Examples of such limitations include but are not limited to: inadequate randomization, lack of blinding of study participants or outcome assessors, inadequate power, outcomes of interest that are not prespecified for the primary outcomes, low follow-up rates, and findings based on subgroup analyses. Whether the limitations are considered minor or major is based on the number and severity of flaws in design or execution. Rules for determining whether the limitations are considered minor or major and how they will affect rating of the individual studies will be developed collaboratively with the methodology team.

§Nonrandomized controlled studies refer to intervention studies where assignment to intervention and comparison groups is not random (e.g., quasi-experimental study design).

¶Observational studies include prospective and retrospective cohort, case-control, and cross-sectional studies.

Applying Classification of Recommendations and Level of Evidence

		Size of Treatment Effect
		CLASS I Benefit >>> Risk Procedure/Treatment SHOULD be performed/ administered	CLASS IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment	CLASS IIb Benefit ≥ Risk Additional studies with broad objectives needed; additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED	CLASS III No Benefit or Class III Harm
						Procedure/Test	Treatment
					COR III: No Benefit	Not helpful	No proven benefit
					COR III: Harm	Excess cost without benefit or harmful	Harmful to patients
Estimate of Certainty (Precision) of Treatment Effect	LEVEL A Multiple populations evaluated* Data derived from multiple randomized clinical trials or meta-analyses	Recommendation that procedure or treatment is useful/effective Sufficient evidence from multiple randomized trials or meta-analyses	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from multiple randomized trials or meta-analyses	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from multiple randomized trials or meta-analyses	Recommendation that procedure or treatment is not useful/effective and may be harmful Sufficient evidence from multiple randomized trials or meta-analyses
	LEVEL B Limited populations evaluated* Data derived from a single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is useful/effective Evidence from single randomized trial or nonrandomized studies	Recommendation in favor of treatment or procedure being useful/effective Some conflicting evidence from single randomized trial or nonrandomized studies	Recommendation's usefulness/efficacy less well established Greater conflicting evidence from single randomized trial or nonrandomized studies	Recommendation that procedure or treatment is not useful/effective and may be harmful Evidence from single randomized trial or nonrandomized studies
	LEVEL C Very limited populations evaluated* Only consensus opinion of experts, case studies, or standard of care	Recommendation that procedure or treatment is useful/effective Only expert opinion, case studies, or standard of care	Recommendation in favor of treatment or procedure being useful/effective Only diverging expert opinion, case studies, or standard of care	Recommendation's usefulness/efficacy less well established Only diverging expert opinion, case studies, or standard of care	Recommendation that procedure or treatment is not useful/effective and may be harmful Only expert opinion, case studies, or standard of care

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.

*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use.

†For comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

The following algorithms are provided in the original guideline document:

• Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults
• Initiating Statin Therapy in Individuals with Clinical ASCVD
• Initiating Statin Therapy in Individuals without Clinical ASCVD
• Statin Therapy: Monitoring Therapeutic Response and Adherence