Impact of Statins on Serial Coronary Calcification in Atheroma
Impact of Statins on Serial Coronary Calcification in Atheroma
The present analysis included patients participating in 8 clinical trials assessing the impact of medical therapies on serial changes in coronary atheroma burden using IVUS. Included in this analysis were trials assessing intensive lipid lowering with statins (REVERSAL [Reversal of Atherosclerosis With Aggressive Lipid Lowering] and SATURN [The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin]), antihypertensive therapies (AQUARIUS [Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study] and NORMALIZE [Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation]), the antiatherosclerotic efficacy of acyl-coenzyme A:cholesteryl ester transfer protein inhibition (ACTIVATE [ACAT Intravascular Atherosclerosis Treatment Evaluation]), cholesteryl ester transfer protein inhibition (ILLUSTRATE [Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation]), endocannibanoid receptor antagonism (STRADIVARIUS [Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabont—The Intravascular Ultrasound Study]), and the peroxisome proliferator–activated receptor- gamma agonism (PERISCOPE [Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation]). The ASTERIOD (A Study to Evaluate the Effect of Rouvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden) study was not included in this analysis because smoking status and C-reactive protein (CRP) levels were not collected. From each of these trials, patients receiving HIST (n = 1,545), LIST (n = 1,726), or no-statin therapy (n = 224) were included in the present analysis. In the present analysis, HIST was defined as atorvastatin 80 mg or rosuvastatin 40 mg, whereas LIST was defined as atorvastatin dosing <40 mg, rosuvastatin <20 mg, simvastatin <40 mg, pravastatin <80 mg, lovastatin <20 mg, and fluvastatin dosing <40 mg. Hence, the present analysis comprises a patient-level analysis of 8 randomized trials in which patients were stratified on the basis of statin treatment (or no-statin treatment).
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 at least 30mmlength. 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 pre-specified 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 thismethod have been reported previously. The percent 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:
The total atheroma volume (TAV) was calculated by summating the plaque areas in all measured images. To account for heterogeneity of segment length in individual subjects, the TAV was normalized by multiplying the mean atheroma area in each pullback by the median segment length for the entire study cohort as follows:
Calcium was identified by an echogenic signal brighter than the adventitia with corresponding acoustic shadowing. A calcium grade was assigned for each analyzed image, reflecting the degree of acoustic shadowing (0 = no calcium; 1 = calcium with acoustic shadowing <90°; 2 = calcium with shadowing ≥90° but <180°; 3 = calcium with shadowing ≥180° but <270°; 4 = calcium ≥270°). For images containing multiple calcium deposits, the grade represented the summation of all angles of acoustic shadowing. For each pullback, a calcium index (CaI) was thus calculated as follows:
Change in CaI was defined as follow-up CaI minus baseline CaI.
Continuous variables were reported as mean ± SD if normally distributed and as median (interquartile range) if non-normally distributed. Demographics, baseline clinical characteristics, baseline medications, laboratory biochemical data, and baseline IVUS parameters were compared. Twosample Student t tests were used for normally distributed continuous variables, Wilcoxon rank sum tests for non-normally distributed continuous variables, and chi-square tests (or exact tests) for categorical variables.
Because of differences in various baseline characteristics across the treatment groups, a propensity score weighting method was applied. The multiple treatment propensity scores and corresponding inverse probability of treatment weight (the reciprocal of the propensity scores) were estimated by generalized boosted models using an iterative estimation procedure, using all the related baseline characteristics and medications as covariates. The balance of the pre-treatment covariates was assessed, and significant improvement in baseline balance was achieved following weighting.
All subsequent analyses were weighted by inverse probability of treatment weight, except the analysis of baseline CaI. Serial changes in IVUS measurements were analyzed by analysis of covariance, adjusting for their baseline counterparts, and are reported as least squares mean ± SE, and the causal effects of each therapy were examined using inverse probability of treatment weight weighted generalized linear regression models in the context of survey design controlling for baseline IVUS values. Such surveyweighted generalized linear models have robust design-based standard errors. Because the CaI (both baseline and change) had many zero values, a ranktransformation was performed, and the same strategy of survey-design generalized linear models was created using the rank-transformed CaI changes as the outcome. Because calcium is a component of plaque, atheroma volume (PAV or TAV) was adjusted within the model for CaI. Clinical trial and baseline CaI were controlled for in the CaI model as well. Average treatment effects on IVUS and on CaI were compared in a pairwise fashion among the statin therapy groups. Given that each trial's duration varied between 18 and 24 months, changes in PAV, TAV, and CaI were also interpolated at 1 year and thus reported as annualized changes. Because of the intrinsic relationships between plaque progression and calcification, changes in coronary atheroma volume and CaIs were also compared according to plaque progression/nonprogression. A 2-sided probability value of 0.05 was considered statistically significant. Analyses were performed using SAS software version 9.2 (SAS Institute, Cary, North Carolina) and the twang package and survey package in (open-source) R software.
Methods
Study Population
The present analysis included patients participating in 8 clinical trials assessing the impact of medical therapies on serial changes in coronary atheroma burden using IVUS. Included in this analysis were trials assessing intensive lipid lowering with statins (REVERSAL [Reversal of Atherosclerosis With Aggressive Lipid Lowering] and SATURN [The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin]), antihypertensive therapies (AQUARIUS [Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study] and NORMALIZE [Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation]), the antiatherosclerotic efficacy of acyl-coenzyme A:cholesteryl ester transfer protein inhibition (ACTIVATE [ACAT Intravascular Atherosclerosis Treatment Evaluation]), cholesteryl ester transfer protein inhibition (ILLUSTRATE [Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation]), endocannibanoid receptor antagonism (STRADIVARIUS [Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabont—The Intravascular Ultrasound Study]), and the peroxisome proliferator–activated receptor- gamma agonism (PERISCOPE [Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation]). The ASTERIOD (A Study to Evaluate the Effect of Rouvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden) study was not included in this analysis because smoking status and C-reactive protein (CRP) levels were not collected. From each of these trials, patients receiving HIST (n = 1,545), LIST (n = 1,726), or no-statin therapy (n = 224) were included in the present analysis. In the present analysis, HIST was defined as atorvastatin 80 mg or rosuvastatin 40 mg, whereas LIST was defined as atorvastatin dosing <40 mg, rosuvastatin <20 mg, simvastatin <40 mg, pravastatin <80 mg, lovastatin <20 mg, and fluvastatin dosing <40 mg. Hence, the present analysis comprises a patient-level analysis of 8 randomized trials in which patients were stratified on the basis of statin treatment (or no-statin treatment).
Acquisition and Analysis of Serial IVUS Images
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 at least 30mmlength. 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 pre-specified 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 thismethod have been reported previously. The percent 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:
The total atheroma volume (TAV) was calculated by summating the plaque areas in all measured images. To account for heterogeneity of segment length in individual subjects, the TAV was normalized by multiplying the mean atheroma area in each pullback by the median segment length for the entire study cohort as follows:
Calcium was identified by an echogenic signal brighter than the adventitia with corresponding acoustic shadowing. A calcium grade was assigned for each analyzed image, reflecting the degree of acoustic shadowing (0 = no calcium; 1 = calcium with acoustic shadowing <90°; 2 = calcium with shadowing ≥90° but <180°; 3 = calcium with shadowing ≥180° but <270°; 4 = calcium ≥270°). For images containing multiple calcium deposits, the grade represented the summation of all angles of acoustic shadowing. For each pullback, a calcium index (CaI) was thus calculated as follows:
Change in CaI was defined as follow-up CaI minus baseline CaI.
Statistical Analysis
Continuous variables were reported as mean ± SD if normally distributed and as median (interquartile range) if non-normally distributed. Demographics, baseline clinical characteristics, baseline medications, laboratory biochemical data, and baseline IVUS parameters were compared. Twosample Student t tests were used for normally distributed continuous variables, Wilcoxon rank sum tests for non-normally distributed continuous variables, and chi-square tests (or exact tests) for categorical variables.
Because of differences in various baseline characteristics across the treatment groups, a propensity score weighting method was applied. The multiple treatment propensity scores and corresponding inverse probability of treatment weight (the reciprocal of the propensity scores) were estimated by generalized boosted models using an iterative estimation procedure, using all the related baseline characteristics and medications as covariates. The balance of the pre-treatment covariates was assessed, and significant improvement in baseline balance was achieved following weighting.
All subsequent analyses were weighted by inverse probability of treatment weight, except the analysis of baseline CaI. Serial changes in IVUS measurements were analyzed by analysis of covariance, adjusting for their baseline counterparts, and are reported as least squares mean ± SE, and the causal effects of each therapy were examined using inverse probability of treatment weight weighted generalized linear regression models in the context of survey design controlling for baseline IVUS values. Such surveyweighted generalized linear models have robust design-based standard errors. Because the CaI (both baseline and change) had many zero values, a ranktransformation was performed, and the same strategy of survey-design generalized linear models was created using the rank-transformed CaI changes as the outcome. Because calcium is a component of plaque, atheroma volume (PAV or TAV) was adjusted within the model for CaI. Clinical trial and baseline CaI were controlled for in the CaI model as well. Average treatment effects on IVUS and on CaI were compared in a pairwise fashion among the statin therapy groups. Given that each trial's duration varied between 18 and 24 months, changes in PAV, TAV, and CaI were also interpolated at 1 year and thus reported as annualized changes. Because of the intrinsic relationships between plaque progression and calcification, changes in coronary atheroma volume and CaIs were also compared according to plaque progression/nonprogression. A 2-sided probability value of 0.05 was considered statistically significant. Analyses were performed using SAS software version 9.2 (SAS Institute, Cary, North Carolina) and the twang package and survey package in (open-source) R software.