What is the primary treatment for a genetic cardiac condition that causes coronary blockage, such as Familial Hypercholesterolemia (FH)?

Primary Treatment for Familial Hypercholesterolemia (FH)

The primary treatment for Familial Hypercholesterolemia (FH) is maximally tolerated high-potency statins (such as atorvastatin, rosuvastatin, or pitavastatin) with or without ezetimibe and/or bempedoic acid, combined with a fat-modified, heart-healthy diet to achieve LDL-cholesterol goals. 1

Treatment Algorithm for FH

First-Line Therapy

• Start with maximally tolerated high-potency statins (atorvastatin, rosuvastatin, or pitavastatin) as the foundation of treatment 1
• Combine with dietary modifications (fat-modified, heart-healthy diet) 1
• For extremely high-risk HeFH patients (post-myocardial infarction or with multivessel coronary atherosclerosis), consider combination therapy with high-potency statin, ezetimibe, and PCSK9-targeted therapy as first-line treatment 1

Second-Line Therapy (If LDL-C Goals Not Achieved)

• Add ezetimibe to statin therapy 1, 2
• Consider adding bempedoic acid if available 1
• Plant sterols (stanols) or bile acid sequestrants (such as colesevelam) may be considered as adjunctive therapies 1

Third-Line Therapy

• Add PCSK9-targeted therapy (monoclonal antibodies like evolocumab or alirocumab, or small interfering RNA like inclisiran) if LDL-C goals are not achieved with diet, maximally tolerated statins, ezetimibe, and other adjunctive therapies 1
• Evolocumab dosage: 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously 3
• Alirocumab dosage: typically starting at 75 mg every 2 weeks with potential up-titration to 150 mg every 2 weeks if additional LDL-C lowering is required 4

LDL-C Treatment Goals

LDL-C goals should be determined based on ASCVD risk level after achieving approximately 50% reduction in LDL-C concentration 1:

• LDL-C < 2.5 mmol/l (<100 mg/dl) in patients without ASCVD or other major ASCVD risk factors 1
• LDL-C < 1.8 mmol/l (<70 mg/dl) in patients with imaging evidence of ASCVD or other major ASCVD risk factors 1
• LDL-C < 1.4 mmol/l (<55 mg/dl) in patients with clinical ASCVD 1
• Consider LDL-C < 1.0 mmol/l (<40 mg/dl) in patients with recurrent ASCVD events within 2 years while on maximally tolerated statin treatment 1

Special Considerations for Homozygous FH (HoFH)

HoFH requires more aggressive treatment starting at diagnosis (ideally by age 2) 1:

• Sequential medication use starting with high-potency statins, rapidly up-titrated to maximally tolerated doses 1
• Add ezetimibe within 8 weeks, and possibly colesevelam if tolerated 1
• Add PCSK9 inhibitor within a further 8 weeks for patients without biallelic LDLR null mutations 1
• Consider lipoprotein apheresis if LDL-C goals not achieved with medications (ideally starting at age 3 and no later than age 8) 1
• For patients with markedly elevated LDL-C despite conventional therapy or rapidly progressive ASCVD, consider lomitapide or evinacumab 1
• Liver transplantation may be considered in severe cases with rapidly progressive ASCVD who don't achieve LDL-C goals with all available treatments 1

Monitoring and Follow-up

• Use non-fasting lipid profiles to monitor treatment in stable patients 1
• Use fasting LDL-C concentration when making decisions on changing treatment, especially in patients with hypertriglyceridaemia 1
• Before starting drug therapy, measure plasma levels of hepatic aminotransferases, creatine kinase, glucose, and creatinine 1
• Monitor hepatic aminotransferases in patients taking statins, particularly those with increased risk of hepatotoxicity 1
• Measure creatine kinase if musculoskeletal symptoms are reported 1
• Monitor plasma glucose or HbA1c if there are risk factors for diabetes 1

Additional Management Strategies

• Address all cardiovascular risk factors (smoking, hypertension, obesity, metabolic syndrome, diabetes mellitus) 1
• Encourage lifestyle modifications beyond diet: regular physical exercise, reduction in psychological stress, moderation in alcohol intake, and sleep hygiene 1
• Consider low-dose aspirin as a primary prevention measure in asymptomatic patients at higher risk of ASCVD (those with marked elevation of lipoprotein(a), diabetes, or adverse findings on cardiovascular imaging) 1
• Continue cholesterol-lowering therapies during acute illness unless specifically contraindicated 1

Treatment Challenges and Pitfalls

• FH remains underdiagnosed and undertreated despite high risk of premature coronary heart disease 2, 5
• Early detection is critical to prolonging life in FH patients 2
• Many patients fail to reach treatment guidelines even with currently available statins 2
• For patients not achieving LDL-C goals with standard therapies, consider newer combination approaches or clinical trials of emerging therapies 6, 7
• Ensure proper counseling for adolescent girls regarding contraception and lipid-lowering medications in pregnancy 1

The evidence strongly supports aggressive lipid-lowering therapy starting with high-potency statins and adding additional agents as needed to achieve target LDL-C levels, with the ultimate goal of preventing premature cardiovascular disease and death in patients with FH.