We explored for geographic variations in coronary atheroma progression rates in the United States compared to other world regions (Canada, Latin America, Western Europe, and Central–Eastern Europe) and sought to ascertain if this associated with regional differences in major adverse cardiovascular events (MACE; cardiovascular death, nonfatal myocardial infarction, coronary revascularization). Across 7 randomized trials with a global recruitment pattern, 5,451 participants with angiographic coronary disease underwent serial coronary intravascular ultrasonography during 18 or 24 months, with adjudicated MACE. Change in coronary percent atheroma volume (ΔPAV) and MACE in the United States versus other world regions were assessed. Despite similar baseline angiographic and plaque characteristics across participants and regions, following propensity-weighted and multivariate analysis, US (n = 3,706) versus non-US (n = 1,745) participants demonstrated marginal but significantly greater annualized ΔPAV (least-square means ± SE: 0.27 ± 0.14% vs 0.062 ± 0.14%, p = 0.005). However, MACE rates were disproportionately higher in US compared to non-US participants (23.5% vs 10.9%, p <0.001), driven by a doubling in crude rates of coronary revascularization procedures (16.1% vs 7.8%, p <0.001). The US participants hospitalized with unstable angina demonstrated more significant disease progression than their non-US counterparts (ΔPAV: 0.57 ± 0.19% vs −0.30 ± 0.36%, p = 0.033) and greater MACE (9.1% vs 4.8%, p <0.001). A US geographic disposition independently associated with MACE (hazard ratio 1.53, 95% confidence interval 1.22 to 1.92, p <0.001). In conclusion, in participants with stable coronary disease, coronary atheroma progression rates are modestly higher in US-based compared to non-US–based participants. Elective coronary revascularization rates however are disproportionately greater in US-based participants.
In a quest to optimize the generalizability of clinical trial data and to enroll sufficiently large numbers of participants in a timely fashion, randomized clinical trials are increasingly recruiting participants on a global scale. Although controversy exists regarding the interpretation of geographic variations in treatment effect, the potential impact of geographic disposition on the natural history of coronary atheroma remains unexplored. Furthermore, a systematic appraisal of regional differences in the serial progression of coronary atheroma and its potential impact on subsequent clinical outcomes and treatment strategy has yet to be evaluated on a global scale. Our primary aim was to compare serial plaque progression and major adverse cardiovascular event (MACE; cardiovascular death, nonfatal myocardial infarction, coronary revascularization) rates in the United States compared to certain other non-US world regions. We thus undertook a patient-level pooled analysis of clinical trials, with global recruitment patterns, using serial coronary intravascular ultrasound (IVUS). Given the reportedly higher elective coronary revascularization rates in the United States compared to other regions, we tested the hypothesis that serial coronary atheroma progression rates are significantly greater in the United States compared to non-US participants and that such differences may be linked with possible MACE rates.
Methods
The present analysis included raw patient data participating in 7 prospective randomized controlled clinical trials that assessed the impact of medical therapies on serial changes in coronary atheroma volume using IVUS, which also prospectively collected adjudicated MACE (defined as cardiovascular death, nonfatal myocardial infarction, or coronary revascularization). Institutional review board approval was obtained at all worldwide participating centers for trial conduct. 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 (NORMALISE [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]), peroxisome proliferator-activated receptor-gamma agonism (PERISCOPE [Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation]), and endocannabinoid receptor antagonism (STRADIVARIUS [Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabont–The Intravascular Ultrasound Study]). Each of these studies enrolled participants with coronary artery disease, defined as the presence of at least 1 luminal narrowing of >20% diameter severity in an epicardial coronary artery during clinically indicated coronary angiography. 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 as clinical events were not collected.
The acquisition and serial analysis of IVUS images in each of these trials have 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 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. Participants 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 part 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 primary efficacy measure in each of these trials was the change in percent atheroma volume (PAV) from baseline. PAV was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest as follows:
P A V = ∑ ( E E M a r e a − L u m e n a r e a ) ∑ E E M a r e a × 100
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