Methods

Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM) is an international, multicenter, observational registry of 27,125 consecutive patients who underwent ≥64–detector row CCTA for suspected CAD at 12 centers from 2003 to 2009. The study design has been previously described. Each center obtained approval from an ethics or institutional review board. Of 27,125 adult patients, we excluded 2,350 with known CAD (previous MI and/or coronary revascularization) and 7,453 patients for whom FH information was lacking. Among the remaining 17,322 patients, 6,308 young patients (men aged <55 years and women aged <65 years) met the inclusion criteria for the study, with cut points for young patients chosen on the basis of age strata from the National Cholesterol Education Program Adult Treatment Panel and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. A “very young” group of 2,934 patients (men aged <45 years and women aged <55 years) was examined in secondary analyses.

Before CCTA, we prospectively collected information on the presence of CAD risk factors. Hypertension was defined as a history of high blood pressure or treatment with antihypertensive medications. Diabetes mellitus was defined by previously made diagnosis and/or the use of insulin or hypoglycemic agents. Dyslipidemia was defined as known but untreated dyslipidemia or current treatment with lipid-lowering medications. Smoking history was defined as current smoking or cessation <3 months before testing. Positive FH was defined as MI, cardiac death, or need for coronary revascularization in a first-degree relative with early onset. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Angina typicality was diagnosed by the interviewing physician at the time of CCTA.

CCTA was performed using a single-source 64-slice scanner or a dual-source scanner. Timing bolus or automated bolus tracking at the proximal ascending aorta was used to determine the time from contrast injection to optimal coronary artery enhancement. Contrast (80 to 140 ml, depending on site) was injected at 5 to 6 ml/s, and whole-volume image acquisition was completed in a single breath-hold. In selected patients, noncontrast computed tomography was also performed to quantify coronary calcium score, according to the method of Agatston et al. Acquired image data were initially reconstructed in mid-diastole (always) and end-systole (when available). Reconstructed data were evaluated by ≥1 highly experienced reader (level III equivalent and/or board certified in CCTA) using all necessary postprocessing techniques to determine the presence of CAD in any visible segment ≥2 mm in diameter.

Coronary computed tomographic angiographic interpretation was performed in an intent-to-diagnose fashion, with any uninterpretable segment scored as having the same stenosis severity as the most adjacent proximal evaluable segment, in accordance with previous multicenter studies. A 16-segment American Heart Association coronary artery tree model was used. Coronary lesions were quantified for luminal diameter stenosis by visual estimation and graded as none (0% luminal stenosis), mild (1% to 49%), moderate (50% to 69%), or severe (≥70%). Plaque composition in each coronary segment was classified as calcified, noncalcified, or partially calcified, as we have previously described. Plaque severity was scored at per patient, per vessel, and per segment levels. Any CAD was defined as any plaque, irrespective of grade of stenosis. On a per patient basis, obstructive CAD was defined at the ≥50% stenosis threshold, with nonobstructive CAD defined as by a 0% to 49% maximal stenosis. Per vessel CAD was defined by ≥50% stenosis in 0, 1, 2, or 3 coronary artery vessels. Per segment analysis was graded for individual coronary artery segments. The numbers of segments with calcified, noncalcified, and partially calcified plaque were calculated. The ratios of the number of segments with plaque were calculated as the number of segments with a specific plaque type divided by 16 and multiplied by 100. A segment involvement score (SIS) was calculated as the total number of segments with plaque, irrespective of the grade of luminal stenosis within each segment (minimum 0, maximum 16). A segment stenosis score (SSS), measuring overall plaque extent, was graded as follows: each individual segment was graded as having no to severe plaque (i.e., scores from 0 to 3). Then, the extent scores of all 16 segments were summed to yield a total score ranging from 0 to 48. The primary clinical end points were time to nonfatal MI and all-cause death. MI was adjudicated at each site and was defined in accordance with the World Health Organization’s universal definition of myocardial infarction. Death status for centers outside the United States was collected by clinical visits, telephone contacts, and questionnaires sent by mail, with verification of all reported events by hospital records or direct contact with a patient’s attending physician. Death status for United States centers was ascertained either by query of the Social Security Death Index or by interview by physician and/or nurse study investigators.

All statistical calculations were performed using Stata version 11 (StataCorp LP, College Station, Texas) and SAS version 9.2 (SAS Institute Inc., Cary, North Carolina) for Windows. Categorical variables are presented as frequencies and continuous variables as mean ± SD. Variables were compared using chi-square statistics for categorical variables and Student’s unpaired t tests for continuous variables. Comparisons of body mass index, coronary calcium score, SIS, SSS, and the number and ratio of segments with plaque were performed using Kruskal-Wallis nonparametric tests. Coronary calcium score in the overall population was compared after logarithmic transformation to adjust for its non-normal distribution. Stepwise multivariate logistic regression analysis including age, gender, and coronary risk factors was performed to determine the association between these variables and the presence of obstructive CAD; these relations were expressed as odds ratios and 95% confidence intervals. A p value <0.05 was considered significant. Times to MI and death were calculated using Cox proportional-hazards models. In each case, the proportional-hazards assumption was met. Adjusted models were also devised including multivariate stepwise models adjusting for baseline demographics and cardiac risk factors. A hazard ratio and 95% confidence interval were calculated from the Cox models. A 2-tailed p value <0.05 was considered statistically significant.