Prediction of Carotid Intraplaque Hemorrhage Using Adventitial Calcification and Plaque Thickness on CTA

Clinical Study Design

Institutional review board approval was obtained for this retrospective cohort study from 2009 to 2016 in patients who underwent both CTA and MRA work-up of carotid disease at the University Medical Center and VA Medical Center in Salt Lake City, Utah. Due to the retrospective nature, informed consent was not required by the institutional review board. The only inclusion criteria were MRA and CTA performed within 1 month in the same patient within the study timeframe. Ninety-six patients qualified for the study, with 192 carotid arteries. Exclusions included carotid occlusions (n = 4) and near occlusions (n = 0) because lumen markers are difficult or impossible to determine in these cases. No vessels underwent carotid surgery or stent placement between scans. One hundred eighty-eight carotid arteries were left in the final analysis. Although a few scans exhibited mild motion artifacts primarily from swallowing, no carotid images were sufficiently limited to be excluded from interpretation.

MR Imaging Protocol

Images were obtained on 1.5 and 3T MR imaging scanners (Trio, Verio, and Prisma; Siemens, Erlangen, Germany) with standard or custom carotid coils.²⁰ Our standard clinical MRA protocol includes axial TOF, axial MPRAGE, coronal precontrast, postcontrast arterial, and venous phase T1-weighted images. Coronal postcontrast MRA neck images extended from the aortic arch through the circle of Willis.

IPH Determination by MPRAGE

Our prior research has shown that MPRAGE images have high intra- and interobserver agreement at both field strengths, with or without specialized coils, and that the MPRAGE-positive area highly correlates with the IPH area on histology.⁶ MPRAGE parameters included the following: 3D, TR/TE/TI = 6.39/2.37/370 ms, flip angle = 15°, FOV = 130 × 130 × 48 mm³, matrix = 256 × 256 × 48, voxel = 0.5 × 0.5 × 1.0 mm³, fat saturation, acquisition time ∼ 5 minutes. Images were obtained from 20 mm below to 20 mm above the carotid bifurcation at a 1.0-mm section thickness.²¹ To produce 3D images, we used a secondary phase-encoding gradient in the section-select direction, and measurements for all section-selection phase encodings were performed with rapid acquisition in each segment. Carotid IPH was determined by MPRAGE-positive plaque with at least 1 voxel demonstrating at least 2-fold higher signal intensity relative to adjacent sternocleidomastoid muscle as previously described.⁶

CTA Protocol

CTA was performed with a 64-section scanner (Definition or Definition AS; Siemens), with dose modulation and 100–120 kV(peak). Images were obtained from the aortic arch through the skull vertex at a thickness of 0.625 mm. Intravenous access was through an antecubital vein by using an 18- or 20-ga angiocatheter. A total of 100 mL of iopamidol (Isovue 370; Bracco, Princeton, New Jersey) was injected at 4 mL/s. Bolus monitoring used an ROI in the ascending aorta and a trigger at 100 HU. Injections were performed with a 10-second delay. Multiplanar reformats were created, and images were reviewed on a PACS workstation on CTA settings (window 96, level 150 HU) and were modified as required to depict CTA lumen markers and calcification.

Imaging Reviewers

All carotid imaging markers were determined by consensus of 2 reviewers blinded to stroke status and clinical covariates. In cases of disagreement, consensus was obtained with a third reviewer. CTA lumen and calcification markers were determined separately, and reviewers were blinded to MR imaging IPH status. All reviewers had experience with neurovascular imaging interpretation and included a radiology resident in training (L.B.E.), neuroradiology fellow (B.W.A.), and board-certified neuroradiology attending physician (J.S.M.). κ analysis was performed to determine the rim sign interrater reliability (0.85) and intrarater reliability (0.86). CTA calcification examples are shown in Figs 1 and 2.

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Fig 1.

Positive rim sign and carotid IPH. Top: Carotid CTA with positive rim signs (arrows) in both carotid plaques. Bottom: MPRAGE with bilateral carotid IPH (arrows) in the same patient. IPH was defined by MPRAGE-positive plaque, using a signal threshold of 2-fold signal intensity over the adjacent sternocleidomastoid muscle.

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Fig 2.

CTA calcification. Left: Positive rim sign (arrow), adventitial calcification measuring <2 mm in thickness with adjacent soft plaque measuring ≥2 mm in thickness. Middle: Adventitial calcification without a rim sign (arrow), adventitial calcification measuring <2 mm in thickness with <2 mm adjacent soft plaque. Right: Bulky calcification (arrow), calcified plaque of ≥2 mm.

CTA Markers

CTA markers included the time between MR imaging and CTA, presence of calcification, adventitial calcification pattern, percentage diameter stenosis, millimeter stenosis, maximum total plaque thickness, maximum soft-plaque thickness, maximum hard-plaque thickness, ulceration, and intraluminal thrombus. All measurements were obtained by using the submillimeter tool on a PACS workstation.

Time between CTA and MR Imaging

The time between scans was recorded in days and was used as a potential confounder for the association between CTA markers and MR imaging–detected IPH.

CTA Calcification Markers

Carotid arteries with thin adventitial calcification of <2 mm were subdivided into 2 groups: A positive rim sign was defined as adventitial calcification (<2-mm thick) with internal soft plaque (≥2-mm thickness), and a negative rim sign was defined as adventitial calcification (<2-mm thick) with minimal if any internal soft plaque (<2-mm thickness). “Bulky calcification” was defined as calcification measuring ≥2-mm thick without associated thin adventitial calcification measuring <2-mm thick.

CTA Lumen Markers

Percentage diameter stenosis was determined by using NASCET criteria on contrast CTA. Briefly, the diameter (b) at the level of maximal stenosis and diameter (a) of the ICA distal to the stenosis were used to calculate percentage diameter stenosis by using the formula [(a − b) / a]× 100%. Carotid stenosis was measured at the narrowest segment of the carotid plaque (b) on axial images, perpendicular to the long axis of the vessel on multiplanar reformats by using a submillimeter measurement tool on a PACS workstation. The distal ICA diameter (a) was measured beyond the bulb where the walls are parallel and no longer tapering per NASCET criteria.^22⇓–24 We performed the multivariable regression analysis by using both the NASCET measurement of percentage diameter stenosis [(a − b) / a] × 100% and the previously described millimeter stenosis (b) measurement.²⁵ Near occlusions were excluded from percentage stenosis calculation and were identified by the following CTA criteria: visible bulb stenosis, distal ICA diameter of ≤3 mm, and distal ICA/distal external carotid artery ratio of ≤1.25 originally adapted from standard conventional angiography.^24,25 The presence of ulceration was determined on CTA images by using a size threshold of 2 mm reported in prior studies.⁹ Intraluminal thrombus was defined by an intraluminal filling defect on CTA as previously described.²⁶ Maximum plaque thickness was measured in the transverse plane on CTA. These CTA lumen markers are shown in the On-line Fig 1. In addition, maximum soft-plaque and hard-plaque thicknesses were measured on CTA, as previously described.²⁷

Clinical Demographics

Clinical demographics were determined by retrospective chart review. Carotid atherosclerosis risk factors of age, male sex, diabetes, hypertension, hyperlipidemia, body mass index, and smoking status were identified. These were determined by retrospective chart review, with standard clinical definitions. For hypertension, the diagnosis was made when the average of ≥2 diastolic blood pressure measurements on at least 2 subsequent visits was ≥90 mm Hg or when the average of multiple systolic blood pressure readings on ≥2 subsequent visits was ≥140 mm Hg. For hyperlipidemia, the diagnosis was made when low-density lipoprotein was >100 mg/dL. Cardiovascular medications were recorded, including antiplatelets, anticoagulants, statins, and antihypertensives.

Statistical Analysis

Intrarater (test-retest) reliability for the presence of the rim sign was assessed for 1 reviewer (J.S.M.), and interrater reliability for the presence of the rim sign was assessed for 2 reviewers (J.S.M. and L.B.E.), both with a κ coefficient. Statistical modeling was performed by using generalized estimating equations to account for data clustering, with up to 2 carotid arteries per patient. Carotid arteries were treated as separate units or units of analysis grouped within each subject because IPH may be associated with local markers of carotid plaque vulnerability (plaque calcification pattern, thickness, stenosis, and other lumen markers). At the patient level, systemic clinical factors affecting both carotid arteries (age, male sex, and other cardiovascular risk factors and medications) were considered in the model as potential confounding variables. Given that >1 marker for IPH was being studied, potential confounding was investigated on the outcome variable or groups positive and negative for IPH, so only 1 data table was required, with P values from univariable generalized estimating equation Poisson regression models. The Poisson regression approach directly estimates the risk ratio, or prevalence ratio in our case, which is more intuitive to interpret than an odds ratio from a logistic regression approach.²⁸ Next, all potential confounding variables with P < .10 from a univariable model were placed in an initial multivariable generalized estimating equation Poisson regression model for IPH and then were eliminated in a backward fashion until all remaining variables met the threshold P < .10. Liberal significance criteria, P < .10, were used to protect against residual confounding.²⁹

For hypothesis testing of which markers are predictive of IPH, we used the traditional P < .05. In binary outcome models, 5 outcome events for every predictor variable are sufficient to avoid overfitting.³⁰ With 44 carotid IPH events and 144 non-IPH events, 44/5 = 8.8, or up to 8 predictor variables could be included in the model without overfitting, exceeding the number of variables remaining in the final model. To assess the discriminatory potential of each marker or combination of markers, we reported clustered data area under the receiver operating characteristic (ROC) curve (AUC), with bootstrapped 95% confidence intervals.³¹ Similarly, AUCs were compared by using the clustered method of Pepe et al.³¹ To guard against overfitting and optimism of the AUCs, in which an AUC could be higher in the present sample of patients than it would in future patients, we performed a bootstrap validation for each clustered data AUC calculation on the fixed list of predictors in the model.³² Given that in all cases the optimism was <1%, so that the original AUCs and bootstrapped validated AUCs were identical to the precision reported, there was no need to report both. All statistical analyses were performed with STATA 13.1 statistical software (StataCorp, College Station, Texas).