What were the patient population, atorvastatin dosing (80 mg vs 10 mg), and cardiovascular outcomes of the TNT (Treat‑to‑New‑Targets) trial evaluating intensive LDL‑cholesterol lowering in secondary prevention?

TNT (Treating to New Targets) Study: Key Details and Clinical Implications

Study Design and Population

The TNT trial enrolled 10,001 patients with clinically evident stable coronary heart disease (CHD) who had already achieved LDL-C <130 mg/dL during an 8-week open-label run-in period with atorvastatin 10 mg/day. 1

• The study population was predominantly White (94%), male (81%), with 38% aged ≥65 years. 1
• All patients had documented coronary disease at baseline, making this a secondary prevention trial. 2, 1
• The trial included 1,501 patients with diabetes (15% of total cohort), allowing for robust subgroup analysis. 3
• Patients with prior coronary artery bypass grafting (CABG) comprised 4,654 participants (46.5% of the cohort). 4

Drug Dosing and Treatment Protocol

Patients were randomized to receive either atorvastatin 80 mg/day (high-intensity) or atorvastatin 10 mg/day (moderate-intensity) and followed for a median duration of 4.9 years. 1, 5

• The 80 mg dose achieved mean LDL-C levels of 77 mg/dL (range 72–79 mg/dL across subgroups). 2, 1, 3
• The 10 mg dose achieved mean LDL-C levels of 101 mg/dL (range 98–102 mg/dL across subgroups). 2, 1, 3
• This represented an absolute LDL-C difference of approximately 24–26 mg/dL (20–26% relative difference) between treatment arms. 2, 1
• Maximal lipid-lowering effects were achieved by 12 weeks of treatment. 1

Primary Outcome and Results

Atorvastatin 80 mg reduced major cardiovascular events by 22% compared with atorvastatin 10 mg (hazard ratio 0.78,95% CI 0.69–0.89, p=0.0002). 2, 1, 6

• The primary endpoint was time to first major cardiovascular event (MCVE), defined as: CHD death, non-fatal myocardial infarction, resuscitated cardiac arrest, or fatal/non-fatal stroke. 1, 5
• Primary events occurred in 8.7% (434/4,995) of patients on 80 mg versus 10.9% (548/5,006) on 10 mg. 1
• This translates to an absolute risk reduction of 2.2% and a number needed to treat (NNT) of approximately 45 patients over 5 years to prevent one major cardiovascular event. 1

Individual Component Outcomes

The benefit of intensive therapy was driven primarily by reductions in non-fatal MI and stroke, not mortality. 1

• Non-fatal MI: reduced by 22% (4.9% vs 6.2%, HR 0.78,95% CI 0.66–0.93). 1
• Fatal and non-fatal stroke: reduced by 25% (2.3% vs 3.1%, HR 0.75,95% CI 0.59–0.96, p=0.02). 1, 7
• Cerebrovascular events overall: reduced by 23% (HR 0.77,95% CI 0.64–0.93, p=0.007). 7
• CHD death: numerically lower but not statistically significant (2.0% vs 2.5%, HR 0.80,95% CI 0.61–1.03). 1
• All-cause mortality: no significant difference (5.7% vs 5.6%, HR 1.01,95% CI 0.85–1.19). 1, 6

Secondary Endpoints

Intensive therapy significantly reduced the need for coronary revascularization and hospitalization for heart failure. 1

• Coronary revascularization (CABG or PCI): reduced by 28% (13.4% vs 18.1%, HR 0.72,95% CI 0.65–0.80, p<0.0001). 1
• Hospitalization for heart failure: reduced by 26% (2.4% vs 3.3%, HR 0.74,95% CI 0.59–0.94). 1
• Documented angina: reduced by 12% (10.9% vs 12.3%, HR 0.88,95% CI 0.79–0.99). 1

Key Subgroup Analyses

Diabetes Subgroup

Among 1,501 patients with diabetes, atorvastatin 80 mg reduced major cardiovascular events by 25% compared with 10 mg (HR 0.75,95% CI 0.58–0.97, p=0.026). 3

• Primary events occurred in 13.8% (103/748) on 80 mg versus 17.9% (135/753) on 10 mg. 3
• Cerebrovascular events were reduced by 31% (HR 0.69,95% CI 0.48–0.98, p=0.037). 3
• The absolute risk reduction in diabetic patients was 4.1%, yielding an NNT of 24 over 5 years—nearly twice the benefit seen in the overall population. 2, 3

Post-CABG Subgroup

Among 4,654 patients with prior CABG, atorvastatin 80 mg reduced major cardiovascular events by 27% (HR 0.73,95% CI 0.62–0.87, p=0.0004). 4

• Primary events occurred in 9.7% on 80 mg versus 13.0% on 10 mg. 4
• Repeat revascularization was reduced by 30% (11.3% vs 15.9%, HR 0.70,95% CI 0.60–0.82, p<0.0001). 4
• Patients with prior CABG had higher baseline event rates (11.4% vs 8.5% in non-CABG patients, p<0.001), making intensive therapy particularly valuable in this high-risk subgroup. 4

Elderly Subgroup (≥65 Years)

The relative risk reduction with intensive therapy was consistent in patients ≥65 years, with similar magnitude of benefit as younger patients. 2

• Mean LDL-C achieved was 72 mg/dL on 80 mg versus 97 mg/dL on 10 mg in elderly patients. 2
• Because baseline event rates are higher in elderly patients, the absolute risk reduction is approximately twice as large as in younger cohorts, despite similar relative risk reductions. 2

Safety Profile

Atorvastatin 80 mg was generally well tolerated, with no increase in serious adverse events except for elevated liver enzymes. 1, 3

• Elevated ALT (>3× upper limit of normal): occurred in 3.3% on 80 mg versus 1.1% on 10 mg. 1
• Severe myopathy/rhabdomyolysis: no cases were observed in the TNT trial. 1
• Hemorrhagic stroke: occurred in 16 patients on 80 mg versus 18 on 10 mg, with no relationship to achieved LDL-C levels across quintiles. 7
• New-onset diabetes: not specifically reported in TNT, but meta-analyses suggest statins increase diabetes risk by approximately 0.2% per year. 8
• Non-cardiovascular death: numerically higher on 80 mg (3.2% vs 2.5%), though not statistically significant and not attributed to statin therapy. 1

Dose-Response Relationship

Each 1 mg/dL reduction in LDL-C was associated with a 0.6% relative risk reduction in cerebrovascular events and 0.5% reduction in stroke. 7

• The Cholesterol Treatment Trialists' (CTT) meta-analysis, which included TNT, demonstrated that each 38.7 mg/dL (1 mmol/L) reduction in LDL-C reduces cardiovascular events by approximately 28%. 2
• This dose-response relationship supports the "lower is better" hypothesis for LDL-C reduction in secondary prevention. 2, 6

Clinical Implications and Guideline Integration

The 2013 ACC/AHA guidelines cite TNT as Class I, Level A evidence supporting high-intensity statin therapy (atorvastatin 80 mg) for all patients with established ASCVD. 2, 8

• TNT demonstrated that achieving LDL-C levels of 70–80 mg/dL provides superior cardiovascular protection compared with LDL-C levels of 100 mg/dL in stable CHD patients. 2
• Current guidelines recommend an LDL-C target of <55 mg/dL for very high-risk patients (recent ACS, multivessel disease, diabetes with ASCVD), which is even lower than TNT achieved. 8, 9
• For patients with stable CHD, initiate atorvastatin 40–80 mg daily (both doses are classified as high-intensity therapy). 8, 9

Common Pitfalls to Avoid

• Do not use moderate-intensity statins (atorvastatin 10 mg, pravastatin 40 mg, simvastatin 20–40 mg) as initial therapy for secondary prevention, as TNT definitively showed inferior outcomes compared with high-intensity therapy. 2, 9, 1
• Do not accept LDL-C levels of 100 mg/dL as adequate in patients with established CHD; TNT proved that lowering to 77 mg/dL provides additional 22% event reduction. 2, 1, 6
• Do not assume elderly patients derive less benefit; TNT subgroup analyses confirm equal or greater absolute benefit in patients ≥65 years. 2
• Do not delay high-intensity statin initiation in post-CABG patients, as this subgroup had particularly high event rates and derived substantial benefit from intensive therapy. 4
• Do not overlook the diabetes subgroup, where the NNT was only 24 over 5 years—nearly half that of the overall population—making intensive therapy especially cost-effective. 3