What are the criteria for initiating ezetimibe/rosuvastatin (Repatha) in patients with elevated low‑density lipoprotein cholesterol despite maximally tolerated statin therapy?

Criteria to Initiate Repatha (Evolocumab)

Repatha should be added when LDL-C remains ≥70 mg/dL despite maximally tolerated statin therapy plus ezetimibe in patients with established atherosclerotic cardiovascular disease (ASCVD) or very high cardiovascular risk. 1, 2

Stepwise Algorithm Before Considering Repatha

You must exhaust the following steps before initiating a PCSK9 inhibitor like Repatha:

Step 1: Maximize Statin Therapy

• Ensure the patient is on high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) that achieves ≥50% LDL-C reduction 1
• If the patient cannot tolerate high-intensity statins due to muscle symptoms or other adverse effects, use the maximally tolerated dose 1, 3

Step 2: Add Ezetimibe First

• Ezetimibe 10 mg daily must be added before considering Repatha 1, 4, 2
• This provides an additional 15-25% LDL-C reduction beyond statin monotherapy 1, 4, 2
• Reassess LDL-C levels 4-12 weeks after adding ezetimibe 4
• The 2018 ACC/AHA guidelines give ezetimibe a Class IIa recommendation for patients with clinical ASCVD on maximally tolerated statin therapy with LDL-C ≥70 mg/dL 2

Step 3: Consider Bempedoic Acid (Optional)

• If LDL-C remains above target after statin plus ezetimibe, bempedoic acid 180 mg daily can be added before proceeding to PCSK9 inhibitors 2
• This yields an additional 15-25% LDL-C reduction and is particularly useful in statin-intolerant patients 2

Specific Criteria for Repatha Initiation

Only proceed to Repatha after completing Steps 1-2 above when the following criteria are met:

Primary Indication

• LDL-C remains ≥70 mg/dL despite maximally tolerated statin therapy plus ezetimibe 1, 2, 5
• Patient has established ASCVD (prior MI, stroke, symptomatic peripheral arterial disease) 5

Very High-Risk Features (Target LDL-C <55 mg/dL)

• Recent myocardial infarction (within 2 years) 1
• Multivessel coronary disease 1
• Diabetes with established ASCVD 1, 4
• Recurrent atherothrombotic events despite optimal therapy 2

High-Risk Features (Target LDL-C <70 mg/dL)

• Established ASCVD without recent events 1
• Diabetes with multiple cardiovascular risk factors 4

Severe Hypercholesterolemia

• LDL-C ≥190 mg/dL with <50% reduction or LDL-C ≥100 mg/dL despite maximal statin plus ezetimibe therapy 2
• Homozygous familial hypercholesterolemia 5

FDA-Approved Indications for Repatha

Per the FDA label, Repatha is indicated for: 5

• Adults with established cardiovascular disease and LDL-C ≥70 mg/dL on maximally tolerated statin therapy
• Adults and pediatric patients ≥10 years with homozygous familial hypercholesterolemia requiring additional LDL-C lowering

Expected Efficacy

• Repatha reduces LDL-C by approximately 50-60% when added to statin therapy 1, 2
• In the FOURIER trial, Repatha significantly reduced major cardiovascular events (cardiovascular death, MI, stroke, coronary revascularization, hospitalization for unstable angina) with a hazard ratio of 0.85 (95% CI: 0.79-0.92, p<0.0001) 5
• The key secondary endpoint (cardiovascular death, MI, or stroke) was also significantly reduced (p<0.0001) 5

Dosing Regimen

• 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly 5
• In the FOURIER trial, 86% of patients used the every-2-week regimen 5

Critical Pitfall to Avoid

Do not skip ezetimibe and proceed directly to PCSK9 inhibitors – most patients achieve adequate LDL-C lowering with statin plus ezetimibe, making ezetimibe the cost-effective and evidence-based choice before considering the significantly more expensive PCSK9 inhibitors 4, 2. The ACC/AHA guidelines establish a clear hierarchical approach: maximize statin → add ezetimibe → consider PCSK9 inhibitor only if LDL-C remains ≥70 mg/dL 4.

Background Therapy Requirements

• Most patients in the FOURIER trial were on high-intensity (69%) or moderate-intensity (30%) statin therapy, with only 5% also taking ezetimibe at baseline 5
• Ensure patients are also on appropriate cardiovascular medications including antiplatelet agents, beta blockers, ACE inhibitors, or ARBs as indicated 5