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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1091 CLINICAL STATEMENTS AND GUIDELINES

evaluated.S3.2.1-19 Statin-associated side effects are discussed in Section 5. Common medications that may potentially interact with statins are listed in Table S5 in the Web Supplement. More information on statin drug–drug interactions can be obtained from the ACC LDL-C Manager.S3.2.1-20

3.2.2 Nonstatin Therapies

Ezetimibe is the most commonly used nonstatin agent. It lowers LDL-C levels by 13% to 20% and has a low incidence of side effects.S3.2.2-1,S3.2.2-2 Bile acid sequestrants reduce LDL-C levels by 15% to 30% depending on the dose. Bile acid sequestrants are not absorbed and do not cause systemic side effects, but they are associated with gastrointestinal complaints (eg, constipation) and can cause severe hypertriglyceridemia when fasting triglycerides are ≥300 mg/dL (≥3.4 mmol/L). PCSK9 inhibitors are powerful LDL-lowering drugs. They generally are well tolerated, but long-term safety remains to be proven.S3.2.2-4–S3.2.2-6 Two categories of triglyceride-lowering drugs, niacin and fibrates, may also mildly lower LDL-C levels in patients with normal triglycerides. They may be useful in some patients with severe hypertriglyceridemia, but in the present document they are not listed as LDL-lowering drugs. See Table S4 in the Web Supplement.

3.2.3 Nonstatin Add-on Drugs to Statin Therapy

Under certain circumstances, nonstatin medications (ezetimibe, bile acid sequestrants, and PCSK9 inhibitors) may be useful in combination with statin therapy. The addition of a bile acid sequestrant or ezetimibe to a statin regimen increases the magnitude of LDL-C lowering by approximately 15% to 30% and 13% to 20%, respectively.S3.2.3-1,S3.2.3-2 The addition of a PCSK9 inhibitor to a statin regimen has been shown to further reduce LDL-C levels by 43% to 64%.S3.2.3-3,S3.2.3-4 See Table S5 in the Web Supplement.

4 PATIENT MANAGEMENT GROUPS

4.1 Secondary ASCVD Prevention

Recommendations for Statin Therapy Use in Patients With ASCVD Referenced studies that support recommendations are summarized in Online Data Supplements 6 to 8 and in the Systematic Review Report.

COR LOE Recommendations

I A 1.  In patients who are 75 years of age or younger with clinical ASCVD,* highintensity statin therapy should be initiated or continued with the aim of achieving a 50% or greater reduction in LDL-C levels.S4.1-1–S4.1-5

I A 2.  In patients with clinical ASCVD in whom high-intensity statin therapy is contraindicated or who experience statin-associated side effects, moderateintensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in LDL-C levels.S4.1-3,S4.1-6–S4.1-13

I B-NR 3.  In patients with clinical ASCVD who are judged to be very high risk and considered for PCSK9 inhibitor therapy, maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimibe.S4.1-14,S4.1-15

IIa ASR 4.  In patients with clinical ASCVD who are judged to be very high risk and who are on maximally tolerated LDL-C lowering therapy with LDL-C 70 mg/dL or higher (≥1.8 mmol/L) or a non–HDL-C level of 100 mg/dL or higher (≥2.6 mmol/L), it is reasonable to add a PCSK9 inhibitor following a clinician– patient discussion about the net benefit, safety, and cost.S4.1-15–S4.1-19

IIa B-R 5.  In patients with clinical ASCVD who are on maximally tolerated statin therapy and are judged to be at very high risk and have an LDL-C level of 70 mg/dL or higher (≥1.8 mmol/L), it is reasonable to add ezetimibe therapy.S4.1-14,S4.1-15

Table 3.  High-, Moderate-, and Low-Intensity Statin Therapy*

High Intensity Moderate Intensity Low Intensity LDL-C lowering† ≥50% 30%–49% <30% Statins Atorvastatin (40 mg‡) 80 mg

Rosuvastatin 20 mg (40 mg) Atorvastatin 10 mg (20 mg)

Rosuvastatin (5 mg) 10 mg Simvastatin 20–40 mg§ Simvastatin 10 mg ... Pravastatin 40 mg (80 mg)

Lovastatin 40 mg (80 mg) Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 1–4 mg Pravastatin 10–20 mg

Lovastatin 20 mg Fluvastatin 20–40 mg

Percent LDL-C reductions with the primary statin medications used in clinical practice (atorvastatin, rosuvastatin, simvastatin) were estimated using the median reduction in LDL-C from the VOYAGER database.S3.2.1-2 Reductions in LDL-C for other statin medications (fluvastatin, lovastatin, pitavastatin, pravastatin) were identified according to FDA-approved product labeling in adults with hyperlipidemia, primary hypercholesterolemia, and mixed dyslipidemia.S3.2.1-4 Boldface type indicates specific statins and doses that were evaluated in RCTs,S3.2.1-3,S3.2.1-5–S3.2.1-16 and the Cholesterol Treatment Trialists’ 2010 meta-analysis.S3.2.1-17 All these RCTs demonstrated a reduction in major cardiovascular events. *Percent reductions are estimates from data across large populations. Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.S3.2.1-2 †LDL-C lowering that should occur with the dosage listed below each intensity. ‡Evidence from 1 RCT only: down titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental Decrease through Aggressive Lipid Lowering) study.S3.2.1-3 §Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of the increased risk of myopathy, including rhabdomyolysis. BID indicates twice daily; FDA, US Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; VOYAGER, an indiVidual patient data meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin; and XL, extended release.

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