What were the design, patient population, atorvastatin dosing, and primary outcomes of the Treating to New Targets (TNT) trial evaluating intensive LDL‑cholesterol lowering in stable coronary heart disease?

TNT Study: Intensive LDL-Cholesterol Lowering in Stable Coronary Heart Disease

Study Design and Population

The TNT trial randomized 10,001 patients with stable coronary heart disease to atorvastatin 80 mg daily versus atorvastatin 10 mg daily, demonstrating that intensive LDL-lowering to a mean of 77 mg/dL provides superior cardiovascular protection compared to moderate lowering to 101 mg/dL. 1, 2, 3

Patient Population Characteristics

• Enrollment criteria: Patients with clinically evident coronary heart disease who achieved LDL-cholesterol <130 mg/dL after an 8-week open-label run-in period with atorvastatin 10 mg daily 4, 3
• Demographics: 94% White, 81% male, 38% aged ≥65 years, with 18% having diabetes 1, 5
• Baseline cardiovascular history: 18% prior MI, 38% prior CHD, 15% prior PCI, 11% prior CABG 1
• Median follow-up duration: 4.9 years 1, 2, 4, 3

Drug Dosing and LDL-Cholesterol Reduction

Atorvastatin Dosing Regimen

• High-intensity arm: Atorvastatin 80 mg daily, achieving mean LDL-cholesterol of 77 mg/dL (approximately 50-52% reduction from baseline) 1, 2, 4, 3
• Moderate-intensity arm: Atorvastatin 10 mg daily, achieving mean LDL-cholesterol of 101 mg/dL 1, 2, 4, 3
• Absolute LDL-cholesterol difference: Approximately 24 mg/dL lower with 80 mg versus 10 mg dose 1, 2
• Time to maximal effect: LDL-cholesterol reduction reached steady state by 12 weeks 6, 4

Primary Outcomes and Clinical Benefits

Major Cardiovascular Events (Primary Endpoint)

• Primary endpoint definition: Composite of CHD death, non-fatal non-procedure-related MI, resuscitated cardiac arrest, or fatal/non-fatal stroke 2, 4, 3
• Event rates: 8.7% with atorvastatin 80 mg versus 10.9% with atorvastatin 10 mg 1, 2, 4, 3
• Relative risk reduction: 22% (HR 0.78; 95% CI 0.69-0.89; p<0.001) 1, 2, 4, 3
• Absolute risk reduction: 2.2% over 4.9 years 2, 3
• Number needed to treat: Approximately 45 patients over 5 years to prevent one major cardiovascular event 6

Individual Cardiovascular Outcomes

• Non-fatal MI: 22% relative risk reduction (HR 0.78; 95% CI 0.66-0.93) 6, 4
• Fatal and non-fatal stroke: 25% relative risk reduction (HR 0.75; 95% CI 0.59-0.96; p=0.02), with event rates of 2.3% versus 3.1% 2, 4
• Coronary revascularization (CABG or PCI): 28% relative risk reduction (HR 0.72; 95% CI 0.65-0.80; p<0.0001) 6, 4
• Hospitalization for heart failure: 26% relative risk reduction (HR 0.74; 95% CI 0.59-0.94) 6, 4
• CHD death: No statistically significant difference between groups (HR 0.80; 95% CI 0.61-1.03) 4

Mortality Outcomes

• All-cause mortality: No significant difference between groups (5.7% with 80 mg versus 5.6% with 10 mg; HR 1.01; 95% CI 0.85-1.19) 1, 4
• Cardiovascular mortality: Numerically lower with 80 mg (2.5% versus 3.1%; HR 0.81; 95% CI 0.64-1.03) but not statistically significant 4
• Non-cardiovascular mortality: Numerically higher with 80 mg (3.2% versus 2.5%; HR 1.25; 95% CI 0.99-1.57) 4

High-Risk Subgroup Analyses

Patients with Diabetes

• Population: 1,501 patients with diabetes and stable CHD 5
• Primary endpoint reduction: 25% relative risk reduction (HR 0.75; 95% CI 0.58-0.97; p=0.026) 1, 5
• Absolute risk reduction: 4.1% (17.9% with 10 mg versus 13.8% with 80 mg) 6, 5
• Number needed to treat: Approximately 24 patients over 5 years—roughly half the NNT of the overall population 6
• Cerebrovascular events: 31% relative risk reduction (HR 0.69; 95% CI 0.48-0.98; p=0.037) 5

Elderly Patients (≥65 Years)

• Relative risk reduction: 19% for major cardiovascular events, similar to younger patients 2
• Absolute benefit: Approximately twice that of younger patients due to higher baseline event rates 6
• Safety profile: Well tolerated with no increased adverse events compared to younger patients 2, 6

Post-CABG Patients

• Population: 4,654 patients with prior CABG 6
• Major cardiovascular events: 27% relative risk reduction (HR 0.73; 95% CI 0.62-0.87; p=0.0004) 6
• Repeat revascularization: 30% relative risk reduction (HR 0.70; 95% CI 0.60-0.82; p<0.0001) 6

Women

• Population: 1,902 women (19% of total cohort) 7
• Relative risk reduction: 27% for major cardiovascular events (HR 0.73; 95% CI 0.54-1.00; p=0.049) 7
• Absolute risk reduction: 2.7% 7
• Number needed to treat: 29 women over 4.9 years, nearly identical to men (NNT=30) 7

Safety Profile

Hepatic Safety

• Persistent liver enzyme elevations: 1.2% with atorvastatin 80 mg versus 0.2% with 10 mg (p<0.001) 4, 3
• Clinical significance: Elevations were generally manageable and did not result in excess hepatic morbidity 2, 6

Overall Tolerability

• Adverse event rates: No clinically important differences across LDL-cholesterol quintiles 8
• Muscle complaints: No increase observed at the lowest LDL-cholesterol levels 8
• Hemorrhagic stroke, suicide, or cancer deaths: No increase with very low LDL-cholesterol levels 8

Clinical Significance and Guideline Impact

Guideline Recommendations

• ACC/AHA 2013 guidelines: Cite TNT as Class I, Level A evidence supporting high-intensity statin therapy (atorvastatin 80 mg) for all patients with established ASCVD 6
• KDOQI 2007 guidelines: Recommend intensive statin therapy to achieve LDL-cholesterol <70 mg/dL in very high-risk patients with diabetes and CKD, based on TNT results 1
• NCEP ATP III update: TNT results led to the recommendation that LDL-cholesterol <70 mg/dL provides significant clinical benefit beyond the standard <100 mg/dL target 1

Dose-Response Relationship

• Very low LDL-cholesterol levels: Post-hoc analysis demonstrated a highly significant reduction in major cardiovascular events with descending on-treatment LDL-cholesterol levels (p<0.0001 for trend) 8
• No safety threshold: Further risk reduction without sacrifice of safety was achieved by reducing LDL-cholesterol to very low levels 8

Common Clinical Pitfalls to Avoid

• Do not initiate moderate-intensity statins (atorvastatin 10 mg) as first-line therapy for secondary prevention in stable CHD—TNT demonstrated inferior outcomes compared to high-intensity therapy 6
• Do not accept LDL-cholesterol ≈100 mg/dL as adequate in established CHD—lowering to ~77 mg/dL yielded a 22% additional event reduction 6
• Do not assume elderly patients benefit less from intensive therapy—TNT subgroup data confirm equal or greater absolute benefit in those ≥65 years 2, 6
• Do not delay high-intensity statin initiation after CABG—this high-risk subgroup derived substantial relative (27%) and absolute gains 6
• Do not overlook the diabetes subgroup—the NNT was only 24 over 5 years, making intensive therapy especially cost-effective 6, 5
• Do not base treatment decisions solely on isolated LDL-cholesterol values without comprehensive cardiovascular risk assessment—TNT enrolled only patients with clinically evident CHD 9