Magnetic Resonance Characterization of Carotid Atherosclerotic Plaque in Vivo: Effect of High Density Lipoprotein Elevation on Plaque Morphology

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1.0 SYNOPSIS The primary objective of this randomized, double blind, placebo controlled pilot study is to determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase inhibitor - simvastatin) or increasing HDL cholesterol (Niaspan) will induce regression of carotid atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at baseline will be compared to that after 6 and 12 months of therapy and changes in MR characteristics will be compared to changes in lipoprotein parameters and urinary isoprostanes. The effect of moderate LDL reduction, aggressive LDL reduction and the combination of aggressive LDL reduction and HDL elevation on MRI plaque characteristics will be compared by randomly assigning subjects (n=69) with carotid disease (>30% stenosis by ultrasound criteria) to one of three treatment arms;

1. Simvastatin 20 mg daily and placebo Niaspan (n=23)
2. Simvastatin 80 mg daily and placebo Niaspan (n=23)
3. Simvastatin 20 mg daily and active Niaspan (n=23) Treatment group 2 and 3 will have roughly equivalent LDL lowering because of the synergistic LDL lowering effect of the combination of simvastatin and Niaspan.

2.0 BACKGROUND Atherosclerotic carotid disease is the largest single etiological factor known to produce focal cerebral ischemia (1). Only a small percentage of patients with asymptomatic carotid atherosclerosis develop stroke but the majority of these have have no warning symptoms. The degree of internal carotid stenosis at ultrasound angiography, the commonest methods of assessing the risk of stroke, are poor predictors of stroke in patients with asymptomatic carotid atherosclerosis (2) and clinical risk factors have a high prevalence but a low relative risk of stroke in these patients. Most plaque rupture occurs in unstable lipid rich plaques with thin fibrous caps weakened by inflammation and apoptosis (3). Thus, the morphological characteristics of carotid plaques may provide important information regarding ischemic risk of carotid lesions. We, and others, are using high resolution MR imaging (4-6) to differentiate carotid plaque elements such as the lipid core, the fibrous cap and hemorrhage with the ultimate goal of determining the ischemic potential of carotid atherosclerotic plaques.

Lipid lowering therapy with statins is considered standard treatment for patients with atherosclerosis and hypercholesterolemia (7-9). Statin therapy reduces LDL cholesterol levels, cardiovascular events and death and retards the progression of atherosclerosis as assessed by noninvasive intima-media thickness (IMT) on carotid ultrasound (10). However, the optimal degree of LDL cholesterol lowering with statins in patients with atherosclerosis remains unclear (7,8) - thus there are a number of ongoing large clinical trials comparing the effect of low dose to high doses of statins on cardiovascular effects in patients with coronary atherosclerosis (eg "Treatment to New Targets"). Low HDL cholesterol is an independent risk factor for the development and progression of atherosclerosis (11). Niacin is one of a few effective therapies that significantly elevates HDL levels and was shown to reduce cardiovascular events in patients with known coronary atherosclerosis prior to the development of statin drugs (12,13). Increased HDL is thought to promote reverse cholesterol transport from the peripheral tissues including atherosclerotic plaque (14-16). Presently, niacin is not considered standard therapy in patients with known atherosclerosis. Niaspan is a new controlled-release form of niacin that is administered once daily, is better tolerated than crystalline niacin which is given 3 times a day (17,18). It has been shown to result in a greater than 30% increase in HDL cholesterol and preliminary data suggest that it is safe and effective and not associated with hepatotoxicity (19). In the proposed study patients (n=60) with carotid disease (>30% stenosis by ultrasound criteria) will be randomly assigned to one of three treatment arms;