Transcript ORION study
ORION study Rosuvastatin Treatment and Its Effects on Plaque Composition of Carotid Atherosclerosis in Moderately Hypercholesterolemic Subjects: A High-Resolution Magnetic Resonance Imaging Trial Tobias Saam1, Chun Yuan1, Xue-Qiao Zhao1, Norihide Takaya1, Hunter Underhil1, Baocheng Chu1, Jianming Cai1, William Kerwin1, Lawrence W. Kraiss2, Dennis L. Parker2 , Wendy Hamar1 , Joel Raichlen3 , Valerie Cain 3, John Waterton 4 , and Thomas S. Hatsukami1.5 University of Washington, Seattle, Wash, USA; University of Utah, Salt Lake City, Utah, USA; AstraZeneca, Wilmington, Del, USA, and 4Macclesfield, UK; VA Puget Sound Health Care System, Seattle, Wash, USA ORION study Background Atherosclerosis and its thrombotic complications are the leading cause of morbidity and mortality in industrialized countries Previous studies suggest that the plaques likely to cause thrombotic complications are those with large lipid-rich necrotic cores (LRNC) and thin fibrous caps Recent trials have shown slowed progression in atheroma size with statin therapy. However, the effects of statin therapy on plaque composition were not reported in those trials Magnetic resonance imaging (MRI) has been extensively validated with histology and has been shown to accurately identify6,7 and quantify8 the structure and composition of carotid atherosclerosis in vivo. Therefore, MRI provides an opportunity to study changes in atheroma size and composition The ORION (Outcome of Rosuvastatin treatment on carotid artery atheroma: a magnetic resonance Imaging ObservatioN) trial examined the effects of 2 yrs of treatment with low versus high doses of rosuvastatin (Crestor®) on carotid plaque composition using highresolution MRI ORION study Methods 43 subjects with fasting low-density lipoprotein cholesterol (LDL-C) > 100 and <250 mg/dL (> 2.6 and <6.5 mmol/L) and either 16%-79% carotid stenosis by ultrasound or plaque with a LRNC by MRI were randomized to rosuvastatin 5 or 40mg for 2 yrs (see Table 1 for baseline characteristics) Multi-sequence carotid MRI was performed at 1.5T, with phased-array carotid coils Expert readers, blinded to dosage and time sequence, reviewed all scans As appropriate, data were analyzed by parametric or nonparametric tests. P-values represent within-group comparisons vs. baseline Primary end point was the change in atherosclerotic carotid artery wall composition ORION study 35 subjects (n5mg=15; n40mg=20) had matched baseline and 2-yr scans (63% men; mean age 65 yrs; mean baseline LDL-C 156 mg/dL [4.0 mmol/L]) At 2 yrs, LDL-C was reduced from baseline by 39% and 58% in 5- and 40mg groups, respectively (p <0.001) In 5- and 40-mg groups, median (mean) % changes in carotid artery wall volume were 0.5% (-1.2%) and -1.4% (1.1%), respectively (p=NS) Subjects whose wall volume regressed (n=16) had an on-treatment mean LDL-C of 69 mg/dL (-56%), whereas subjects whose wall volume progressed (n=19) had an LDL-C of 84 mg/dL (-45%) ORION study In plaques with a LRNC at baseline (n5mg=8; n40mg=10), LRNC comprised 28.5% and 24.7% of the most diseased section (% LRNC) in the 5- and 40-mg groups. Rosuvastatin 5 and 40 mg reduced % LRNC at this location by 17.6% (P=NS) and 35.5% (p=0.006), with 75% and 90% of the plaques, respectively, showing regression from baseline In subjects without a LRNC lesion at baseline (n5mg=7; n40mg=10), none developed such a lesion after 2 yrs Both rosuvastatin doses were well tolerated over 2 yrs No deaths or treatment-related serious adverse events were reported No subjects progressed to endarterectomy ORION study Results Table 1. Subject demographic and baseline characteristics Sex, Male, n (%) Age, range, years (mean) Current smoker, n (%) Type 2 diabetes, n (%) History of angina n (%) Prior myocardial infarction, n (%) Total cholesterol*, range, mmol/L (mean) LDL-C*, range, mmol/L (mean) Triglycerides*, range, mmol/L (mean) HDL-C*, range, mmol/L (mean) *intention-to-treat population 29 (67) 40-78 (65) 9 (21) 8 (19) 8 (19) 7 (16) 4.5-9.0 (6.2l 2.9-6.3 (4.0) 0.9-4.8 (2.1) 0.7-2.2 (1.2) ORION study T1-weighted images at baseline and after 2 years of treatment with rosuvastatin 40 mg Baseline 2 years ORION study Multi-contrast weighted images from the same subject at one location Baseline 2 years ORION study Reduction in LDL-C and lipid rich necrotic core with rosuvastatin 5 mg and 40 mg Mean change from baseline (%) 0 Rosuvastatin 5 mg Rosuvastatin 40 mg -10 -20 -30 -40 † * -50 -60 -70 LDL-C %LRNC *‡ * p <0.001 vs. baseline † p <0.01 vs. baseline ‡ p <0.005 rosuvastatin 40 mg vs. rosuvastatin 5 mg ORION study Conclusions • Our findings suggest that substantial LDL-C reduction with rosuvastatin is associated with arrested progression of carotid atherosclerosis in moderately hypercholesterolemic subjects, as assessed by non-invasive MRI. • Furthermore, intensive LDL-C lowering with rosuvastatin resulted in regression of the proportion of the lipid-rich necrotic core in the most diseased location of the atherosclerotic plaques.