Effect of Rosuvastatin Therapy on Carotid Plaque Morphology
Background: Magnetic resonance imaging (MRI) can noninvasively assess changes in atherosclerotic plaque morphology and composition. The ORION trial assessed the effects of rosuvastatin on carotid plaque volume and composition.
Methods: The randomized, double-blind ORION trial used 1.5-T MRI to image carotid atherosclerotic plaques at baseline and after 24 months of treatment. Forty-three patients with fasting low-density lipoprotein cholesterol ≥100 and <250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive either a low (5 mg) or high (40/80 mg) dose of rosuvastatin.
Results: After 24 months, 33 patients had matched serial MRI scans to compare by reviewers blinded to clinical data, dosage, and temporal sequence of scans. Low-density lipoprotein cholesterol was significantly reduced from baseline in both the low- and high-dose groups (38.2% and 59.9%, respectively, both P < .001). At 24 months, there were no significant changes in carotid plaque volume for either dosage group. In all patients with a lipid-rich necrotic core (LRNC) at baseline, the mean proportion of the vessel wall composed of LRNC (%LRNC) decreased by 41.4% (P = .005).
Conclusions: In patients with moderate hypercholesterolemia, both low- and high-dose rosuvastatin were effective in reducing low-density lipoprotein cholesterol. Furthermore, rosuvastatin was associated with a reduction in %LRNC, whereas the overall plaque burden remained unchanged over the course of 2 years of treatment. These findings provide evidence that statin therapy may have a beneficial effect on plaque volume and composition, as assessed by noninvasive MRI.
According to the National Heart, Lung and Blood Institute, diseases caused by atherosclerosis are the leading cause of morbidity and mortality in the developed world. Because an observable effect of atherosclerotic disease is luminal narrowing, traditional medical doctrine has dictated intervention based on degree of stenosis. Recent investigations, however, suggest that luminal narrowing is only one of several markers of the vulnerable, high-risk plaque.
Histologic examination of the coronary arteries obtained from surgical specimens and postmortem tissue have characterized the vulnerable plaque in even moderately stenotic lesions as having a large, lipid-rich necrotic core (LRNC), a thin fibrous cap, and inflammatory activity. Natural progression of these elements predisposes the atheroma to fibrous cap rupture, which may lead to the thrombotic complications of atherosclerosis. As such, the in vivo identification and monitoring of plaque composition are critical to optimize risk assessment and patient management.
High-resolution magnetic resonance imaging (MRI) is a noninvasive technique that enables the morphological and compositional assessment of the carotid arterial wall. Through histologic validation, multisequence, high-resolution carotid MRI has been proven to detect fibrous tissue, LRNC, and calcification in the in vivo human carotid atherosclerotic plaque. Furthermore, developments in image processing have enabled the automated identification and quantification of these compositional features. The coupling of advanced image analysis tools with the high spatial resolution afforded by MRI has yielded highly reproducible measurements, which has enabled the successful serial monitoring of the natural history of carotid atherosclerotic disease.
High-resolution MRI has also been used to evaluate the effects of pharmacologic intervention on plaque burden. Recently published studies have reported that 2 years of treatment with low- and high-dose simvastatin were associated with a significant reduction in MRI-assessed atherosclerotic area in hypercholesterolemic patients with coronary or carotid artery disease. Although other imaging investigations have reported a spectrum of responses to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), none of these studies have evaluated the effects of statin therapy on plaque composition.
We designed the ORION trial for patients with moderate hypercholesterolemia to evaluate the response of carotid atherosclerotic disease with MRI during conventional and intensive treatment with rosuvastatin (Crestor; licensed to AstraZeneca, Wilmington, DE, from Shionogi & Co, Ltd, Osaka, Japan). The primary prespecified efficacy parameter was change in carotid wall volume as measured by high-resolution MRI after 24 months of rosuvastatin therapy. Change in plaque composition was prespecified as a secondary efficacy parameter.
Background: Magnetic resonance imaging (MRI) can noninvasively assess changes in atherosclerotic plaque morphology and composition. The ORION trial assessed the effects of rosuvastatin on carotid plaque volume and composition.
Methods: The randomized, double-blind ORION trial used 1.5-T MRI to image carotid atherosclerotic plaques at baseline and after 24 months of treatment. Forty-three patients with fasting low-density lipoprotein cholesterol ≥100 and <250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive either a low (5 mg) or high (40/80 mg) dose of rosuvastatin.
Results: After 24 months, 33 patients had matched serial MRI scans to compare by reviewers blinded to clinical data, dosage, and temporal sequence of scans. Low-density lipoprotein cholesterol was significantly reduced from baseline in both the low- and high-dose groups (38.2% and 59.9%, respectively, both P < .001). At 24 months, there were no significant changes in carotid plaque volume for either dosage group. In all patients with a lipid-rich necrotic core (LRNC) at baseline, the mean proportion of the vessel wall composed of LRNC (%LRNC) decreased by 41.4% (P = .005).
Conclusions: In patients with moderate hypercholesterolemia, both low- and high-dose rosuvastatin were effective in reducing low-density lipoprotein cholesterol. Furthermore, rosuvastatin was associated with a reduction in %LRNC, whereas the overall plaque burden remained unchanged over the course of 2 years of treatment. These findings provide evidence that statin therapy may have a beneficial effect on plaque volume and composition, as assessed by noninvasive MRI.
According to the National Heart, Lung and Blood Institute, diseases caused by atherosclerosis are the leading cause of morbidity and mortality in the developed world. Because an observable effect of atherosclerotic disease is luminal narrowing, traditional medical doctrine has dictated intervention based on degree of stenosis. Recent investigations, however, suggest that luminal narrowing is only one of several markers of the vulnerable, high-risk plaque.
Histologic examination of the coronary arteries obtained from surgical specimens and postmortem tissue have characterized the vulnerable plaque in even moderately stenotic lesions as having a large, lipid-rich necrotic core (LRNC), a thin fibrous cap, and inflammatory activity. Natural progression of these elements predisposes the atheroma to fibrous cap rupture, which may lead to the thrombotic complications of atherosclerosis. As such, the in vivo identification and monitoring of plaque composition are critical to optimize risk assessment and patient management.
High-resolution magnetic resonance imaging (MRI) is a noninvasive technique that enables the morphological and compositional assessment of the carotid arterial wall. Through histologic validation, multisequence, high-resolution carotid MRI has been proven to detect fibrous tissue, LRNC, and calcification in the in vivo human carotid atherosclerotic plaque. Furthermore, developments in image processing have enabled the automated identification and quantification of these compositional features. The coupling of advanced image analysis tools with the high spatial resolution afforded by MRI has yielded highly reproducible measurements, which has enabled the successful serial monitoring of the natural history of carotid atherosclerotic disease.
High-resolution MRI has also been used to evaluate the effects of pharmacologic intervention on plaque burden. Recently published studies have reported that 2 years of treatment with low- and high-dose simvastatin were associated with a significant reduction in MRI-assessed atherosclerotic area in hypercholesterolemic patients with coronary or carotid artery disease. Although other imaging investigations have reported a spectrum of responses to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), none of these studies have evaluated the effects of statin therapy on plaque composition.
We designed the ORION trial for patients with moderate hypercholesterolemia to evaluate the response of carotid atherosclerotic disease with MRI during conventional and intensive treatment with rosuvastatin (Crestor; licensed to AstraZeneca, Wilmington, DE, from Shionogi & Co, Ltd, Osaka, Japan). The primary prespecified efficacy parameter was change in carotid wall volume as measured by high-resolution MRI after 24 months of rosuvastatin therapy. Change in plaque composition was prespecified as a secondary efficacy parameter.