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ORLANDO-In a study of 10,001 patients with stable coronary disease, treatment with high dose atorvastatin (Lipitor) to mean LDL levels of 77 mg/dL was associated with a 22% reduction in risk of major cardiovascular events compared with patients treated to a mean LDL of 101 mg/dL.

The study, Treating to New Targets (TNT), was reported Tuesday at the American College of Cardiology meeting in Orlando. At the same time, the data were published online by the New England Journal of Medicine.

"We have entered a new era in the treatment of established coronary disease from starting at an LDL of 100," said principal investigator John C. LaRosa, MD, of the State University of New York Health Science Center in Brooklyn. Dr. LaRosa presented the findings at the ACC plenary session.

The patients all had clinically evident coronary disease. All patients went through an 8-week run period of open label treatment with 10 mg atorvastatin (Lipitor). All patients who achieved a mean LDL of less than 130 mg/dL were randomized to 10 mg (n=5006) or 80 mg atorvastatin (n=4995) per day. The patients were followed for 5 years.

The primary endpoint was occurrence of of first stroke (fatal or non-fatal), nonfatal, non-procedure-related MI, resuscitation after cardiac arrest, or death from coronary heart disease.

Among the significant results:

• Patients in the 80 mg treatment arm achieved a mean LDL of 77 mg/dL, while patients in the 10 mg arm achieved mean LDL of 101 mg/dL.

• In the 80 mg arm there were 434 events and there were 558 in the 10 mg treatment group. This was an absolute risk reduction of 2.2% and a relative risk reduction of 22% (p=)0.0002) This significance was presented by Dr. LaRosa at the meeting; in the NEJM it p<0.001. Both, however, are highly significant.**

• The risk for a major coronary event was reduced by 20% in the 80 mg group compared with the 10 mg arm (p=0.002).

• The risk of stroke was reduced by 25% in the 80 mg arm compared with the 10 mg group (p=0.007)

• The risk of hospitalization for congestive heart failure was reduced by 25% in the high dose arm versus low dose (p=0.01).

Importantly, the benefits were achieved without any significant increases in adverse events. There were five cases of rhabdomyolysis (only two in the high dose arm). There was, however, no difference in overall mortality between the two groups, but Dr. LaRosa said the study was not powered to show a difference.

Sidney Smith, MD, director of the Center for Cardiovascular Science and Medicine at the University of North Carolina in Chapel Hill and a spokesperson for the American Heart Association, was enthusiastic about the results, noting that he and other cardiologists have been anticipating them since last March when a study from Harvard researchers reported that aggressive LDL lowering to less than 70 mg/dL was associated with a 28% reduction in all cause mortality and a 25% reduction in risk of death from MI or need for urgent revascularization compared with less aggressive treatment. That study compared 80 mg Lipitor to 40 mg Pravachol.

Dr. Smith said, however, that it is probably too soon to change guideline recommendations because two more large studies comparing high dose statins to lower dose statins are expected to be reported in the next 12 months.

Christopher P. Cannon, MD, the Harvard cardiologist who was the principal investigator of last year's statin study, said he thinks that is time to incorporate aggressive statin treatment into clinical practice, although he added that guideline changes probably should wait for results from the two pending studies.

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