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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2023;148:e9–e119. DOI: 10.1161/CIR.0000000000001168 August 29, 2023

Virani et al 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Chronic Coronary Disease Guideline

risk reduction; 2% absolute risk reduction) at a median follow-up of 6 years.15 An analysis using the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2 P) found the addition of ezetimibe was associated with significantly greater risk reduction (19% relative risk reduction; 6.3% absolute risk reduction) among patients with ≥3 high-risk features, with more modest benefit among those with 2 high-risk features and no benefit among those with 0 or 1 additional features.14 Ezetimibe was allowed at study entry in both PCSK9 monoclonal antibody trials,23,24 but only 3% and 5%, respectively, were on ezetimibe. No RCT has evaluated whether an ezetimibe-first strategy is preferred before adding a PCSK9 monoclonal antibody; however, clinicians should generally add ezetimibe first, then a PCSK9 monoclonal antibody, if necessary, to achieve desired LDL-C levels, given the generic availability of ezetimibe, its once-daily oral administration, and proven long-term safety and tolerability. This is supported by 2 well-designed simulation studies showing that a high proportion of patients will achieve an LDL-C level of <70 mg/ dL with the addition of ezetimibe to high-intensity statin therapy.18,19

6 Generic ezetimibe is an inexpensive drug, with net

price of <$10 for a 1-month supply. To the extent that LDL-C lowering with ezetimibe translates to fewer lifetime MACE, the use of generic ezetimibe is likely to be improve health outcomes at modest increase in cost, especially in very high-risk patients, resulting in high value (<$50 000 per QALY gained).12,20,21 However, the cost-effectiveness of adding generic ezetimibe to maximally tolerated statin therapy is sensitive to the assumption regarding the effect of ezetimibe on cardiovascular and all-cause death. 7.	 Very high risk ASCVD is defined in Table 10. The effi-

cacy of alirocumab and evolocumab was shown in 2 RCTs.22,23 The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition Subjects with Elevated Risk) trial evaluated evolocumab among those with established ASCVD with an LDL-C level of ≥70 mg/dL or non–HDL-C level of ≥100 mg/dL on maximal statin with or without ezetimibe. Cardiovascular events were significantly reduced by 15% with evolocumab, with greater benefit observed among those with additional high-risk clinical factors. No increased risk of neurocognitive adverse effects was observed, even among those achieving the very low levels of LDL-C.29 The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) trial evaluated alirocumab use in patients with an ACS event 1 to 12 months earlier on maximal statin with or without ezetimibe. Cardiovascular events were significantly reduced by 15% with alirocumab, especially in those with additional highrisk clinical factors.25–27 The absolute risk reduction was relatively modest (1.5% and 0.6%, respectively) in both trials, given the ∼60% reduction in LDL-C levels. However, analyses from both FOURIER and ODYSSEY Outcomes trials subsequently showed that among several groups of patients noted in the very high-risk ASCVD category (Table 10), the

Table 11.  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.11 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.60 Boldface type indicates specific statins and doses that were evaluated in RCTs and the Cholesterol Treatment Trialists’ 2010 meta-analysis.2,3 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.11

†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.61 §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. FDA indicates 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.

Reprinted with permission from Grundy SM, et al.42 Copyright 2019 American Heart Association, Inc., and American College of Cardiology Foundation.

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