Feasibility of gadolinium-diethylene triamine pentaacetic acid enhanced multidetector computed tomography for the evaluation of coronary artery disease

Journal of Cardiovascular Computed Tomography (2007) 1, 86 –94

Original Research Article

Feasibility of gadolinium-diethylene triamine pentaacetic acid enhanced multidetector computed tomography for the evaluation of coronary artery disease Patricia Carrascosa, MD, PhDa*, Carlos Capuñay, MDa, Marcelo Bettinotti, MDb, Alejandro Goldsmit, MDb, Alejandro Deviggiano, MDa, Jorge Carrascosa, MDa, Mario J. García, MDc a

Department of Radiology, Diagnóstico Maipú, Av. Maipú 1668 (A1602ABQ) Vicente López, Buenos Aires, Argentina; the Department of Cardiology, Sanatorio Güemes, Buenos Aires, Argentina; and the cCardiovascular Medicine Institute, Mount Sinai Hospital, New York, NY, USA b

KEYWORDS: Contrast agents; Coronary artery disease; CT angiography; gadolinium; Multidetector computed tomography

Abstract BACKGROUND: Multidetector computed tomography (MDCT) has been proposed as a noninvasive method for the diagnosis of obstructive coronary artery disease (CAD). In patients with high risk of iodinated contrast adverse effects such as acute allergic-type reactions, the use of gadolinium could be an alternative. OBJECTIVE: We sought to evaluate the feasibility of gadolinium-enhanced MDCT for the diagnosis of obstructive CAD. METHODS: Twenty patients (mean age, 61 years; range, 50 –73 years) referred for X-ray coronary angiography were studied by both gadolinium and iodine-enhanced 16-row MDCT coronary angiography. The degree of enhancement and the accuracy for detection of obstructive CAD (⬎50% diameter reduction) were evaluated with X-ray coronary angiography as the standard. Renal nephrotoxicity was strictly monitored. RESULTS: Gadolinium- and iodine-enhanced MDCT showed adequate visualization of the coronary arteries in 310 of the 312 coronary artery segments that were available by X-ray angiography, respectively. The average density of the coronary arteries in both iodine and gadolinium CT scans was 253.65 Hounsfield unit (HU) and 135.20 HU, respectively. In a per-coronary segment analysis, gadolinium- and iodine-enhanced MDCT showed sensitivities of 89% vs 84%, specificities of 96% vs 95%, and negative predictive values of 97% vs 96%, respectively. In a per-patient analysis, both gadolinium- and iodine-enhanced MDCT showed sensitivities of 92.85% vs specificities of 83.33%. Intermethod agreement between gadolinium- and iodine-enhanced MDCT (␬) was 0.95 (P ⬍ 0.0001). CONCLUSION: Our preliminary results indicate lower attenuation with gadolinium but similar diagnostic accuracy for the detection of obstructive CAD when compared with iodine-enhanced MDCT. Therefore, gadolinium is a feasible alternative contrast agent for patients with iodine contrast allergy referred for MDCT coronary angiography. © 2007 Society of Cardiovascular Computed Tomography. All rights reserved.

Conflict of interest: The authors report no conflicts of interest. * Corresponding author. E-mail address: [email protected] Submitted March 14, 2007. Accepted for publication June 24, 2007.

1934-5925/$ -see front matter © 2007 Society of Cardiovascular Computed Tomography. All rights reserved. doi:10.1016/j.jcct.2007.06.003

Carrascosa et al

Detection of CAD using gadolinium-enhanced MDCT

Introduction Computed tomographic angiography is routinely used for clinical applications in the head and neck, thorax, and abdomen.1-3 With the development of multidetector computed tomography (MDCT), the coronary anatomy may be evaluated. Several studies have shown the accuracy, in particular, the negative predictive value of MDCT for the detection of obstructive coronary artery disease (CAD).4-8 The usual intravascular radiographic contrast agent used in MDCT studies is iodine, given its high attenuation and relatively low incidence of adverse physiologic effects.9 Nonetheless, some patients are at high risk of important adverse effects such as acute allergic-type reactions10,11 or are apprehensive about the consequences of the injection of iodinated contrast agents. For this reasons an alternative contrast agent is desirable. Magnetic resonance (MR) angiography is an alternative noninvasive diagnostic method that may be applied in patients who have contraindications to iodinated contrast material. However, MR angiography of the coronary arteries is technically challenging, has limited spatial resolution, and is not widely available in the community. The potential use of gadolinium as an alternative contrast agent for MDCT studies was suggested in 1989, when the first case report was published.12 More recently, case series reports were published with gadolinium as a MDCT contrast agent for imaging the aorta and abdominal vessels.1,13-15 Evaluation of the coronary arteries using gadolinium-enhanced three-dimensional electron beam and multislice computed coronary angiography was also reported.16,17 The purpose of this study was to evaluate the feasibility of gadolinium-enhanced MDCT of the coronary arteries and its potential clinical utility for the diagnosis of CAD.

Methods Study group The protocol for this prospective study was approved by the institutional review boards of Diagnóstico Maipú and Sanatorio Güemes, and all the patients signed an informed consent. Study patients were consecutively enrolled from a population of patients referred for X-ray coronary angiography for evaluation of suspected CAD. Twenty patients [19 men; mean age, 61 years; range, 50 –73 years; body mass index (calculated as weight divided by height squared; kg/ m2), 27.05; range, 21.32–36.73] underwent gadolinium-enhanced MDCT followed by the iodine-enhanced MDCT angiography of the coronary arteries on the same day. The mean time between MDCT and X-ray angiography was 4.5 days (range, 2–7 days). All patients were in regular sinus

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rhythm and had normal renal function. The mean baseline serum creatinine in the study patients was 1.02 mg/mL (⫾0.23 mg/dL).

MDCT protocols Patients were placed on the MDCT table in the supine position. A 20-gauge intravenous catheter was then placed in an antecubital vein in all patients, and the heart rate was determined. ␤-Blockers were administrated to patients with a heart rate ⬎ 65 beats/min. Bolus application of intravascular propranolol (Oposim Richet; Laboratorios Richet S.A., Buenos Aires, Argentina) at 5-mg aliquots up to a total of 15 mg was used to achieve a heart rate ⬍65 beats/min. With the use of a 16-row MDCT scanner (Brilliance 16; Philips Medical Systems, Highland Heights, OH) a volume data set was acquired that covered the total coronary tree. To ensure optimum contrast enhancement of the coronary arteries, both scans were performed with automatic bolus triggering. To be certain that the opacification of the coronary arteries was only due to the gadolinium enhancement and also to avoid that residual iodine contrast increased the coronary opacity and had influenced the final image analysis and interpretation, the gadolinium-enhanced MSCT acquisition was performed first. The patients remained on the table and after a short interval (range, 15–20 minutes), the iodine-enhanced MDCT study was performed. Gadolinium MDCT The limited maximum volume of gadolinium that could be administered required modifications in the scanning limits to reduce the z-axis length and scan duration. A lower tube voltage was applied, to improve the gadolinium-enhanced image quality.18 We used a collimation of 16 ⫻ 0.75 mm, gantry rotation time of 420 msec, tube voltage of 120 kV, 360 mAs, and modulated tube current according to the electrocardiogram (ECG), with a maximum current of 360 mA centered at 75% of the cardiac cycle (mid diastole), pitch of 0.29, table speed of 8.3 mm/sec, mean scan length of 106.5 mm, and mean scan time of 14.75 sec. A maximum dose of ⱕ0.4 mmoL gadolinium/kg of body weight (gadopentetate dimeglumine; Magnevist; Schering AG, Berlin, Germany) was injected at a rate of 5 mL/sec. The maximum dose used was 56 mL (range, 48 –56 mL; mean, 52.05 mL). Scanning was triggered once the contrast material reached a density of ⱖ70 Hounsfield units (HU) at the left atrium. The estimated total radiation exposure for this protocol was 3.98 mSv. Iodine MDCT For this protocol we used a collimation of 16 ⫻ 0.75 mm, gantry rotation time of 420 msec, tube voltage of 140 kV, 560 mAs, and modulated tube current according to the ECG, with a maximum current of 560 mA centered at 75% of the cardiac

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cycle (mid diastole), pitch of 0.20; table speed of 5.7 mm/sec, mean scan length of 112.4 mm, and mean scan time of 22.4 sec. The MDCT scan was performed after the intravenous administration of 100 mL contrast material containing 350 mg iodine/mL (meglumine ioxitalamate; Telebrix C; Temis-Lostalo Laboratories, Buenos Aires, Argentina) with the use of a power injector. The first 60 mL were injected at a rate of 4 mL/sec and the last 40 mL at a rate of 2.5 mL/sec. Scanning was triggered once the contrast material reached a density of ⱖ150 HU at the aortic root. The estimated total radiation exposure for this protocol was 6.2 mSv. For both the iodinated and the gadolinium-enhanced MDCT coronary angiographies, cross-sectional images were reconstructed with a slice thickness of 1.0 mm in 0.5-mm intervals with the use of an ECG-gated reconstruction algorithm centered at 0%, 50%, 75%, and 95% phases of the cardiac cycle.

MDCT image analysis Attenuation measurements were obtained at the level of the aortic sinuses in the 75% phase, using a 40-mm2 circular region of interest. The axial images, multiplanar reconstructions, volume-rendered reconstructions, and maximum intensity projection images of the coronary tree from both the iodine-enhanced MDCT and the gadolinium-enhanced MDCT were reviewed by independent blinded investigators. The degree of contrast enhancement and the classification of segmental stenosis were compared between both studies, based on a 16-segment model of the coronary arterial tree.18 Coronary artery stenosis with a diameter reduction of ⱖ50% were considered as positive findings.

X-ray coronary angiography X-ray coronary angiograms were performed and stored in digital format. Vascular access was obtained through the femoral approach with the Seldinger technique and a 6-French or 7-French catheter. Coronary angiograms were analyzed quantitatively with the use of manually positioned electronic calipers by an interventional cardiologist who was blinded to the MDCT results. Invasive coronary angiography results were considered as the standard for data analysis.

Evaluation of tolerance to renal contrast agents To evaluate renal function, the primary variable was the change in serum creatinine level 48 hours after MDCT angiography. Contrast material-induced nephrotoxicity was defined as an increase in the serum creatinine concentration by at least 0.5 mg/dL 48 hours after administration of the contrast agents.

Statistical analysis All analyses were performed with commercially available software (StatsDirect, Version 2.3.8; Cheshire,

United Kingdom). Continuous variables are presented as mean ⫾ SD. Sensitivity, specificity, diagnostic accuracy, positive predictive value, and negative predictive value were calculated per segment, after censoring ⬎50% luminal stenosis by X-ray angiography as positive results. The intermethod agreement among X-ray angiography, gadolinium-enhanced, and iodine-enhanced MDCT studies was calculated with the use of ␬ statistics. For all statistical comparisons, a level of P ⬍ 0.05 was considered significant.

Results All gadolinium- and iodine-enhanced MDCT studies were successfully completed. No severe adverse events or complications, including delayed reactions to contrast agents occurred in the study group during the procedure. Only 2 patients experienced contrast negligible nephrotoxicity, with increase in the serum creatinine concentration of 0.5 mg/dL and 0.6 mg/dL, respectively, 48 hours after the administration of the contrast agents. Mean 48-hour serum creatinine in the study patients was ⬍1.11 mg/dL (⫾0.32 mg/dL). From the 20 patients, 6 patients did not show evidence of CAD, 2 patients had 1-vessel stenosis, 3 patients had 2-vessel stenosis, 8 patients had 3-vessel stenosis, and 1 patient had significant stenosis of the left main coronary artery. The patient’s mean basal heart rate before the scans was ⬍65 beats/min. The mean heart rate before gadolinium-enhanced CT scan was 56 ⫾ 4 beats/min, and the mean heart rate before iodine-enhanced CT scan was 58 ⫾ 5 beats/min. Axial and multiplanar reconstruction images showed adequate visualization of the coronary arteries in all cases (Figs. 1–3). Intraluminal contrast enhancement was lower on gadolinium-enhanced MDCT images than those obtained with iodine contrast. The mean peak attenuation during iodine-enhanced MDCT was 253.65 HU (range, 180-344 HU), whereas during gadolinium-enhanced MDCT it was 135.20 HU (range, 85–179 HU; P ⬍ 0.001; Fig. 4). The standard deviations of contrast enhancement in individual patients were similar in the gadolinium (13–53 HU) than in the iodine (12– 43 HU) scans, indicating that noise was similar in both types of scan. In the 20 patients evaluated, 310 (99%) of 312 coronary artery segments were assessable by gadolinium-enhanced MDCT and by iodine-enhanced MDCT. The remaining segments were nonevaluable because of cardiac motion; these nonevaluable segments were corresponding in both scans. For the statistical analysis, nonassessable segments were considered as false-negative findings. Per-segment and per-patient diagnostic performance characteristics of gadolinium- and iodine-enhanced MDCT are summarized in Tables 1 and 2. The ␬ values of intermethod agreement for the diagnosis or exclusion of stenosis ⬎ 50% were 0.84 [95% confidence interval (CI): 0.72, 0.95; P ⬍ 0.0001]

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Figure 1 (A) Gadolinium-enhanced volume-rendered, (B) iodine-enhanced volume-rendered, and (C) angiographic images from a 62-year-old man showing 2 mild stenoses in the middle (white arrow) and distal (black arrow) portion of the left anterior descending. The distal stenosis was best depicted on the gadolinium-enhanced images.

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Figure 2 (A) Gadolinium-enhanced axial and curved multiplanar reformatted images, (B) iodine-enhanced axial and curved multiplanar reformatted images, and (C) angiographic image from a 54-year-old man showing a severe stenosis in the proximal segment of the left anterior descending artery (arrow).

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Figure 3 (A) Gadolinium-enhanced volume-rendered and iodine-enhanced volume-rendered, and (B) angiographic images from a 58-year-old man show normal right coronary artery.

between iodine-enhanced MDCT and X-ray angiography; 0.87 (95% CI: 0.76, 0.98; P ⬍ 0.0001] between gadoliniumenhanced MDCT and X-ray angiography; and 0.95 (95% CI: 0.83, 1.06; P ⬍ 0.0001) between iodine-enhanced and gadolinium-enhanced MDCTs. Analysis of iodine-enhanced MDCT contrast of soft, intermediate, and calcified plaques were 66.5 ⫾ 30.3 HU, 109.2 ⫾ 33.8 HU, and 385.3 ⫾ 174.7 HU, respectively (P ⬍ 0.001), whereas the analysis of gadolinium-enhanced MDCT contrast of soft, intermediate, and calcified plaques were 36.5 ⫾ 19.2 HU, 69.2 ⫾ 22.6 HU, and 332.5 ⫾ 162.4 HU, respectively (P ⬍ 0.001) (Fig. 5).

Discussion Gadolinium is widely used as a contrast agent in MR imaging and it has also been successfully used as an alternative contrast agent for digital subtraction angiography.19,20 Its use as an alternative MDCT vascular contrast agent was previously proposed.9,12-15 The use of gadolinium as a contrast agent to evaluate the coronary arteries was recently proposed by Gul et al17 who evaluated the image quality of gadolinium-based contrast agents during MDCT coronary angiography, showing an adequate enhancement of the coronary vasculature. To

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Figure 4 Comparison of attenuation of gadolinium and iodine measured at the aortic root in the study patients. Data are presented as mean ⫾ standard deviation.

date, no report about the diagnostic accuracy of gadolinium-enhanced MDCT of the coronary arteries has been published. It is well established that gadolinium has higher X-ray attenuation than does iodine at equimolar concentrations.21 However, available gadolinium agents have a concentration of only 0.5 mol/L and the greatest achievable intraluminal molar concentration is only one-fifth of that obtainable with iodinated agents. Thus, even when using equal doses of gadolinium and iodine, the attenuation of gadolinium would be 4-fold lower.17 The maximum dose of gadolinium up to which safety has been established is 0.4 mmol/kg. A review of records of patients undergoing MR imaging who had also received iodinated contrast media showed that contrast nephropathy occurred in 11 of 64 patients after administration of iodinated contrast media but in no patients after highdose gadolinium.22 However, the risk of nephropathy with gadolinium is higher at higher doses. At high intraarterial doses of gadolinium chelates (80 – 440 mL, equivalent to 0.5–2.9 mmol/kg), nephropathy [increase of ⱖ0.6 mg/dL (53.0 ␮mol/L) in serum creatinine] devel-

oped in 8 (40%) of 20 patients.23 The 2006 warning by the Food and Drug Administration strongly emphasizes the precaution of high-dose applications of gadolinium in patients with chronic renal failure, and in view of the circumstances it would be wise to use less contrast agent to create the better enhancement effect.24 Therefore, a lower volume of gadolinium needs to be injected, compared with iodine. As a result, lower intraluminal attenuation is attained. The lower attenuation may increase scan noise but also facilitates the differentiation between the lumen and calcified plaques. Another limitation of gadolinium is its higher cost. Despite these limitations, the results of this study show that diagnostic-quality gadolinium-enhanced MDCT is possible. Both the rate of contrast agent injection and the delay time to imaging are important considerations. In our protocol, 0.4 mmol gadolinium/kg of body weight was injected at a rate of 5 mL/sec. The duration of the gadolinium bolus was thus only 10 sec, and timing was essential for the shorter injection bolus of gadolinium. With the use of automatic timing software, the scanning was triggered once the contrast material reached a density of ⱖ70 HU at the left

Table 1 Diagnostic accuracy of iodine-enhanced and gadolinium-enhanced multidetector computed tomography for the detection of ⬎50% coronary luminal diameter reduction (per segment-based analysis) Method

TP (m)

TN (m)

FP (m)

FN (m)

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Diagnostic accuracy (%)

Gadolinium Iodine

56 54

239 237

10 11

7 10

89 84

96 95

85 83

97 96

94 93

FN ⫽ false-negative findings; FP ⫽ false-positive findings; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; TN ⫽ true negative findings; TP ⫽ true positive findings.

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Table 2 Diagnostic accuracy of iodine-enhanced and gadolinium-enhanced multidetector computed tomography for the detection of ⬎50% coronary luminal diameter reduction (per patient analysis) Method

TP (m)

TN (m)

FP (m)

FN (m)

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Gadolinium Iodine

13 13

5 5

1 1

1 1

92.85 92.85

83.33 83.33

92.85 92.85

83.33 83.33

FN ⫽ false-negative findings; FP ⫽ false-positive findings; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; TN ⫽ true negative findings; TP ⫽ true positive findings.

atrium, and scan pitch was increased, assuring that the region of interest was adequately scanned during the peak enhancement of the gadolinium bolus in all cases. With this scanning protocol, the level of enhancement and image quality produced appear potentially adequate to exclude significant CAD. Performing the gadolinium-enhanced CT coronary angiography first assured us that the opacification of the coronary arteries was only due to the gadolinium enhancement and also prevented that residual iodine contrast increased the coronary opacification. The time between first and second CT scans (15–20 minutes) was sufficient enough to avoid coronary contaminant opacification or myocardial contrast enhancement resulting from gadolinium in the iodine-contrast acquisition. The low intraluminal attenuation appeared to improve the identification of calcified plaques, because of a better contrast between the plaque and the intraluminal enhancement. The improvement in temporal and spatial resolution available with current 64-row MDCT equipment allows shorter scan times and better image quality, without the need to perform changes in the protocols of iodine CT coronary angiography scans. The use of double-power injectors is also a main factor to increase intraarterial coronary opacification. On the basis of these premises, we have every

Figure 5 plaques.

expectation of 64-row gadolinium-enhanced MDCT coronary angiography.

Conclusion The results of our study indicate that gadolinium-enhanced MDCT is a promising technique that may be useful in an important subset of patients that have absolute or relative contraindications to iodinated contrast agents (iodine-based allergies, severe hyperthyroidism). The short scan time available with 64-row MDCT equipment should facilitate further improvement in image quality with the same scan protocols as the iodine scan. Nevertheless, further studies, in particular with 64-row CT technology, are needed to evaluate safety and diagnostic accuracy in selected populations with contraindications to iodine contrast media.

Acknowledgment We thank Dr. Graciela Fernández Alonso for her assistance in editing this manuscript.

CT analysis of (A) gadolinium-enhanced and (B) iodine-enhanced cross-section CT images, showing soft and calcified coronary

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