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3/9/2004

Intensive Atorvastatin Therapy Shows Dramatic Benefits

Kate Traynor

Two recently reported studies comparing atorvastatin and pravastatin give evidence that intensive therapy to reduce low-density-lipoprotein (LDL) cholesterol levels provides major benefits for patients with heart disease.

The studies compared the effects of a high-dose atorvastatin regimen—80 mg per day—with a pravastatin dosage, 40 mg per day, that is associated with moderate LDL-cholesterol lowering.

The more recent report, funded by Bristol-Myers Squibb Co., was designed to show the "noninferiority" of the company's pravastatin product, Pravachol, to the intensive atorvastatin regimen. About 350 sites in 8 countries recruited more than 4,000 patients who had been hospitalized for an acute myocardial infarction or unstable angina in the preceding 10 days. The results of this study are to appear in the April 8 issue of the New England Journal of Medicine but were released online yesterday to coincide with a presentation at the American College of Cardiology annual meeting.

In a surprise twist, the study results strongly favored atorvastatin over pravastatin for reducing the risk of death from any cause, including coronary events, and also reduced the risk for major coronary events except stroke. At the study's two-year endpoint, 26 percent of the patients in the pravastatin group and 22 percent of those who received atorvastatin had died or suffered a serious coronary event. This corresponded to a 16-percent reduction in the risk for these study outcomes among patients who received atorvastatin.

Compared with the pravastatin group, patients in the atorvastatin group were 14 percent less likely to require revascularization of a coronary artery and 29 percent less likely to have recurrent unstable angina.

According to the report, the protective effects of atorvastatin therapy were evident after 30 days of therapy and remained so through 18-36 months of follow-up. The benefit—a reduction in the risk of death or serious coronary events—was greatest among patients whose baseline serum LDL-cholesterol was at least 125 mg/dL.

Median LDL-cholesterol levels at the end of the study were 62 mg/dL in the atorvastatin group and 95 mg/dL in the pravastatin group.

Current national guidelines define "optimal" LDL-cholesterol as less than 100 mg/dL, and this value is considered a target for cholesterol-lowering therapy for people at high risk for coronary events. The report's authors stated that it may be appropriate to lower the LDL-cholesterol target in patients who have suffered an acute coronary event.

About one in five patients in both treatment groups stopped taking their study medication before the end of the trial. According to the report, there were "significantly more liver-related side effects with high-dose atorvastatin than with standard-dose pravastatin" among study participants. No cases of rhabdomyolysis occurred during the study.

In a separate report comparing atorvastatin and pravastatin, a research team led by Cleveland Clinic cardiologist Steven Nissen described the drugs' effects on atheroma burden in patients with stable coronary disease. The report appeared in the March 3 Journal of the American Medical Association.

Using intravascular ultrasound, Nissen and his colleagues found that, on average, the intensive atorvastatin regimen halted the progression of atheroma, while the atheroma volume in patients who received pravastatin increased slightly during the study.

The study's findings were based on a comparison of atheroma volume at baseline and 18 months later in 502 patients at 34 sites in the United States.

Both drug regimens improved the study participants' lipid profiles, but the effects of atorvastatin were more pronounced than those of pravastatin. Notably, atorvastatin reduced serum LDL-cholesterol levels to an average of 79 mg/dL—a 46-percent reduction from baseline, compared with a 25-percent reduction, to 110 mg/dL, among those taking pravastatin.

Nissen said in a press release that the study's findings suggest that "if we want to prevent the progression of coronary disease, we need to treat patients to much lower [LDL-cholesterol] levels" than currently recommended.

Although the overall results pointed to a benefit with atorvastatin therapy, Nissen and his coauthors cautioned that "many patients in both groups had significant [atheroma] progression despite statin treatment." The authors also noted that the small number of "clinical events" that occurred during the study period precluded "any meaningful analysis of morbidity and mortality," which were not a focus of the study.

The study was funded by Pfizer Inc., the maker of the Lipitor brand of atorvastatin.