What is a concise summary of the Scandinavian Simvastatin Survival Study (4S) regarding LDL‑cholesterol management, including the trial dose and the significance of the study groups?

Scandinavian Simvastatin Survival Study (4S): Summary and Clinical Significance

Trial Design and Dosing

The 4S trial randomized 4,444 patients with established coronary artery disease to simvastatin 20-40 mg daily versus placebo, with 37% of patients requiring dose escalation from 20 mg to 40 mg to achieve target total cholesterol <200 mg/dL. 1, 2

• Study population: Adults aged 35-69 years with stable angina or previous myocardial infarction and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L) with triglycerides <220 mg/dL 1, 3, 4
• Median follow-up: 5.4 years 1, 3
• Starting dose: Simvastatin 20 mg daily, with uptitration to 40 mg permitted to achieve cholesterol targets 2, 1

Lipid Changes Achieved

Simvastatin therapy produced mean reductions of 35% in LDL-C, 25% in total cholesterol, and 10% in triglycerides, with an 8% increase in HDL-C. 1, 3

• These lipid changes were consistent across all patient subgroups, including those with diabetes 2
• The magnitude of LDL-C reduction directly correlated with clinical benefit: each 1% reduction in LDL-C reduced major coronary event risk by 1.7% 5

Mortality and Morbidity Outcomes

Simvastatin reduced all-cause mortality by 30% (182 deaths vs 256 deaths, p=0.0003) and coronary heart disease mortality by 42% (111 deaths vs 189 deaths, p=0.00001). 1, 3

Major coronary events were reduced by 34% (431 vs 622 patients, p<0.00001), establishing 4S as the first statin trial to demonstrate mortality benefit in secondary prevention. 1, 3

• Non-fatal myocardial infarction risk was reduced by 37% 1
• Coronary revascularization procedures (CABG or PTCA) were reduced by 37% (252 vs 383 patients, p<0.00001) 1, 3
• Combined stroke and transient ischemic attacks were reduced by 28% (75 vs 102 patients, p=0.033) 1

Significance of Key Subgroups

Diabetic Patients

In the diabetic subgroup (202 patients at baseline), simvastatin produced a 55% reduction in major coronary events (p=0.002), with a non-significant 43% reduction in overall mortality. 2

• A subsequent analysis identifying 483 diabetic patients by baseline plasma glucose confirmed a 42% reduction in major coronary events and 48% reduction in revascularizations 2
• This established that patients with diabetes achieve similar relative risk reductions as non-diabetics, but with greater absolute benefit due to higher baseline risk 2

Elderly Patients (≥65 Years)

Elderly patients (n=1,021) experienced similar relative risk reductions as younger patients, but the absolute risk reduction for mortality was approximately twice as large due to higher baseline event rates. 6

• All-cause mortality relative risk: 0.66 (95% CI 0.48-0.90) 6
• CHD mortality relative risk: 0.57 (95% CI 0.39-0.83) 6
• Major coronary events relative risk: 0.66 (95% CI 0.52-0.84) 6
• This finding established that aggressive lipid-lowering should not be withheld based on age alone. 6

Women

Women (n=827) achieved a 34% reduction in major coronary events (60 vs 91 events), with relative risk 0.66 (95% CI 0.48-0.91). 1, 6

• The number of female deaths (53 total) was insufficient to assess mortality benefit reliably 1, 6
• Lipid changes in women were similar to those observed in men 6

Patients with Low Baseline LDL-C

The benefit of simvastatin was consistent across the entire range of baseline LDL-C levels, including patients in the lowest quartile. 2, 5

• This finding challenged the prevailing notion that only patients with markedly elevated cholesterol required treatment 2
• The relationship between LDL-C reduction and event reduction was linear, with no threshold effect 5

Clinical Implications and Historical Context

4S established the foundation for aggressive LDL-lowering in secondary prevention, demonstrating that statin therapy reduces mortality in patients with established coronary disease regardless of baseline cholesterol levels. 2

• The trial validated the "lower is better" principle that now guides contemporary lipid management 2
• 4S results directly informed the National Cholesterol Education Program ATP-III guidelines recommending LDL-C <100 mg/dL for secondary prevention 2
• Current guidelines have evolved beyond 4S, now recommending high-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) targeting LDL-C <55 mg/dL for secondary prevention, based on subsequent trials demonstrating additional benefit with greater LDL-C reduction. 7, 2

Safety Profile

No significant adverse effects were reported, including no significant increase in myopathy, cancer incidence, or hospitalization for non-vascular causes. 1, 3

• Non-cardiovascular mortality was similar between groups (49 placebo vs 46 simvastatin deaths) 3
• The safety profile established in 4S supported the widespread adoption of statin therapy 1

Common Pitfalls When Applying 4S Data

• Do not use simvastatin 20-40 mg as initial therapy for contemporary secondary prevention patients; current evidence supports high-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) as superior 7, 2
• Do not accept LDL-C levels of 100-130 mg/dL as adequate in secondary prevention; modern targets are <55 mg/dL based on trials demonstrating incremental benefit with lower LDL-C 7, 2
• Do not exclude elderly patients from aggressive lipid-lowering based on age; 4S demonstrated equal or greater absolute benefit in patients ≥65 years 6, 7
• Do not withhold statin therapy in patients with "normal" baseline LDL-C; 4S showed benefit across the entire cholesterol spectrum in secondary prevention 2, 5