Ultrasound protocols to measure carotid intima-media thickness in trials; comparison of reproducibility, rate of progression, and effect of intervention in subjects with familial hypercholesterolemia and subjects with mixed dyslipidemia

Abstract

Background. Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials rather differ. The ideal protocol combines high reproducibility with a high precision in the measurement of the rate of change in CIMT over time and with a precise estimate of a treatment effect. To study these aspects, a post-hoc analysis was performed using data from two randomized double-blind, placebo-controlled trials: one among 872 subjects with familial hypercholesterolemia (FH) and the other among 752 subjects with mixed dyslipidemia (MD), respectively. Participants were randomized to torcetrapib or placebo on top of optimal atorvastatin therapy.

Methods. CIMT information was collected from the left and right carotid artery from two walls (the near and far wall) of three segments (common carotid, bifurcation, and internal carotid artery) at four different angles (right: 90, 120, 150, and 180 degrees on Meijer's carotid arc; left: 270, 240, 210, and 180 degrees, respectively). Based on combinations of these measurements, 60 different protocols were constructed to estimate a CIMT measure per participant (20 protocols for mean common CIMT, 40 protocols for mean maximum CIMT). For each protocol we assessed reproducibility (intra-class correlation coefficient (ICC), mean difference of duplicate base-line scans); 2-year progression rate in the atorvastatin group with its standard error (SE); and treatment effect (difference in rate of change in CIMT between torcetrapib and placebo) with its SE.

Results. Reproducibility: ICC ranged from 0.77 to 0.91 among FH patients and from 0.68 to 0.86 among MD patients. CIMT progression rates ranged from −0.0030 to 0.0020 mm/year in the FH trial and from 0.00084 to 0.01057 mm/year in the MD trial, with SE ranging from 0.00054 to 0.00162 and from 0.00083 to 0.00229, respectively. The difference in CIMT progression rate between treatment arms ranged from −0.00133 to 0.00400 mm/year in the FH trial and from −0.00231 to 0.00486 mm/year in the MD trial. The protocol with the highest reproducibility, highest CIMT progression/precision ratio, and the highest treatment effect/precision ratio were those measuring mean common CIMT with measurements of the near and far wall at multiple angles. When the interest is in the mean maximum CIMT, protocols using multiple segments and angles performed the best.

Conclusion. Our findings support the position that the number and specific combination of segments, angles, and walls interrogated are associated with differences in reproducibility, magnitude, and precision of progression of CIMT over time, and treatment effect. The best protocols were mean common CIMT protocols in which both the near and far walls are measured at multiple angles.

Trial registration: ClinicalTrials.gov identifier: NCT00136981.

Trial registration: ClinicalTrials.gov identifier: NCT00134264.

Key words::

• Carotid intima-media thickness
• epidemiology
• statins
• trial
• ultrasound

Acknowledgements

The authors thank Rudy Meijer in Schoorl, the Netherlands, for the design of the image-acquisition protocol, training, and quality control; and P. Barter, T. Roberts, D. Ambrose, A. Chin, W. Davidson, R. Burnside, A. Caffrey, M. Li, A. O'Reilly, Tu T. Nguyen, and T. Thuren. We thank the following staff at CIMT Laboratory Europe: C. van Everdingen, A. Geerts, M. Geurtsen, M. Djuanda, A. Kuin, F. Leus, R. Meijer, D. Mooiweer-Bogaerdt, K. Nijssen, H. Noordzij, L. Romkes, B. Sies, E. Stooker, F. Verhey, B. van der Vlist, L. van der Vlist, E. Wineke, and H. Wisse; and at the CIMT Core Laboratory United States: M. Barr, K. Bettermann, S. Burton, A. Conner-Day, B. Ettenger, J. Griffin, C. Halverson, B. Holley, L. Hoots, J. Fleshman, M. Lauffer, L. Passmore, C. Sharpe, M. Wilder, P. Miller, T. Vitek, and G. Wolgast.

Declaration of interest: Dr Dogan and Dr Duivenvoorden report no conflict of interest. Dr Kastelein reports receiving consulting fees and lecture fees from Pfizer, Astra-Zeneca, Merck, and Schering-Plough and grant support from Pfizer and Astra-Zeneca. Dr Shear was a former employee of Pfizer. Dr Grobbee reports receiving consulting fees, lecture fees, and grant support from Pfizer, Astra-Zeneca, Servier, Organon, Merck, and Unilever. Dr Evans reports receiving honoraria, consulting fees, and grant support for professional input on CIMT issues from Astra-Zeneca, Organon, and Pfizer. Dr Visseren reports receiving research grants from Merck and the Netherlands Organisation for Health Research and Development. Dr Bots reports receiving consulting fees, lecture fees, and grant support from Pfizer, Astra-Zeneca, Servier, Organon, Merck, and Unilever.

No other potential conflict of interest relevant to this article was reported.