ORION study
Tobias Saam 1 , Chun Yuan 1 , Xue-Qiao Zhao 1 , Norihide Takaya 1 , Hunter
Underhil 1 , Baocheng Chu 1 , Jianming Cai 1 , William Kerwin 1 , Lawrence W.
Kraiss 2 , Dennis L. Parker 2 , Wendy Hamar 1 , Joel Raichlen 3 , Valerie Cain 3 ,
John Waterton 4 , and Thomas S. Hatsukami 1.5
University of Washington, Seattle, Wash, USA; University of Utah, Salt Lake
City, Utah, USA; AstraZeneca, Wilmington, Del, USA, and 4 Macclesfield,
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 identify 6,7 and quantify 8 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 (n mmol/L])
5mg
=15; n
40mg
=20) had matched baseline and 2-yr scans
(63% men; mean age 65 yrs; mean baseline LDL-C 156 mg/dL [4.0
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 (n
5mg
=8; n
40mg
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
=10), LRNC comprised 28.5% and 24.7% of the most diseased section (% LRNC) in the 5- and 40-mg groups.
In subjects without a LRNC lesion at baseline (n such a lesion after 2 yrs
5mg
=7; n
40mg
=10), none developed
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 (%)
29 (67)
40-78 (65)
9 (21)
8 (19)
History of angina n (%)
Prior myocardial infarction, n (%)
8 (19)
7 (16)
Total cholesterol*, range, mmol/L (mean) 4.5-9.0 (6.2l
LDL-C*, range, mmol/L (mean) 2.9-6.3 (4.0)
Triglycerides*, range, mmol/L (mean)
HDL-C*, range, mmol/L (mean)
*intention-to-treat population
0.9-4.8 (2.1)
0.7-2.2 (1.2)

ORION study
Baseline
2 years

ORION study
Baseline
2 years

ORION study
Rosuvastatin 5 mg Rosuvastatin 40 mg
0
-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.