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Va s c u l a r a n d I n t e r ve n t i o n a l R a d i o l o g y • O r i g i n a l R e s e a r c h

Loewe et al.
3-T MRA of Peripheral Arterial Disease With
Two Different Contrast Agents

Vascular and Interventional Radiology


Original Research

MR Angiography at 3 T of
Peripheral Arterial Disease:
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A Randomized Prospective
Comparison of Gadoterate
Meglumine and Gadobutrol
Christian Loewe1 OBJECTIVE. This large-scale randomized study aimed to show the noninferiority in
Javier Arnaiz 2 terms of diagnostic performance of gadoterate meglumine–enhanced versus gadobutrol-en-
Denis Krause 3 hanced 3-T MR angiography (MRA) using digital subtraction angiography (DSA) as the ref-
Luis Marti-Bonmati 4,5 erence standard in patients with peripheral arterial occlusive disease (PAOD).
SUBJECTS AND METHODS. In this prospective international randomized double-
Stefan Haneder 6
blind phase IV trial, 189 patients were enrolled. Of them, 156 could be included in the per-
Ulrich Kramer 7 protocol population for on-site assessments and 154 for off-site readings. Subjects underwent
for the DALIA study group peripheral MRA, after injection of 0.1 mmol/kg of either gadoterate meglumine or gadobu-
Loewe C, Arnaiz J, Krause D, Marti-Bonmati L, trol, and DSA within 30 days. The diagnostic accuracy was evaluated and compared using a
Haneder S, Kramer U noninferiority analysis. Secondary endpoints included sensitivity, specificity, diagnostic con-
Keywords: 3 T, gadobutrol, gadoterate meglumine, MR fidence, contrast-to-noise ratio, and signal-to-noise ratio evaluations.
angiography, peripheral arterial occlusive disease RESULTS. The percentage agreement between MRA and DSA for stenosis detection was
DOI:10.2214/AJR.14.12604 similar for on-site readings for both groups (mean ± SD, 80.6% ± 16.1% with gadoterate meglu-
Received January 19, 2014; accepted after revision
mine vs 77.1% ± 19.6% with gadobutrol; 3.5% difference), and the same was true for off-site
October 29, 2014. readings (73.9% ± 16.9% with gadoterate meglumine vs 75.1% ± 13.8% with gadobutrol; 1.1%
Based on presentations at the European Congress of
difference). The noninferiority of gadoterate meglumine to gadobutrol was shown for both
Radiology 2013 annual meeting, Vienna, Austria, and the on- and off-site readings. Sensitivity in detecting significant stenosis (> 50%) was 72.3% for
RSNA 2013 annual meeting, Chicago, IL. gadoterate meglumine versus 70.6% for gadobutrol, whereas specificity (92.6% vs 92.3%), di-
This study was supported and data analysis was agnostic confidence (87.0% vs 86.0%), signal-to-noise ratio (165.5 vs 161.0), and contrast-to-
performed by Guerbet. The integrity of the data was noise ratio (159.5 vs 155.3) did not differ statistically significantly between the two groups.
assessed and approved by the coordinating investigator. CONCLUSION. Gadoterate meglumine was found to be not inferior to gadobutrol in
1
Section of Cardiovascular and Interventional Radiology, terms of diagnostic performance in patients with PAOD undergoing 3-T contrast-enhanced
Department of Bioimaging and Image-Guided Therapy, MRA. No statistically significant differences were detected between the two MRA groups.
Medical University of Vienna, Waehringer Guertel 18-20,
Vienna 1090, Austria. Address correspondence to

T
he prevalence of peripheral arte- invasively with either CT or contrast-en-
C. Loewe (christian.loewe@meduniwien.ac.at).
2
rial occlusive disease (PAOD) in hanced MR angiography (MRA) [3–6]. In
Department of Radiology, Hospital Universitario Marquès
the general population is as high clinical practice, contrast-enhanced MRA
de Valdecilla University Hospital, Santander, Spain.
3
as 14.5%, and PAOD can affect has some advantages over CT angiography,
Département de Radiologie et d’Imagerie Médicale
up to 20% of individuals older than 75 years including the lack of radiation exposure and
Diagnostique et Thérapeutique, CHU Le Bocage, Dijon,
France.  [1]. The diagnosis of PAOD can be made on its negligible risk for contrast-induced renal
4 the basis of medical history and physical ex- failure; thus, it is widely used for treatment
Department of Radiology, Hospital Universitario y
Politécnico La Fe, Valencia, Spain. amination. However, for treatment decisions decision making and treatment planning.
5 and planning, information about lesion length, The risk for nephrogenic systemic fibrosis
Department of Radiology, Department of Medicine,
University of Valencia, Valencia, Spain. distribution, number, and localization is re- is quite low if the existing European Medi-
6 quired, whereas pretherapeutic noninvasive cines Agency and U.S. Food and Drug Ad-
Department of Radiology, University Medical Center
Mannheim, Institute of Clinical Radiology and Nuclear imaging of the peripheral vasculature is need- ministration guidelines on the classification
Medicine, Mannheim, Germany. ed after the clinical diagnosis of PAOD has of contrast media are followed [7]. With an
7
Department of Diagnostic Radiology, University of been made. This information is required to re- increasing number of whole-body 3-T MRI
Tuebingen, Tuebingen, Germany. fer the patient to either endovascular treatment scanners becoming clinically available,
or a surgical procedure and to establish a de- there is the potential to acquire high-spatial-
AJR 2015; 204:1311–1321 tailed treatment plan (including, for example, resolution datasets with an almost isotropic
0361–803X/15/2046–1311
access site and distal outflow vessel) [2]. resolution of 1 mm3 or even less.
It is the current consensus that this pre- Some studies have already described the
© American Roentgen Ray Society treatment imaging should be performed non- feasibility of peripheral 3-T contrast-en-

AJR:204, June 2015 1311


Loewe et al.

hanced MRA [8–10], but, to our knowledge, Fig. 1—Schema of


trial design. AE = Gadoterate
no prospective randomized trial compar- Meglumine–
adverse event, DSA =
ing peripheral 3-T contrast-enhanced MRA digital subtraction
Enhanced
MRA
to the reference standard, digital subtraction angiography, MRA = MR
angiography (DSA), has been performed yet angiography.
Maximum:
in a large population of patients with PAOD. Minimum 1 d
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21 d
Maximum: 30 d
Screening DSA
Previous contrast-enhanced MRA stud-
ies showed that higher gadolinium concen-
trations (1.0 M) at 1.5 T are useful, provid-

Randomization

End of Study
ing high diagnostic accuracy compared with Gadobutrol-
DSA [11, 12]; however, it was also shown Enhanced
MRA
that contrast agents with higher gadolinium
concentrations provide little difference in re-
Safety Follow-Up (AEs and Serious AEs)
laxivity at 1.5 T over 0.5 M gadolinium che-
lates, such as gadoterate meglumine [13]. The Trial Duration
(Minimum 2 days, maximum 51 days)
primary objective of this large-scale study
was, therefore, to show the noninferiority
of gadoterate meglumine–enhanced versus
gadobutrol-enhanced 3-T MRA in terms of
diagnostic performance compared with DSA
in a large population of patients with PAOD. 184 Patients included in the
189 Patients enrolled 5 Patients safety population
Subjects and Methods (women / men = 40 / 149) not injected
(group A / group B = 92 / 92)
Study Design
This study was designed as a prospective phase
IV double-blind randomized international trial
(Dotarem-Enhanced MRA Compared to Gadovist- 3 Patients withdrawn before
Enhanced MRA in the Diagnosis of Clinically the randomization
Significant Abdominal or Limb Arterial Disease
[DALIA]. Institutional review board and regulato-
ry approval were granted from each of the 15 par- 186 Patients randomized
ticipating European centers (Austria, France, Ger-
many, Italy, and Spain). The study was registered (group A / group B = 93 / 93)
at www.clinicaltrials.gov (registration no. NCT
01026389). Figure 1 summarizes the steps and im-
aging procedures performed within this study. 10 Patients withdrawn during MRA or between MRA and DSA
and 1 additional patient with no evaluable MRA examination
Patients
Peripheral contrast-enhanced MRA was per-
2 DSA not
formed for 189 patients with PAOD (149 men and 173 Patients included in the off-site
175 Patients included in the on-site available for
40 women), with a mean (± SD) age of 66.4 ± 10.7 off-site reading intent-to-treat efficacy population
intent-to-treat efficacy population
(range, 24–91 years), who were scheduled to un- with DSA evaluation
dergo peripheral DSA (with or without endovas- (group A / group B = 88 / 87)
(group A / group B = 87 / 86)
cular therapy) because of PAOD in clinical stages
II–IV (according to the classification of Leriche and
Fontaine [14]). DSA is still considered the reference
Major protocol deviations in further 19 patients
standard for arterial imaging [15] and was, conse- (11 in group A / group B) (out-of-range doses of contrast agent [12], contrast agent
quently, used as a reference standard in this study. allocation problem [6], one selection criterion not fulfilled [2], and more than 30 days between
After providing written informed consent, pa- MRA and DSA [3])
tients were randomized to either of the two MRA
groups. Patients’ baseline characteristics were well 2 DSA not
balanced between the two contrast agent groups 156 Patients included in the on-site
available for 154 Patients included in the off-site
off-site reading per protocol population with DSA
with respect to demographic data and severity of per-protocol efficacy population
evaluation
the disease. Patients underwent peripheral 3-T con-
(group A / group B = 77 / 79)
trast-enhanced MRA with the administration of ei- (group A / group B = 76 / 78)
ther gadoterate meglumine (group A) or gadobu-
trol (group B) within 1–30 days before the planned Fig. 2—Flowchart for patient inclusion (group A received gadoterate meglumine, and group B received
DSA, with or without endovascular therapy. gadobutrol). DSA = digital subtraction angiography, MRA = MR angiography.

1312 AJR:204, June 2015


3-T MRA of Peripheral Arterial Disease With Two Different Contrast Agents

To be eligible, patients had to be older than 18 formed, 92 in each group. Patients underwent con- Study Endpoints
years. Inclusion criteria were no history of allergic trast-enhanced stepping-table MRA during the Efficacy endpoints were evaluated by on- and
reaction to MRI contrast media and no contraindi- administration of either gadoterate meglumine off-site readers, separately. For analysis purpos-
cation to MRI because of pacemakers, implanted (0.5 mmol gadolinium/mL; Dotarem, Guerbet; es, the arterial vascular system was divided into
metallic devices, aneurysm clips, severe claustro- group A) or gadobutrol (1.0 mmol gadolinium/mL; 21 segments per patient: aorta, common iliac, ex-
phobia, or metallic joint replacement. Exclusion Gadovist, Bayer HealthCare; group B). All con- ternal iliac and common femoral (counted as one
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criteria were abdominal aortic or iliac grafts or trast agent injections were performed via an ante- segment), superficial femoral, deep femoral, popli-
stents, or a history of a major cardiovascular event cubital venous access using a power injector. All teal, anterior tibial, posterior tibial, peroneal, dorsal
within 30 days before the screening. Chronic re- patients received 0.1 mmol gadolinium/kg of body pedal, and media pedal. For each vascular segment,
nal failure was not mentioned as an exclusion cri- weight, independently of contrast agent injected. the degree of arterial stenosis was assessed. Steno-
terion by definition. European Medicines Agen- Given the difference in the gadolinium concentra- ses were quantified according to diameter measure-
cy guidelines [7] suggest that patients at risk are tion between the agents used in this trial, different ments and were calculated as follows: percentage
those with severe renal insufficiency (glomerular injection parameters were used for the two different stenosis = 100 × (1 − [narrowest diameter / normal
filtration rate < 30 mL/min/1.73 m 2), but gadoter- groups: Gadoterate meglumine was administered diameter]). According to this calculation, each le-
ate meglumine and gadobutrol are classified as at a flow rate of 1.0 mL/s, followed by 25–30 mL of sion was graded as follows: 0, no significant ste-
low-risk gadolinium-based contrast agents and are saline flush (1.0 mL/s) in group A. Gadobutrol was nosis (0–50%); 1, moderate stenosis (51–69%); 2,
not contraindicated in this at-risk population [6]. given at a flow rate of 0.5 mL/s, followed by 25–30 severe stenosis (70–99%); and 3, occlusion (100%).
mL of saline flush (0.5 mL/s) in group B. Half the The primary efficacy endpoint was the agree-
MRI Technique flow rate was used for the gadobutrol injection to ment between MRA and the DSA used as the ref-
All examinations were performed on either Sie- compensate for the double gadolinium concentra- erence standard for stenosis detection. This per-
mens Healthcare n = 80; 45.7%; 40 in each group), tion (1.0 M) and to reach the same injection dura- centage of agreement was assessed on a per-patient
Philips Healthcare n = 72; 41.1%; 34 in group tion to cover the entire multistep acquisition and to level and was compared for the two groups. Sec-
A and 38 in group B), or GE Healthcare n = 23; reach comparability between the two groups. ondary endpoints included additional quantitative
13.1%; 14 in group A and nine in group B) 3-T and qualitative efficacy and safety assessments and
whole-body systems. For all patients, a bolus-trig- Digital Subtraction Angiography were evaluated either on site, off site, or both.
gering technique in the coronal plane was applied All DSAs were performed within 1–30 days af- For efficacy endpoints, sensitivity and specific-
to ensure exact timing of contrast agent injection ter the study MRA (at least 24 hours after contrast ity values in stenosis evaluation, as well as positive
for the pelvic region. No dedicated timing was per- agent injection during MRA). DSA examinations predictive values (PPVs) and negative predictive
formed for the thigh or calf. The scan was initi- were performed as part of the standard medical values (NPVs), were assessed on a per-segment
ated after visual detection of the bolus arrival in treatment, and patients underwent DSA indepen- level. Diagnostic confidence was rated on a per-
the ROI. A centric k-space sample order was used. dently of MRA. In cases where endovascular treat- patient level using a 5-point scale (5, excellent;
The sequence protocol comprised vessel localiz- ment was required for the PAOD, the diagnostic 4, high; 3, moderate; 2, poor; and 1, not assess-
ers and 3D T1-weighted spoiled gradient-echo se- angiograms obtained before the intervention were able). Visualization of arterial segments and col-
quences in a coronal orientation in a stepping-table used for comparison with contrast-enhanced MRA. lateral circulation was assessed on and off site by
technique that included three steps. A mask se- means of a 4-point scale, as follows: 1, providing
quence before the administration of contrast agent Image Analysis the expected information (totally satisfactory); 2,
was acquired in three FOVs, covering the complete Evaluation of the study images obtained was providing sufficient information (satisfactory); 3,
vascular tree from the abdominal aorta to the lev- performed in two steps, consisting of on- and off- not providing all the expected information (not
el of the feet, which was subsequently subtracted site readings. satisfactory, may need further investigation); and
from the contrast-enhanced images to reduce back- On-site reading — For on-site reading, all 4, not providing enough information (not satisfac-
ground signal. For examinations on the Siemens available MRA data, including source data, sub- tory, further investigation recommended). In addi-
Healthcare scanner, TR/TE ranged from 2.5/0.9 tracted images, and maximum intensity projec- tion, venous overlap that interfered with artery vi-
to 4.1/1.3 (mean, 3.1/1.1). The mean slice thick- tions, were interpreted by one experienced read- sualization was also graded using a 4-point scale
ness was 1.3 mm (range, 1–1.6 mm), and the mean er from each site. The reader was blinded to the (4, not seen; 3, partially seen; 2, seen; and 1, not
flip angle was 24° (range, 9–40°). For the Philips contrast agent used. Another reader, who was not assessable). Contrast enhancement was assessed
Healthcare scanner, TR/TE values ranged from involved in MRA acquisition or reading and was from signal intensity (SI) measurements obtained
3.5/1.3 to 4.2/1.5 (mean, 3.9/1.3). The mean slice unaware of contrast-enhanced MRA findings, as- at predefined ROIs (i.e., the iliac, popliteal, and
thickness was 1.6 mm (range, 0.9–3.4 mm), and sessed the DSA images. calf territories). For all measurements, source
the flip angle for all examinations was 20°. For the Off-site reading — For the centralized blind- data were used. Contrast-to-noise ratio (CNR) and
GE Healthcare scanner, TR/TE values ranged from ed reading, images were transferred anonymous- signal-to-noise ratio (SNR) were derived from the
3.3/1.1 to 5.2/1.8 (mean, 4.1/1.4). The mean slice ly to a core laboratory. Two independent readers, following equations: SNR = SIa / NO and CNR =
thickness was 3.25 mm (range, 2.8–3.4 mm), and who had 10 and 4 years of experience and who (SIa − SIm) / NO, where SIa is the SI measured in
the mean flip angle was 26° (range, 18–40°). were blinded to the type of contrast agent used, as- the ROI positioned in the common iliac artery,
sessed the MRAs. No consensus reading was per- the popliteal artery, and the calf artery; SIm is the
Contrast Agents formed. All readings were performed in a random signal intensity measured only once in the psoas
Of 189 patients included, five did not receive order, with the readers blinded to patient data. muscle; and NO is noise defined as the SD of SIm
contrast agent (for reasons described later), re- One experienced reader, also blinded to the clini- measured in the subtraction image at the same lo-
sulting in 184 contrast agent administrations per- cal history of patients, assessed the DSAs. cation as the SIm to be measured.

AJR:204, June 2015 1313


Loewe et al.

For safety endpoints, vital signs (blood pres- Results group B, resulting in a mean difference of
sure and heart rate) were monitored just before Patients Eligible for Analysis −1.1% (95% CI, −5.3% to 3.1%). On- and
and 15 and 30 minutes after each MRA proce- A total of 189 patients were enrolled in off-site readings showed the noninferiority
dure. Injection-site tolerance was assessed and, in 15 centers in five European countries, here- of gadoterate meglumine–enhanced versus
case of pain, a questionnaire (visual analog scale) after referred to as the all-included popula- gadobutrol-enhanced MRA in patients with
was to be filled in by the patients 30 minutes af- tion (Fig. 2). From this all-included popula- PAOD, because the lower limits of 95% CI
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ter the procedure. Furthermore, all patients were tion were defined the safety population and (−2.2% and −5.3%) were superior to the non-
monitored for adverse events (AEs) and serious several efficacy populations (on-site and off- inferiority margin (−6.5%) (Figs. 3 and 4).
AEs throughout the study. In brief, AEs were de- site intent to treat and on-site and off-site per The results of primary endpoint according to
fined as all untoward medical occurrences with a protocol). Results are presented for this per- vascular territories are described in Table 3.
possible, but not necessarily causal, relationship protocol population (156 patients for on-site
to the administered drug. Per definition, serious reading and 154 patients for off-site reading). Secondary Quantitative and Qualitative
AEs were all untoward medical events that led to As shown in Table 1, there were no demo- Efficacy Endpoints
death, were life threatening, required hospitaliza- graphic differences between the two groups Sensitivity, specificity, positive predictive
tion, resulted in persistent or significant disability of patients. The mean total volume of con- value, and negative predictive value—Ste-
or incapacity, or were related to congenital anom- trast material administered was double in noses with 50% or more luminal narrowing
aly. The on-site radiologist rated the event’s sever- group A (gadoterate meglumine: 15.4 ± 3.1 were considered relevant. Applying this cut-
ity (mild, moderate, or severe) and its causal rela- mL; range, 8.0–28.0 mL) than in group B off for clinical significance, 502 relevant ste-
tionship (possible, doubtful, and not related) to the (gadobutrol: 7.6 ± 1.3 mL; range, 4.5–11.5 noses greater than 50% were identified by
contrast agent, as well as the outcome of AEs (re- mL), whereas the total amount of gadolinium DSA (264 in group A and 238 in group B),
solved with or without sequelae, persisting at the was the same in both groups. The most com- out of 2145 assessable segments. The percent-
time of follow-up, or death). mon stenosis locations were femoral (49.2% age of relevant stenoses did not differ statis-
left, 51.3% right) and popliteal (34.9% left, tically significantly between the two groups
Sample Size Calculation and Statistical Analysis 38.1% right). A history of diabetes was found (p = 0.79). Significant stenoses were correctly
All statistical analyses were conducted us- in 37.6% of the study population (34.4% in diagnosed by MRA in 191 of 264 patients in
ing SAS software (version 9.2, SAS Institute). group A and 40.9% in group B). group A and in 168 of 238 patients in group
For sample size calculation, it was hypothesized B. Conversely, 763 of 824 nonsignificant ste-
that the within-patient agreement for gadoter- Primary Efficacy Endpoint noses were correctly diagnosed by MRA in
ate meglumine–enhanced MRA with the refer- In the per-protocol population, the num- group A versus 756 of 819 in group B. Sensi-
ence standard would be around 85%. With a 2.5% ber of assessable arterial segments taken tivity and specificity values (72.3% vs 70.6%
one-sided type I error and 80% power, a sample into account in the analysis was dependent and 92.6% vs 92.3%, respectively) showed
size of 170 patients was considered sufficient to on the reader (1940 for off-site reader 1, 2036 no statistically significant difference between
show the noninferiority of gadoterate meglu- for off-site reader 2, and 2145 for the on-site groups for the detection of relevant stenosis
mine–enhanced to gadobutrol-enhanced MRA. reader). Within-patient agreement between (p = 0.79 and p = 0.98, respectively) (Fig. 5).
Noninferiority was statistically shown if the low- MRA and DSA was similar and did not dif- PPVs and NPVs for the diagnosis of sig-
er bound of the 95% CI between agreements was fer statistically significantly between groups nificant stenosis were similar in both groups
above −6.5%, set as the clinical noninferiority A and B for on-site readings (80.6% ± 16.1% (PPV, 75.8% in group A vs 72.7% in group
limit (minimum clinically relevant difference). vs 77.1% ± 19.6%; p = 0.23; Table 2). The B; NPV, 91.3% in group A vs 91.5% in group
Considering a 10% drop-out rate during the study, mean difference in percentage agreement B) in the per-protocol population (Fig. 5).
a sample size consisting of 188 patients was cal- (groups A minus group B) was 3.5% (95% Off-site reading results were comparable and
culated to be sufficient to achieve the study ob- CI, −2.2% to 9.1%) for the on-site reader. are displayed in Figure 6.
jectives. Secondary efficacy endpoints were in- Pooled data from off-site readers showed a Diagnostic confidence—No difference was
vestigated using a logistic regression model with mean percentage agreement in group A of found between the two groups, even for on-
adjustment for centers. 73.9% ± 16.9% versus 75.1% ± 13.8% in site readings, with respect to diagnostic confi-

TABLE 1: Demographic and Other Baseline Characteristics for the Per-Protocol Population
Group A, Gadoterate Group B, Gadobutrol Total
Baseline Characteristics Meglumine (n = 77) (n = 79) (n = 156) Test
Age (y), mean ± SD (minimum/maximum) 66.7 ± 10.5 (43/85) 66.3 ± 10.7 (42/89) 66.5 ± 10.5 (42/89) Student t test (p = 0.803)
Sex, no. (%) of patients Chi-square test (p = 0.602)
Male 63 (81.8) 62 (78.5) 125 (80.1)
Female 14 (18.2) 17 (21.5) 31 (19.9)
BMI, mean ± SD (minimum/maximum) 27.2 ± 4.6 (17.6/39.9) 26.6 ± 3.5 (20.0/38.2) 26.9 ± 4.1 (17.6/39.9) Student t test (p = 0.366)
Relevant stenosis > 50% narrowing by DSA 264 238 502 Chi-square test (p = 0.339)
(vascular segments)
Note—BMI = body mass index (weight in kilograms divided by the square of height in meters), DSA = digital subtraction angiography.

1314 AJR:204, June 2015


3-T MRA of Peripheral Arterial Disease With Two Different Contrast Agents

TABLE 2: Primary Efficacy Endpoint: Percentage Agreement Between MR tery segments and collateral circulation were
Angiography (MRA) and Digital Subtraction Angiography (DSA) on similar to those found for on-site readings.
a Per-Patient Level in the Per-Protocol Population Venous overlap—Venous overlap was
Percentage Agreement Between partially or not seen in 31 (40.3%) and 36
MRA and DSA (46.8%) patients, respectively, from group A
Percentage versus 27 (34.2%) and 37 (46.8%) patients,
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Group A, Difference Between


Gadoterate Group B, Group A and Group B respectively, from group B (Table 4) for on-
Reading Site Meglumine Gadobutrol (95% CI) p site reading. Off-site reading results are dis-
played in Table 5.
On-site reading (n = 77 for group A 3.5 (−2.2 to 9.1) 0.23
and n = 79 for group B) Signal intensity, Contrast-to-Noise Ratio,
and Signal-to-Noise Ratio measurements—
Mean ± SD 80.6 ± 16.1 77.1 ± 19.6
MRA parameters were site and brand depen-
Minimum/maximum 0/100 0/100 dent and ranged within routine limits. Un-
Off-site readings pooled (n = 152 for −1.1 (−5.3 to 3.1) 0.60 der these conditions, contrast enhancement
group A and n = 156 for group B) was measured in specified ROIs (i.e., the iliac,
Mean ± SD 73.9 ± 16.9 75.1 ± 13.8 popliteal, and calf territories) for gadoterate
meglumine and gadobutrol. Pooling all territo-
Minimum/maximum 16.7/100 31.6/100
ries, mean artery SI values did not differ sta-
tistically significantly between groups A and B
TABLE 3: Primary Efficacy Endpoint: Percentage Agreement Between MR (1167 ± 930 vs 1243 ± 964; p = 0.19). No statis-
Angiography (MRA) and Digital Subtraction Angiography (DSA)
tically significant differences were detected be-
on a Per-Patient Level According to Vascular Territories in the
­Per-Protocol Population (On-Site Reading) tween groups A and B for SNR (165.5 ± 200.2
vs 161.0 ± 201.6; p = 0.72) and CNR (159.5 ±
Percentage Agreement Between MRA and DSA 198.0 vs 155.3 ± 198.8; p = 0.73).
Group A, Group B, Overall, both contrast agents did not ap-
Vascular Territory Gadoterate Meglumine Gadobutrol pear to differ quantitatively with regard to
arterial enhancement despite different gado-
Aorta (n = 65 for group A; n = 61 for group B)
linium concentrations.
Mean ± SD 90.8 ± 29.2 88.5 ± 32.1
Minimum/maximum 0.0/100 0.0/100 Safety Endpoints
Iliac (n = 69 for group A; n = 69 for group B) No clinically significant change in vital signs
compared with baseline was observed in either
Mean ± SD 77.9 ± 25.9 81.2 ± 27.3
group. In two patients from group A (2.2%),
Minimum/maximum 0.0/100 0.0/100 four AEs occurred after gadoterate meglumine
Femoral (n = 76 for group A; n = 77 for group B) injection. The reported event in one patient was
Mean ± SD 81.9 ± 24.7 80.1 ± 27.0 a burning sensation (mild and possibly contrast
related). In addition, one 51-year-old man from
Minimum/maximum 0.0/100 0.0/100
group A developed three events, including fol-
Popliteal (n = 74 for group A; n = 77 for group B) liculitis (mild unrelated event), severe acute cor-
Mean ± SD 75.0 ± 37.2 72.1 ± 38.5 onary syndrome for 14 days, and severe carotid
Minimum/maximum 0.0/100 0.0/100 artery stenosis for 90 days, but these two last se-
rious AEs were considered by the investigator
Calf (n = 72 for group A; n = 75 for group B)
to be unrelated to gadoterate meglumine. This
Mean ± SD 70.5 ± 29.0 60.9 ± 35.1 patient with a body mass index (weight in kilo-
Minimum/maximum 0.0/100 0.0/100 grams divided by the square of height in meters)
of 20.6 had an ongoing history of dyslipidemia,
dence, which was rated high or excellent in 67 adequate to excellent for pedal or foot vessels hypertension, lower limb arteriopathy, and al-
(87.0%) patients in group A versus 68 (86.0%) in 33.9% (n = 62) of group A patients, com- cohol and tobacco abuse. In two patients from
in group B (Table 4). Results from off-site pared with 32.8% (n = 67) of group B patients. group B (2.2%), two AEs developed after gado-
readings are displayed in Table 5. Expected or sufficient information was butrol injection. These events included an injec-
Visualization of arterial segments and col- obtained for on-site visualization of the tion site extravasation (mild and unrelated) and
lateral circulation—Visualization of arter- collateral circulation in 65 of 77 patients a hot flush (mild and possibly contrast related).
ies was assessed on site from a total of 3154 (84.4%) who underwent gadoterate meglu-
artery segments (1558 in group A vs 1596 in mine–enhanced MRA, versus 66 of 79 pa- Discussion
group B). In 80.9% of segments (n = 1261) for tients (83.5%) who underwent gadobutrol- Within a medical environment with rap-
group A versus 80.2% of segments (n = 1279) enhanced MRA (Table 4). id technologic developments, the benefit of
for group B, expected or sufficient information As shown in Figure 8 and Table 5, off-site contrast media always remains to be inves-
could be obtained (Fig. 7). Image quality was results for the quality of visualization of ar- tigated. This study was designed to assess

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Loewe et al.

TABLE 4: Secondary Efficacy Endpoints, On-Site Reading, Per-Protocol Population Actually, because of the increasing current
availability of clinical 3-T whole-body MRI
Group A, Gadoterate Group B, Gadobutrol
Category Meglumine (n = 77) (n = 79) scanners, the advantages of 3 T can now be
used even for peripheral vascular imaging
Visualization of collateral circulation purposes. These advantages are manifold, in-
Providing the expected information 29 (37.7) 28 (35.4) cluding the ability to acquire high-spatial-res-
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Providing sufficient information 36 (46.8) 38 (48.1) olution datasets with an almost isotropic res-
olution of 1 mm3 or even less. Especially for
Not applicable or not providing enough or all the 12 (15.6) 13 (16.5)
expected information vascular imaging by means of contrast-en-
hanced MRA, 3 T offers increased SNR and
Venous overlap
higher CNR values compared with 1.5 T. The
Not seen 36 (46.8) 37 (46.8) prolongation of the longitudinal tissue relax-
Partially seen 31 (40.3) 27 (34.2) ation time (T1) in background tissue, which
Seen 8 (10.4) 13 (16.5) leads to increased CNR between contrast-en-
hanced vascular structures and the surround-
Not assessable 2 (2.6) 2 (2.5)
ing background tissue, reflects one of the most
Diagnostic confidence important benefits of contrast-enhanced high-
Excellent 28 (36.4) 31 (39.2) field MRA [16, 17]. However, because of lim-
High 39 (50.6) 37 (46.8) itations in the homogeneity of the magnetic
field, the smaller FOV of 3-T scanners was
Moderate 9 (11.7) 11 (13.9)
once a drawback when imaging the peripher-
Poor or nil 1 (1.3) 0 (0.0) al arterial tree. Recent improvements in scan-
Note—Data are number (%) of patients. Not all percentages total 100 because of rounding. ner technologies, including new whole-body
coils, now enable imaging of the peripheral
the clinical equivalence of gadoterate meglu- the detection of relevant stenosis substantiate arterial tree within three FOVs, even at 3 T
mine–enhanced and gadobutrol-enhanced the clinical usefulness of contrast-enhanced [18]. These advantages of 3 T over 1.5 T for
peripheral 3-T MRA, using DSA as the ref- MRA of the peripheral arteries at 3 T. Sensi- contrast-enhanced MRA have already been
erence standard, in patients with abdominal tivity, specificity, NPVs, and PPVs obtained evaluated and proven [8–10, 16]. However,
or lower limb arterial diseases during a large from a large study population are clear proof- despite promising results, a large prospective
prospective randomized blinded trial. The re- of-concept that peripheral 3-T MRA can be PAOD trial comparing the diagnostic perfor-
sults provided here for diagnostic accuracy in performed in the clinical routine. mance of peripheral 3 T MRA with the refer-
TABLE 5: Secondary Efficacy Endpoints, Off-Site Reading, Per-Protocol Population
Reader 1 Reader 2
Group A, Gadoterate Group B, Gadobutrol Group A, Gadoterate Group B, Gadobutrol
Category Meglumine (n = 77) (n = 79) Meglumine (n = 77) (n = 79)
Visualization of collateral circulationa
Providing the expected information 22 (28.6) 27 (34.2) 27 (35.1) 21 (26.6)
Providing sufficient information 43 (55.8) 41 (51.9) 38 (49.4) 42 (53.2)
Not applicable or not providing enough or all the expected information 12 (15.6) 11 (13.9) 12 (15.6) 16 (20.3)
Venous overlapb
Not seen 26 (33.8) 31 (39.2) 8 (10.4) 14 (17.7)
Partially seen 37 (48.1) 29 (36.7) 50 (64.9) 47 (59.5)
Seen 11 (14.3) 18 (22.8) 17 (22.1) 16 (20.3)
Not assessable 3 (3.9) 1 (1.3) 2 (2.6) 2 (2.5)
Diagnostic confidencec
Excellent 14 (18.2) 18 (22.8) 27 (35.1) 26 (32.9)
High 37 (48.1) 38 (48.1) 27 (35.1) 28 (35.4)
Moderate 17 (22.1) 19 (24.1) 13 (16.9) 20 (25.3)
Poor or nil 9 (11.7) 4 (5.1) 10 (13.0) 5 (6.4)
Note—Data are number (%) of patients. Not all percentages total 100 because of rounding.
ap = 0.795 for reader 1; p = 0.477 for reader 2.
bp = 0.281 for reader 1; p = 0.656 for reader 2.
cp = 0.475 for reader 1; p = 0.377 for reader 2.

1316 AJR:204, June 2015


3-T MRA of Peripheral Arterial Disease With Two Different Contrast Agents
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A B C D
Fig. 3—51-year-old man with pain in left leg at rest for 3 days (peripheral arterial occlusive disease stage III).
A–C, Maximum intensity projections of gadobutrol-enhanced MR angiograms are shown. Image of peripheral arteries (A) shows occlusion of tibiofibular trunk and
of left posterior tibial artery. Magnification of pelvic region (B) shows thromboembolic material within left external iliac artery. Magnification of calf region (C) shows
thromboembolic occlusion of left tibiofibular trunk and left posterior tibial artery.
D, Digital subtraction angiography performed during endovascular treatment confirms thromboembolic occlusion of left tibiofibular trunk and left posterior tibial artery.

ence standard, DSA, had not been published. Our study shows the noninferiority of 0.5 PAOD. The lower levels of accuracy reached
This is important because, in addition to im- M gadoterate meglumine compared with 1.0 within this trial, compared with those recent-
proved diagnostic image quality, there are M gadobutrol in peripheral MRA at 3 T and ly published [20], may be attributable to sev-
more beneficial effects of MRA at 3 T. How- shows the robustness of this technique in a eral different factors. First, this study was
ever, specific artifacts may interfere with the multipractice environment. Furthermore, the performed as a double-blind multicenter trial
diagnostic accuracy at 3 T. For example, the fact that results from the on-site evaluation with a predefined examination protocol. It is
B1 inhomogeneity represents a well-known could be confirmed by off-site readers fur- well known that such an approach provides
artifact problem for MRI at 3 T [19], possibly ther shows the reliability of peripheral MRA less-homogeneous results compared with sin-
influencing the diagnostic accuracy. at 3 T for diagnosis and treatment planning in gle-center studies. Second, additional dedi-

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Loewe et al.
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A B C D
Fig. 4—86-year-old woman with tissue loss at left forefoot (peripheral arterial occlusive disease stage IV).
A and B, Maximum intensity projections of gadoterate dimeglumine–enhanced MR angiograms are shown. Image of peripheral arteries (A) shows multiple high-grade
stenoses of superficial femoral arteries on both legs. There is also occlusion of anterior and posterior tibial arteries on both legs. Magnification image of left superficial
femoral artery (B) shows multiple high-grade stenoses.
C, Digital subtraction angiography (DSA) of left leg shows multiple high-grade stenoses of left superficial femoral arteries. There is also occlusion of left anterior and left
posterior tibial arteries.
D, DSA of left superficial femoral artery (magnification) confirms MR angiography findings of multiple high-grade stenoses.

cated or time-resolved scans for calf vessels [21–25]. Injection parameters and bolus tim- even at 3 T. Finally, the use of a single dose
(i.e., hybrid scans) were not allowed to en- ing for the thigh and calf areas could not be of gadolinium for the entire peripheral MRA
sure comparability between the two macro- adjusted individually to the patients’ require- in all patients could also explain the slightly
cyclic contrast agents, although the combina- ments to allow comparability between the poorer results than those reported previously.
tion of a moving-table MRA technique with two groups in this multicenter trial. Diagnos- The influence of gadolinium concentra-
dynamic single-station MRA of the calf has tic confidence could be further improved by tions of both contrast agents was also as-
been shown to improve diagnostic accuracy adding dedicated scans for the calf arteries, sessed for diagnostic performance. Apart

1318 AJR:204, June 2015


3-T MRA of Peripheral Arterial Disease With Two Different Contrast Agents

100 100
92.6 92.3 91.3 91.5 91.4 91.1
90 85 85.2
80 75.8 80
72.3 72.7 69.9 71
70.6 70
62
Percentage

61.5

Percentage
60 60
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50
40 40
30

20 20
10
0
0 Gadoterate Gadobutrol Gadoterate Gadobutrol
Sensitivity Specificity PPV NPV
Meglumine Meglumine
Gadoterate Meglumine Gadobutrol
Reader 1 Reader 2
Sensitivity Specificity

Fig. 5—Sensitivity, specificity, positive predictive value (PPV), and negative Fig. 6—Sensitivity and specificity assessment for off-site reading, per-protocol
predictive value (NPV) assessment for on-site reading, per-protocol population. population.

from gadolinium concentration, relaxivity nostic performance in the assessment of pa- trast agent and that the use of gadobutrol at
is a key factor in determining the SNR and tients with PAOD at 3 T. the same injection speed and volume could
CNR and, ultimately, image quality, know- The results presented in this article show have increased the CNR, but this would have
ing that gadoterate meglumine and gadobu- the clinical equivalence of gadoterate meglu- led to doubling the total gadolinium dose,
trol are not high-relaxivity molecules. Ear- mine–enhanced and gadobutrol-enhanced which leads to increased risk for nephrogenic
ly MRA studies found higher SNRs with 1.0 MRA for the detection of relevant stenoses in systemic fibrosis as well as increased costs.
M gadobutrol compared with convention- the peripheral vasculature, as previously re- Our study has limitations. Because of the
al 0.5 M gadolinium chelates at 1.5 T, but ported for smaller sample sizes [13, 26]. In different techniques used, some artery seg-
smaller differences in SNR between 1.0 M addition, the comparability of both agents ments were not available for evaluation, be-
gadobutrol and 0.5 M contrast agents, such was shown with regard to other findings in cause they were not visualized by DSA if an
as gadoterate meglumine, could be expect- patients with PAOD: no differences were anterograde arterial access was used. How-
ed at 3 T [26]. Because of the better back- found between groups, particularly for the vi- ever, these were mostly proximal segments,
ground suppression of unenhanced tissues at sualization of collateral arteries and the pres- where no relevant problems for noninvasive
3 T, vessel conspicuity is usually higher than ence of venous overlap. So that comparability imaging usually occur. Thus, results should
at 1.5 T. To test this assumption in subjects of examination protocols in the two groups not be influenced by this factor. Another
with PAOD, we randomized patients to two could be ensured, injection parameters were limitation of the study might be the fact that
groups who underwent peripheral 3-T MRA, adjusted to the injection of gadolinium per different MRI scanner types and imaging
during the administration of either a 0.5 M second. Half the volume of gadobutrol, com- techniques were used as a result of the mul-
(gadoterate meglumine, group A) or 1.0 M pared with gadoterate meglumine, was in- ticenter design. However, we strongly think
(gadobutrol, group B) concentration of con- jected at half the injection speed, which that the advantages of a multicenter design,
trast agent. This study showed the lack of a resulted in the same gadolinium flow per sec- combined with centralized reading, over-
clinically relevant difference between the ond in all patients. Thus, it can assumed that come the limitations due to mild inhomoge-
two contrast agents when evaluating diag- the injection was not optimized for each con- neity of data and wide SI variations among
magnet brands. Theoretically, a higher gado-
100 linium concentration should provide a higher
intravascular signal, thus maximizing vessel
80 conspicuity and image quality, because the
same amount of gadolinium is injected in a
60.6 63.0
Percentage

60 shorter time. However, in this study, no sta-


tistically significant difference was found be-
40 tween gadoterate meglumine and gadobutrol
Fig. 7—Visualization for SI, SNR, CNR, or image quality, if all
20.3 17.2 19.1 19.9 of patients’ arteries, vascular territories were pooled. Compari-
20
on-site reading, per-
protocol population.
son with a true reference standard (DSA) was
0 Asterisk denotes made in this trial, resulting in a robust meth-
Providing the Providing Other* not providing all the odologic approach, and the sample size was
expected sufficient expected information, large enough to show clinically reliable and
information information not providing enough
information, or not significant results. Finally, a single contrast
Gadoterate Meglumine Gadobutrol
applicable. material injection was allowed by the study

AJR:204, June 2015 1319


Loewe et al.

Fig. 8—Visualization subtraction angiography in 106 patients. AJR


100 of patients’ arteries,
Providing the Providing Other* 2002; 179:1013–1021
expected sufficient off-site reading, per-
protocol population. 7. European Medicines Agency (EMA). Questions
information information
Asterisk denotes and answers on the review of gadolinium-­
80 not providing all the containing contrast agents: document reference
expected information,
EMEA/727399/2009. EMA website. www.ema.
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not providing enough


information, or not europa.eu/docs/en_GB/document_library/Referrals_
60 applicable. document/gadolinium_31/WC500015635.pdf.
Percentage

Published 2009. Accessed January 2010


44.6 % 8. Frydrychowicz A, Winterer JT, Zaitsev M, et al.
42.9 % 43.7 % 43.1 %
Visualization of iliac and proximal femoral artery
40
34.3 % 35.1 % hemodynamics using time-resolved 3D phase
30 % 30.8 %
27.1 % contrast MRI at 3T. J Magn Reson Imaging 2007;
25.4 %
21 % 21.9 % 25:1085–1092
20 9. Achenbach M, Figiel JH, Burbelko M, Heverha-
gen JT. Prospective comparison of image quality
and diagnostic accuracy of 0.5 molar gadobenate
0 dimeglumine and 1.0 molar gadobutrol in con-
Gadoterate Gadobutrol Gadoterate Gadobutrol trast-enhanced run-off magnetic resonance angi-
Meglumine Meglumine
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protocol to ensure comparability between (Hôpital Pontchaillou, Rennes, France), Ann eral arterial occlusive disease: evaluation of a high
the two groups, although it has been shown Leicher-Düber (Universitätmedizin der Jo- spatial and temporal resolution 3-T MR protocol with
that a time-resolved MRA, or the acquisition hannes Gutenberg-Universität Mainz, Mainz, a low total dose of gadolinium versus conventional
of an additional high-resolution static MRA Germany), Barbara Krug (Clinical Universi- angiography. Radiology 2010; 257:879–887
with a second contrast material bolus, could ty of Cologne Medical School, Cologne, Ger- 11. Hentsch A, Aschauer M, Balzer J, et al. Gadobu-
further improve the results of 3-T MRA be- many), and Charles Arteaga (Centre Hospit- trol-enhanced moving-table magnetic resonance
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such additional scans, the level of diagnostic disease: a prospective, multicenter blinded com-
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