Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 3

Intravascular Ultrasound Assessment of Atherosclerosis Progression and Regression

Steven E. Nissen, M.D.
Cleveland Clinic Foundation

Intravascular ultrasound (IVUS) has many potential advantages as a research tool for characterizing atherosclerotic disease progression. IVUS uses high-frequency ultrasound to image not only the coronary lumen, vessel wall including the atherosclerotic plaque.

Background: Although angiography is still the most widely used method for definition of coronary anatomy, radiographic imaging depicts coronary anatomy as a simple two-dimensional projection of the lumen. A silhouette or “luminogram” is a relatively poor representation of coronary atheroma burden and a limited standard upon which to evaluate optimal therapy. Angiography is particularly confounded by the phenomenon of coronary "remodeling," first described in 1987 by Glagov. The remodeling process is observed histologically as the outward displacement of the external vessel wall in vascular segments with significant atherosclerosis. The adventitial enlargement opposes luminal encroachment thereby concealing the presence of the atheroma. Ultrasound commonly reveals atherosclerosis at coronary sites when no apparent disease is found by angiography.

Results of Clinical Trials: Studies have examined the application of intravascular ultrasound to the study of atherosclerosis progression or regression. In the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, the effects of 2 statin regimens were compared using IVUS to measure atheroma burden. One of the regimens (pravastatin 40 mg) was designed to produce a moderate LDL-C lowering effect, while the other (atorvastatin 80 mg) was designed to produce an intensive LDL-C lowering effect. The rate of progression of atherosclerosis (percentage change in total atheroma volume) was examined over an 18-month treatment period. The final mean LDL-C levels were 78.9 mg/dL in the atorvastatin group and 110.4 mg/dL in the pravastatin group. Reduction from baseline in C-reactive protein (CRP) was significantly greater in patients treated with atorvastatin 80 mg than in patients treated with pravastatin 40 mg (-36.4% versus -5.2%; P<0.001). Atorvastatin 80 mg halted the percentage change in atheroma volume over 18 months (-0.4%), while pravastatin 40 mg allowed atheroma volume to increase (2.7%; P=0.02). Post-hoc analysis of the REVERSAL database has demonstrated that reduction in CRP in the intensive treatment arm contributed substantially to the benefits observed.

Regression with Statin Therapy: The REVERSAL Trial slowed progression with statins, but not regression. In the more recent ASTEROID Study, IVUS was performed in 349 coronary disease patients at baseline and following 24 months of rosuvastatin 40mg daily. Low-density lipoprotein cholesterol (LDL-C) was reduced from 130.4 mg/dL to 60.8 mg/dL and high-density lipoprotein cholesterol (HDL-C) increased 14.7%. Two primary efficacy parameters were assessed. The median change in percent atheroma volume was -0.79%, p<0.001 compared with baseline. The median change in atheroma volume in the most diseased 10 mm subsegment was -5.6 mm3, p<0.001 compared with baseline. The secondary efficacy parameter, change in total atheroma volume showed a 6.8% median reduction, -12.5 mm3, p<0.001 compared with baseline. Very high intensity statin therapy to LDL-C levels below current guidelines, accompanied by increased HDL-C, can regress atherosclerosis in coronary disease patients.

HDL-C Raising Trials: A small study, published in 2003, using infusion of an HDL mimetic, ApoA1 Milano showed rapid regression of plaque volume as measured by IVUS. More recently, the ILLUSTRATE Trial randomized 1190 patients to receive either atorvastatin alone or the combination of atorvastatin and torcetrapib, an inhibitor of Cholesterol Ester Transfer Protein (CETP). This therapy raised HDL-C by more than 60% and reduced LDL-C by 20% compared with atorvastatin alone. Despite these large changes in HDL-C and LDL-C, torcetrapib did not decrease the rate of progression of coronary atherosclerosis.

Conclusion: IVUS is a pivotal tool to assess the progression and regression of coronary atherosclerosis, which is enabling development of the next generation of anti-atherosclerotic therapies.

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