TNT: Intensive lipid lowering in stable CHD patients reduces the risk of major cardiovascular events

March 08, 2005

Orlando, FL - Lowering LDL cholesterol levels beyond the currently recommended guidelines received another boost from a new study supporting the 'lower-is-better" premise. The findings, from the Treating to New Targets (TNT) study, presented today during a late-breaking clinical-trials session at the American College of Cardiology (ACC) 2005 Scientific Sessions and published online in the New England Journal of Medicine, showed that lowering LDL cholesterol levels in stable coronary heart disease (CHD) patients substantially below current targets results in better clinical outcomes.[1]

In the TNT study, intensive lipid lowering with atorvastatin (Lipitor®, Pfizer) 80 mg daily provided greater protection from major cardiovascular events compared with low-dose atorvastatin in stable CHD patients. High-dose atorvastatin reduced the primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 22% compared with patients treated with atorvastatin 10 mg, according to the results of a new study.

"In summary, our findings demonstrate that the use of an 80-mg dose of atorvastatin to reduce LDL cholesterol levels to 77 mg/dL provides additional clinical benefit in patients with stable CHD that is perceived to be well controlled at an LDL level of approximately 100 mg/dL," write Dr John C LaRosa (State University of New York Health Science Center, Brooklyn) and colleagues. "These data confirm and extend the growing body of evidence indicating that lowering LDL cholesterol levels well below currently recommended levels can have clinical benefit."

Reduction of 22% in the primary end point

Last year at the ACC in New Orleans, LA, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) investigators, led by Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA), showed that intensive lipid lowering with atorvastatin 80 mg daily provided greater protection from death and cardiovascular events compared with pravastatin (Pravachol®, Bristol-Myers Squibb) 40 mg daily in patients recently hospitalized with acute coronary syndromes (ACS).[2]

On the basis of PROVE-IT and data from the Heart Protection Study (HPS), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) updated the guidelines for cholesterol management, with significant changes in the treatment of high-risk and moderate-risk patients. The panel also introduced a more aggressive, but optional, LDL cholesterol goal of <70 mg/dL for patients at very high risk for CHD, even if baseline LDL cholesterol was <100 mg/dL.

Still, there was no definitive evidence that intensive statin therapy—with a goal of reducing LDL cholesterol levels to <70 mg/dL—was associated with better outcomes than moderate LDL cholesterol treatment targets of approximately 100 mg/dL in a population of stable CHD patients. The primary hypothesis of the TNT study was that an incremental reduction in risk could be achieved by lowering LDL cholesterol levels beyond the currently recommended minimum targets.

The TNT trial is a parallel-group study randomizing 10 001 patients from 14 countries to a double-blind treatment with either atorvastatin 10 mg or 80 mg. Patients included were men and women aged 35 years to 75 years with clinically evident CHD, defined as previous myocardial infarction (MI), previous or present angina with evidence of atherosclerotic CHD, or having undergone a coronary revascularization procedure. All patients entered an eight-week period of open-label treatment with atorvastatin 10 mg to reduce LDL cholesterol levels to <130 mg/dL before randomization.

After a median follow-up of 4.9 years, treatment with atorvastatin 80 mg resulted in greater reductions in LDL cholesterol, reducing LDL levels to 77 mg/dL, whereas those treated with atorvastatin 10 mg had an average LDL cholesterol level of 101 mg/dL. This greater reduction in LDL cholesterol levels in patients treated with atorvastatin 80 mg was associated with a 22% relative reduction in the risk of major cardiovascular events. Individually, the risk of myocardial infarction was reduced 22% and the risk of nonfatal or fatal stroke 25%.

TNT: Baseline and final LDL cholesterol levels

LDL cholesterol level Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995)
Mean baseline LDL cholesterol levels (mg/dL) 98 97
Final LDL cholesterol levels (mg/dL) 101 77

TNT: Primary efficacy outcomes

Outcome Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) Hazard ratio (95% CI) p
Total major cardiovascular events (%) 10.9 8.7 0.78 (0.69-0.89) <0.001
Death from coronary heart disease (% 2.5 2.0 0.80 (0.61-1.03) 0.09
Nonfatal MI (%) 6.2 4.9 0.78 (0.66-0.93) 0.004
Resuscitation after cardiac arrest (%) 0.5 0.5 0.96 (0.56-1.67) 0.89
Fatal or nonfatal stroke (%) 3.1 2.3 0.75 (0.59-0.96) 0.02

 "Our findings indicate that the quantitative relationship between reduced LDL cholesterol and reduced CHD risk demonstrated in prior secondary-prevention trials of statins holds true even at very low levels of LDL cholesterol," write the TNT investigators in their paper. "If these results were extrapolated to clinical practice, the use of an 80-mg dose of atorvastatin to reduce LDL cholesterol levels from a baseline of 101 mg/dL to 77 mg/dL in 1000 patients with stable CHD would prevent 34 major cardiovascular events over a period of five years; in other words, approximately 30 patients would need to be treated to prevent one event."

A total of 60 patients treated with high-dose atorvastatin had a persistent elevation in alanine aminotransferase, aspartate aminotransferase, or both, compared with nine patients receiving atorvastatin 10 mg. (1.2% vs 0.2%, p<0.001). There were no persistent elevations in creatine kinase.

Caution still urged

In an editorial accompanying the published study, Dr Bertram Pitt (University of Michigan School of Medicine, Ann Arbor) writes that clinicians will need to look critically at the TNT data to determine whether the results are sufficient to alter clinical practice.[3] Specifically, Pitt notes that although the study was not adequately powered to observe differences in overall mortality, there were no differences in this end point between the two therapies and even an increase in the number of deaths from noncardiovascular causes in those treated with atorvastatin 80 mg.

 
We need further reassurance as to the safety of this approach before we can advocate a major shift in our current goals for LDL cholesterol levels in patients with stable CHD.
 

He notes that while the number of deaths from CHD was reduced by 26 among patients assigned to high-dose atorvastatin, the number of deaths from noncardiovascular causes increased by 31, despite no significant increase in the number of deaths due to cancer, accidents, or any other type of death. If there is an increase in the risk of death from noncardiovascular causes associated with the 80-mg dose in stable CHD patients, further efforts will be needed to select the subgroup of patients who are at an increased risk for adverse cardiovascular events to preserve the benefits of the dose on MI and stroke, he writes. While this increase in noncardiovascular events may be due to chance, it is still a matter of concern, notes the editorialist.

"We need further reassurance as to the safety of this approach before we can advocate a major shift in our current goals for LDL cholesterol levels in patients with stable CHD," writes Pitt.

A remaining question, Pitt notes, is whether the effects of the 80-mg dose are due entirely to a reduction in LDL cholesterol levels or to the pleiotropic effects of high-dose atorvastatin. If the results are due to reductions in LDL cholesterol, there might be other means of achieving LDL cholesterol levels of 70 mg/dL that would be equally beneficial with respect to cardiovascular events but possibly safer, especially in light of the lack of an effect of the 80-mg dose of atorvastatin on overall mortality, he suggests. Pitt notes that other strategies, including ezetimibe, nicotinic-acid derivatives, fibrates, and inhibitors of cholesterol ester transfer protein (CETP), used in combination with a low-dose statin, are potential alternatives to high-dose lipid-lowering therapy, but all need to be tested and compared with the safety and efficacy of the 80-mg dose of atorvastatin.

The TNT study was sponsored by Pfizer. LaRosa has received lecture fees from Pfizer, as well as research grants from Pfizer , Merck, Bristol-Myers Squibb, and AstraZeneca.

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