Management Algorithm for Statin-Intolerant CAD Patients on Ezetimibe 10 mg Daily
Add bempedoic acid 180 mg daily to the current ezetimibe regimen as the next step, followed by a PCSK9 inhibitor if LDL-C targets remain unmet. 1, 2
Immediate Next Step: Add Bempedoic Acid
Bempedoic acid 180 mg daily should be added to ezetimibe 10 mg daily for statin-intolerant patients with established CAD, providing an additional 15-25% LDL-C reduction beyond ezetimibe alone. 1, 2
The combination of bempedoic acid plus ezetimibe achieves approximately 35% total LDL-C reduction, which is substantially more effective than ezetimibe monotherapy. 2
Bempedoic acid works upstream from statins in the liver, resulting in minimal muscle-related adverse effects, making it particularly valuable for statin-intolerant patients. 1, 2
The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events (MACE) in statin-intolerant patients treated with bempedoic acid. 2
Target LDL-C Goals
For very high-risk CAD patients, target LDL-C <55 mg/dL with ≥50% reduction from baseline. 1, 2
For high-risk CAD patients without additional very high-risk features, target LDL-C <70 mg/dL. 2
Secondary target: non-HDL-C <85 mg/dL for very high-risk patients. 2
Subsequent Step: Add PCSK9 Inhibitor if Needed
If LDL-C remains ≥70 mg/dL despite ezetimibe plus bempedoic acid, add a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran). 1, 2
PCSK9 inhibitors reduce LDL-C by approximately 50-60% and are well-tolerated in statin-intolerant patients with minimal muscle-related adverse effects. 1, 2
The combination of ezetimibe plus PCSK9 inhibitor achieves the greatest LDL-C reduction with comparable safety profiles. 2
PCSK9 inhibitors demonstrated a 15% relative risk reduction in MACE over 2-3 years in clinical trials, with greater absolute benefit in patients enrolled closer to their ACS event. 1
Monitoring Requirements
Monitor liver function tests (ALT/AST) when initiating bempedoic acid, as it can increase risk of elevated liver enzymes. 2
Reassess lipid profile 4-8 weeks after adding bempedoic acid to adjust therapy as needed. 1, 2
For patients on PCSK9 inhibitors, assess LDL-C response every 3-6 months initially, then annually once at goal. 2
Monitor for gout and gallstones with bempedoic acid, as these are known adverse effects. 3
Important Clinical Caveats
Do not attempt to re-challenge with statins unless true statin intolerance has been confirmed by attempting at least 2 different statins, including one at the lowest approved daily dose. 2
The 2025 ACC/AHA guideline provides a Class 1 recommendation (highest level) for nonstatin lipid-lowering therapy in statin-intolerant ACS patients to lower LDL-C and reduce MACE risk. 1
Avoid using PCSK9 inhibitors as first-line therapy after ezetimibe without trying bempedoic acid first, due to the high cost of PCSK9 inhibitors and the established efficacy of bempedoic acid in this population. 2
Consider referral to a lipid specialist if the patient has baseline LDL-C ≥190 mg/dL not due to secondary causes, severe hypertriglyceridemia, or complex mixed dyslipidemia. 2
Alternative Options for Specific Scenarios
If triglycerides are >500 mg/dL, consider fenofibrate 160 mg daily to prevent acute pancreatitis, though this addresses a different lipid abnormality. 2
For triglycerides 135-499 mg/dL in high-risk patients on optimized lipid therapy, consider adding icosapent ethyl 2 grams twice daily for additional cardiovascular risk reduction. 2
Bile acid sequestrants (colesevelam 3.8 g daily) may be considered if the patient cannot tolerate bempedoic acid and triglycerides are <300 mg/dL, though they provide only modest LDL-C reduction of 15-18%. 2
Rationale for This Algorithm
The 2025 ACC/AHA Acute Coronary Syndromes guideline explicitly states that in statin-intolerant patients with ACS, nonstatin lipid-lowering therapy is recommended (Class 1, Level B-R) to lower LDL-C and reduce MACE risk. 1 The guideline identifies ezetimibe, PCSK9 inhibitors, and bempedoic acid as the primary nonstatin options. 1 Since the patient is already on ezetimibe, the logical next step is bempedoic acid before escalating to the more expensive PCSK9 inhibitors, unless LDL-C is markedly elevated or the patient is at very high risk with inadequate response to the combination. 2