High-dose statins reduce cardiac risk, study says

Orlando -- Skeptics who questioned the need to treat LDL cholesterol to ever-lower targets finally could have the proof they're waiting for. Results of the aptly-named TNT -- Treating to New Targets -- atorvastatin study effectively demolished any resistance to the concept that lower is better.

Results of the 10,001-patient TNT study were reported last month at a late-breaking clinical trials session at the American College of Cardiology 2005 Scientific Sessions. Results also were released in the online edition of the New England Journal of Medicine.

TNT found that, in a population of patients with stable coronary disease, aggressive lipid-lowering treatment with high-dose atorvastatin (80mg) to mean LDL levels of 77 mg/dL was associated with a 22% reduction in risk of major cardiovascular events compared with patients treated with 10 mg atorvastatin to LDL goals of 100 mg/dL. Absolute reduction was 2.2%.

Additionally, the risk of stroke was reduced by 25% among patients who received 80 mg atorvastatin. The risk for major coronary event was 20% lower in the 80 mg arm compared with the 10 mg arm. Also, the risk of hospitalization for congestive heart failure was reduced by 25% in the 80 mg arm versus the 10 mg treatment group.

John C. LaRosa, MD, from the State University of New York Health Science Center in Brooklyn, presented the results for the TNT investigators and trumpeted the findings: "We have entered a new era in the treatment of established coronary disease from starting at an LDL of 100."

Added to the positive findings was news of little toxicity associated with the high-dose regimen. There was no increase in myalgia and only five cases of rhabdomyolysis, three of which were in the low-dose arm.

One disappointment: There was no difference in overall mortality between the two treatment arms, but Dr. LaRosa said the study was not powered to show an overall mortality difference. "We would have needed 17,000 patients in each arm to show a difference."

Still unanswered is the question of "how low can you go" as well as the nagging issue of whether the reported benefit comes from the lower target -- LDL less than 80 mg/dL -- or from the drug (atorvastatin 80mg) used to get the patients to that goal. And those remaining questions are likely to delay changes in cholesterol guidelines until the results of two more low-target studies are reported, explained Sidney Smith, MD, director of the Center for Cardiovascular Science and Medicine at the University of North Carolina in Chapel Hill.

Those trials are the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), a 7,600-patient study that compares 80 mg atorvastatin with 20 mg to 40 mg of simvastatin in patients with established coronary disease, and the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine with Simvastatin and folic acid/vitamin B13 (SEARCH), a 12,000-patient study that compares 20 mg simvastatin with 80 mg simvastatin using a 2 x 2 factorial design. Both will be reported in the next year.

Dr. Smith noted that sometimes a "second or third study can come along that causes us to question earlier results, which was the case with ACE inhibitors." He referred to two very positive ACE-inhibitor trials -- the Heart Outcomes Prevention Evaluation (HOPE), which reported that ramipril reduced death, myocardial infarction and stroke in patients with stable coronary artery disease; and the European trial on Reduction of Cardiac Events with perindopril in stable coronary artery disease (EUROPA), which reported a 20% reduction in cardiovascular death, MI and cardiac arrest, and an additional 11% reduction in total death among patients treated with perindopril.

But the Prevention of Events with Angiotensin Converting Enzyme Protection (PEACE), a study of trandolapril on top of best medical therapy in patients with stable disease, found that adding the ACE inhibitor had no clinical benefit.

Why wait?

Minutes after Dr. LaRosa reported the TNT results, Christopher P. Cannon, MD, an associate professor of medicine at Harvard Medical School, said he thought it was time to change the guidelines, but he backtracked on his "why wait" stance when reminded of the conflicting ACE-inhibitor data. "But even while we wait for the other studies, I think that we need to recognize that there are early adopters who are already doing this in practice. I'm doing this."

Dr. Cannon has championed the lower-is-better approach since his involvement with Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), a study that compared 80 mg atorvastatin with 40 mg pravastatin. Patients in the study's high-dose arm lowered LDL to less than 70 mg/dL and achieved a 28% reduction in all-cause mortality as well as a 25% reduction in fatal MI or need for urgent revascularization.

Steven Nissen, MD, a Cleveland Clinic Foundation cardiologist who has conducted his own studies of high-dose atorvastatin, also leans toward an earlier-rather-than-later change in cholesterol guidelines. He pointed out that the "effect size is really large, actually larger than I expected. This is especially true for stroke."

Dr. Smith agreed the reduction in stroke was particularly compelling. "Let's face it -- it's better to survive without a stroke than with a stroke," but maintained that guideline changes are too important to be rushed.

The last word came from Dr. LaRosa, who said that in his practice he would "absolutely use high-dose atorvastatin. It's safe." But when asked if TNT presented a strong enough case to change guidelines so that the LDL treatment goal is lowered to less than 80 mg/dL, he said "No. I don't think a single study should be the basis for a change in guidelines. I think we should wait."