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Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) is a prospective, randomized, controlled trial assessing the effectiveness of an intensive or aggressive lipid-lowering approach (atorvastatin 80 mg) to a moderate one (pravastatin 40 mg).
The study used IVUS assessment of coronary atherosclerosis in a coronary artery disease (CAD) population of 502 subjects who were randomized to atorvastatin (A) or pravastatin (P) and followed for 18 months. The cohort averaged 65 years of age and had symptomatic CAD with at least one stenosis of > 20% and one coronary artery with a < 50% lesion. Baseline entry LDL cholesterol was 125-210 mg following an 8-week washout of lipid therapy. Investigator-blinded IVUS was carried out at baseline and at trial completion, using a motorized pullback in the index vessel with 1-mm "slices." The primary end point was the percentage change in total atheroma volume. The secondary end point was the absolute change in percent stenosis obstruction volume. Baseline mean LDL cholesterol was 150 mg/dL.
A induced a 46% decrease in LDL-C, with the mean on treatment LDL of 79 mg/dL for A vs 110 mg/dL for P (P = .0001). P patients experienced a 2.7% mean increase in total plaque volume vs no (-0.4%) change with A (P = .02). The obstruction volume analysis demonstrated a 1.6% increase with P vs no change with A (P = .0002). Baseline C-reactive protein was 3 mg/dL and fell 36% in the A group vs 5.2% with P (P =.0001).
All subgroup analyses in the 2 cohorts were comparable, including in diabetics, who represented 20% of the REVERSAL cohort (P = increase in diabetic plaque volume 3.4%, A no change; nondiabetics 1.5% increase with P, no change with A). Baseline LDL in subjects below the mean progressed with P but not A, including 167 P whose mean LDL-C was 88 mg/dL at study end but still progressed. Sixty-seven percent of P patients reached an LDL of < 100 mg/dL. There were no adverse events or clinical event differences. Regression was confirmed in some individual A subjects but was variable; overall group regression was not seen.
Dr. Steven Nissen, the primary investigator of REVERSE, suggested that the potent efficacy of atorvastatin supports the hypothesis of additional pleotropic actions of the statin in addition to LDL-C lowering.
Comment by Jonathan Abrams, MD
The REVERSAL results, while remarkably robust, are not a real surprise. The dictum "lower is better" was first suggested by the post-CABG trial, and much data since have supported this view. In the Heart Protection Study, all levels of LDL-C, including a baseline of < 100 mg/dL, benefited from 40 mg of simvastatin in these high-risk subjects. The ASAP trial also indicated that powerful LDL-C reduction with 80 mg atorvastatin is beneficial in familial hypercholestemia subjects, when compared to lesser LDL reduction with simvastatin.
What is new in REVERSAL is the use of the intravascular plaque volume assessment with ultrasound, a powerful tool that is far more sensitive and precise than quantitative computer-assisted coronary angiography. IVUS assesses intraluminal plaque, as well as atherosclerosis outside the intima (ie, within the vessel wall). This technique was used in an equally exciting recent trial evaluating short-term efficacy of APO A1 Milano infusion and is the most persuasive tool available to monitor coronary atherosclerosis. Body counts and cardiovascular event rates are the ultimate clinical method for evaluating statin therapy but require thousands of patients and many trial years. REVERSAL raises the bar for approaches to atherosclerosis therapy and diagnosis and clearly confirms the cholesterol hypothesis. Whether the nonlipid effects of A are important remains an interesting issue that is not resolved by this study; Dr. Nissen believes pleiotropism is a key to the A results. Of interest in this regard are the greater "anti-inflammatory" actions of A (CRP analysis), which could, however, be solely due to greater LDL reduction and reduced oxidized LDL effects.
Dr. Abrams, Professor of Medicine in the Division of Cardiology at the University of New Mexico in Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.