High-Dose Atorvastatin Stops Progression of Atherosclerosis

Peggy Peck

November 13, 2003

Nov. 13, 2003 (Orlando) -- Aggressive lipid-lowering therapy with 80 mg atorvastatin to mean low-density lipoprotein (LDL) cholesterol levels of less than 80 mg/dL stopped the progression of plaque in patients with symptomatic coronary artery disease as measured by intravascular ultrasound (IVUS), according to the results of the Reversal of Atherosclerosis with Lipitor (REVERSAL) study.

Principal investigator Steven E. Nissen, MD, from the Cleveland Clinic Foundation in Ohio, presented the results during the closing late-breaking clinical trials session at the American Heart Association Scientific Sessions. The study compared pravastatin 40 mg, considered moderate-dose statin therapy, with aggressive atorvastatin therapy.

After 18 months of treatment, IVUS analysis found "zero progression in the atorvastatin arm" compared with 2.7% progression in the pravastatin arm.

Although the study started with 654 patients, only 249 randomized to pravastatin and 253 randomized to atorvastatin completed the study. The average age of patients was 55 years, more than 70% were men, and 20% were diabetic.

At baseline, the median total cholesterol (TC), LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride measurements in both treatment groups were: 233 mg/dL, 150 mg/dL, 43 mg/dL, and 198 mg/dL, respectively. After 18 months, the values in the pravastatin group were: TC, 188 ± 32 mg/dL; LDL, 110 ± 26 mg/dL; HDL, 45 ± 11 mg/dL; and triglycerides, 166 ± 92 mg/dL. These corresponded to percentage changes of TC, -18.4%; LDL, -25.2%; HDL, +5.6%; and triglycerides, -6.8%.

But in the atorvastatin group, after 18 months of treatment, the values were: TC, 151 ± 39 mg/dL; LDL was 79 ± 30 mg/dL; HDL, 43 ± 11 mg/dL; and triglycerides, 148 ± 95 mg/dL. These corresponded to percentage changes of TC, -34%; LDL, -46%; HDL, +2.9%; and triglycerides, -20%. Changes in TC and LDL cholesterol were significant at P < .0001.

When the study was initiated, Dr. Nissen said, "I was quoted as saying 'It's the LDL, stupid.' I was only partly right, it was the drug as well." Moreover, he said that atorvastatin stopped plaque progression in each of 22 predetermined subgroups, while "we were unable to stop progression in any of the subgroups in the pravastatin arm." Pravastatin did not stop plaque progression, even when pravastatin achieved LDL cholesterol reductions similar to those achieved by patients in the atorvastatin group.

Patients in the atorvastatin group also posted much greater reductions in C-reactive protein: 36.4% vs. 5.2%. This potent anti-inflammatory effect might be a factor in the observed differences between the two treatments, Dr. Nissen said.

He told Medscape that the results are robust enough that he is changing his clinical practice, but he is not yet ready to make a clinical recommendation because there are no clinical outcomes to support the IVUS data.

Pfizer, the maker of atorvastatin, sponsored the study.

It is premature to make any clinical recommendations, according to Raymond J. Gibbons, MD, professor of medicine at Mayo Clinic Medical School in Rochester, Minnesota. "We practice evidence-based medicine and evidence-based medicine tells us that statins as a class reduce mortality and morbidity," Dr. Gibbons told Medscape.

The study results "were wonderful because they show that lowering LDL does appear to stop progression of the disease by IVUS...but the caution is that IVUS is a surrogate endpoint," said Christopher Cannon, MD, associate physician in the Cardiovascular Division at Brigham & Women's Hospital and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts. He is an investigator in a trial supported by Bristol-Myers Squibb, which makes pravastatin, comparing the same doses of the two drugs. Dr. Cannon noted that clinical results can often confound surrogate results. For example, clinical studies of some antiplatelet therapies found no benefit when angiographic studies appeared to demonstrate benefit, he said.

The results of his clinical study comparing pravastatin and atorvastatin will be presented next spring at the American College of Cardiology meeting, Dr. Cannon said. Although the drugs and doses are the same in his study, the patient population is different: patients with acute coronary syndrome rather than those with symptomatic coronary artery disease.

AHA 2003 Scientific Sessions: Late-Breaking Clinical Trials. Presented Nov. 12, 2003.

Reviewed by Gary D. Vogin, MD

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