What LDL‑cholesterol reduction and cardiovascular benefit did the TNT (Treating to New Targets) trial demonstrate for atorvastatin 80 mg versus 10 mg in patients with stable coronary heart disease (average age early 60s, baseline LDL ≈130 mg/dL)?

TNT Study Results: LDL Reduction and Cardiovascular Outcomes

The TNT trial demonstrated that high-dose atorvastatin 80 mg reduced LDL-cholesterol from 101 mg/dL to 77 mg/dL (a 24 mg/dL or approximately 24% reduction compared to atorvastatin 10 mg) and achieved a 22% relative risk reduction in major cardiovascular events in patients with stable coronary heart disease. 1, 2

Primary Trial Design and Population

The Treating to New Targets (TNT) trial randomized 10,001 patients with stable coronary heart disease and baseline LDL-cholesterol <130 mg/dL to either atorvastatin 80 mg/day or atorvastatin 10 mg/day, with a median follow-up of 4.9 years. 1, 2

Patient characteristics included:

• 94% White, 81% male, 38% aged ≥65 years 2
• All had clinically evident coronary heart disease 2
• Mean age in early 60s with baseline LDL around 130 mg/dL 1

LDL-Cholesterol Reduction Achieved

The achieved LDL-cholesterol levels were:

• Atorvastatin 80 mg group: mean LDL-C of 77 mg/dL 1, 3
• Atorvastatin 10 mg group: mean LDL-C of 101 mg/dL 1, 3
• Absolute difference: 24 mg/dL reduction (approximately 24% additional lowering) 1

At 12 weeks, mean lipid levels in the high-dose group were: LDL-C 73 mg/dL, total cholesterol 145 mg/dL, triglycerides 128 mg/dL, non-HDL 98 mg/dL, and HDL 47 mg/dL. 2

Cardiovascular Outcomes: Mortality and Morbidity

Primary Endpoint (Major Cardiovascular Events):

• High-dose group: 8.7% event rate (434 events) 1, 2
• Low-dose group: 10.9% event rate (548 events) 1, 2
• Hazard ratio: 0.78 (95% CI 0.69-0.89, P=0.0002) 1, 2
• This represents a 22% relative risk reduction and 2.2% absolute risk reduction 1

Individual Component Outcomes:

Stroke reduction (critical for quality of life):

• Fatal and non-fatal stroke reduced by 25% (HR 0.75,95% CI 0.59-0.96, P=0.02) 1
• Stroke rate: 2.3% in high-dose group vs 3.1% in low-dose group 1, 2

Myocardial infarction:

• Non-fatal, non-procedure related MI reduced by 22% (HR 0.78,95% CI 0.66-0.93) 2
• MI rate: 4.9% in high-dose group vs 6.2% in low-dose group 2

Heart failure hospitalization (quality of life impact):

• First CHF hospitalization reduced by 26% (HR 0.74,95% CI 0.59-0.94) 2
• Rate: 2.4% in high-dose group vs 3.3% in low-dose group 2

Coronary revascularization procedures:

• Reduced by 28% (HR 0.72,95% CI 0.65-0.80, P<0.001) 2, 3
• Rate: 13.4% in high-dose group vs 18.1% in low-dose group 2

Mortality Outcomes

All-cause mortality:

• No significant difference between groups (5.7% vs 5.6%, HR 1.01,95% CI 0.85-1.19) 2
• However, cardiovascular death showed a favorable trend (2.5% vs 3.1%, HR 0.81,95% CI 0.64-1.03) 2

Important context: The ACC/AHA guidelines note that each 1-mmol/L (38.7 mg/dL) reduction in LDL-C reduces the relative risk for cardiovascular events by approximately 28%. 1, 4

High-Risk Subgroup Benefits

The absolute risk reduction was particularly pronounced in high-risk subgroups:

• Patients with diabetes: 37% relative risk reduction in major cardiovascular events (HR 0.75, P=0.026) 1, 5
• Patients aged 65-75 years: 19% relative risk reduction in composite endpoint 1
• Patients with chronic kidney disease: 20% additional LDL-C reduction with significant event reduction 1, 4
• Patients with treatment-resistant hypertension: 30% relative risk reduction (HR 0.70,95% CI 0.52-0.93, P=0.01) 6

Safety Profile

The trial enrolled 18,696 patients who took atorvastatin 80 mg in clinical trials for 4-5 years with an excellent safety record. 3

Specific safety findings:

• Liver enzyme elevations (ALT/AST) occurred but were manageable 1
• No significant increase in non-cardiovascular deaths 2
• The treatment was well-tolerated across age groups, including those ≥65 years 1, 2

Cost-Effectiveness and Quality of Life

The economic analysis from the US perspective demonstrated that high-dose atorvastatin was nearly cost-neutral over 5 years, with an incremental cost of only $252 (95% CI -$722 to +$1,276). 7

The cost to prevent one additional primary endpoint event was $8,964, which is comparable to other accepted cardiovascular interventions like drug-eluting stents. 7

Clinical Implications from Guidelines

The American Heart Association/American Stroke Association guidelines endorse these findings, recommending that patients with known coronary artery disease and high-risk hypertensive patients receive statin therapy even with normal LDL cholesterol levels. 1

The ACC/AHA 2013 cholesterol guidelines classify atorvastatin 80 mg as high-intensity statin therapy that achieves ≥50% LDL-C reduction and recommend it for secondary prevention in patients with clinical atherosclerotic cardiovascular disease. 1, 4

Common pitfall to avoid: The residual cardiovascular risk remains elevated even with intensive statin therapy, underscoring the need for comprehensive risk factor management beyond lipid lowering alone. 1