Guidelines now recommend high-intensity statin therapy in all patients with proven atherosclerotic disease. Yet the impact of baseline lipoprotein and C-reactive protein (CRP) levels on measures of disease regression to this therapy are unknown. The aim of this study was to test the hypothesis that high-intensity statin therapy causes equivalent degrees of coronary atheroma regression irrespective of baseline lipoprotein and CRP levels. In 8 prospective randomized trials using serial coronary intravascular ultrasound, 1,881 patients who maintained or switched to 18- to 24 months of high-intensity statin therapy (rosuvastatin 40 mg or atorvastatin 80 mg) were stratified according to baseline lipoprotein and CRP levels. Changes in coronary percentage atheroma volume (PAV) and total atheroma volume (TAV) were evaluated. High-intensity statin therapy produced significant reductions from baseline in low-density lipoprotein cholesterol by 38.4%, non–high-density lipoprotein (HDL) cholesterol by 33.6%, triglycerides by 13.1%, and CRP by 33.3%, while increasing HDL cholesterol by 11.7% (p <0.001 for all). This was associated with regression of PAV by 0.7% and of TAV by 8.2 mm 3 (p <0.001 for both). No significant differences of changes in PAV and TAV were observed across baseline quintiles of low-density lipoprotein cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, or CRP. Moreover, across all measured lipoproteins and CRP, most patients demonstrated plaque regression (defined as any change from baseline in PAV or TAV <0). In conclusion, high-intensity statin therapy attenuated the natural progression of coronary atherosclerosis in all strata of patients with coronary artery disease irrespective of baseline lipoprotein or CRP levels. These findings provide support for the latest United States guideline recommendations for the broad use of high-intensity statin therapy in all patients with atherosclerosis, regardless of baseline lipid status.
Randomized controlled trials have consistently demonstrated the prognostic benefits of statin-mediated low-density lipoprotein (LDL) cholesterol lowering. Although European lipid-lowering guidelines continue to advocate an LDL cholesterol target of <70 mg/dl (or a ≥50% reduction from baseline LDL cholesterol levels) for higher risk patients, United States guidelines now broadly recommend the use of high-intensity statin therapy in all adults with documented atherosclerotic cardiovascular disease. Treatment guidelines, however, are unanimous in recommending LDL cholesterol lowering with statins as the primary means of contemporary cardiovascular risk reduction. Advances in arterial wall imaging have permitted evaluation of the effect of various medical therapies on the rate of atheroma progression, and accumulating evidence now associates the serial change in coronary atheroma volume with incident cardiovascular events. Despite this knowledge, the impact of potent statin therapy on coronary atheroma progression has yet to be characterized according to baseline lipoprotein levels. We tested the hypothesis that maximally intensive statin therapy would result in equivalent degrees of coronary atheroma regression in patients irrespective of baseline lipoprotein and C-reactive protein (CRP) levels.
Methods
The present analysis included patients participating in 8 clinical trials assessing the impact of medical therapies on serial changes in coronary atheroma burden using intravascular ultrasound (IVUS). Included in this analysis were trials assessing intensive lipid lowering with statins (Reversal of Atherosclerosis With Aggressive Lipid Lowering) [REVERSAL], (A Study to Evaluate the Effect of Rosuvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden) [ASTEROID], and (The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) [SATURN], antihypertensive therapies (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) [AQUARIUS], the antiatherosclerotic efficacy of acyl-coenzyme A:cholesteryl ester transfer protein inhibition (ACAT Intravascular Atherosclerosis Treatment Evaluation) [ACTIVATE], cholesteryl ester transfer protein inhibition (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) [ILLUSTRATE], endocannibanoid receptor antagonism (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabont – The Intravascular Ultrasound Study) [STRADIVARIUS], and peroxisome proliferator–activated receptor-γ agonism (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) [PERISCOPE]. Patients randomized to torcetrapib in ILLUSTRATE were also excluded from this analysis because of the compound’s off-target toxicity despite its significant high-density lipoprotein (HDL) cholesterol–increasing effects. High-intensity statin therapy was defined as rosuvastatin 40 mg or atorvastatin 80 mg, and only patients who maintained or switched to this treatment during the study protocol were included in the present analysis.
The acquisition and serial analysis of IVUS images in each of these trials has been previously described in detail. Briefly, target vessels for imaging were selected if they contained no luminal stenosis >50% angiographic severity within a segment of ≥30 mm length. Imaging was performed within the same coronary artery at baseline and at study completion, which ranged from 18 to 24 months. Imaging in all trials was screened by the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic Coordinating Center for Clinical Research. Patients meeting prespecified requirements for image quality were eligible for randomization. An anatomically matched segment was defined at the 2 time points on the basis of proximal and distal side branches (fiduciary points). Cross-sectional images spaced precisely 1 mm apart were selected for measurement. Leading edges of the lumen and external elastic membrane were traced by manual planimetry. Plaque area was defined as the area occupied between these leading edges. The accuracy and reproducibility of this method have been reported previously. The percentage atheroma volume (PAV) was determined by calculating the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest as follows:
Total atheroma volume (TAV) was calculated by summing the plaque areas in all measured images. To account for heterogeneity of segment length in individual subjects, TAV was normalized by multiplying the mean atheroma area in each pullback by the median segment length for the entire study cohort as follows:
TAV normalized = ∑ ( EEM area − Lumen area ) Number of images inpullback × Median number of images in cohort .
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