Measurement of CIMT in trials
Algorithms to measure carotid intima–media thickness in trials: a comparison of reproducibility, rate of progression and treatment effect
Soner Dogan, Yvonne Plantinga, John R. Crouse III, Gregory W. Evans, Joel S. Raichlen, Daniel H. O’Leary, Mike K. Palmer, Diederick E. Grobbee, Michiel L. Bots, on behalf of the METEOR Study Group
Journal of Hypertension 2011,29 [Epub ahead of print]
Current ultrasound protocols to measure carotid intima–media thickness (CIMT) in trials differ considerably. The best CIMT protocol would be one that combines high reproducibility, a large and precise estimate of the rate of CIMT progression and a large and precise estimate of the treatment effect. We performed a post-hoc analysis to determine the best algorithm for determining CIMT using data from the METEOR study, a randomized double-blind, placebo-controlled study of the effect of rosuvastatin on CIMT progression in 984 low coronary heart disease risk individuals with increased CIMT.
CIMT information was collected from two walls (near and far wall), three segments (common carotid, bifurcation and internal carotid artery), five different angles (for the right carotid artery – 60, 90, 120, 150, and 180 degrees on the Meijer’s carotid arc; for the left – 300, 270, 240, 210, and 180 degrees) of two sides (left and right carotid artery), resulting in possibly (2T3T5T2U) 60 measurements. On the basis of combinations of these measurements, we built 66 different ultrasound protocols to estimate a CIMT for each individual (22 protocols for mean common CIMT, 44 protocols for mean maximum CIMT). For each protocol we assessed reproducibility [intraclass correlation (ICC), mean difference of duplicate scans], 2- year progression rate in the placebo group with its corresponding standard error and treatment effect (difference in CIMT progression between rosuvastatin and placebo) and its corresponding standard error.
Data of duplicate ultrasound examinations at baseline and end of study were available for 688 participants (70% of 984). The ICC based on duplicate baseline examinations ranged from 0.81 to 0.95. CIMT progression rates in the placebo group ranged from 0.0046 to 0.0177 mm/year, with SE ranging from 0.00134 to 0.00337. Treatment effects ranged from 0.0141 to 0.0388 mm/year. The protocols with highest reproducibility, highest CIMT progression/precision ratio and highest treatment effect/precision ratio were those measuring both near and far wall for at least two angles.
Ultrasound protocols that include CIMT measurements at multiple angles of both near and far wall give the best balance between reproducibility, rate of CIMT progression, treatment effect and their associated precision in this low-risk population with subclinical atherosclerosis.
Carotid intima–media thickness (CIMT) is a noninvasive alternative marker of atherosclerotic disease that has been used for the last 25 years with a growing number of publications every year. CIMT is widely used in observational population-based studies to study determinants of atherosclerosis and its consequences for cardiovascular events [1–28]. Change in CIMT over time is currently used as a primary outcome in intervention studies to provide guidance for anticipated outcome in cardiovascular events trials [29–31]. Although CIMT measurements have been performed for years in several studies and settings, considerable differences exist between ultrasound protocols . The most commonly used ultrasound protocols allow CIMT measurements to be taken from combinations of segments [common carotid artery (CCA); CCA and bifurcation (BIF); CCA, BIF and internal carotid artery (ICA)], walls (far wall; near and far wall) and angles (single angle or a combinations of several angles). With these measurements one can estimate at least two different outcome measures: the mean common CIMT and the mean maximum CIMT. The mean common CIMT is generally estimated as the average value of the mean CIMT measurement that is performed over a 10mm length of the far wall or both the far and near wall of the CCA segment. The mean maximum CIMT is a summary measure that is computed as the mean of the single maximum CIMT measurements that are measured in 4–12 standard carotid artery wall segments: the far wall or both the far and near walls of the two or three distinct carotid segments: CCA, BIF and ICA segment of both the left and right sides.
The aim of this study was to evaluate differences in methodological aspects between ultrasound protocols using data from the Measuring Effects on intima-media Thickness: an Evaluation Of Rosuvastatin (METEOR) study, a randomized double-blind, placebo-controlled study of the effect of rosuvastatin on CIMT progression in 984 low coronary heart disease (CHD) risk individuals with increased CIMT.
The intraclass correlation (ICC) of the CIMT measurements ranged from 0.829 to 0.945 for mean common CIMT protocols, and from 0.805 to 0.924 for the mean maximum CIMT protocols. Protocols assessing all three segments had higher ICC than two segment protocols.
CIMT progression over time
CIMT progression rate ranged from 0.0046 to 0.0177 mm/year (SE 0.00134-0.00337). The protocols with measurements of both walls for at least two angles had the highest ratios in the mean common CIMT protocols.
The effect of treatment on CIMT progression as compared to placebo ranged from -0.0138 to -0.0205 mm/year for the mean common CIMT protocols and from -0.0141 to -0.0388 mm/year for the mean maximum CIMT protocols. Corresponding treatment/precision ratios ranged from 2.18 to 5.36 and 1.75 to 6.50 for the mean common and the mean maximum CIMT protocols, respectively.
Almost all protocols showed statistically significant treatment effects of rosuvastatin on CIMT progression as compared to placebo.
Overall ranking of ultrasound protocol
Mean maximum CIMT protocols with measurements at both near and far wall for at least three angles were the protocols with the highest overall summation scores.
These findings indicate that the best balance between high reproducibility, large and precise magnitude of rate of CIMT progression over time and the largest and precise magnitude of effect of treatment is achieved with protocols in which both the near and far walls are measured at multiple angles. Mean maximum CIMT protocols overall performed slightly better than mean common CIMT protocols.
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