1. Letter to the Editor
Comparison of contrast enhancement, image quality and tolerability in
Coronary CT angiography using 4 contrast agents: A prospective
randomized trial☆
Lily Honoris, Yan Zhong, Edwin Chu, David Rosenthal, Dong Li, Franklin Lam, Matthew J. Budoff ⁎
1124W Carson St, Torrance, CA 90502, United States
a r t i c l e i n f o
Article history:
Received 21 February 2015
Accepted 17 March 2015
Available online 19 March 2015
Keywords:
Contrast
Iodine
Cardiac CT
Coronary CT angiography
Cardiac CT angiography (CCTA) is a robust method for detecting ob-
structive CAD, with high sensitivity and specificity. Accuracy in analyz-
ing coronary stenosis is reliant on quality of CCTA images and is
largely heart rate dependent [1,2]. Several studies have suggested that
low-osmolality contrasts affect heart rate variability, through hyper-
emia due to their interaction with endothelial cells and injection pain
[3,4]. Iso-osmolality contrasts may not cause dilution which can de-
grade and affect intravascular enhancement. The beneficial effects of
non-ionic contrast agents on image quality and resolution of CCTA and
patient satisfaction are not well studied. We hypothesized that while
image brightness varies by iodine content, both low-osmolality and
iso-osmolality contrasts will yield high image quality and good safety
profile. We undertook a prospective randomized trial to compare
image quality, safety and patient tolerability between four contrasts
with varying iodine contents: low-osmolal iohexol (350 mg I/mL) and
iopamidol (370 I/mL) with two concentrations of iso-osmolal iodixanol
(270 I/mL and 320 I/mL) during cardiac CT angiography.
513 sequential subjects undergoing outpatient CCTA for evaluation
of CAD in a single CT scanning center were enrolled into the study
(mean age 57 ± 11 years). Patients randomly received one of 4 different
contrast agents: iodixanol 270, iodixanol 320, iohexol 350 or iopamidol
370. The CT readers (Level 3 cardiologists) were blinded to the contrast
administration used. Inclusion criteria: N18 years old, undergoing
contrast-enhanced CCTA examination, and provided written informed
consent. Exclusion criteria: renal insufficiency (GFR b 50), known con-
trast allergy, pregnancy or prior revascularization. A 64-detector
MDCT (Lightspeed VCT, GE healthcare, Milwaukee, USA) was used for
image acquisition and scanning protocols followed the prior studies'
protocols [5,6]. A research assistant collected a survey quantifying side
effects of different contrasts: flushing, headache, nausea, and pain at in-
jection site as mild, moderate or severe. Readers, blinded to the contrast
media used, assessed image quality by measuring contrast enhance-
ment in the aorta, myocardium, and left main, proximal left anterior de-
scending, and proximal and distal right coronary arteries. Standardized
regions of interest were used (1 cm) in the ascending aorta, mid-LV ven-
tricle and left atrium on axial slices. The largest region of interest in each
coronary artery was used (manually drawn on axial slices). Heart rate
(HR) variability during the scan was evaluated. A comparison of the de-
gree of contrast enhancement of the coronary lumen as well as their dif-
ferences on each of the contrast agents were measured, stratified by
100 kVp and 120 kVp acquisition. The image quality of 17 coronary ar-
tery segments was graded by two cardiologists in consensus with the
use of a four-point scale (1 = excellent, 2 = good, 3 = fair, 4 = poor en-
hancement) blinded to contrast agent administration.
Subjects' characteristics were collected prior to CCTA acquisition and
heart rate was captured before and following contrast delivery and the
results are shown in Table 1.
The vascular enhancement using the different contrast agents:
iohexol, iopamidol and iodixanol all show clear delineation between en-
hancement in lumen, calcified and non-calcified plaques. Mean vascular
enhancement across all segments measured is highest in iopamidol
followed by iohexol, iodixanol 320 and iodixanol 270 respectively
(p b 0.002). Image quality (4 point scale) was highest with iodixanol
320 and 270 (3.27/4.0), and lower with iohexol (3.20) and iopamidol
(3.07), p = 0.09, Table 3. Although iopamidol yields the brightest vascu-
lar enhancement, the images obtained using iohexol and iodixanol were
similarly of high image quality and interpretable. The most commonly
cited side effect was flushing and most frequently caused by iopamidol
(78%; 95% CI 59–87%) followed by iohexol (72%; 95% CI 55–85),
iodixanol 320 (58%; 95% CI 44–79%), and iodixanol 270 (46%; 95% CI
36–56%) respectively (all p b 0.01). Other commonly cited side effects
include injection site pain, headache and nausea which are infrequently
reported across all contrast agents. Heart rate variability was lowest
among the iodixanol 320 (2.5 ± 3.0), followed by iodixanol 270
International Journal of Cardiology 186 (2015) 126–128
☆ ClinicalTrials.gov Identifier: NCT01534975.
⁎ Corresponding author.
E-mail address: mbudoff@labiomed.org (M.J. Budoff).
http://dx.doi.org/10.1016/j.ijcard.2015.03.240
0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard

2. (3.4 ± 5.2), iohexol 350 (4.1 ± 5.0) and iopamidol 370 (4.9 ± 5.8),
p b 0.001.
This trial is the first study comparing four different contrast agents
with varying iodine contents for CCTA. In over 500 consecutive patients
enrolled, we found that enhancement in the aorta, LV cavity, and myo-
cardium and image noise of the aorta showed no statistically significant
differences between iodixanol and iohexol (Table 2), however image
quality and heart rate variability were the lowest with iso-osmolar
agents and highest with low-osmolar agents (Table 3).
Iopamidol yields the brightest vascular enhancement, presumably
by having the most iodine content. However, this bright vascular en-
hancement is at the expense of having the most side effects, (i.e., flush-
ing) and the highest heart rate variability. Among our subjects, there
were no differences in image quality using the four agents, so one
could use a lower iodine content contrast to enhance safety and tolera-
bility without compromising image quality. This also confirms an earlier
study by Cademartiri et al. [7] which evaluated iodixanol 320 versus
iohexol 350 for coronary artery enhancement in 16-MDCT and found
no significant difference (mean 333 ± 51 H vs 320 ± 55 H, respective-
ly). Iodixanol, despite a lower iodine concentration than iohexol, still
provides similar enhancement [8]. In this study, iohexol offered better
vascular enhancement compared to iodixanol, even though they were
all of diagnostic image quality. Iohexol has a relative cost reduction
over iopamidol, with less side effects and low heart rate variability,
but higher rates of flushing than both concentrations of iodixanol
(Table 3). Iodixanol has the lowest rates of flushing, moderate-to-
severe pain and warmth [9–11]. Our study confirmed that iodixanol re-
sulted high image quality with the lowest rates of adverse events, such
as flushing and heart rate variability. Several studies reported that
iodixanol showed less HR changes during cardiac angiography than
iopamidol [12–14]. In a randomized study of 300 patients, iodixanol
320 showed less HR changes compared to iohexol 350 during the
scan. The current study supports this finding.
Cardiac CT requires reliable and consistent heart rates, and agents
that reduce heart rate variability are good options. Iodixanol 270 had
the lowest rates of flushing and heart rate variability. The use of
reconstructive software such as iterative reconstruction and lowered
KVp (e.g., 100 kV) with iodixanol 270 may provide additional benefit
of lower radiation and lower CM exposure minimizing adverse
events, while maintaining image quality. This study was not
powered to evaluate renal toxicity of different contrast agents, how-
ever many studies demonstrating the nephro-toxicity of different
agents exist [15]. Given that data presenting that the use of CT angi-
ography improves outcomes [16] and obstructive disease rates
during cardiac catheterization is now emerging [17], utilization of
this technique will continue to rise.
Iso-osmolar and low-osmolar contrast media yield high image qual-
ity. Flushing is the most commonly cited side effect after intravenous
contrast delivery and iodixanol yielded the lowest incidence. This
study shows that adequate quality images may be achieved with
lower iodine concentration which may have important safety and toler-
ability implications.
Conflict of interest
The authors report no relationships that could be construed as a con-
flict of interest. Matthew Budoff received grant support from General
Table 1
Baseline Demographics of the Study Population.
Iohexol
(n = 133)
Iodixanol 320
(n = 136)
Iopamidol
(n = 160)
Iodixanol 270
(n = 84)
p-Value
Age (years) 62.3 ± 11.4 62.0 ± 11.7 61.4 ± 10.8 60.4 ± 11.2 0.648
BMI 0.071
Normal (18.5 b BMI b 24.9) 32 (25.8) 47 (41.6) 41 (27.0) 28 (35.9)
Overweight (25 b BMI b 29.9) 60 (48.4) 37 (32.7) 59 (38.8) 27 (34.6)
Obese (30.0 b BMI b 39.9) 29 (23.4) 24 (21.2) 47 (30.9) 18 (23.1)
Morbidly obese (BMI N 40) 3 (2.4) 5 (4.4) 5 (3.3) 5 (6.4)
Race 0.238
White 78 (66.7) 67 (60.4) 90 (64.3) 41 (54.7)
African-American 12 (10.3) 9 (8.1) 11 (7.9) 11 (14.7)
Hispanic/Latino 17 (14.5) 22 (19.8) 15 (10.7) 11 (14.7)
Asian 9 (7.7) 12 (10.8) 18 (12.9) 8 (10.7)
Others 1 (0.9) 1 (0.9) 6 (4.3) 4 (5.3)
Chest pain 26 (20.3) 21 (17.6) 32 (21.9) 22 (27.2) 0.438
Diabetic 11 (8.6) 10 (8.5) 13 (8.9) 11 (13.4) 0.617
Family history 61 (48.8) 68 (57.1) 75 (51.0) 45 (58.4) 0.416
Hyperlipidemia 61 (49.2) 43 (36.8) 73 (50.7) 43 (54.4) 0.053
Table 2
Attenuation of different sites on the coronary computed tomographic scans across randomized subgroups.
Iohexol
n = 105
Iodixanol 320
n = 101
Iopamidol
n = 111
Iodixanol 270
n = 61
p-Value
100 kV Aorta 482.0 ± 96.5 461.1 ± 102.5 501.2 ± 90.5 401.6 ± 85.8 b0.001
dRCA 424.8 ± 116.5 412.8 ± 116.5 425.1 ± 117.4 356.0 ± 83.4 0.503
pRCA 444.5 ± 92.5 426.7 ± 112.6 469.1 ± 95.3 369.5 ± 82.9 b0.001
LM 474.9 ± 95.2 445.1 ± 109.5 491.6 ± 96.3 391.2 ± 84.6 b0.001
LV 133.2 ± 53.4 120.1 ± 34.0 1448.3 ± 13,851 103.0 ± 19.3 b0.001
pLAD 454.3 ± 110.0 425.2 ± 118.0 474.0 ± 93.8 369.1 ± 85.4 b0.001
Iohexol
n = 28
Iodixanol 320
n = 35
Iopamidol
n = 49
Iodixanol 270
n = 23
p-Value
120 kV Aorta 357.1 ± 64.5 333.3 ± 59.3 362.1 ± 68.2 288.5 ± 61.7 0.0001
dRCA 328.5 ± 83.5 296.3 ± 65.3 321.0 ± 76.8 256.0 ± 76.1 b0.001
pRCA 334.4 ± 61.7 313.3 ± 64.4 341.3 ± 78.5 259.5 ± 62.7 0.005
LM 347.4 ± 59.6 317.6 ± 59.6 359.6 ± 79.2 267.8 ± 61.8 0.012
LV 104.5 ± 23.0 99.7 ± 19.0 106.8 ± 18.3 90.7 ± 19.2 0.001
pLAD 336.6 ± 74.7 328.1 ± 71.6 343.0 ± 73.8 267.0 ± 67.6 b0.001
127L. Honoris et al. / International Journal of Cardiology 186 (2015) 126–128

3. Electric. The study was funded by General Electric. No other author has a
conflict of interest.
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Table 3
Side effects across different contrast agents.
Iodixanol
320
Iohexol Iopamidol Iodixanol
270
p-Value
Flushing, n (%) b0.001
Yes 98 (77.8) 121 (91.0) 152 (95.0) 52 (61.9)
No 28 (22.2) 12 (9.0) 8 (5.0) 32 (38.1)
Nausea, n (%) 0.38
Yes 7 (5.6) 4 (3.0) 12 (7.5) 6 (7.1)
No 118 (94.4) 128 (97.0) 147 (92.5) 78 (92.9)
Allergic reaction, n
(%)
0.04
Yes 4 (3.2) 0 (0.0) 1 (0.6) 0 (0.0)
No 121 (96.8) 132 (100.0) 158 (99.4) 84 (100.0)
Headache, n (%) 0.68
Yes 18 (14.4) 19 (14.3) 28 (17.5) 10 (11.9)
No 107 (85.6) 114 (85.7) 132 (82.5) 74 (88.1)
Pain or warmth, n
(%)
0.05
Yes 34 (27.0) 22 (16.7) 34 (21.3) 11 (13.1)
No 92 (73.0) 110 (83.3) 126 (78.8) 73 (86.9)
P value of subgroups compared to Iodixanol 320.
128 L. Honoris et al. / International Journal of Cardiology 186 (2015) 126–128