ORLANDO, FLA. — “Lower IS better” was the mantra at the annual meeting of the American College of Cardiology following the presentation of the Treating to New Targets trial of intensive lipid lowering in patients with stable coronary heart disease.
“We have entered a new era in the treatment of established coronary disease,” declared Treating to New Targets (TNT) Steering Committee Chairman John C. LaRosa, M.D. “Treating patients with established coronary heart disease to an LDL of 77 mg/dL with 80 mg/day of atorvastatin from their starting LDL of 100 mg/dL [on 10 mg/day of atorvastatin] provided a highly significant reduction in their risk of major coronary events.”
Driving LDL levels far below the National Cholesterol Education Program's recommended target of 100 mg/dL also resulted in other benefits, including a 25% reduction in the relative risk of stroke (2.3% vs. 3.1%) and a 26% decrease in hospitalization for heart failure (2.4% vs. 3.3%), added Dr. LaRosa, president of the State University of New York Health Science Center at Brooklyn.
TNT was a Pfizer-sponsored double-blind, multinational study that randomized 10,001 patients with stable coronary heart disease (CHD) to 10 or 80 mg/day of atorvastatin (Lipitor). After a median 4.9 years of follow-up, the primary study end point—major cardiovascular events as defined by a composite of death due to CHD, nonfatal MI unrelated to a revascularization procedure, fatal or nonfatal stroke, or resuscitation after cardiac arrest—occurred in 8.7% of the high-dose atorvastatin group and 10.9% of those on 10 mg/day.
TNT participants received state-of-the-art background secondary prevention therapy. This was reflected in the fact that mortality in both treatment arms was lower than in any prior major secondary prevention trial. It's a measure of the advances made in secondary prevention in recent years that in this population of 10,000 patients with documented CHD followed for 5 years on atorvastatin, cardiovascular disease was not the number-one cause of death, Dr. LaRosa observed.
The safety profile of 80 mg/day of atorvastatin was noteworthy. The incidence of persistently elevated liver enzyme tests more than three times the upper limit of normal was 1.2%. Treatment-related myalgia was reported by 4.8% of patients. There were no cases of rhabdomyolysis meeting ACC/American Heart Association criteria in either treatment arm. This was particularly reassuring because in the Aggrastat to Zocor (A to Z) trial, roughly 1 in 250 patients on high-dose simvastatin developed serious muscle complications, David D. Waters, M.D., a TNT steering committee member, told this newspaper.
Discussant Carl J. Vaughan, M.D., of the University of Cork (Ireland), said TNT is best appreciated in the context of the earlier Heart Protection Study (HPS) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials. Subgroup analysis in the nearly 21,000-patient HPS showed that patients with relatively low baseline LDL-cholesterol levels had the same clinical benefit from intensive statin therapy as those with higher levels. Last year PROVE-IT showed the superiority of high- over moderate-intensity statin therapy in acute coronary syndrome patients, again regardless of baseline LDL-cholesterol level.
“This is a very impressive trial,” Sidney C. Smith Jr., M.D., told this newspaper. “We're going to have to get this information into our revised guidelines,” added Dr. Smith, director of the center for cardiovascular science and medicine at the University of North Carolina at Chapel Hill, and a member of the committee responsible for joint ACC/AHA secondary prevention guidelines.
The only question remaining in many observers' minds was when the National Cholesterol Education Program will get around to revising its target LDL recommendations for patients with known CHD.
Many physicians don't feel the need to wait for the NCEP. “There are always more data coming along, but I would say this, taken together with HPS and PROVE-IT, is enough,” said Dr. Waters, professor of medicine at the University of California, San Francisco.
The TNT results were published concurrently with the presentation (http://content.nejm.org/cgi/reprint/NEJMoa050461v1.pdf