ATLANTA — Intensive statin therapy that dropped serum levels of low-density lipoprotein cholesterol below 70 mg/dL in most patients led to significant regression of coronary atherosclerosis in a study with 349 patients.
The results are the first from ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden), which uses intravascular ultrasound (IVUS) to show “unequivocal evidence of disease regression,” Dr. Steven E. Nissen said at the annual meeting of the American College of Cardiology.
The results “suggest that lowering LDL cholesterol to these low levels is associated with an anatomic effect,” commented Dr. Robert H. Eckel, president of the American Heart Association and professor of medicine at the University of Colorado at Denver.
The results “are very exciting and break new ground,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence.
But experts also cautioned that while the findings convincingly linked an aggressively lowered level of LDL cholesterol to atheroma regression, the study failed to include control patients, and it wasn't designed to examine the impact of treatment on clinical events such as death and myocardial infarctions, the accepted standards of efficacy for coronary-disease interventions. “IVUS-documented atherosclerosis regression … may not be the best measure of the treatment's effect on hard cardiovascular end points,” commented Dr. Roger S. Blumenthal and Dr. Navin K. Kapur, both of the Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, in an editorial that accompanied the on-line release of Dr. Nissen's report (JAMA 2006;295 [Epub doi:10.1001/jama.295.13.jed60019]).
The study was carried out because prior angiographic and IVUS studies had shown slowed progression of coronary atherosclerosis with statin therapy, but none had convincingly demonstrated regression, said Dr. Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic.
He and his associates enrolled 507 patients who required angiography for a clinical indication, and had at least one coronary artery stenosis that obstructed more than 20% of the vessel. Participants also had to be statin naive, which meant they received statin therapy for no more than 3 months during the year before enrollment. Patients entered the study during November 2002-October 2003 at 53 U.S. centers.
A target coronary vessel was selected that had no more than 50% stenosis throughout a segment that was at least 40 mm in length. This segment was examined by IVUS at baseline and after 2 years of treatment. Patients were all put on a regimen of 40 mg of rosuvastatin (Crestor) daily, the highest approved dosage for this drug. The study did not specify any other drug or diet management.
Evaluable IVUS examinations at baseline and after 2 years of treatment were available for 349 patients, who were the focus of the analysis. After 2 years, serum levels of LDL cholesterol in these 349 patients had dropped from an average of 130.4 mg/dL at baseline to an average of 60.8 mg/dL, a decline of 53%. The treatment regimen also produced a “surprisingly” large boost in serum levels of HDL cholesterol, Dr. Nissen said, which rose from an average of 43.1 mg/dL at baseline to 49.0 mg/dL after 2 years, a boost of 15%. “To our knowledge, this is the highest increase in HDL ever observed in a statin trial,” he said. The ratio of LDL to HDL cholesterol fell from an average of 3.2 at baseline to 1.3.
The study had two primary efficacy measures: the median change in percent atheroma volume in the coronary segment studied, which dropped by 0.79%, and the median change in total atheroma volume in the most diseased 10-mm segment examined, which fell by 5.6 mm
Atheroma volume significantly declined in the subgroup of 254 patients whose serum level of LDL cholesterol was less than 70 mg/dL. The 78 patients who maintained an LDL-cholesterol level of 70–99 mg/dL, and the 17 patients whose LDL-cholesterol levels remained at 100 mg/dL or higher despite treatment had no significant fall in their atheroma volume. The relationship of atheroma regression to levels of HDL cholesterol in this study has not yet been thoroughly examined.
The researchers plotted their new finding, of an average 0.79% reduction in atheroma volume with an average achieved LDL-cholesterol level of 61 mg/dL, along with correlations between serum cholesterol and atheroma volume changes reported in four prior IVUS studies. The five data points, which all fell on a line with a high correlation coefficient, indicated that atheroma regresses when a patient's serum level of LDL cholesterol falls below 75 mg/dL. “These findings suggest [that] attaining the lowest levels of LDL cholesterol achievable without adverse effects may represent the optimal strategy,” Dr. Nissen said.