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1 Department of Radiology, Universitätsklinikum Charité,
Medizinische Fakultät, Humboldt-Universität zu Berlin, Schumannstr.
20/21, 10098 Berlin, Germany.
2 Department of Radiology, Leiden University Medical Center, Albinusdreef 2,
2333 AA Leiden, The Netherlands.
3 Department of Radiology, Erasmus University Medical Center Rotterdam, 40,
Doctor Molewaterplein, NL 3015 GD Rotterdam, The Netherlands.
4 Department of Radiology, University Hospital Nijmegen—St. Radboud, 6500
HB Nijmegen, The Netherlands.
5 Abt. Röntgendiagnostik I, Klinikum der Georg-August-Universität,
Robert-Koch-Str. 40, D-37075 Göttingen, Germany.
6 Department of Radiology, University Hospital Leuven, Herestr. 49, 3000 Leuven,
Belgium.
7 Department of Radiology, German Cancer Research Center, Im Neuenheimer Feld
280, D-69120 Heidelberg, Germany.
8 Department of Diagnostic Radiology, University Hospital, 66421 Homburg/Saar,
Germany.
9 Instituto di Scienze Radiologiche e Formazione dell'Immagine, Ospedale SS.
Annunziata, Via P Valignani 66100, Chieti, Italy.
10 Magnetic Resonance Unit, Royal Brompton Hospital, Sidney St., London SW3 6NP,
United Kingdom.
11 Department of Radiology, Scientific Institute S. Raffaele, University
Hospital, Milan, Italy.
12 Bracco-Byk Gulden, Max Stromeyer Str., 57, 78467 Konstanz, Germany.
13 Worldwide Medical Affairs, Bracco Imaging SpA, Via E. Folli, 50, 20134,
Milano, Italy.
Received July 30, 2001;
accepted after revision June 7, 2002.
Address correspondence to T. J. Kroencke.
Abstract
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SUBJECTS AND METHODS. Ninety-four patients with suspected abnormality of the abdominal aorta or renal arteries underwent unenhanced three-dimensional gradient-recalled echo time-of-flight MR angiography and contrast-enhanced MR angiography after the IV injection of one of four doses of gadobenate dimeglumine (0.025, 0.05, 0.1, and 0.2 mmol/kg of body weight). Efficacy was assessed on-site and by two blinded off-site reviewers in terms of change in total diagnostic quality score and diagnostic quality score per vessel segment from baseline unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography. Secondary efficacy end points included lesion count and level of confidence in lesion characterization. Safety assessments comprised adverse event monitoring, physical evaluation, vital signs, ECG, and laboratory investigations.
RESULTS. A significant change in the total diagnostic quality score from unenhanced to contrast-enhanced MR angiography was observed at all doses. The change increased with increased dose, plateauing at the 0.1 mmol/kg dose level. More patients with lesions detected and increased reviewer confidence for lesion characterization were noted on contrast-enhanced MR angiography compared with unenhanced MR angiography, although no dose-related trends were observed. All doses were well tolerated, and no significant changes in safety parameters were observed.
CONCLUSION. Gadobenate dimeglumine is an effective and safe agent for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. A dose of 0.1 mmol/kg of body weight appears to be the most suitable.
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Gadobenate dimeglumine is a gadolinium-based contrast agent approved in Europe for MR imaging of the central nervous system and liver. Its T1 relaxivity in blood (R1 = 9.7 mmol-1 · sec-1) [3] exceeds that of other available gadolinium agents because it has a capacity for weak and transient interaction with serum albumin [7]. Preliminary studies in healthy volunteers have shown that gadobenate dimeglumine achieves a higher and longer lasting vascular signal enhancement in the abdominal aorta than gadopentetate dimeglumine, a non—protein-interacting MR imaging contrast agent, when administered at the same dose and injection rate [8]. Our study was conducted in patients with suspected abnormalities of the abdominal aorta or renal arteries to determine more precisely the dose—response relationship of various qualitative determinants of diagnostic efficacy after the administration of gadobenate dimeglumine for contrast-enhanced MR angiography of these vascular areas. The study was a phase II clinical trial designed for regulatory approval and was subject to regulatory control.
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Patients
Ninety-four patients (63 men, 31 women; mean age, 58.3 years) were enrolled
in the study. Patients were included if they were 18-80 years old and had a
suspected vessel abnormality of the abdominal aorta or renal arteries on the
basis of clinical history or any imaging study. Patients were excluded if they
were pregnant or lactating, addicted to drugs, suffering from dementia or some
form of psychiatric disorder, had a serious medical condition or other
circumstances that made it highly unlikely that they would complete the study,
had severe claustrophobia, or had other contraindications for MR imaging.
Patients were also excluded if they had received another investigational drug
within 30 days before administration of the study agent, had received any
other contrast agent within 48 hr before administration of the study agent, or
were scheduled to receive another contrast agent before completion of a 24-hr
follow-up examination. Finally, patients with class III or IV congestive heart
failure according to the New York Heart Association classification
[9] were also excluded.
Although these patients are likely to benefit markedly from contrast-enhanced
MR angiography as opposed to unenhanced time-of-flight MR angiography, the
successful outcome of the study required the inclusion of only patients who
were likely to complete the study.
Patients were randomly selected to receive one of four doses of gadobenate dimeglumine: 25 patients (16 men, nine women; mean age, 56.6 ± 12.6 years) received a dose of 0.025 mmol/kg, 23 patients (18 men, five women; mean age, 61.7 ± 13.1 years) received a dose of 0.05 mmol/kg, 22 patients (17 men, five women; mean age, 57.5 ± 13.1 years) received a dose of 0.1 mmol/kg, and 24 patients (12 men, 12 women; mean age, 57.6 ± 14.3 years) received a dose of 0.2 mmol/kg. The four dose groups were comparable with respect to weight (ranging between mean weights of 72.9 and 85.3 kg) and height (ranging between mean heights of 168.5 and 172.8 cm).
Contrast Agent
An 0.5-mol formulation of gadobenate dimeglumine (MultiHance; Bracco,
Milan, Italy) was administered at the allocated dose through an injection
cannula placed in a cubital vein of the arm. An automatic infusion system
operating at an injection rate of 2 mL/sec was used. Each injection of
gadobenate dimeglumine was followed by a 20-mL saline flush injected at the
same rate.
MR Imaging
Each patient underwent MR imaging on a 1.5-T system (Magnetom Vision,
Siemens Medical Systems, Erlangen, Germany; Signa, General Electric Medical
Systems, Milwaukee, WI; or Gyroscan NT power track 4000, Philips Medical
Systems, Eindhoven, The Netherlands) operating with a gradient strength of 20
mT/m or greater and equipped with a phased array body coil. The field of view
was tailored to include the abdominal aorta, the left and right renal arteries
from their origin to the segmental branches, and both kidneys.
Patients underwent both unenhanced time-of-flight MR angiography and contrast-enhanced MR angiography. The unenhanced time-of-flight images (image set 1) were acquired in the axial plane before administration of gadobenate dimeglumine using a three-dimensional gradient-recalled echo time-of-flight sequence. The minimum requirements for the gradient-recalled echo time-of-flight sequence (image set 1) were a field of view of 360 mm, a slab thickness of 70 mm, a slice thickness of 1.5 mm, spatial resolution of 1.37 x 1.37 x 1.5 mm, two excitations, and a scanning time of no more than 10 min. Contrast-enhanced MR angiography (image set 2) was performed during breath-hold using a three-dimensional gradient-recalled echo sequence after a bolus injection of the assigned dose. For contrast-enhanced MR angiography the following parameter ranges were required: TR/TE, 7/2.8 or shorter; flip angle, 40°; coronal plane; field of view, 360-400 mm; slice thickness, 1.5 mm; slab thickness, 80 mm; spatial resolution, 1.38 x 1.37 x 3 mm (3 mm measured, 1.5 mm after interpolation); one excitation; scanning time, 19-26 sec. The center of k-space of the sequence was acquired after 20% of the total acquisition time had passed.
Timing of the bolus for contrast-enhanced MR angiography was calculated on
the basis of a dynamic single-slice two-dimensional gradient-recalled echo
sequence performed in the axial plane with a frequency of one image per second
after a bolus injection of 2 mL of the study compound and a flush of 20 mL of
saline solution at an injection rate of 2 mL/sec. The delay between the start
of the injection and the start of the acquisition was calculated according to
the following formula:
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Digital Subtraction Angiography
Digital subtraction angiography was not required as part of the study
protocol and was performed as an adjunct in fewer than 30% of the patients.
Therefore, no statistical analysis was performed.
Image Analysis
All images were evaluated on-site by the principal investigator and
off-site by two independent reviewers who were unaffiliated with any of the
centers in the study. The on-site principal investigator was unaware of the
dose of gadobenate dimeglumine administered, whereas the off-site reviewers
were unaware of both the dose administered and all data concerning the patient
(identity, medical history, clinical profile, laboratory results, and findings
of other imaging procedures). Each reviewer assessed the images in a random
order.
Nine vessel segments were designated for evaluation by on-site and off-site reviewers: segment I, the ostium of the renal arteries (left and right); segment II, the proximal section of the extraparenchymal renal arteries (left and right); segment III, the distal section of the extraparenchymal renal arteries (left and right); segment IV, the intraparenchymal segmental arteries (left and right); and segment V, the abdominal aorta from just above the celiac axis to the level just above the aortic bifurcation.
Technical Quality
On-site reviewers assessed whether the unenhanced time-of-flight MR
angiography and contrast-enhanced MR angiography images were of sufficient
technical quality. Patients with at least one image set of insufficient
technical quality were excluded from further on-site evaluation. Off-site
reviewers evaluated each image set for technical quality in a more detailed
manner with respect to coverage and the presence of motion, enfolding, and
ferromagnetic artifacts and determined whether image assessment was
compromised. Only if a reviewer considered that an image set was compromised
because of incomplete coverage of the nine designated vessel segments was no
further efficacy assessment performed for that patient.
Efficacy Evaluation
The primary efficacy end point of the study was the change in the total
diagnostic quality score per patient from unenhanced time-of-flight MR
angiography to contrast-enhanced MR angiography.
Diagnostic quality score.—Diagnostic quality for each of the nine vessel segments was determined by means of the following 5-point scale: 0, diagnostic information is poor, impossible to detect or exclude vascular lesions; la, diagnostic information is moderate, vascular lesions are possibly absent; 1p, diagnostic information is moderate, vascular lesions are possibly present; 2a, diagnostic information is adequate, vascular lesions are definitely absent; and 2p, diagnostic information is adequate, vascular lesions are definitely present.
On the basis of this scale, a vessel segment received a score of 0 if it was impossible to determine whether vascular lesions were present or absent, a score of 1 if the reviewers considered that vascular lesions were possibly present or possibly absent, and a score of 2 if vascular lesions were considered to be definitely present or definitely absent.
For each image set, the total diagnostic quality score was calculated as the sum of the numeric scores assigned to each of the nine segments assessed by on-site and off-site reviewers; the range of scores possible for each image set was therefore 0-18. A mean total diagnostic quality score for the unenhanced image sets and the contrast-enhanced image sets was calculated for each dose group as the (adjusted mean) change in the mean total diagnostic quality score from baseline unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography. The overall dose effect was calculated by comparison of the change in the mean total diagnostic quality score for each dose group.
Additionally, the number of patients with a change (decrease or increase) from unenhanced to contrast-enhanced MR angiography in the number of segments with adequate diagnostic information (i.e., segments assigned a score of 2a, definitely absent, or 2p, definitely present) was assessed by off-site reviewers, as was the number of patients with no change. Finally, the total number of segments with adequate diagnostic information, as assessed by the off-site reviewers, was calculated for the unenhanced and contrast-enhanced image sets.
Secondary efficacy end points in the study were lesion count and the level of confidence in lesion characterization. All lesions (i.e., vessel abnormalities) detected on each image set were annotated and numbered on paper maps.
Lesion count.—The number of patients with at least one lesion detected on unenhanced time-of-flight MR angiography and contrast-enhanced MR angiography image sets was calculated for both on-site investigators and off-site reviewers.
Confidence in lesion characterization.—Each lesion detected was characterized by on-site and off-site reviewers and assigned to one of the following categories: stenosis, occlusion without collateral vessels, occlusion with collateral vessels, aneurysm, accessory artery (single), accessory artery (multiple), vessel displacement, or "other." If a reviewer identified a lesion not included in this list, the lesion was classified as "other" and the actual characterization specified. If a reviewer was unable to characterize a lesion, a classification of "unknown" was recorded. Finally, if no lesions were identified, the finding was recorded as "no abnormality."
The level of confidence for the characterization assigned to each lesion was scored according to the following scale: 0, doubtful (i.e., character of lesion is unknown); 1, possible (other differential diagnoses might be possible); 2, likely (although other differential diagnoses may be possible, this diagnosis is the most likely); and 3, certain (any other differential diagnosis can be excluded).
For the level of confidence in lesion characterization, a score of -1 was assigned if a lesion was not detected on either unenhanced time-of-flight MR angiography or contrast-enhanced MR angiography but was detected on the other method. The numbers of lesions for which reviewer confidence increased, remained unchanged, or decreased from unenhanced time-of-flight to contrast-enhanced MR angiography were calculated.
Statistical Analysis
Regarding the primary efficacy parameter (i.e., the total diagnostic
quality score), comparison among dose groups for contrast-enhanced MR
angiography was performed using analysis of covariance with the total baseline
score (unenhanced time-of-flight MR angiography) as covariate. Adjusted means
(including 95% confidence intervals) and p values from the F test
were calculated for determination of the overall dose effect. The level of
significance used was 5%, and all tests were two-sided. The overall
dose—response curves for the two off-site reviewers and the on-site
principal investigator were plotted using the mean response at each dose.
Safety Evaluations
Clinical monitoring (physical examination, vital sign measurements) and the
recording of ECGs were performed before the patient entered the bore of the
magnet (predose), immediately after the patient left the magnet
(postcontrast), and 24 hr after the MR imaging procedure (follow-up).
Additionally, blood and urine samples were obtained predose and at the 24-hr
follow-up examination.
The safety of the four doses of gadobenate dimeglumine was assessed in
terms of the incidence of clinical adverse events and in terms of changes from
predose findings in physical examination, vital signs, ECGs, and safety
laboratory variables. The latter comprised evaluations of hematology
(hematocrit; hemoglobin; and counts of RBCs, WBCs, and platelets), blood
chemistry (glucose, creatinine, total bilirubin, total protein, albumin,
aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase,
-glutamyl transpeptidase, sodium, potassium, and chloride), and
urinalysis (protein, glucose, ketones, blood, and pH). Adverse events were
classified as either serious (i.e., death, life-threatening, requiring or
prolonging hospitalization) or not serious (rated as mild, moderate, or
severe). The relationship of each adverse event to the study agent was
classified as probable, possible, not related, or unknown.
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Off-site reviewers 1 and 2 excluded eight patients and two patients, respectively, from further evaluation on the basis of insufficient segment coverage. Off-site reviewer 1 excluded seven patients because of insufficient segment coverage in the unenhanced image set and one patient because only an unenhanced image set was available. Off-site reviewer 2 excluded one patient because of insufficient segment coverage in the unenhanced image set and one patient because only an unenhanced image set was available. Although both reviewers considered the contrast-enhanced image sets of all 93 evaluable patients to have sufficient segment coverage, the number of patients available for further off-site evaluation was 86 for reviewer 1 and 92 for reviewer 2.
Reviewers 1 and 2 considered most unenhanced time-of-flight MR angiography image sets to be compromised. For both reviewers, the principal reason for compromised unenhanced images was motion artifacts, which were noted in 19, 18, 18, and 16 patients by reviewer 1 and in 23, 20, 19, and 22 patients by reviewer 2 for the 0.025, 0.05, 0.1, and 0.2 mmol/kg dose groups, respectively. Enfolding (phase wrap) artifacts on unenhanced images were noted by reviewer 1 for only one patient in the 0.2 mmol/kg dose group but by reviewer 2 for 12, seven, seven, and six patients in each of the four dose groups, respectively. Ferromagnetic artifacts on unenhanced images were noted for just one patient in the 0.1 mmol/kg dose group by reviewer 2.
Motion artifacts on contrast-enhanced images were reported for just one patient in the 0.025 mmol/kg dose group by reviewer 1 but for six. nine, seven, and 11 patients in the 0.025, 0.05, 0.1, and 0.2 mmol/kg dose groups, respectively, by reviewer 2. Reviewer 2 also noted enfolding artifacts on contrast-enhanced images in 10, 12, six, and six patients for each of the four dose groups, respectively, whereas reviewer 1 noted no enfolding artifacts at all on contrast-enhanced images. Neither reviewer noted ferromagnetic artifacts on contrast-enhanced images.
Efficacy Evaluation
Diagnostic quality score.—For the on-site reviewers, the
mean total diagnostic quality scores for the unenhanced time-of-flight MR
angiography image sets were 3.2, 0.8, 2.2, and 2.6 for the 0.025, 0.05, 0.1,
and 0.2 mmol/kg dose groups, respectively. For the contrast-enhanced MR
angiography image sets, the corresponding scores were 9.2, 11.4, 13.6, and
12.8, respectively. The adjusted mean change from unenhanced to
contrast-enhanced MR angiography showed an increase with increased dose that
plateaued at the 0.1 mmol/kg dose group. The overall dose effect observed by
the on-site reviewers was statistically significant (p = 0.041).
For off-site reviewer 1, the mean total diagnostic quality scores for unenhanced time-of-flight MR angiography were similar among the four dose groups (4.0, 3.3, 3.6, and 4.3 for the 0.025, 0.05, 0.1, and 0.2 mmol/kg dose groups, respectively). For contrast-enhanced MR angiography, the corresponding total diagnostic quality scores were 11.5, 12.6, 13.7, and 13.9, respectively. Although the overall dose effect was not significant (p = 0.078), evidence was seen of improved diagnostic quality with increased dose that appeared to plateau at the 0.1 mmol/kg dose. Similar results were obtained for off-site reviewer 2. For that reviewer, the mean total diagnostic quality scores for the 0.025, 0.05, 0.1, and 0.2 mmol/kg dose groups were 4.6, 3.9, 4.6, and 4.5, respectively, for unenhanced time-of-flight MR angiography, and 11.0, 12.0, 13.6, and 12.7, respectively, for contrast-enhanced MR angiography. In this case, the mean increase in diagnostic quality score from unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography ranged from a minimum of 6.5 for the 0.025 mmol/kg dose group to a maximum of 9.1 for the 0.1 mmol/kg dose group, and the overall dose effect was again statistically significant (p = 0.035). On-site and off-site results for the change in mean total diagnostic quality score among the four dose groups are shown in Figure 1.
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Because unenhanced time-of-flight MR angiography is only infrequently performed in routine clinical practice, it is the diagnostic quality of the contrast-enhanced images alone that is of direct clinical relevance. Analysis of the diagnostic quality scores for all patients with evaluable contrast-enhanced image sets (n = 93 for reviewers 1 and 2, n = 92 for the on-site investigators) revealed few differences from that observed in patients with both unenhanced time-of-flight and contrast-enhanced MR angiography images available (mean diagnostic quality scores after contrast enhancement of 11.3, 12.7, 13.5, and 13.6 for reviewer 1; 11.0, 12.0, 13.6, and 12.7 for reviewer 2; and 10.2, 12.1, 13.1, and 12.4 for the on-site investigators for the 0.025, 0.05, 0.1, and 0.2 mmol/kg treatment groups, respectively). Statistical comparison among treatment groups is shown in Table 1. For both the on-site investigators and reviewers 1 and 2, significantly (p < 0.05) greater diagnostic quality was noted for images from the 0.1 mmol/kg treatment group than for images from the 0.025 mmol/kg treatment group. Similar findings were noted also by the on-site investigators and reviewer 1 for images from the 0.2 mmol/kg treatment group compared with images from the 0.025 mmol/kg treatment group. On the other hand, no significant differences were noted by any reviewer for any other comparison, including the comparison between images from the 0.1 and the 0.2 mmol/kg treatment groups.
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The number of patients with a change from unenhanced to contrast-enhanced
MR angiography in the number of segments having adequate diagnostic
information is shown in Table
2. For reviewer 1, most patients (
87.5% in all dose groups)
had an increase in the number of segments with adequate diagnostic information
from unenhanced time-of-flight MR angiography to contrast-enhanced MR
angiography. Some evidence was also seen that the percentage of patients with
an increase in adequate diagnostic information increased with increased dose
(i.e., from 87.5% in the 0.025 mmol/kg group to 100% in the 0.2 mmol/kg
group). Similarly for reviewer 2, most patients (84.0% in all dose groups)
had an increase in the number of segments with adequate diagnostic information
after contrast agent administration. Again, some evidence was seen that the
percentage of patients with an increase in adequate diagnostic information
increased with increased dose (i.e., from 84.0% in the 0.025 mmol/kg group to
95.7% in the 0.2 mmol/kg group).
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A breakdown of segments with adequate diagnostic information on unenhanced time-of-flight MR angiography and contrast-enhanced MR angiography image sets is presented in Table 3. For both reviewers, the percentage of segments with adequate diagnostic information increased substantially for segments I, II, III, and V from unenhanced to contrast-enhanced MR angiography for all dose groups, and evidence was seen that the percentage tended to increase with increased dose and to plateau beginning at the 0.1 mmol/kg dose. For segment IV, neither reviewer classified any segment as having adequate diagnostic information on unenhanced time-of-flight MR angiography image sets, and only minimal improvement was seen for contrast-enhanced MR angiography.
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Lesion count.—Table 4 shows the number of patients with at least one lesion detected on unenhanced time-of-flight MR angiography and contrast-enhanced MR angiography per dose group. The number of lesions detected by on-site and off-site reviewers increased by more than 50% (mean) from unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography for all dose groups. No dose-related trends were seen.
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Confidence in lesion characterization.—The numbers and percentages of lesions in each dose group for which a change in confidence was noted from unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography are reported in Table 5 for both off-site reviewers and the on-site investigators. Both off-site reviewers reported increased confidence in lesion characterization from unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography for most lesions in each dose group. For both reviewers, the largest percentage of lesions for which confidence was increased was seen in the 0.1 mmol/kg dose group (96.2% for reviewer 1 and 95.0% for reviewer 2). However, whereas no dose-related trend was seen for reviewer 1, a slight trend with increased dose, which appeared to plateau at the 0.1 mmol/kg dose group, was noted for reviewer 2.
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The mean change in diagnostic confidence score was also greatest for the 0.1 mmol/kg dose group for both off-site reviewers. For reviewer 1, the mean increases in confidence score from unenhanced time-of-flight to contrast-enhanced MR angiography were 3.1, 2.8, 3.3, and 2.4 for the 0.025, 0.05, 0.1, and 0.2 mmol/kg dose groups, respectively. For reviewer 2 the corresponding scores were 2.3, 2.8, 3.4, and 2.7, respectively.
The on-site investigators similarly reported increased confidence in lesion characterization from unenhanced to contrast-enhanced MR angiography for most lesions in each dose group. For these investigators, few differences among the four dose groups were noted either in terms of the percentages of lesions for which confidence was increased (between 94.1% and 96.3%) or in terms of the mean increase in diagnostic confidence score (2.8, 3.3, 3.0, and 3.3 for the four dose groups, respectively).
Although comparative digital subtraction angiography was not a requisite part of the study, this procedure, when used, suggested that doses of gadobenate dimeglumine as low as 0.025 mmol/kg (Fig. 2A,2B) or 0.05 mmol/kg (Fig. 3A,3B) may frequently be sufficient for accurate detection and diagnosis of stenosis. On the other hand, improved image quality and better depiction of small branching vessels is achieved with gadobenate dimeglumine doses of 0.1 mmol/kg (Fig. 4) or 0.2 mmol/kg (Fig. 5).
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Safety
Ten patients (10.6%) experienced 12 nonserious adverse events after the
administration of the contrast agent. Four of these patients (4.3%) reported
four adverse events that were considered to be unrelated to the administration
of study agent, and the remaining six patients (6.4%) reported eight adverse
events that were considered to potentially have some relationship to the study
agent. No evidence of any dose-related trend was apparent, and no event was
reported by more than one patient in any dose group.
The nonserious adverse events considered to potentially have some
relationship to the study agent comprised three reports (nausea, palpitation,
and hematuria) by one patient in the 0.025 mmol/kg dose group, one report
(lowered albumin) by one patient in the 0.05 mmol/kg dose group, two reports
(nausea; and increased -glutamyl transpeptidase, alanine
aminotransferase, and aspartate aminotransferase) by two patients in the 0.1
mmol/kg dose group, and two reports (nausea and urticaria) by two patients in
the 0.2 mmol/kg dose group. All patients experiencing an adverse event
recovered without sequelae, and medication was given only to the patient
experiencing urticaria. No patient was removed from the study because of
adverse events after the administration of the contrast agent, and no patient
experienced a serious adverse event. All adverse events reported were
classified by the investigators as either mild or moderate in intensity. No
overall trends in vital signs were considered to be clinically significant;
and no clinically meaningful trends in hematology, clinical chemistry, or
urinalysis parameters were noted.
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Attempts are being made to further improve contrast-enhanced MR angiography through developments in gradient systems, pulse sequences, and contrast agents. Recent advances in gradient performance and sequence design have led to improvements of contrast-enhanced MR angiography to the extent that image acquisition during breathholding has become possible, yielding high-contrast images with no motion artifacts [4]. Further approaches to improving the performance of contrast-enhanced MR angiography are the use of gadolinium-based contrast agents with higher T1 relaxation rates than conventional agents and the use of contrast agents whose intravascular stay is prolonged so as to extend the period of maximum contrast enhancement. Although agents of the latter group (the so-called blood pool agents) are currently undergoing clinical trials [17,18,19,20], gadobenate dimeglumine, a member of the former group, has already been approved in Europe for MR imaging of the central nervous system and the liver.
Unlike conventional agents, gadobenate dimeglumine has a capacity for weak and transient interaction with serum albumin [7], which results in R1 and R2 relaxivity values that are about twice those of conventional agents (R1 = 9.7 mmol-1 · sec-1 compared with 4.3-5.0 mmol- · sec-1 for conventional agents; R2 = 12.5 mmol-1 · sec-1 compared with 5.0-6.3 mmol-1 · sec-1 for conventional agents) [5]. Early studies have shown that gadobenate dimeglumine provides greater and longer lasting vascular enhancement in the abdominal aorta than does gadopentetate dimeglumine when administered at the same dose and injection rate [8]. More recently, Völk et al. [21] have shown a significantly (p < 0.05) improved signal-to-noise ratio for 0.1 mmol/kg of gadobenate dimeglumine compared with 0.1 mmol/kg of gadopentetate dimeglumine for both the aorta and the left and right renal arteries. An improved signal-to-noise ratio was also noted for 0.05 mmol/kg of gadobenate dimeglumine compared with 0.1 mmol/kg of gadopentetate dimeglumine and for 0.1 mmol/kg of gadobenate dimeglumine compared with 0.2 mmol/kg of gadopentetate dimeglumine. In these cases, however, the improvements in the signal-to-noise ratio were not statistically significant. The purpose of our study was to determine the optimal dose of gadobenate dimeglumine for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. To the best of our knowledge, our study is the first randomized and double-blinded trial in this vascular area that evaluates the efficacy and safety of an MR angiography contrast agent over a wide range of doses.
Because the study was a phase II clinical trial performed for regulatory purposes, its overall design was necessarily governed by regulatory requirements. Thus, the pulse sequences chosen had to be readily available in a standardized fashion at each center at the time the study was begun. In our study, a three-dimensional unenhanced time-of-flight MR angiography sequence was clinically feasible and efficient, and the technique was more readily available at each center than other unenhanced time-of-flight sequences. Although three-dimensional unenhanced time-of-flight MR angiography is not used frequently in routine clinical practice, its use in this study was deemed appropriate in terms of regulatory requirements. Moreover, given that the primary end point of the study was to determine the optimal dose of gadobenate dimeglumine for contrast-enhanced MR angiography of the abdominal aorta and renal arteries, the choice of unenhanced reference sequences cannot be considered as having any bearing on the overall results because the sequence was identical for each of the dose groups tested.
With respect to contrast efficacy, the principal finding to emerge from this study is that a dose of 0.1 mmol/kg of gadobenate dimeglumine appears the most appropriate for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. For the primary efficacy end point of the study (i.e., the change in the mean total diagnostic quality score from unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography), the trends for the on-site investigators and off-site reviewers were similar, with evidence suggesting that diagnostic quality increases with increased dose up to a dose of 0.1 mmol/kg and that little, if any, additional benefit occurs at the highest dose investigated, 0.2 mmol/kg. Similar conclusions were reached by Völk et al. [21], who reported a saturation pattern at a dose of 0.1 mmol/kg and an effective diagnostic range of 0.05-0.15 mmol/kg of gadobenate dimeglumine. Support for these conclusions in our study comes also from the assessment by dose of segments with adequate diagnostic information on contrast-enhanced image sets compared with unenhanced time-of-flight image sets. On the other hand, evaluation of the secondary end points of the study revealed equivocal results and no specific dose-related trends. These secondary evaluations, however, were limited by the fact that a true gold standard comparison was not available for most patients in the study because this was a phase II trial for regulatory purposes in which a reference standard examination (e.g., digital subtraction angiography) was not a requirement. As stated previously, the conclusions of the study are limited to the primary end point of the study only.
Studies using conventional MR imaging contrast agents show that signal intensity increases with increased dose in a nonlinear fashion until T2 and T2* effects eventually lead to signal loss [22, 23]. A quantitative parameter such as measurement of signal intensity in the aorta for each dose group and acquired image set might have shown that a steady increase occurs in signal intensity from the 0.025 mmol/kg dose group to the 0.2 mmol/kg dose group. However, in our study a qualitative parameter was chosen that was linked to the diagnostic quality of each segment and then summed over all nine segments. That diagnostic quality is related to intravascular signal intensity enhancement does not mean that the gain in signal intensity enhancement at greater doses corresponds to an equivalent gain in diagnostic quality. Therefore, the degree of signal intensity enhancement cannot be considered the primary indicator of diagnostic quality. The absence of a marked improvement for the 0.2 mmol/kg dose compared with the 0.1 mmol/kg dose is possibly a consequence of the high image quality already achievable at a dose of 0.1 mmol/kg. If so, the need for a dose of only 0.1 mmol/kg would give this agent a potential advantage over other agents that have no capacity for protein interaction and for which doses greater than 0.1 mmol/kg are frequently and necessarily used [24].
In our study, images acquired with a dose of 0.2 mmol/kg were often more visually impressive than images obtained with the other doses (Fig. 5). However, on the basis of the assessment criteria, these "better" images were not considered to markedly improve lesion detection, confidence, or diagnostic quality beyond that achievable with a 0.1 mmol/kg dose. Images acquired with a dose of 0.05 mmol/kg, on the other hand, were considered to be less satisfactory overall than images acquired with a dose of 0.1 mmol/kg, although clearly, for some patients in routine practice, a 0.05 mmol/kg dose is already satisfactory.
Each dose in our study was administered at a constant injection rate of 2 mL/sec, which resulted in a different bolus duration for each dose. For instance, in a 70-kg patient given a dose of 0.1 mmol/kg (0.2 mL/kg of a 0.5-mol formulation), this dose results in an overall injection time of 7 sec as opposed to an overall injection time of 14 sec for a dose of 0.2 mmol/kg and 3.5 and 1.75 sec for doses of 0.05 and 0.025 mmol/kg, respectively. The shorter injection times for the lower doses might lead to a short duration of blood T1 shortening and result in poorer image quality for those doses than might otherwise have been expected. However, diagnostic images were obtained even with the lowest dose used in this study.
With respect to the assessment of segments with improved diagnostic information on contrast-enhanced images, increases with increased dose were noted primarily for the main renal arteries (segments I, II, and III) and the abdominal aorta (segment V). For the intrarenal arteries (segment IV), a diagnostic quality score of 0 (diagnostic information very poor) was assigned to all unenhanced time-of-flight image sets, and only minimal improvement was seen on contrast-enhanced images regardless of the dose administered. In many respects, this finding was not unexpected, and it may be explained by visualization difficulties in this segment caused by the location and the small size of the vessels, enhancement of the surrounding renal parenchyma, the overlap of venous structures, calices, and the spatial resolution of the technique used (1.7 x 1.5 x 1.5 mm) [25].
Safety data collected from this trial confirm that gadobenate dimeglumine administered IV at a dose of up to 0.2 mmol/kg of body weight is safe and well tolerated. We observed no clinically serious effects on vital signs, ECG measurements, or laboratory parameters; and no dose-related trends in the incidence of adverse events were observed. The overall incidence of adverse events compares favorably with that observed elsewhere for the gadobenate dimeglumine clinical development program as a whole [26].
In conclusion, our study shows contrast-enhanced MR angiography with gadobenate dimeglumine to be safe and efficacious for imaging vessel abnormalities in the region of the abdominal aorta and renal arteries. Although efficacy was shown for all four doses, a dose of 0.1 mmol/kg of body weight appears the most appropriate and is in accordance with the conclusions of others [21]. Because recent technical improvements are largely based on a reduction of the TR and TE values of MR angiography sequences, the availability of an agent with a higher T1 relaxivity may allow a further reduction of either the TR and TE or the amount of contrast medium administered, without a loss of image quality. A further increase in signal intensity may also be achievable by optimizing the flip angle of MR angiography sequences with respect to the dose—response curve of gadobenate dimeglumine. Future work might usefully be directed at comparing gadobenate dimeglumine with other gadolinium-based agents for contrast-enhanced MR angiography of the abdominal arteries, and at comparing contrast-enhanced MR angiography using gadobenate dimeglumine with other techniques such as intraarterial digital subtraction angiography.
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= off-site reviewer 1, 
= off-site reviewer 2, 
= on-site
principal investigators.
