What is the optimal treatment approach for achieving LDL targets in stroke secondary prevention, including the use of Inclisiran (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor)?

Stroke Secondary Prevention: LDL Targets and Inclisiran

Primary Recommendation

For stroke secondary prevention, initiate high-intensity statin therapy (atorvastatin 80 mg or rosuvastatin 20 mg daily) immediately, targeting LDL-C <70 mg/dL; if this target is not achieved on maximally tolerated statin therapy, add ezetimibe as second-line therapy, and reserve inclisiran (or other PCSK9 inhibitors) for patients at very high risk who remain above target despite statin plus ezetimibe. 1

LDL-C Target Goals

• Target LDL-C <70 mg/dL (1.8 mmol/L) for all patients with ischemic stroke or TIA attributable to atherosclerotic causes 1, 2
• The TST trial demonstrated superiority of achieving LDL-C <70 mg/dL versus 90-110 mg/dL for preventing major cardiovascular events in stroke survivors 1
• Target LDL-C <55 mg/dL may be considered for patients at very high risk (history of ischemic stroke plus multiple high-risk conditions such as age ≥65 years, diabetes, hypertension, chronic kidney disease, or current smoking) 1

Stepwise Treatment Algorithm

Step 1: High-Intensity Statin Therapy (First-Line)

• Initiate atorvastatin 80 mg daily OR rosuvastatin 20 mg daily as soon as possible after ischemic stroke or TIA 1, 3
• The SPARCL trial demonstrated that atorvastatin 80 mg reduced stroke recurrence by 16% (HR 0.84,95% CI 0.71-0.99) over 4.9 years 1, 3
• Check fasting lipids 4-12 weeks after initiation to assess response and adherence 1, 2
• High-intensity statins reduce LDL-C by ≥50% from baseline 1

Critical Pitfall: Avoid statins in patients with hemorrhagic stroke unless there is documented atherosclerotic disease or high cardiovascular risk 3

Step 2: Add Ezetimibe (Second-Line)

• If LDL-C remains ≥70 mg/dL on maximally tolerated statin, add ezetimibe 10 mg daily 1, 2
• The TST trial used ezetimibe as second-line therapy to achieve LDL-C <70 mg/dL, supporting this approach before PCSK9 inhibitors 1
• Ezetimibe provides an additional 15-25% LDL-C reduction when added to statin therapy 1
• Recheck lipids 4-12 weeks after adding ezetimibe 1

Step 3: Consider PCSK9 Inhibitors Including Inclisiran (Third-Line)

Inclisiran is reasonable for patients who meet ALL of the following criteria: 1, 4

1. Very high-risk status: History of ischemic stroke PLUS multiple high-risk conditions (age ≥65 years, diabetes, hypertension, chronic kidney disease with eGFR 15-59 mL/min/1.73m², current smoking, history of other vascular procedures, or heterozygous familial hypercholesterolemia) 1

2. On maximally tolerated statin therapy (high-intensity preferred) 1

3. Already taking ezetimibe 1

4. LDL-C remains >70 mg/dL despite the above therapies 1

Inclisiran-Specific Considerations

Dosing and Administration

• Inclisiran 284 mg subcutaneous injection at Day 1, Day 90 (3 months), then every 6 months thereafter 4, 5
• The twice-yearly dosing schedule may improve adherence compared to other PCSK9 inhibitors requiring monthly or biweekly injections 5

Efficacy

• Reduces LDL-C by approximately 38-53% at 180 days after initial dosing 4
• Following the full dosing regimen (Day 1, Day 90, Day 270, Day 450), sustained LDL-C reductions are maintained 4
• Reduces PCSK9 levels by approximately 69-75% at Days 120-180 4
• Effect persists beyond 6 years of therapy with no diminution 5

Safety Profile

• No dose adjustment needed for mild, moderate, or severe renal impairment 4
• No dose adjustment needed for mild to moderate hepatic impairment 4
• No dose adjustment needed for elderly patients (54% of trial participants were ≥65 years) 4
• Primary side effects are mild and transient injection site reactions 5
• Does not prolong QT interval 4
• Not metabolized by CYP450 enzymes, minimizing drug-drug interactions 4

Mechanism Advantage

• Inclisiran is a small interfering RNA (siRNA) that catalytically degrades PCSK9 mRNA in hepatocytes, providing sustained effect with infrequent dosing 4, 6
• This differs from monoclonal antibody PCSK9 inhibitors (alirocumab, evolocumab) which bind circulating PCSK9 protein 6

Monitoring Strategy

• Baseline: Obtain fasting lipid panel, liver enzymes (ALT), and creatine kinase before initiating therapy 3
• 4-12 weeks after statin initiation or dose adjustment: Recheck fasting lipids to assess response 1, 2
• After adding ezetimibe: Recheck lipids in 4-12 weeks 1
• After initiating inclisiran: Check lipids at Day 90 and Day 180 to confirm adequate response 4
• Ongoing: Monitor lipids every 3-12 months based on adherence and stability 1, 2
• Safety monitoring: Check liver enzymes and creatine kinase if patient develops muscle symptoms or other concerning signs 3

Special Populations

Chronic Kidney Disease

• Statins provide 40% reduction in stroke risk in CKD patients, with similar relative benefit as non-CKD patients 1
• PCSK9 inhibitors (including inclisiran) are recommended for CKD patients with ASCVD who achieve <50% LDL-C reduction on high-intensity statins 1
• No dose adjustment of inclisiran needed for any degree of renal impairment, though not studied in end-stage renal disease 4

Hemorrhagic Stroke History

• Avoid statins after hemorrhagic stroke unless atherosclerotic disease or high cardiovascular risk is present 3
• SPARCL trial showed increased hemorrhagic stroke risk with atorvastatin (HR 1.66,95% CI 1.08-2.55), particularly in patients with prior hemorrhagic stroke (HR 5.65,95% CI 2.82-11.30) 3

Critical Pitfalls to Avoid

1. Never delay statin initiation in eligible stroke patients—start as soon as possible after the acute event 3

2. Do not skip ezetimibe and go directly to PCSK9 inhibitors—the TST trial and guidelines support ezetimibe as second-line therapy before PCSK9 inhibitors 1

3. Do not use inclisiran in patients who are NOT at very high risk—current evidence supports its use only in very high-risk patients (stroke plus multiple high-risk conditions) 1

4. Do not stop statin therapy when adding ezetimibe or inclisiran—these are add-on therapies, not replacements 1

5. Do not use PCSK9 inhibitors as monotherapy—they should be added to maximally tolerated statin (and ezetimibe) therapy 1

Defining "Very High Risk" for PCSK9 Inhibitor Consideration

A patient qualifies as very high risk if they have ischemic stroke (major ASCVD event) PLUS one or more of the following high-risk conditions: 1

• Age ≥65 years
• Heterozygous familial hypercholesterolemia
• History of coronary artery bypass surgery or percutaneous coronary intervention
• Diabetes mellitus
• Hypertension
• Chronic kidney disease (eGFR 15-59 mL/min/1.73m²)
• Current smoking

Strength of Evidence

The recommendation hierarchy is based on:

• Class I, Level A evidence for high-intensity statins in stroke secondary prevention (SPARCL trial) 1, 3
• Class I, Level B evidence for ezetimibe as add-on therapy (TST trial) 1
• Class IIa evidence for PCSK9 inhibitors in very high-risk patients on maximally tolerated statin plus ezetimibe with LDL-C >70 mg/dL 1

The 2021 AHA/ASA Stroke Prevention Guidelines provide the most authoritative and recent guidance for this clinical scenario 1