CLINICAL STATEMENTS AND GUIDELINES Synopsis Patients with severe hypercholesterolemia have a high lifetime risk, and decisions about statins in these pa- tients do not require ASCVD risk scoring. These pa- tients derive net ASCVD risk reduction benefit from interventions that increase expression of LDL receptors. The strongest data have been derived from statin RCTs, which have demonstrated greater risk reduction with statins than with placebo and greater reduction from higher-intensity statin therapy than with moderate- intensity statin therapy. Ezetimibe plus a moderate-in- tensity statin is associated with greater LDL-C reduction than is statin monotherapy in patients with hetero- zygous FH, and the combination reduces ASCVD risk more than moderate-intensity statin monotherapy in patients who have had a recent ACS. In selected pa- tients with severe hypercholesterolemia whose LDL-C is inadequately controlled with drug therapy, LDL apher- esis is an option. Referral to a lipid specialist may be indicated. Recommendation-Specific Supportive Text 1. Patients with primary severe hypercholesterolemia (LDL-C levels 190 mg/dL [ 4.9 mmol/L]) have a high-risk of ASCVDS4.2-2,S4.2-4,S4.2-18 and premature and recurrent coronary events.S4.2-3 Although there have been no randomized, placebo-controlled tri- als of statin therapy done exclusively in subjects with LDL-C levels 190 mg/dL ( 4.9 mmol/L), a placebo-controlled primary prevention study performed in men with a mean baseline LDL-C level of 192 17 mg/dL (4.9 0.4 mmol/L) demon- strated a reduced incidence of MI and cardiovas- cular death in those receiving pravastatin 40 mg These findings were extended in a post hoc analysis of 2560 exclusively primary-preven- tion subjects in that RCT and in a 20-year observa- tional post-trial long-term follow-up study.S4.2-19 In addition, retrospective cohort studies have dem- onstrated that statin therapy reduces risk of inci- and of CHD and all-cause deathS4.2-1 in patients with phenotypic or genetically con- firmed FH. 