Patients with very high-risk ASCVD (e.g., multiple major ASCVD events or one major ASCVD event plus multiple risk factors) who cannot reach an LDL threshold of 70 mg/dL (1.8 mmol/L) with a statin: ezetimibe add-on is reasonable. Failing that, a PCSK9 inhibitor* could be added.
Adding ezetimibe to simvastatin 40 mg post-ACS prevents one CV event for every 50 patients treated for seven years vs simvastatin alone.5 Added to a high- or moderate-intensity statin, evolocumab prevents one CV death, MI, or stroke for every 67 high-risk ASCVD patients treated for about two years (FOURIER study). CV death as a stand-alone outcome not affected. Most patients had a prior MI, and about one third had diabetes and/or smoked.4 Patients 20 to 75 years of age with LDL ≥190 mg/dL (4.9 mmol/L) who cannot achieve a 50% LDL reduction and/or LDL <100 mg/dL (2.6 mmol/L) with a statin: ezetimibe add-on is reasonable. If LDL threshold still not met and fasting triglycerides ≤300 mg/dL (3.4 mmol/L), add-on bile acid sequestrant can be considered. Failing this, if the patient has multiple risk factors, consider a PCSK9 inhibitor.*
Patients 30 to 75 years of age with heterozygous familial hypercholesterolemia with an LDL ≥100 mg/dL (2.6 mmol/L) despite statin and ezetimibe, consider adding a PCSK9 inhibitor.*
Patients 40 to 75 years of age with LDL ≥220 mg/dL (5.7 mmol/L) who cannot achieve an LDL <130 mg/dL (3.4 mmol/L) with a statin plus ezetimibe, consider adding a PCSK9 inhibitor.*
Primary prevention in adults 40 to 75 years of age with LDL 70 to 189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year risk of ASCVD of 7.5% or higher and CKD, can combine ezetimibe with a moderate-intensity statin.
Primary prevention in adults with diabetes and 10-year ASCVD risk ≥20%, it may be reasonable to add ezetimibe to a statin to achieve a ≥50% LDL reduction.
Triglycerides ≥500 mg/dL (5.7 mmol/L) and especially ≥1,000 mg/dL (11.3 mmol/L) despite lifestyle changes (very low-fat diet with increased omega-3 consumption, cutting refined carbohydrates and alcohol) and ruling out secondary causes: fibrate. Do not add gemfibrozil to statin.
As a statin substitute in patients with severe or recurrent statin muscle symptoms despite appropriate rechallenge.
Keep in mind that there is no proof adding a non-statin to a statin prevents events in patients without clinical ASCVD.
*PCSK9 inhibitor: safety past three years is unclear and cost is high. Benefit for event reduction is uncertain in patients without clinical ASCVD.
Risk-enhancing factors: metabolic syndrome, LDL persistently ≥160 mg/dL (≥4.1 mmol/L), CKD (see below), history of preeclampsia, family history of premature ASCVD, menopause at <40 years of age, chronic inflammatory disease (e.g., rheumatoid arthritis, HIV), ethnicity (e.g., South Asian), triglycerides persistently ≥175 mg/dL. In some patients (e.g., with estimated 10-year risk ASCVD risk <20%), elevated apolipoprotein B and/or lipoprotein (a), high-sensitivity C-reactive protein ≥2 mg/L, or ABI <0.9, may better-inform the risk/benefit discussion regarding statin therapy. In patients with triglyceride ≥200 mg/dL, apolipoprotein B ≥130 mg/dL corresponds to an LDL ≥160 mg/dL, and thus is a risk-enhancing factor. Persistent apolipoprotein B elevation can also be considered a risk-enhancing factor. Note that measurement may be inaccurate in some labs. Consider checking lipoprotein (a), a particularly atherogenic form of LDL, in patients with a family history of premature ASCVD. Levels ≥50 mg/dL (≥125 nmol/L) may be considered a risk-enhancing factor in men, especially at higher levels. In women, its ability to improve risk prediction is minimal, and only in women with hypercholesterolemia. CKD: use a moderate-intensity statin ±ezetimibe. Do not start a statin in dialysis patients, but it is reasonable to continue one if they are already taking it.