TNT

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LaRosa JC, et al. "Intensive lipid lowering with atorvastatin in patients with stable coronary disease". The New England Journal of Medicine. 2005. 352(14):1425-1435.
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Clinical Question

Among patients with stable CAD and hyperlipidemia, does atorvastatin 80 mg PO daily have a greater reduction in CAD mortality, non-fatal MI not related to procedures, resuscitation after cardiac arrest, or fatal or nonfatal stroke when compared to atorvastatin 10 mg PO daily?

Bottom Line

In patients with stable CAD and hyperlipidemia, atorvastatin 80 mg PO daily is associated with a greater reduction in CAD mortality, non-fatal MI not related to procedures, resuscitation after cardiac arrest, or fatal or nonfatal stroke when compared to atorvastatin 10 mg PO daily.

Major Points

Trials like 4S (1994), CARE (1996), LIPID (1998), and HPS (2002) established statins as effective in secondary prevention in patients with CAD and hyperlipidemia. However, the ideal statin choice and LDL goal in these patients was not known. PROVE IT-TIMI 22 (2004) demonstrated a reduction in CV complications with high-intensity statin therapy (atorvastatin 80 mg PO daily) over moderate-intensity (pravastatin 40 mg PO daily) in patients with recent ACS. Whether high-intensity statin therapy would benefit patients with stable CAD and hyperlipidemia was unknown.

The 2005 Treating to New Targets (TNT) trial randomized 10,001 patients with CAD and hyperlipidemia to atorvastatin 80 mg or 10 mg PO daily, doses chosen as they were thought to reduce LDL to 75 and 100 mg/dL respectively.[1] With median follow-up of 4.9 years the higher dose was associated with a significant reduction in CAD mortality, non-fatal MI not related to procedures, resuscitation after cardiac arrest, or fatal or nonfatal stroke (8.7% vs. 10.9%; NNT 45). This was driven by reductions in non-fatal MI not related to procedures (4.9% vs. 6.2%) and stroke (2.3% vs. 3.1%). There was no difference in CAD mortality or all-cause mortality. The average LDL achieved was lower with the higher dose (77 vs. 101 mg/dL). The higher dose had a higher rate of adverse events.

Guidelines

ACC/AHA Cholesterol treatment to reduce ASCVD risk (2013, adapted)[2]

  • Secondary prevention with high-intensity statin therapy for patients ≤75 years in age with clinical ASCVD (i.e. stable CAD) unless contraindicated (grade A, class I, level A)
  • Moderate-intensity therapy for above group if contraindication to high-intensity statin therapy or risk for statin-associated adverse events (grade A, class I, level A)
  • For patients ≥75 years with clinical ASCVD, evaluate risks and benefits when initiating high- or moderate-intensity statin therapy (grade E, class IIa, level B)
  • No recommendation for specific targets for LDL- and non-HDL-cholesterol for primary or secondary prevention of ASCVD.
  • Definition of intensity of statin therapy as:
    • High-intensity (LDL reduction ≥50%): Atorvastatin 40-80 mg, rosuvastatin 20-40 mg
    • Moderate-intensity (LDL reduction 30-<50%): Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg BID, pitavastatin 2-4 mg
    • Lower-intensity (LDL reduction <30%): Simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, pitavastatin 1 mg

ATP III (2004, adapted)[3][4]

  • For patients with CAD or a risk equivalent, goal LDL <100 mg/dL
  • An LDL-cholesterol <70 mg/dL is an optional goal for patients at very high risk, including:
    • Multiple major risk factors, including DM
    • Poor control of severe risk factors, including smoking
    • Multiple metabolic syndrome risk factors including TG ≥200 mg/dL plus non-HDL-cholesterol ≥130 mg/dL with HDL-cholesterol <40 mg/dL
    • ACS

Design

  • Multicenter, randomized, double-blinded, comparative trial
  • N=10,001
    • Atorvastatin 10 mg (n=5,006)
    • Atorvastatin 80 mg (n=4,995)
  • Setting: Multiple centers in 14 countries on 4 continents
  • Enrollment: 1998-1999
  • Median follow-up: 4.9 years
  • Analysis: Intention-to-treat
  • Primary outcome: Major CV events (CAD mortality, non-fatal MI not related to procedures, resuscitation after cardiac arrest, or fatal or nonfatal stroke)

Population

Inclusion Criteria

  • Age 35-75
  • CAD defined by prior MI, prior or current anginal symptoms with evidence of CAD, prior revascularization

Exclusion Criteria

  • Cholesterol levels before randomization not in specified range:
    • After wash-out: LDL 130-250 mg/dL, TG <600 mg/dL
    • After run-in: LDL <130 mg/dL
  • Statin hypersensitivity
  • Active liver disease or AST or ALT >1.5x ULN
  • CK >6x ULN
  • Pregnancy or breastfeeding
  • Nephrotic syndrome
  • Uncontrolled DM or HTN
  • MI, coronary revascularization, severe angina, or unstable angina in the prior month or planned surgical intervention for atherosclerotic disease
  • LVEF <30%
  • Valvular disease causing hemodynamic abnormalities
  • Decreased absorption from GI disease or GI surgery
  • Malignancy other than non-melanotic skin cancer
  • Disease likely to limit survival
  • Immunosuppressant therapy
  • Use of other lipid modifying medications
  • Alcohol abuse
  • Participation in another clinical trial in the prior 30 days

Baseline Characteristics

From the atorvastatin 10 mg group.

  • Demographics: Age 60.9 years, male 80.8%, White race 94.1%
  • Baseline health data: BP 131/78, BMI 28.6
  • Baseline labs (after run-in): LDL 98 mg/dL, Tchol 175 mg/dL, TG 151 mg/dL, HDL 47 mg/dL
    • LDL before run-in: 152 mg/dL (average of both groups)
  • PMH: Smoker 13.4% (former 63.3%), HTN 54.4%, DM 15.0%, MI 57.7%, angina 81.2%, CVA 5.3%, PAD 11.4%, HF 8.1%, arrhythmias 18.5%
  • PSH: Angioplasty 54.3%, CABG 46.7%

Interventions

  • Wash-out: Discontinuation of statins for up to 8 weeks
  • Run-in: those with LDL cholesterol 130-250 mg/dL and TG ≤600 mg/dL were started on open-label atorvastatin 10 mg daily for eight weeks
  • Randomization: Patients with LDL <130 mg/dL were randomized to atorvastatin 10 mg daily or atorvastatin 80 mg daily

Outcomes

Presented as atorvastatin 10 mg vs. atorvastatin 80 mg.

Primary Outcome

Major CV events

CAD mortality, non-fatal MI not related to procedures, resuscitation after cardiac arrest, or fatal or nonfatal stroke.

10.9% vs. 8.7% (HR 0.78; 95% CI 0.69-0.89; P<0.001; NNT 45)

Secondary Outcomes

CAD mortality
2.5% vs. 2.0% (HR 0.80; 95% CI 0.61-1.03; P=0.09)
Non-fatal MI not related to procedures
6.2% vs. 4.9% (HR 0.78; 95% CI 0.66-0.93; P=0.004; NNT 77)
Resuscitation after cardiac arrest
0.5% vs. 0.5% (HR 0.96; 95% CI 0.56-1.67; P=0.89)
Stroke
3.1% vs. 2.3% (HR 0.75; 95% CI 0.59-0.96; P=0.02; NNT 125)
Major coronary event

CAD mortality, non-fatal MI not related to procedures, or resuscitation after cardiac arrest. This was the original primary outcome.

8.3% vs. 6.7% (HR 0.80; 95% CI 0.69-0.92; P=0.002; NNT 63)
Cerebrovascular event

Stroke or TIA.

5.0% vs. 3.9% (HR 0.77; 95% CI 0.64-0.93; P=0.007; NNT 91)
HF hospitalization
3.3% vs. 2.4% (HR 0.74; 95% CI 0.59-0.94; P=0.01; NNT 111)
PAD

New diagnosis of PAD, PAD hospitalization, incidental discovery of plaques or stenosis.

5.6% vs. 5.5% (HR 0.97; 95% CI 0.83-1.15; P=0.76)
Any coronary event

Major coronary event as listed above, revascularization procedure, procedure-related MI, or angina.

26.5% vs. 21.6% (HR 0.79; 95% CI 0.73-0.86; P<0.001; NNT 20)
Any CV event

Any coronary event, cerebrovascular event, PAD, or HF hospitalization.

33.5% vs. 28.1% (HR 0.81; 95% CI 0.75-0.87; P<0.001; NNT 18)
All-cause mortality
5.6% vs. 5.7% (HR 1.01; 95% CI 0.85-1.19; P=0.92)

Additional Analyses

Cholesterol
LDL: 101 vs. 77 mg/dL
Tchol: Lower in atorvastatin 80 mg group (P<0.001)
TG: Lower in atorvastatin 80 mg group (P<0.001)
HDL: No difference

Adverse Events

Any
289 vs. 406 patients (P<0.001)
Myalgias: 4.7% vs. 4.8% (P=0.72)
Persistently elevated AST and/or ALT: 0.2% vs. 1.2% (P<0.001)
Rhabdomyolisis: 3 vs. 2 patients

Criticisms

  • Not powered to detect outcomes in all-cause mortality
    • Unclear if lack of mortality benefit is due to increase in non-cardiovascular mortality[5]
  • Medication-related adverse events may have been excluded from the analysis[5]
  • The publication lacks analysis of outcomes by LDL and HDL levels achieved[5]
  • No subgroup analysis by baseline LDL[5]

Funding

Pfizer, the manufacturer of Lipitor (brand name atorvastatin)

Further Reading

  1. Waters DD, et al. "Treating to New Targets (TNT) Study: Does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?" The American Journal of Cardiology. 2004;93(2)154-158.
  2. Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.
  3. NHLBI, ATP III At-a-glance. http://www.nhlbi.nih.gov. Accessed 2013-12-05.
  4. Grundy SM, et al. "Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines." Circulation. 2004;110(6):763.
  5. 5.0 5.1 5.2 5.3 Multiple authors. "Correspondence: Intensive lipid lowering with atorvastatin in coronary disease." The New England Journal of Medicine. 2005;353:93-96.