What does the Scandinavian Simvastatin Survival Study (4S) demonstrate about low‑density lipoprotein cholesterol (LDL‑C) management in adults with established coronary heart disease, and what high‑intensity statin regimen (including drug name and dose) and step‑by‑step treatment plan should be used?

The 4S Study and LDL Management in Coronary Heart Disease

The Scandinavian Simvastatin Survival Study (4S) definitively established that lowering LDL cholesterol with simvastatin 20-40 mg daily in patients with established coronary heart disease reduces total mortality by 30% and coronary death by 42%, making aggressive LDL reduction a cornerstone of secondary prevention. 1

Key Findings from the 4S Study

The 4S trial enrolled 4,444 adults with established CHD (history of angina and/or previous myocardial infarction) and baseline total cholesterol between 212-309 mg/dL who were followed for a median of 5.4 years 1. The study demonstrated:

• 30% reduction in all-cause mortality (182 deaths vs 256 deaths, p=0.0003) 1
• 42% reduction in coronary heart disease mortality (111 deaths vs 189 deaths, p=0.00001) 1
• 34% reduction in major coronary events (CHD death, non-fatal MI, silent MI, or cardiac arrest) 1
• 37% reduction in non-fatal myocardial infarction 1
• 37% reduction in myocardial revascularization procedures (CABG or PTCA) 1
• 28% reduction in cerebrovascular events (stroke and TIA) 1

The lipid changes achieved were: 25% reduction in total cholesterol, 35% reduction in LDL-C, 10% reduction in triglycerides, and 8% increase in HDL-C 1.

Critical Subgroup Findings

Elderly patients (≥65 years) derived even greater absolute benefit despite similar relative risk reductions. In patients ≥65 years, simvastatin reduced CHD mortality by 43% compared to 42% in younger patients, but because baseline mortality rates were higher in the elderly, the absolute risk reduction was approximately twice as great 2, 3.

Women experienced similar relative risk reductions for major coronary events (34% reduction, 60 vs 91 events), though the study had insufficient power to assess mortality effects in women due to only 53 female deaths 1, 3.

The benefit was consistent across all baseline cholesterol quartiles. Simvastatin reduced major coronary events by 35% in the lowest LDL-C quartile and 36% in the highest quartile, demonstrating that even patients with "moderate" cholesterol elevations benefit substantially 4.

Current High-Intensity Statin Regimen (Based on Modern Guidelines)

While 4S used simvastatin 20-40 mg, current evidence supports high-intensity statin therapy for all patients with established ASCVD 2. Modern guidelines recommend:

First-Line Therapy

• Atorvastatin 40-80 mg daily OR
• Rosuvastatin 20-40 mg daily 5, 6

These high-intensity regimens achieve mean LDL-C levels of 62-79 mg/dL and produce greater event reduction than moderate-intensity statins 2. Each 38.7 mg/dL (1 mmol/L) reduction in LDL-C reduces cardiovascular events by approximately 28% 2.

Target LDL-C Level

• <55 mg/dL for all patients with established ASCVD 5, 6

This represents a more aggressive target than what was achieved in 4S, based on subsequent trials showing that "lower is better for longer" 2.

Step-by-Step Treatment Algorithm

Step 1: Initiate High-Intensity Statin

• Start atorvastatin 40-80 mg daily (preferred) or rosuvastatin 20-40 mg daily 5, 6
• Check baseline ALT levels before initiation 5
• Recheck lipid panel in 4-6 weeks

Step 2: Assess LDL-C Response

• If LDL-C <55 mg/dL: Continue current regimen with annual monitoring 5, 6
• If LDL-C ≥55 mg/dL: Proceed to Step 3

Step 3: Add Ezetimibe

• Add ezetimibe 10 mg daily to high-intensity statin 5, 6
• This combination can reduce LDL-C by up to 47% 5, 6
• Recheck lipid panel in 4-6 weeks

Step 4: Add PCSK9 Inhibitor if Needed

• If LDL-C remains >55 mg/dL after statin plus ezetimibe, add:
  • Alirocumab OR
  • Evolocumab OR
  • Inclisiran 5, 6

Step 5: Monitor for Safety

• Check ALT levels periodically, as atorvastatin 80 mg causes >3-fold ALT elevations in 3.3% of patients 5
• Monitor for muscle symptoms, though severe myopathy (rhabdomyolysis) is rare 5

Common Pitfalls to Avoid

Do not use moderate-intensity statins (such as simvastatin 20-40 mg, pravastatin 40 mg, or atorvastatin 10 mg) as initial therapy for patients with established CHD, as they achieve inadequate LDL-C reduction compared to high-intensity regimens 2, 5.

Do not accept LDL-C levels above 55 mg/dL in patients with established ASCVD. While 4S demonstrated benefit with more modest LDL reduction, subsequent trials (TNT, PROVE-IT, IDEAL) have shown superior outcomes with lower LDL-C targets 2.

Do not delay combination therapy in very high-risk patients. The 2024 International Lipid Expert Panel recommends considering upfront combination therapy (statin plus ezetimibe) in extremely high-risk individuals to improve adherence and effectiveness 2.

Do not assume elderly patients benefit less. The 4S study and subsequent analyses demonstrate that patients ≥65 years derive equal or greater absolute benefit from LDL lowering, with similar relative risk reductions across all age groups 2, 3.

Evolution Beyond 4S

While 4S established the mortality benefit of statin therapy in secondary prevention, modern practice has evolved to more intensive LDL lowering based on trials like TNT, PROVE-IT, and IDEAL, which demonstrated that high-intensity statins (atorvastatin 80 mg) achieving LDL-C of 62-79 mg/dL reduce cardiovascular events more than moderate-intensity regimens achieving LDL-C of 95-102 mg/dL 2. The addition of non-statin therapies (ezetimibe, PCSK9 inhibitors) allows achievement of even lower LDL-C targets (<55 mg/dL) with further event reduction 2, 5, 6.