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.
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.


CONCLUSIONS
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.
Dogan
Soner
S
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Duivenvoorden
Raphaël
R
Grobbee
Diederick E
DE
Kastelein
John J P
JJ
Shear
Charles L
CL
Evans
Greg W
GW
Visseren
Frank L
FL
Bots
Michiel L
ML
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069059:Atorvastatin; D002343:Carotid Artery, Internal / Q000000981:diagnostic imaging* / Q000187:drug effects; D018450:Disease Progression; D050171:Dyslipidemias / Q000000981:diagnostic imaging* / Q000188:drug therapy; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000000981:diagnostic imaging* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D017539:Tunica Intima / Q000000981:diagnostic imaging* / Q000187:drug effects; D014463:Ultrasonography
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin