Guideline sources The following summarized guidelines for the evaluation and management of familial hypercholesterolemia are prepared by our editorial team based on guidelines from the Canadian Pediatric Cardiology Association (CPCA/CCS 2022), the Canadian Cardiovascular Society (CCS 2021; 2018), the European Society of Cardiology (ESC/EAS 2020), and the American College of Preventive Medicine (ACPM/ADA/PCNA/ABC/ASPC/AAPA/AGS/AHA/ACC/APhA 2019). 1 2 3 4 5 Calculator DLCN criteria for familial hyperc Guidelines 1. Screening and diagnosis f https://web.pathway.md/diseases/rec3NR9IfcU05ASZA I di ti i 1/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway Indications for screening: As per CCS 2022 guidelines, obtain universal lipid screening (fasting or nonfasting, non-HDL cholesterol or LDL cholesterol) within the first decade of life (after 2 years old), coupled with cascade screening for identified cases of probable/definite familial hypercholesterolemia or other monogenic lipid disorders. Consider obtaining selective screening at any time in pediatric patients with identified cardiovascular risk factors or risk conditions or a positive family history of premature CVD or dyslipidemia. E As per AHA 2019 guidelines, consider obtaining fasting or nonfasting lipoprotein profile as early as age 2 years to detect familial hypercholesterolemia or rare forms of hypercholesterolemia in pediatric and adolescent patients with a family history of either early CVD or significant hypercholesterolemia. C Screening of family relatives: As per ESC 2020 guidelines, obtain family screening for familial hypercholesterolemia once the index case is diagnosed. B As per AHA 2019 guidelines, consider obtaining reverse-cascade screening of family members of pediatric and adolescent patients found to have moderate-to-severe hypercholesterolemia, including cholesterol testing for first-, second-, and when possible, third-degree biological relatives, for detection of familial forms of hypercholesterolemia. C As per CCS 2018 guidelines: Implement cascade screening (lipid profile) protocols at the local, provincial and national level and offer in first-degree relatives of patients with familial hypercholesterolemia. B Consider obtaining universal cholesterol level screening for the detection of familial hypercholesterolemia in children with reverse cascade screening of parents when warranted. C Diagnosis: As per CCS 2022 guidelines, consider obtaining genetic testing, when accessible, to achieve definitive diagnoses of familial hypercholesterolemia or other genetic dyslipidemias. Consider establishing clinical diagnosis independent of genetic testing using available non-genetic criteria. E As per ESC 2020 guidelines, suspect the diagnosis of familial hypercholesterolemia in patients with: premature coronary artery disease (males < 55 years old; females < 60 years old) severely elevated LDL cholesterol in adults (> 5 mmol/L; > 190 mg/dL) and in pediatrics (> 4 mmol/L; > 150 mg/dL) relatives having premature fatal or non-fatal CVD relatives having tendon xanthomas. B Show 2 more As per CCS 2018 guidelines, define familial hypercholesterolemia using the Dutch Lipid Clinic Network Criteria, Simon Broome Registry or Familial Hypercholesterolemia Canada definition. A 2. Classification and risk stratification https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 2/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway CVD risk stratification: do not use current risk calculators (Framingham Risk Score, Pooled Cohort Equation, European SCORE) to determine cardiovascular risk in patients with familial hypercholesterolemia. D Show 2 more 3. Diagnostic investigations Genetic testing: As per CCS 2022 guidelines, consider obtaining genetic testing, when accessible, to achieve definitive diagnoses of familial hypercholesterolemia or other genetic dyslipidemias. E As per ESC 2020 guidelines, obtain testing for familial hypercholesterolemia in pediatric patients from the age of 5, or earlier if homozygous familial hypercholesterolemia is suspected. B As per CCS 2018 guidelines, offer genetic testing, when available, to complement a diagnosis of familial hypercholesterolemia and enable cascade screening. A 4. Medical management General principles: Institute a personalized treatment plan taking into account at a minimum age, additional cardiovascular risk factors, psychosocial and socioeconomic factors, and personal and family preferences, developed as a shared decision process as the diagnosis of familial hypercholesterolemia using validated clinical criteria and/or genotyping may occur at any age and imparts a high, lifelong risk of ASCVD. B Include statins as the primary therapy and secondary agents as required including ezetimibe and PCSK9 inhibitors in a personalized treatment plan in patients with familial hypercholesterolemia requiring medications. B Treatment targets: As per ESC 2020 guidelines, treat patients with familial hypercholesterolemia and ASCVD or another major risk factor as very high risk patients, and patients without ASCVD or other risk factors as high risk patients. B Show 3 more As per CCS 2018 guidelines, consider targeting LDL cholesterol < 2.0 mmol/L and non-HDL cholesterol < 2.6 mmol/L in patients with familial hypercholesterolemia and ASCVD. C Statins: As per ESC 2020 guidelines: Initiate high-intensity statin therapy up to the highest tolerated dose to reach the goals set for the specific level of risk. A Initiate statins in pediatric patients with familial hypercholesterolemia from 8-10 years of age. B As per AHA 2019 guidelines, consider initiating statin therapy in > 10 years old pediatric and adolescent patients with LDL cholesterol level persistently 190 mg/dL ( 4.9 mmol/L) or https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 3/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway 160 mg/dL ( 4.1 mmol/L) with a clinical presentation consistent with familial hypercholesterolemia not responding adequately to 3-6 months of lifestyle therapy. C As per CCS 2018 guidelines: Initiate statins as first-line therapy in patients with familial hypercholesterolemia. A Do not use statins during pregnancy. D Ezetimibe: As per ESC 2020 guidelines: Add ezetimibe to statins if the goals are not achieved with the maximum tolerated dose of statins. B Consider initiating ezetimibe if statins are not tolerated at any dosage, even after rechallenge. C As per CCS 2018 guidelines, consider initiating ezetimibe as second-line agent to achieve unmet LDL cholesterol goals. C PCSK9 inhibitors: As per CCS 2021 guidelines: Initiate PCSK9 inhibitor (alirocumab or evolocumab) to lower LDL cholesterol level in patients with heterozygous familial hypercholesterolemia without clinical ASCVD, if LDL cholesterol remains above the target (LDL cholesterol 2.5 mmol/L or < 50% reduction from baseline or ApoB 0.85 mg/dL or non-HDL cholesterol 3.2 mmol/L) despite maximally tolerated statin therapy with or without ezetimibe therapy. A Initiate PCSK9 inhibitor (alirocumab or evolocumab) in patients with heterozygous familial hypercholesterolemia and ASCVD, if LDL cholesterol remains above the threshold 1.8 mmol/L (or ApoB 0.7 mg/dL or non-HDL cholesterol 2.4 mmol/L) despite maximally tolerated statin therapy with or without ezetimibe. A Updated evidence: FOURIER-OLE In patients with a history of established ASCVD and a fasting low-density lipoprotein cholesterol level 70 mg/dL while on statin, evolocumab was superior to placebo in parent study with respect to the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Michelle L O'Donoghue et al. Circulation. 2022 Oct 11. As per ESC 2020 guidelines, initiate or add a PCSK9 inhibitor in very high risk patients with familial hypercholesterolemia if the goal is not achieved with a maximum tolerated dose of a statin and ezetimibe. B As per AHA 2019 guidelines: Consider adding a PCSK9 inhibitor in 30-75 years old patients with heterozygous familial hypercholesterolemia and LDL cholesterol level of 100 mg/dL ( 2.6 mmol/L) with maximally tolerated statin and ezetimibe therapy. C Insufficient evidence to support addition of a PCSK9 inhibitor in patients with familial hypercholesterolemia without evidence of clinical ASCVD receiving maximally tolerated https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 4/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway statin and ezetimibe therapy. I As per CCS 2018 guidelines, consider initiating monoclonal antibody inhibitors of PCSK9 in adult patients with familial hypercholesterolemia without ASCVD if they have not achieved a 50% reduction in LDL cholesterol from baseline level and reached an LDL cholesterol level of at least < 3.5 mmol/L or lower (as determined by the shared decision process between physician and patient) on maximally tolerated statin therapy with or without ezetimibe. B Bile acid sequestrants: consider adding a bile acid sequestrant if the goal is not achieved with statins. C MTP inhibitors: consider initiating lomitapide and mipomersen exclusively in patients with homozygous familial hypercholesterolemia. C 5. Nonpharmacologic interventions Lifestyle modifications: As per ESC 2020 guidelines, educate pediatric patients with familial hypercholesterolemia to adopt a proper diet. B As per CCS 2018 guidelines, consider advising a healthy lifestyle in patients with familial hypercholesterolemia. C 6. Specific circumstances Pediatric patients: as per CCS 2018 guidelines, consider initiating statin therapy usually between 8-10 years of age if LDL cholesterol remains 4.9 mmol/L or 4.1 mmol/L with a family history of premature ASCVD or other cardiovascular risk factors or risk conditions. C 7. Follow-up and surveillance Indications for referral: refer patients with homozygous familial hypercholesterolemia to a specialized lipid clinic. Obtain complete evaluation for genetic analysis, presence of ASCVD and initiate aggressive lipid-lowering therapies including consideration for extracorporeal LDL cholesterol removal, lomitapide and PCSK9 inhibitors. B Clinical findings Symptoms Past medical history Ankle pain Cerebrovascular disease Arthralgia Ischemic heart disease Peripheral vascular disease Family history Ocular exam Hypercholesterolemia Corneal arcus Musculoskeletal exam Xanthelasma palpebrarum https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 5/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway Tendon xanthomas Integument exam Lab findings Planar xanthomas Tuberous xanthomas serum LDL serum cholesterol Imaging findings Aortic stenosis Studies 2023 CLEAR Outcomes In patients who were unable or unwilling to take statins owing to unacceptable adverse effects and had or were at high risk for CVD, bempedoic acid was superior to placebo with respect to major adverse cardiovascular events. Steven E Nissen et al. N Engl J Med. 2023 Apr 13. 2019 CLEAR Harmony In patients taking the maximum tolerated dose of statin therapy with ASCVD, bempedoic acid was not superior to placebo with respect to adverse events. Kausik K Ray et al. N Engl J Med. 2019 Mar 14. References 1. Liam R Brunham, Isabelle Ruel, Sumayah Aljenedil et al. Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018. Can J Cardiol. 2018 Dec;34 12 1553 1563. Open 2. Fran ois Mach, Colin Baigent, Alberico L Catapano et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41 1 111 188. Open 3. Glen J Pearson, George Thanassoulis, Todd J Anderson et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021 Aug;37 8 1129 1150. Open 4. Scott M Grundy, Neil J Stone, Alison L Bailey et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139 25):e1082-e1143. Open 5. Michael Khoury, Jean-Luc Bigras, Elizabeth A Cummings et al. The Detection, Evaluation, and Management of Dyslipidemia in Children and Adolescents: A Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association Clinical Practice Update. Can J Cardiol. 2022 Aug;38 8 1168 1179. Open 6. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 6/7 6/29/23, 4:02 AM Familial hypercholesterolemia Pathway https://web.pathway.md/diseases/rec3NR9IfcU05ASZA 7/7