Can a potent statin actually regress coronary atherosclerosis?

SINCE THE INITIAL REPORT BY SONES AND SHIREY IN 1962, coronary angiography has been the standard method used to define the severity and extent of coronary atherosclerosis. By only providing a silhouette of the coronary lumen, however, coronary angiography frequently underestimates the true burden of atheroma in the arterial wall. In this issue of JAMA, Nissen et al present important new data on coronary atherosclerosis based on their findings from the ASTEROID (A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial. This multicenter, intravascular ultrasound (IVUS) study assessed the extent of coronary atheroma at baseline and after 2 years of treatment with the maximally approved dose (40 mg) of rosuvastatin, the statin most effective at reducing levels of low-density lipoprotein cholesterol (LDL-C). Each pair of baseline and 24-month IVUS studies was analyzed in blinded fashion. The investigators found that 349 of 507 participants had “evaluable” serial IVUS studies. After 2 years of treatment with rosuvastatin, mean LDL-C levels decreased by 53% (from 130 to 61 mg/dL) and mean high-density lipoprotein cholesterol (HDL-C) levels increased by 15% (from 43 to 49 mg/dL). Rosuvastatin therapy was associated with a modest decrease in mean percent atheroma volume (from 39.6% to 38.6%) and mean atheroma volume in the most diseased 10-mm subsegment (from 65 to 59 mm). Importantly, all patients either had no statin therapy for more than 3 months during the preceding year or required a 28-day washout period before enrollment to obtain accurate baseline lipid values prior to the initiation of therapy. The authors conclude that very aggressive LDL-C lowering in the setting of a moderate increase in HDL-C results in regression of coronary atherosclerosis. While the results of this study are exciting, they are tempered by the lack of a control group receiving a somewhat less intensive LDL-C lowering regimen, the absence of paired IVUS measurements in less diseased coronary segments to demonstrate reproducibility of atheroma volume measurements, and exclusion of patients with coronary stenoses measuring greater than 50% throughout a target segment. Furthermore, the study design raises questions about whether differences in the amount of atheroma regression depend on whether a patient is “statin naive” in comparison with those previously receiving statin therapy. This is particularly important when trying to evaluate the findings of this study in the context of the Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study, in which patients were allowed to be taking lipid-lowering therapy prior to study enrollment. The authors of the ASTEROID trial deemed it “ethically unacceptable to randomize patients in this high-risk group to low-intensity treatment.” However, it appears that most enrolled patients were not at extremely high risk (eg, the clinical indication for angiography typically consisted of stable or unstable ischemic chest pain syndromes or abnormal exercise testing results for angina and only 13% had diabetes mellitus). Furthermore, the baseline LDL-C level for enrolled patients was only mildly elevated, the HDL-C level was average, and 17% of individuals were not taking aspirin at baseline. Given current guidelines, such patients would not necessarily be considered high risk and treatment with a less aggressive lipid-lowering regimen (target LDL-C level of approximately 90-100 mg/dL) would be accepted as standard of care. Unfortunately, the ASTEROID study does not provide definitive information regarding the relationship of LDL-C lowering and extent of coronary atherosclerosis regression to determine if high-intensity treatment is required to achieve regression. Since the authors report a similar magnitude of regression for patients above and below the median HDL-C and LDL-C levels (Table 4 in the article), less intensive changes in LDL-C levels, non–HDL-C levels, or both, and HDL-C levels also may have led to modest regression. Comparison of high-dose rosuvastatin with simvastatin— which performed well in the Heart Protection Study (even in patients with baseline LDL-C levels 100 mg/dL)— would have been a more informative study design. The choice of simvastatin would have been a good one because