The TRUTH confirmed: validation of an intraindividual comparison of gadobutrol and gadoteridol for imaging of glioblastoma using quantitative enhancement analysis.

BACKGROUND: Previous intraindividual comparative studies evaluating gadobutrol and gadoteridol for contrast-enhanced magnetic resonance imaging (MRI) of brain tumours have relied on subjective image assessment, potentially leading to misleading conclusions. We used artificial intelligence algorithms to objectively compare the enhancement achieved with these contrast agents in glioblastoma patients. METHODS: Twenty-seven patients from a prior study who received identical doses of 0.1 mmol/kg gadobutrol and gadoteridol (with appropriate washout in between) were evaluated. Quantitative enhancement (QE) maps of the normalised enhancement of voxels, derived from computations based on the comparison of contrast-enhanced T1-weighted images relative to the harmonised intensity on unenhanced T1-weighted images, were compared. Bland-Altman analysis, linear regression analysis and Pearson correlation coefficient (r) determination were performed to compare net QE and per-region of interest (per-ROI) average QE (net QE divided by the number of voxels). RESULTS: No significant differences were observed for comparisons performed on net QE (mean difference -24.37 ± 620.8, p = 0.840, r = 0.989) or per-ROI average QE (0.0043 ± 0.0218, p = 0.313, r = 0.958). Bland-Altman analysis revealed better per-ROI average QE for gadoteridol-enhanced MRI in 19/27 (70.4%) patients although the mean difference (0.0043) was close to zero indicating high concordance and the absence of fixed bias. CONCLUSIONS: The enhancement of glioblastoma achieved with gadoteridol and gadobutrol at 0.1 mmol/kg bodyweight is similar indicating that these agents have similar contrast efficacy and can be used interchangeably, confirming the results of a prior double-blind, randomised, intraindividual, crossover study.

Dose-Lowering in Contrast-Enhanced MRI of the Central Nervous System: A Retrospective, Parallel-Group Comparison Using Gadobenate Dimeglumine.

BACKGROUND: Concerns over gadolinium (Gd) retention encourage the use of lower Gd doses. However, lower Gd doses may compromise imaging performance. Higher relaxivity gadobenate may be suited to reduced dose protocols. PURPOSE: To compare 0.05 mmol/kg and 0.1 mmol/kg gadobenate in patients undergoing enhanced MRI of the central nervous system (CNS). STUDY TYPE: Retrospective, multicenter. POPULATION: Three hundred and fifty-two patients receiving 0.05 (n = 181) or 0.1 (n = 171) mmol/kg gadobenate. FIELD STRENGTH/SEQUENCES: 1.5 T and 3.0 T/precontrast and postcontrast T1-weighted spin echo/fast spin echo (SE/FSE) and/or gradient echo/fast field echo (GRE/FFE); precontrast T2-weighted FSE and T2-FLAIR. ASSESSMENT: Images of patients with extra-axial lesions at 1.5 T or any CNS lesion at 3.0 T were reviewed by three blinded, independent neuroradiologists for qualitative (lesion border delineation, internal morphology visualization, contrast enhancement; scores from 1 = poor to 4 = excellent) and quantitative (lesion-to-brain ratio [LBR], contrast-to-noise ratio [CNR]; SI measurements at regions-of-interest on lesion and normal parenchyma) enhancement measures. Noninferiority of 0.05 mmol/kg gadobenate was determined for each qualitative endpoint if the lower limit of the 95% confidence interval (CI) for the difference in precontrast + postcontrast means was above a noninferiority margin of -0.4. STATISTICAL TESTS: Student's t-test for comparison of mean qualitative endpoint scores, Wilcoxon signed rank test for comparison of LBR and CNR values; Wilcoxon rank sum test for comparison of SI changes. Tests were significant for P < 0.05. RESULTS: The mean change from precontrast to precontrast + postcontrast was significant for all endpoints. Readers 1, 2, and 3 evaluated 304, 225, and 249 lesions for 0.05 mmol/kg gadobenate, and 382, 309, and 298 lesions for 0.1 mmol/kg gadobenate. The lower limit of the 95% CI was above -0.4 for all comparisons. Significantly, higher LBR and CNR was observed with the higher dose. DATA CONCLUSION: 0.05 mmol/kg gadobenate was noninferior to 0.1 mmol/kg gadobenate for lesion visualization. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Prospective Cohort Study of Nephrogenic Systemic Fibrosis in Patients With Stage 3-5 Chronic Kidney Disease Undergoing MRI With Injected Gadobenate Dimeglumine or Gadoteridol.

OBJECTIVE: The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD) and moderate-to-severe impairment of kidney function who had not previously been exposed to gadolinium-based contrast agents (GBCAs) or referred to undergo contrast-enhanced MRI with gadobenate dimeglumine or gadoteridol. SUBJECTS AND METHODS: Two multicenter prospective cohort studies evaluated the incidence of unconfounded NSF in patients with stage 3 CKD (estimated glomerular filtration rate [eGFR] in cohort 1, 30-59 mL/min/1.73 m(2)) or stage 4 or 5 CKD (eGFR in cohort 2, < 30 mL/min/1.73 m(2)) after injection of gadobenate dimeglumine (study A) or gadoteridol (study B). A third study (study C) determined the incidence of NSF in patients with stage 4 or 5 CKD who had not received a GBCA in the 10 years before enrollment. Monitoring for signs and symptoms suggestive of NSF was performed via telephone at 1, 3, 6, and 18 months, with clinic visits occurring at 1 and 2 years. RESULTS: For studies A and B, the populations evaluated for NSF comprised 363 and 171 patients, respectively, with 318 and 159 patients in cohort 1 of each study, respectively, and with 45 and 12 patients in cohort 2, respectively. No signs or symptoms of NSF were reported or detected during the 2 years of patient monitoring. Likewise, no cases of NSF were reported for any of the 405 subjects enrolled in study C. CONCLUSION: To our knowledge, and consistent with reports in the literature, no association of gadobenate dimeglumine or gadoteridol with unconfounded cases of NSF has yet been established. Study data confirm that both gadoteridol and gadobenate dimeglumine properly belong to the class of GBCAs considered to be associated with the lowest risk of NSF.

Contrast-enhanced MR angiography: does a higher relaxivity MR contrast agent permit a reduction of the dose administered for routine vascular imaging applications?

PURPOSE: The authors prospectively compared single dose (0.1 mmol/kg bodyweight) gadobenate dimeglumine with double dose (0.2 mmol/kg bodyweight) gadopentetate dimeglumine for contrast-enhanced magnetic resonance angiography (CE-MRA) in patients with suspected or known steno-occlusive disease of the carotid, renal or peripheral vasculature using an intra-individual crossover study design. MATERIALS AND METHODS: Twenty-eight patients with suspected or known steno-occlusive disease of the carotid (n = 16), renal (n = 5) or peripheral arteries (n = 7) were randomised to receive either 0.1 mmol/kg gadobenate dimeglumine or 0.2 mmol/kg gadopentetate dimeglumine for a first CE-MRA procedure. After 3-5 days all patients underwent a second identical CE-MRA procedure with the other contrast agent. Three blinded readers assessed images for vessel anatomical delineation, disease detection/exclusion, and global preference. Diagnostic performance for detection of ≥51 % stenosis was determined for 20/28 patients who also underwent digital subtraction angiography (DSA). Non-inferiority was assessed using the Wilcoxon signed rank, McNemar and Wald tests. Quantitative (signal-to-noise and contrast-to-noise ratio) enhancement based on 3D maximum intensity projection reconstructions was compared. RESULTS: No differences were noted for any qualitative parameter. Equivalence was reported for all diagnostic preference end-points. Superiority for gadobenate dimeglumine was reported by all readers for sensitivity for disease detection (80.8-86.5 vs. 75.0-82.7 %). Quantitative enhancement was similar for single dose gadobenate dimeglumine and double dose gadopentetate dimeglumine. CONCLUSIONS: Under identical examination conditions a single 0.1 mmol/kg body weight dose of gadobenate dimeglumine can fully replace a double 0.2 mmol/kg body weight dose of gadopentetate dimeglumine for routine CE-MRA procedures.

Pharmacokinetics of gadobenate dimeglumine in children 2 to 5 years of age undergoing MRI of the central nervous system.

PURPOSE: To determine the pharmacokinetic profile of gadobenate dimeglumine in children aged between 2 and 5 years. MATERIALS AND METHODS: Fifteen children scheduled to undergo contrast-enhanced MRI for suspected disease of the central nervous system received a single intravenous injection of 0.1 mmol/kg gadobenate dimeglumine. Children were stratified into three age groups: 2 to <3 years, 3 to <4 years, and 4 to 5 (i.e., <6 years). Serial blood and urine samples collected at prespecified time-points before and after contrast administration were analyzed for gadolinium concentrations. Pharmacokinetic parameters were calculated using noncompartmental and compartmental techniques. RESULTS: Mean values of 65.7 µg/mL for highest blood gadolinium concentration, 0.2 L/h/kg for blood clearance, 0.32 L/kg for steady-state volume of distribution, and 1.2 h for terminal elimination half-life were determined across all age groups combined. On average, more than 80% of the dose was eliminated in the urine during the first 24 h after administration. All pharmacokinetic parameters were similar between age groups and no effects of gender were noted. No adverse events considered related to gadobenate dimeglumine administration were reported. CONCLUSION: In terms of pharmacokinetic profile no dosage adjustment from the approved adult gadobenate dimeglumine dose of 0.1 mmol/kg bodyweight is necessary in children aged between 2 and 5 years.

Contrast-enhanced MRA of the renal and aorto-iliac-femoral arteries: comparison of gadobenate dimeglumine and gadofosveset trisodium.

RATIONALE AND OBJECTIVES: Dedicated contrast agents are now available for contrast-enhanced magnetic resonance angiography (CE-MRA). This study retrospectively compares the safety and diagnostic performance data from Phase III regulatory trials performed to evaluate gadobenate dimeglumine (MultiHance(®)) and gadofosveset trisodium (Vasovist®)) for renal and peripheral CE-MRA. MATERIALS AND METHODS: Similar examination and blinded assessment methodology was utilized in all studies to determine the safety and diagnostic performance of the agents for detection of significant (>50%) steno-occlusive disease. Digital Subtraction Angiography (DSA) was used as the standard of truth. Diagnostic performance data (sensitivity, specificity, predictive values [PVs], and likelihood ratios [LRs]) were compared (Chi-square test). RESULTS: CE-MRA with gadobenate dimeglumine was more specific (92.4% vs. 80.5%, p < 0.0001) and accurate (83.6% vs. 77.1%, p = 0.022) than CE-MRA with gadofosveset in the detection of significant renal artery stenosis. The average sensitivity was higher for gadofosveset (74.4% vs. 67.3%, p = 0.011) in peripheral vessels although gadobenate dimeglumine was more specific (93.0% vs. 88.2%, p < 0.0001) with no difference in accuracy (86.6% vs. 86.3%, p = 0.66). PPVs were higher (p < 0.0001) for gadobenate dimeglumine in both vascular territories. Pre- to post-test shifts in the probability of detecting significant disease were greater after gadobenate dimeglumine. Adverse events in the renal and peripheral studies were reported by 9.2% and 7.7% of patients after gadobenate dimeglumine compared with 30.3% and 22.1% of patients after gadofosveset. CONCLUSION: The diagnostic performance of CE-MRA for the detection of significant steno-occlusive disease is similar with gadofosveset and gadobenate dimeglumine although the rate of adverse events appears higher with gadofosveset.

Multicenter, double-blind, randomized, intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine for MR angiography of peripheral arteries.

PURPOSE: To prospectively compare the image quality and diagnostic performance achieved with doses of gadobenate dimeglumine and gadopentetate dimeglumine of 0.1 mmol per kilogram of body weight in patients undergoing contrast material-enhanced magnetic resonance (MR) angiography of the pelvis, thigh, and lower-leg (excluding foot) for suspected or known peripheral arterial occlusive disease. MATERIALS AND METHODS: Institutional review board approval was granted from each center and informed written consent was obtained from all patients. Between November 2006 and January 2008, 96 patients (62 men, 34 women; mean age, 63.7 years +/- 10.4 [standard deviation]; range, 39-86 years) underwent two identical examinations at 1.5 T by using three-dimensional spoiled gradient-echo sequences and randomized 0.1-mmol/kg doses of each agent. Images were evaluated on-site for technical adequacy and quality of vessel visualization and offsite by three independent blinded readers for anatomic delineation and detection/exclusion of pathologic features. Comparative diagnostic performance was determined in 31 patients who underwent digital subtraction angiography. Data were analyzed by using the Wilcoxon signed-rank, McNemar, and Wald tests. Interreader agreement was determined by using generalized kappa statistics. Differences in quantitative contrast enhancement were assessed and a safety evaluation was performed. RESULTS: Ninety-two patients received both agents. Significantly better performance (P < .0001; all evaluations) with gadobenate dimeglumine was noted on-site for technical adequacy and vessel visualization quality and offsite for anatomic delineation and detection/exclusion of pathologic features. Contrast enhancement (P < or = .0001) and detection of clinically relevant disease (P < or = .0028) were significantly improved with gadobenate dimeglumine. Interreader agreement for stenosis detection and grading was good to excellent (kappa = 0.749 and 0.805, respectively). Mild adverse events were reported for four (six events) and five (eight events) patients after gadobenate dimeglumine and gadopentetate dimeglumine, respectively. CONCLUSION: Higher-quality vessel visualization, greater contrast enhancement, fewer technical failures, and improved diagnostic performance are obtained with gadobenate dimeglumine, relative to gadopentetate dimeglumine, when compared intraindividually at 0.1-mmol/kg doses in patients undergoing contrast-enhanced MR angiography for suspected peripheral arterial occlusive disease.

Contrast-enhanced MR mammography: improved lesion detection and differentiation with gadobenate dimeglumine.

OBJECTIVE: The objective of our study was to intraindividually compare 0.1 mmol/kg doses of gadobenate dimeglumine and gadopentetate dimeglumine for contrast-enhanced breast MRI. SUBJECTS AND METHODS: Forty-seven women (mean age +/- SD, 50.8 +/- 12.9 years) with breast lesions classified as BI-RADS category 3, 4, or 5 for suspicion of malignancy underwent two identical MR examinations at 1.5 T separated by 48-72 hours. T1-weighted gradient-echo images were acquired before contrast administration and at 2-minute intervals after the randomized injection of gadopentetate dimeglumine or gadobenate dimeglumine at 2 mL/s. Two blinded readers evaluated randomized image sets for lesion detection and differentiation as benign or malignant compared with histology. The McNemar exact test and the generalized estimating equation (GEE) were used to compare lesion detection rates and diagnostic performance in terms of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Histopathology data were available for 78 lesions. Significantly more lesions overall (75/78 [96%] vs 62/78 [79%], respectively; p = 0.0002) and significantly more malignant lesions (49/50 [98%] vs 38/50 [76%]; p = 0.0009) were detected with gadobenate dimeglumine than gadopentetate dimeglumine. All detected malignant lesions were correctly diagnosed with both agents. More detected benign lesions were correctly diagnosed with gadobenate dimeglumine than with gadopentetate dimeglumine (20/26 [77%] vs 17/24 [71%], respectively). Differentiation of lesions was significantly (p = 0.0001) better with gadobenate dimeglumine. Significantly better diagnostic performance was noted with gadobenate dimeglumine than with gadopentetate dimeglumine, respectively, for sensitivity (98.0% vs 76.0%; p = 0.0064), accuracy (88.5% vs 69.2%; p = 0.0004), PPV (86.0% vs 76.0%; p = 0.0321), and NPV (95.2% vs 57.1%; p = 0.0003). CONCLUSION: Lesion detection and malignant-benign differentiation is significantly better with 0.1 mmol/kg gadobenate dimeglumine than 0.1 mmol/kg gadopentetate dimeglumine.

Renal artery stenosis evaluation: diagnostic performance of gadobenate dimeglumine-enhanced MR angiography--comparison with DSA.

PURPOSE: To prospectively determine diagnostic performance and safety of contrast material-enhanced (CE) magnetic resonance (MR) angiography with 0.1 mmol per kilogram of body weight gadobenate dimeglumine for depiction of significant steno-occlusive disease (> or =51% stenosis) of renal arteries, with digital subtraction angiography (DSA) as reference standard. MATERIALS AND METHODS: This multicenter study was approved by local institutional review boards; all patients provided written informed consent. Patient enrollment and examination at centers in the United States complied with HIPAA. Two hundred ninety-three patients (154 men, 139 women; mean age, 61.0 years) with severe hypertension (82.2%), progressive renal failure (11.3%), and suspected renal artery stenosis (6.5%) underwent CE MR angiography with three-dimensional spoiled gradient-echo sequences after administration of 0.1 mmol/kg gadobenate dimeglumine at 2 mL/sec. Anteroposterior and oblique DSA was performed in 268 (91.5%) patients. Three independent blinded reviewers evaluated CE MR angiographic images. Sensitivity, specificity, and accuracy of CE MR angiography for detection of significant steno-occlusive disease (> or =51% vessel lumen narrowing) were determined at segment (main renal artery) and patient levels. Positive and negative predictive values and positive and negative likelihood ratios were determined. Interobserver agreement was analyzed with generalized kappa statistics. A safety evaluation (clinical examination, electrocardiogram, blood and urine analysis, monitoring for adverse events) was performed. RESULTS: Of 268 patients, 178 who were evaluated with MR angiography and DSA had significant steno-occlusive disease of renal arteries at DSA. Sensitivity, specificity, and accuracy of CE MR angiography for detection of 51% or greater stenosis or occlusion were 60.1%-84.1%, 89.4%-94.7%, and 80.4%-86.9%, respectively, at segment level. Similar values were obtained for predictive values and for patient-level analyses. Few CE MR angiographic examinations (1.9%-2.8%) were technically inadequate. Interobserver agreement for detection of significant steno-occlusive disease was good (79.9% agreement; kappa = 0.69). No safety concerns were noted. CONCLUSION: CE MR angiography performed with 0.1 mmol/kg gadobenate dimeglumine, compared with DSA, is safe and provides good sensitivity, specificity, and accuracy for detection of significant renal artery steno-occlusive disease.

Diagnostic performance of gadobenate dimeglumine enhanced MR angiography of the iliofemoral and calf arteries: a large-scale multicenter trial.

OBJECTIVE: The purpose of this study was to compare gadobenate dimeglumine-enhanced MR angiography and unenhanced time-of-flight MR angiography for the detection of significant peripheral arterial occlusive disease using digital subtraction angiography as our reference standard. SUBJECTS AND METHODS: Two hundred seventy-two patients underwent MR angiography and digital subtraction angiography of the iliofemoral arteries. MR angiography was performed before (2D time-of-flight acquisitions) and after (spoiled gradient-echo acquisitions) the administration of 0.1 mmol/kg of gadobenate dimeglumine at 1-2 mL/s. Contrast-enhanced MR angiography and digital subtraction angiography of the calf arteries were performed in 241 of 272 participants. Images were evaluated on-site and by four blinded reviewers (three for MR angiography, one for digital subtraction angiography). Comparative diagnostic performance for the detection of significant (> or = 51% vessel lumen narrowing) disease was evaluated using the McNemar test and generalized estimating equations. Interobserver agreement was assessed with generalized kappa statistics. The chi-square test was used to compare technical failure rates. RESULTS: Digital subtraction angiography confirmed significant disease (597 stenoses, 386 occlusions) in 983 iliofemoral segments. The sensitivity (54-80.9%), specificity (89.7-95.3%), and accuracy (85-87.5%) of contrast-enhanced MR angiography for the detection of significant iliofemoral disease were significantly (p < 0.001, all reviewers) better than those of time-of-flight MR angiography (33.2-62.8%, 74.3-88.9%, and 68-77.3%, respectively). Similar diagnostic performance was obtained for the calf arteries. The technical failure rate with contrast-enhanced MR angiography (2.5-3.4%) was similar to that of digital subtraction angiography (1.4%) and significantly (p < 0.001) lower than that of time-of-flight MR angiography (6.2-18.0%). Significantly better reproducibility (p < 0.001) was obtained with contrast-enhanced MR angiography (82% vs 65.2% agreement; kappa = 0.66 vs 0.45). CONCLUSION: Improved diagnostic performance and reproducibility are achievable with gadobenate dimeglumine-enhanced MR angiography in patients with peripheral arterial occlusive disease.

Gadobenate dimeglumine-enhanced MR angiography: Diagnostic performance of four doses for detection and grading of carotid, renal, and aorto-iliac stenoses compared to digital subtraction angiography.

PURPOSE: To determine the diagnostic performance of contrast-enhanced MR angiography (CE-MRA) with four doses of gadobenate dimeglumine for detection of significant steno-occlusive disease of the carotid, renal, and pelvic vasculature. MATERIALS AND METHODS: Eighty-four patients with suspected disease of the renal (n = 16), pelvic (n = 41), or carotid (n = 27) arteries underwent CE-MRA (3D-spoiled gradient-echo sequences) at 1.5T. CE-MRA was performed with gadobenate dimeglumine at 0.025, 0.05, 0.1, or 0.2 mmol/kg (23, 24, 19, and 18 patients, respectively) administered at 2 mL/sec. Accuracy, sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) for detection of significant disease (>50% stenosis or occlusion for renal/pelvic arteries; >70% stenosis or occlusion for carotid arteries) was determined by three fully blinded, independent radiologists using conventional digital subtraction angiography (DSA) as reference standard. All comparisons were tested statistically (ANOVA, chi-square, and Mantel-Haenszel tests as appropriate) and reader agreement (kappa) was assessed. RESULTS: Values for accuracy, sensitivity, specificity, PPV, and NPV on CE-MRA were consistently higher for 0.1 mmol/kg gadobenate dimeglumine (accuracy = 95.2-97.3%, sensitivity = 84.2% (all readers), specificity = 96.9-99.2%, PPV = 80.0-94.1%, NPV = 97.6-97.7%). The greater accuracy of the 0.1 mmol/kg dose was significant (P < 0.01, all readers) compared to all other dose groups. Agreement between the three readers was good for all dose groups (kappa >/=0.58), with the highest percent agreement (85.7%) noted for the 0.1 mmol/kg dose. CONCLUSION: Significantly better diagnostic performance on CE-MRA of the renal, pelvic, and carotid arteries is achieved with a gadobenate dimeglumine dose of 0.1 mmol/kg bodyweight.

Safety characteristics of gadobenate dimeglumine: clinical experience from intra- and interindividual comparison studies with gadopentetate dimeglumine.

PURPOSE: To evaluate the safety and tolerability of gadobenate dimeglumine (Gd-BOPTA) relative to that of gadopentetate dimeglumine (Gd-DTPA) in patients and volunteers undergoing MRI for various clinical conditions. MATERIALS AND METHODS: A total of 924 subjects were enrolled in 10 clinical trials in which Gd-BOPTA was compared with Gd-DTPA. Of these subjects, 893 were patients with known or suspected disease and 31 were healthy adult volunteers. Of the 893 patients, 174 were pediatric subjects (aged two days to 17 years) referred for MRI of the brain or spine. Safety evaluations included monitoring vital signs, laboratory values, and adverse events (AE). RESULTS: The rate of AE in adults was similar between the two agents (Gd-BOPTA: 51/561, 9.1%; Gd-DTPA: 33/472, 7.0%; P = 0.22). In parallel-group studies in which subjects were randomized to either agent, the rate of AE was 10.9% for Gd-BOPTA and 7.9% for Gd-DTPA (P = 0.21). In the subset of subjects receiving both agents in intraindividual crossover trials, the rate of AE was 8.0% for Gd-BOPTA and 8.5% for Gd-DTPA (P = 0.84). Results of other safety assessments (laboratory tests, vital signs) were similar for the two agents. CONCLUSION: The safety profile of Gd-BOPTA is similar to Gd-DTPA in patients and volunteers. Both compounds are equally well-tolerated in patients with various disease states undergoing MRI.

Safety of gadobenate dimeglumine (MultiHance): Summary of findings from clinical studies and postmarketing surveillance.

OBJECTIVES: Prospective studies and retrospective analyses were undertaken to evaluate the clinical safety of gadobenate dimeglumine (MultiHance) and to assess tolerability in special populations. MATERIALS AND METHODS: A total of 3092 subjects received MultiHance in 79 clinical trials. Data from comparisons with other contrast agents and studies in children, subjects with hepatic or renal impairment, or subjects with coronary artery disease were reviewed. Postmarketing safety surveillance data after more than 1.5 million applications were also evaluated. RESULTS: In total, 413 of 2982 (14%) adult subjects receiving MultiHance reported at least one adverse event (AE) definitely or potentially related to MultiHance, an incidence that was similar to that observed with placebo (21/127, 17%) or active controls (59/723, 8%). In crossover studies, 23 of 287 (8%) subjects receiving MultiHance experienced AE compared with 25 of 295 (9%) receiving gadopentetate dimeglumine (Magnevist). No increased AE rate was observed in children and no worsening of renal or liver function was observed in subjects with hepatic or renal impairment. No detrimental effect on cardiac electrophysiology could be observed from a retrospective analysis of ECG parameters in more than 1000 patients and healthy volunteers. The AE reporting rate from postmarketing safety surveillance of MultiHance was 0.05%. Serious AEs were rarely reported and included dyspnea, nausea, urticaria, hypotension, and anaphylactoid reactions. CONCLUSIONS: MultiHance appears to be well tolerated in adults and children and in subjects with impaired liver or kidney function or coronary artery disease. In controlled trials, MultiHance demonstrated a similar safety profile to that of Magnevist.

Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadolinium comparators.

RATIONALE AND OBJECTIVES: Gadobenate dimeglumine (Gd-BOPTA) possesses a two-fold higher T1 relaxivity compared to other available gadolinium contrast agents. The study was conducted to evaluate the benefits of this increased relaxivity for MR imaging of intracranial enhancing brain lesions. MATERIALS AND METHODS: Forty-five patients (31 males, 14 females) with suspected glioma or cerebral metastases were evaluated. Patients received Gd-BOPTA and either Gd-DTPA (n = 23) or Gd-DOTA (n = 22) in fully randomized order at 0.1 mmol/kg body weight and at a flow rate of 2 ml/s. The second agent was administered 1-14 days after the first agent. Images were acquired precontrast (T1wSE, T2wFSE sequences) and at sequential postcontrast time-points (T1wSE sequences at 0, 2, 4, 6, and 8 and 15 min and a T1wSE-MT sequence at 12 min) at 1.0 or 1.5 T using a head coil. Determination of contrast enhancement was performed quantitatively (lesion-to-brain ratio, contrast-to-noise ratio, and percent enhancement) and qualitatively (border delineation, internal morphology, contrast enhancement, and diagnostic preference) by two independent, fully blinded readers. RESULTS: Images from 43/45 patients were available for quantitative assessment. After correction for precontrast values, significantly greater lesion-to-brain ratio (P < .003), contrast-to-noise ratio (P < .03), and percent enhancement (P < .0001) was noted by both readers for Gd-BOPTA-enhanced images at all time-points from 2 min postcontrast. Qualitative assessment of all patients similarly revealed significant preference for Gd-BOPTA for lesion border delineation (P < .004), lesion internal morphology (P < .008), contrast enhancement (P < .0001), and diagnostic preference (P < .0005). CONCLUSIONS: The greater T1 relaxivity of Gd-BOPTA permits improved visualization of intracranial enhancing lesions compared to conventional gadolinium agents.

Comparison of gadobenate dimeglumine (Gd-BOPTA) with gadopentetate dimeglumine (Gd-DTPA) for enhanced MR imaging of brain and spine tumours in children.

BACKGROUND: Gadobenate dimeglumine (Gd-BOPTA) demonstrates superior enhancement of brain tumours in adult patients than Gd-DTPA. OBJECTIVE: To determine whether Gd-BOPTA has advantages over Gd-DTPA for enhanced MR imaging of paediatric brain and spine tumours. MATERIALS AND METHODS: Sixty-three subjects, aged 6 months to 16 years, who were enrolled in a prospective, fully blinded, randomized parallel-group phase III clinical trial, received 0.1 mmol/kg doses of either Gd-BOPTA (n=29) or Gd-DTPA (n=34). The MR images were acquired before and within 10 min of contrast agent injection. The primary objective was to compare the difference from pre-dose to post-dose lesion visualization between Gd-BOPTA and Gd-DTPA. Lesion visualization was determined as the sum of individual scores for three criteria of lesion morphological characteristics (lesion border delineation, internal morphology, and contrast enhancement), each assessed qualitatively using 4-point scales. Quantitative evaluation compared changes in lesion-to-background (LBR) and contrast-to-noise (CNR) ratios and per cent enhancement. Monitoring for adverse events and evaluation of vital signs and laboratory values was performed. RESULTS: Pre-dose to post-dose changes in lesion visualization were significantly better for Gd-BOPTA for both lesion level (2.68+/-2.17 vs. 1.05+/-1.90, P=0.0106) and patient level (2.55+/-2.18 vs. 1.14+/-1.68, P=0.0079) comparisons. The mean pre-dose to post-dose change in CNR was greater for Gd-BOPTA (9.13+/-15.36) than Gd-DTPA (2.18+/-9.90), but the difference was only marginally significant (P=0.0779; 95% CI: -0.553, 14.454) because of wide variations of signal intensity between lesions. Similar findings were obtained for LBR and per cent enhancement. No differences between the agents were noted in terms of safety parameters. CONCLUSIONS: At an equivalent dose Gd-BOPTA is significantly better than Gd-DTPA for visualization of enhancing CNS tumours in paediatric patients.

Contrast-enhanced MR Angiography of the renal arteries: blinded multicenter crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine.

PURPOSE: To prospectively and intraindividually compare 0.1 mmol/kg gadobenate dimeglumine with 0.2 mmol/kg gadopentetate dimeglumine for contrast material-enhanced magnetic resonance (MR) angiography of the renal arteries. MATERIALS AND METHODS: Institutional review board approval was granted by each of three participating centers. The study accorded with international standards for good clinical practice and Declaration of Helsinki and subsequent amendments. Patients gave written informed consent before enrollment. Patients (n = 34) underwent two MR angiographic examinations more than 48 hours but less than 12 days apart. Gadobenate dimeglumine followed by gadopentetate dimeglumine was administered in 18 patients; the order of administration was reversed in 16 patients. A 1.5-T MR imager was used with a phase-encoded three-dimensional spoiled breath-hold pulse sequence. Two blinded independent readers qualitatively assessed randomized subtracted maximum intensity projection images. A three-point scale for diagnostic quality (0, poor; 1a or 1p, moderate; and 2a or 2p, adequate [a and p refer, respectively, to absence and presence of vascular lesions]) was used to score each of nine segments of the abdominal aorta and both renal arteries (possible overall score, 18). Quantitative assessment (vessel signal-to-noise ratio [SNR], vessel-muscle contrast-to-noise ratio [CNR]) of source images was performed for regions of interest in supra-, juxta-, and infrarenal aorta segments and psoas muscle. Data were tested with analysis of variance for two-period crossover design. Interreader agreement was evaluated with Cohen kappa statistics. RESULTS: No difference in mean image quality between the two contrast agents was observed; scores for gadobenate dimeglumine and gadopentetate dimeglumine were 15.15 and 15.23 for reader 1 and 16.77 and 17.01 for reader 2. The order of contrast material administration likewise produced no quality differences: readers 1 and 2 reported scores of 14.4 +/- 4.2 (standard deviation) and 16.7 +/- 2.3, respectively, when gadobenate dimeglumine was given first, and 15.2 +/- 1.8 and 16.6 +/- 1.6, respectively, when gadopentetate dimeglumine was given first. Results of quantitative evaluation showed increasing SNR and CNR with gadobenate dimeglumine in segments at progressively lower levels of the aorta, but increases in SNR and CNR at the infrarenal aorta (48.3 vs 40.6 and 44.2 vs 36.4, respectively) were not significant (P = .05 for both). CONCLUSION: Gadobenate dimeglumine at a dose of 0.1 mmol/kg is comparable to gadopentetate dimeglumine at 0.2 mmol/kg for contrast-enhanced renal MR angiography.

Cardiac electrophysiologic monitoring after injection of gadobenate dimeglumine versus placebo in healthy volunteers and patients with cardiovascular disease.

PURPOSE: To prospectively compare intraindividual effects of 0.2 mmol/kg gadobenate dimeglumine and placebo (saline) on cardiac electrophysiology in healthy volunteers and patients with coronary artery disease (CAD). MATERIALS AND METHODS: Gadobenate dimeglumine and saline placebo were injected intravenously approximately 72 hours apart in randomized crossover fashion in 24 healthy volunteers and 23 patients with CAD. Twelve-lead ambulatory (Holter) electrocardiographic (ECG) monitoring was performed from 3 hours preinjection to 24 hours postinjection. Quantitative and qualitative evaluation was performed with automated algorithmic interpretations and blinded assessment by one cardiologist. Possible QT-interval prolongation was evaluated after correction for heart rate on an individualized basis and by means of Bazett formula. Statistical analyses based on two-sided confidence intervals (CIs) were performed by using a linear model for a two-period crossover design. All subjects were monitored for vital signs, laboratory variables, and adverse events. RESULTS: Placebo was administered before contrast agent in 12 volunteers and 12 patients and after contrast agent in 12 volunteers and 11 patients. For mean increase in QTc interval from baseline, a nonsignificant difference of 3.1 msec was noted between gadobenate dimeglumine and placebo (95% CI: -1.8, 8.0) after individualized correction. Overcorrection for heart rate was noted with Bazett formula (mean difference, 5.6 msec; 95% CI: -2.2, 13.5). Cardiologist findings were consistent with automated readings. Similar findings were noted for healthy volunteers and patients with CAD. No differences between treatments were noted for any evaluation, although more frequent qualitative changes were noted in patients with CAD. Adverse events were noted in seven of 47 (15%) subjects after gadobenate dimeglumine injection and in five of 47 (11%) subjects after injection of placebo. CONCLUSION: Injection of 0.2 mmol/kg gadobenate dimeglumine has no detrimental effect on cardiac electrophysiology or other safety parameters in healthy volunteers or patients with CAD.

Gadobenate dimeglumine-enhanced MRI of the breast: analysis of dose response and comparison with gadopentetate dimeglumine.

OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy and dose response relationship of three doses of gadobenate dimeglumine for MRI of the breast and to compare the results with those obtained after a dose of 0.1 mmol/kg of body weight of gadopentetate dimeglumine. SUBJECTS AND METHODS. Gadobenate dimeglumine at 0.05, 0.1, or 0.2 mmol/kg of body weight or gadopentetate dimeglumine at 0.1 mmol/kg of body weight was administered by IV bolus injection to 189 patients with known or suspected breast cancer. Coronal three-dimensional T1-weighted gradient-echo images were acquired before and at 0, 2, 4, 6, and 8 min after the administration of the dose. Images were evaluated for lesion presence, location, size, morphology, enhancement pattern, conspicuity, and type. Lesion signal intensity-time curves were acquired, and lesion matching with on-site final diagnosis was performed. A determination of global lesion detection from unenhanced to contrast-enhanced and combined images was performed, and evaluations were made of the diagnostic accuracy for lesion detection and characterization. A full safety evaluation was conducted. RESULTS: Significant dose-related increases in global lesion detection were noted for patients who received gadobenate dimeglumine (p < 0.04, all evaluations). The sensitivity for detection was comparable for 0.1 and 0.2 mmol/kg of gadobenate dimeglumine, and specificity was highest with the 0.1 mmol/kg dose. Higher detection scores and higher sensitivity values for lesion characterization were found for 0.1 mmol/kg of gadobenate dimeglumine compared with 0.1 mmol/kg of gadopentetate dimeglumine, although more variable specificity values were obtained. No differences in safety were observed, and no serious adverse events were reported. CONCLUSION: Gadobenate dimeglumine is a capable diagnostic agent for MRI of the breast. Although preliminary, our results suggest that 0.1 mmol/kg of gadobenate dimeglumine may offer advantages over doses of 0.05 and 0.2 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadopentetate dimeglumine for breast lesion detection and characterization.