Very high-intensity statin therapy shows promise for inducing regression of coronary atherosclerosis

Patients treated with very intensive statin therapy lowered LDL-C levels on average by about 50 percent, increased HDL-C levels by 15 percent, and showed regression of coronary atherosclerosis, according to a study that will appear in the April 5 issue of JAMA. The study is being released early online to coincide with its presentation at the American College of Cardiology annual conference.

Atherosclerosis (the accumulation of fatty deposits inside arterial walls) is generally viewed as a chronic, progressive disease. Prior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of atherosclerosis regression, as measured using percent atheroma (fatty deposit buildup in an artery) volume (PAV), the most rigorous IVUS indicator of disease progression and regression, according to background information in the article.

Steven E. Nissen, M.D., of the Cleveland Clinic, and colleagues with the ASTEROID Trial conducted a study to determine the effects of high-intensity statin therapy on IVUS-derived measures of coronary atherosclerosis regression. Rosuvastatin is one of the most recently introduced statins and typically produces greater reductions in low-density lipoprotein cholesterol (LDL-C) and larger increases in high-density lipoprotein cholesterol (HDL-C) than previously available agents. The trial was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. Coronary atheroma burden was measured at baseline and after 24 months of treatment. Between November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug, rosuvastatin, 40 mg/d. After 24 months, 349 patients had evaluable serial IVUS examinations.

The researchers found that the average baseline LDL-C level of 130.4 mg/dL declined to 60.8 mg/dL, an average reduction of 53.2 percent. Average HDL-C level at baseline was 43.1 mg/dL, increasing to 49.0 mg/dL, an increase of 14.7 percent. For the primary efficacy parameter of change in PAV, the average decrease was −0.98 percent and 63.6 percent of patients showed regression of atherosclerosis. For the second primary efficacy parameter, change in atheroma volume in the 10-mm subsegment with the greatest disease severity, there was a median (midpoint) reduction of 9.1 percent in atheroma volume, and 78.1 percent of patients demonstrated regression of atherosclerosis. The secondary efficacy parameter, change in total atheroma volume, showed a 6.8 percent median reduction. Adverse events were infrequent and similar to other statin trials.

"We believe that the current study has important implications for understanding the pathophysiology and optimal treatment of coronary artery disease. Traditional thinking has viewed atherosclerosis as an inexorably progressive disease for which even the most active therapies can merely slow advancement. The current study suggests that there is potential for a more optimistic strategy, in which aggressive lipid-modulating strategies can actually reverse the atherosclerotic disease process. The observed increases in HDL-C in the current study suggest that therapies designed to simultaneously lower LDL-C while raising HDL-C have the potential to substantially reduce lesion burden in patients with established disease," the authors write.

"The current study supports several conclusions. For secondary prevention patients, very intensive statin therapy using 40 mg/d of rosuvastatin in patients with preexisting coronary disease reduced LDL-C to 60.8 mg/dL while raising HDL-C by 14.7 percent. These changes were larger in magnitude than has been observed in previous statin trials. The very low LDL-C levels and increase in HDL-C levels resulted in significant regression in atheroma burden for all 3 primary and secondary efficacy parameters. This very intensive statin regimen was well tolerated. These observations support the recommendation to administer very intensive statin therapy for high-risk patients with established coronary disease," the researchers conclude.

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(Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: This study was funded by AstraZeneca. For the financial disclosures of the authors, please see the JAMA article.

Editorial: Can a Potent Statin Actually Regress Coronary Atherosclerosis?

In an accompanying editorial, Roger S. Blumenthal, M.D., and Navin K. Kapur, M.D., of The Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, discuss the findings of Nissen et al.

"Clearly a multimodality approach to the management of risk factors in patients with coronary artery disease is needed. While IVUS-documented atherosclerotic regression is an intriguing finding, clinicians must remember that this may not be the best measure of the treatment's effect on hard cardiovascular end points. Nevertheless, the pioneering work of Nissen et al has revolutionized the current approach to understanding the anatomy and pathophysiology of coronary atherosclerosis as well as its responsiveness to medical therapy. The results of several ongoing trials will help determine what agent or combination of pharmacologic agents is most efficacious in the long-term management of at-risk patients."

(Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: For the financial disclosures of the authors, please see the JAMA article.


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