In a 55‑year‑old man with a prior inferior myocardial infarction who is taking aspirin and high‑intensity atorvastatin (80 mg daily) but still has an LDL‑cholesterol of approximately 4 mmol/L, what lipid‑lowering therapy should be added next?

Add Ezetimibe to Maximize Lipid-Lowering Therapy

In this 55-year-old man with prior inferior MI on maximum-dose atorvastatin (80 mg) and an LDL-cholesterol of approximately 4 mmol/L (≈155 mg/dL), you should add ezetimibe 10 mg daily immediately. This patient has not achieved his target LDL-C of <1.4 mmol/L (<55 mg/dL) despite high-intensity statin therapy, making him a Class I indication for additional lipid-lowering therapy. 1

Why Ezetimibe First, Not a PCSK9 Inhibitor

The treatment algorithm for post-MI patients mandates a stepwise approach: maximize statin therapy first, then add ezetimibe, and only then consider a PCSK9 inhibitor if targets remain unmet. 1, 2, 3 This patient is already on maximum-dose atorvastatin 80 mg (the only true high-intensity dose for this statin), so the next step is ezetimibe, not evolocumab. 2

Evidence Supporting Ezetimibe as Second-Line Therapy

• Ezetimibe provides an additional 15–25% LDL-C reduction when added to statin therapy, which should lower this patient's LDL-C from ≈155 mg/dL to approximately 115–130 mg/dL. 1, 2, 3

• The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy in post-ACS patients reduced major cardiovascular events by 7% over 6 years, with the greatest benefit in patients enrolled closer to their index event. 2, 3

• The 2021 AHA/ASA Stroke Prevention Guideline (Class I, Level A) explicitly recommends ezetimibe as the second-line agent when LDL-C remains ≥70 mg/dL (≈1.8 mmol/L) on maximally tolerated statin therapy in patients with atherosclerotic disease. 1

• The Treat Stroke to Target (TST) trial used ezetimibe as second-line therapy to achieve LDL-C <70 mg/dL, confirming this stepwise approach reduces cardiovascular events more effectively than less aggressive targets. 1

When to Add a PCSK9 Inhibitor (Evolocumab)

Only after 4–12 weeks on atorvastatin 80 mg plus ezetimibe 10 mg should you reassess the lipid profile. 1, 2 If LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) at that point, then adding evolocumab is reasonable (Class IIa recommendation). 1

Why This Sequence Matters

• PCSK9 inhibitors provide an additional 50–60% LDL-C reduction beyond statin plus ezetimibe, but guidelines reserve them for patients who fail dual oral therapy because of cost and the need for injections. 1, 2, 3, 4

• The FOURIER trial showed evolocumab reduced major cardiovascular events by 15% over 2.6 years when added to maximally tolerated statin therapy (with or without ezetimibe), but this benefit must be weighed against a cost-effectiveness ratio exceeding $150,000 per quality-adjusted life-year at 2018 prices. 3, 4

• Patients treated with evolocumab closer to their ACS event experienced greater absolute cardiovascular benefit, supporting early intensification—but only after oral therapy is maximized. 3

Target LDL-C Goal for This Patient

This patient's target LDL-C is <1.4 mmol/L (<55 mg/dL) with at least a 50% reduction from baseline, placing him in the "very high risk" category due to his prior MI. 1, 2, 5 His current LDL-C of ≈4 mmol/L (≈155 mg/dL) represents a 3-fold elevation above target, necessitating aggressive therapy.

Evidence for Very Low LDL-C Targets

• The PROVE-IT trial demonstrated that achieving a median LDL-C of 62 mg/dL with atorvastatin 80 mg resulted in a 16% reduction in major cardiovascular events compared to achieving 95 mg/dL, establishing that lower is better in post-MI patients. 2, 6, 7

• For every 1.0 mmol/L (≈39 mg/dL) reduction in LDL-C, there is approximately a 20–25% reduction in cardiovascular mortality and non-fatal MI, with no lower threshold identified for safety concerns. 5

• Clinical trials have shown continuous cardiovascular benefit with no lower threshold—patients achieving LDL-C <25 mg/dL demonstrate ongoing risk reduction without safety concerns. 5

Practical Implementation

1. Add ezetimibe 10 mg daily to the current atorvastatin 80 mg regimen immediately. 1, 2

2. Recheck fasting lipid profile in 4–12 weeks to assess response and adherence. 1, 2

3. If LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) despite atorvastatin 80 mg plus ezetimibe 10 mg, add evolocumab 140 mg subcutaneously every 2 weeks or 420 mg once monthly. 1, 4

4. Monitor hepatic transaminases when adding ezetimibe to high-dose atorvastatin, as the combination increases the risk of transaminase elevation >3× ULN from 1.1% to 1.3%. 2

Common Pitfalls to Avoid

• Do not skip ezetimibe and go directly to a PCSK9 inhibitor. The evidence-based algorithm requires maximizing oral therapy first. 2, 3

• Do not accept suboptimal LDL-C levels. Only 22% of very high-risk secondary prevention patients in Europe achieve LDL-C <55 mg/dL, representing a major treatment gap. 3

• Do not assume the patient is adherent to atorvastatin 80 mg without verification. Non-adherence is a common cause of treatment failure and should be assessed before adding agents. 2

• Do not delay lipid-lowering intensification. Approximately 20% of ACS patients experience a recurrent cardiovascular event within 24 months, underscoring the need for aggressive early LDL-C lowering. 3