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Vascular and Interventional Radiology |
1 From Department of Radiology, CHUM-Hospital St Luc, Montreal, Quebec, Canada (P.P.); Department of Radiology, Rush North Shore Medical Center, Skokie, Ill (M.A.E.); Department of Radiology, Brigham and Women’s Hospital, Boston, Mass (R.A.B., E.K.Y.); EPIX Medical, Cambridge, Mass (R.M.W.); Berlex Laboratories, Montville, NJ (K.S.); and Cardiovascular Division, Department of Medicine, University of Pennsylvania School of Medicine, PHI Bldg, Rm 432, 51 N 39th St, Philadelphia, PA 19104 (E.R.M.). Received September 19, 2002; revision requested November 26; final revision received March 21, 2003; accepted April 14. Address correspondence to E.R.M. (e-mail: mohlere@uphs.upenn.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: In this randomized, 20-center, double-blind study, 238 men and women who had peripheral vascular disease or were suspected of having it received intravenous injection of placebo or gadofosveset (0.005, 0.01, 0.03, 0.05, or 0.07 mmol per kilogram of body weight). MR angiographic images were evaluated by three blinded readers, and x-ray angiographic images were evaluated by two readers. Hypothesis testing for the presence of a dose response was based on a linear test for trend for increase in area under the receiver operating characteristic curve as a function of dose for each reader of MR angiographic images independently.
RESULTS: Gadofosveset administration resulted in a dose-dependent increase in diagnostic accuracy for detection of aortoiliac occlusive disease as reflected in the area under the receiver operating characteristic curve for each reader (P < .001). The plateau in effectiveness improvement began at the 0.03 mmol/kg dose. At doses of 0.03 mmol/kg and higher, gadofosveset-enhanced MR angiography provided an approximate 20% increase in accuracy over nonenhanced MR angiography for diagnosis of clinically significant aortoiliac occlusive disease. Gadofosveset exhibited a good safety profile in all dose groups. Three serious adverse events were possibly or probably related to gadofosveset administration. There were no dose-related trends in severe or serious adverse events in patients receiving gadofosveset.
CONCLUSION: A dose of 0.03 mmol/kg of gadofosveset was safe and effective for evaluation of aortoiliac occlusive disease with MR angiography.
© RSNA, 2003
Index terms: Angiography, contrast media, 92.12943, 98.12943 • Arteries, extremities, 92.72, 92.721, 98.72 • Magnetic resonance (MR), vascular studies, 92.12942, 98.12942
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Alternative paramagnetic agents for enhancing MR angiographic images, known as blood pool agents, currently are being studied. One such compound is gadofosveset trisodium (EPIX Medical, Cambridge, Mass; Schering, Berlin, Germany), formerly identified with the code name MS-325, which is a small-molecule contrast agent that binds noncovalently to serum albumin. This reversible albumin binding of gadofosveset enhances the paramagnetic effectiveness of gadolinium and allows lower contrast agent doses than are needed with conventional MR agents (12). In addition, the albumin-binding characteristic extends the vascular lifetime of the agent, and thus gadofosveset allows longer vascular imaging time, potentially higher spatial resolution, and larger anatomic coverage.
The purpose of our study was to evaluate the dose response and safety of gadofosveset-enhanced MR angiography compared with nonenhanced two-dimensional time-of-flight MR angiography, with x-ray angiography as the standard of reference.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The evaluation focused on aortoiliac arterial disease in patients who either received a diagnosis of the disease or were suspected of having it on the basis of the physical examination results and medical history. The primary effectiveness end point was comparison of the receiver operator characteristic (ROC) curve for nonenhanced MR angiography with that for gadofosveset-enhanced MR angiography. Secondary outcome measures included evaluation of the sensitivity, specificity, and accuracy of detection of clinically significant stenosis, as well as the rate of uninterpretable MR angiographic images. Clinically significant stenosis was defined as narrowing of 50% or more of the diameter of the vessel. The protocol was approved by the ethics committees of the respective institutions that were participating in the study, and each enrolled patient provided written informed consent.
Patient Selection
Patients who had lower extremity arterial disease or were suspected of having it and in whom angiography that included the aortoiliac vessels was planned were enrolled in the study. Patients were not to undergo therapeutic intervention in the vessel of interest between the time MR angiography was performed with the placebo or with gadofosveset and the time x-ray angiography was performed. Other inclusion criteria included age older than 18 years, at least one side of the body that did not have a hip replacement or an aortic or iliac graft or stent, and availability of at least one unilateral angiographic image. Women were included in the study if they were not pregnant or lactating. Patients were excluded from the study if they had had a major cardiovascular event within 30 days prior to study randomization. Patients treated with bilateral hip replacement, aortic or iliac graft or stent, or all three, also were excluded.
Patients were also excluded if they had a history of abnormal renal function that included, but was not limited to, severe renal impairment, renal transplant, or hemodialysis or if they had a serum creatinine level outside the normal range for the site laboratory. Other exclusionary criteria included a history of hemoglobinopathy or specific MR imaging exclusion criteria, such as presence of a pacemaker, an internal defibrillator, or a ferromagnetic intracranial aneurysm clip. As a precaution, warfarin was not administrated any time during the study and was withheld 3 days prior to contrast agent administration because of the possibility of a drug interaction, as may occur with albumin-bound drugs. Also, patients were not to have received ibuprofen or naproxen within 4 hours prior to administration of the study drug because of the potential interference with renal function.
Patients also were excluded if they had a hypersensitivity to gadolinium-based contrast agents or had previously received gadofosveset. Patients could not have received an iodinated contrast agent within 3 days prior to or after placebo or gadofosveset administration. Also, patients who had undergone a surgical intervention within 30 days prior to drug administration were excluded from the study. Demographic data (ie, age, sex, ethnicity, height, and weight) were obtained from all patients.
Contrast Agent
Gadofosveset is a gadolinium-based small-molecule (molecular weight, 975.88) contrast agent designed specifically for MR angiography. Gadofosveset is 80%–96% noncovalently bound to albumin in human plasma and is primarily excreted renally (12). In plasma, gadofosveset exhibits a relaxivity at 0.5 T that is approximately six to 10 times that of gadopentetate dimeglumine (12).
The volume of gadofosveset required for dosing was specific for each patient and was based on the patient’s body weight measured during the baseline examination. The patient’s weight was measured to the nearest kilogram, and each patient was randomly assigned to receive placebo or one of five gadofosveset doses (ie, 0.005, 0.01, 0.03, 0.05, or 0.07 mmol/kg) according to a predetermined randomization schedule. The doses were chosen on the basis of preclinical data.
Each patient received an intravenous injection (administered during 30 seconds) of the appropriate dose of gadofosveset diluted with an additional amount of saline to achieve a volume of 31 mL. All doses were diluted to this uniform volume so that the same volume of injection could be used for all patients; thus, the blinding of the physicians who both administered the agent and who were responsible for adverse event reporting was preserved. The patients randomly assigned to receive placebo received 31 mL of saline injected intravenously. To preserve blinding, the hospital pharmacy prepared the doses for injection. Sites could administer the injection with a power injector or manually; in both cases, the injection was administered at a rate of 1.0 mL/sec. Because of the dose randomization and inclusion of placebo, timing bolus, fluoroscopic triggering, or automatic bolus detection were not used in the study. Thus, all dynamic acquisitions were initiated with a fixed delay of 30 seconds from the start of administration of the bolus. The principal investigator and all study personnel, with the exception of the dose coordinator at the sites’ pharmacies, were blinded to whether the patient received placebo or gadofosveset.
Imaging
Imaging was performed with 1.5-T MR imaging equipment (GE Medical Systems, Milwaukee, Wis; Siemens, Iselin, NJ; Philips Medical Systems, Bothell, Wash; Picker International, Cleveland, Ohio) with comparable imaging protocols. Nonenhanced images were acquired first in the transverse plane prior to administration of placebo or gadofosveset to obtain MR angiographic images. Two-dimensional time-of-flight imaging was performed according to each institution’s clinical standard and varied somewhat among sites, depending primarily on whether short repetition time with sequential gradient-echo imaging or long repetition time with section-interleaved imaging was used. The parameters for short repetition time typically were repetition time msec/echo time msec of 15–33/2–4, with a flip angle of 30°–60°. The parameters for long repetition time were 600/8–10, with a flip angle of 90°. Cardiac gating was not used.
Gadofosveset-enhanced MR angiographic data were then acquired both in the dynamic phase (ie, during bolus administration) and at higher spatial resolution in the steady state. Dynamic images (7–10/2–3; flip angle, 25°–30°) were acquired as a three-dimensional spoiled gradient-echo coronal slab with a 192 x 512 in-plane matrix. The field of view was 330 x 440 mm and included 25–32 partitions interpolated to 50–64 sections (<4 mm thick, acquired; <2 mm thick, reconstructed). A baseline image for masked subtraction was acquired first, with a second acquisition beginning 30 seconds after initiation of administration of the gadofosveset bolus (dynamic image). Within 15 minutes of injection, steady-state images (19–28/2–3; flip angle, 25°–30°) were acquired as a three-dimensional spoiled gradient-echo coronal slab with a 384 x 512 in-plane matrix. The field of view was 330 x 440, with 50–64 partitions interpolated to 100–128 sections (1.8 mm thick, acquired; 0.9 mm thick, reconstructed). Imaging was fat suppressed, with one fat-saturated pulse per repetition time. The k space was imaged in the standard high-low-high (ie, center of k space at the center of the acquisition) mode. The 30-second delay was designed to have the beginning of the acquisition start as the initial edge of the bolus just reached the volume of interest. For x-ray angiography, imaging of the aortoiliac vessels in at least the left anterior oblique and right anterior oblique planes with an image intensifier matrix of at least 1,024 x 1,024 or cut films was required; additional views were obtained if medically required. X-ray angiography was performed 3–30 days before or after MR angiography; no intervention in the arteries of interest was allowed between the MR angiographic and x-ray angiographic examinations.
Safety Monitoring
Safety was monitored with the following parameters: medical history, physical examination, vital signs that included pulse oximetry, electrocardiogram, clinical laboratory values, and adverse event assessment. The clinical laboratory values included a complete blood cell count, prothrombin time, partial thromboplastin time, chemistry panel with hepatic and renal function tests, and urinalysis. Patients were monitored for 72–96 hours, according to standard good clinical practice. One physician (E.K.Y.) had overall responsibility for medical monitoring and for ensuring its uniformity. An adverse event was defined as any untoward medical occurrence in a clinical investigation subject who received a pharmaceutical product, and the occurrence did not necessarily have to have a causal relationship with the study drug. Any signs and symptoms experienced by the patient from the time the patient received the placebo or gadofosveset through the completion of study were recorded as adverse events.
Effectiveness Analysis
The primary effectiveness analysis was based on blinded interpretation of the MR images and was performed by three blinded readers, who each interpreted all of the images obtained before and after angiography with gadofosveset. The readers had 4, 5, and 16 years of experience with MR angiography. The standard of reference included interpretation of all the x-ray angiographic images by two independent radiologists with 14 and 32 years of experience with x-ray angiography. All blinded readers were certified in their respective field of study, had no affiliation with any clinical site or the sponsor, and were given no clinical information about the patients. The nonenhanced and gadofosveset-enhanced MR angiographic data sets were presented to the readers in random order, with a randomization scheme that eliminated the possibility of the reader seeing the pre- and postcontrast data sets of the same patient in consecutive order. Given the large number of images, the MR angiographic blinded reading for each independent reader took place during approximately 10 separate reading sessions that were approximately a day long.
The focus of the blinded reading was on the seven main vessels in the aortoiliac region: infrarenal abdominal aorta, left and right common iliac artery, left and right external iliac artery, and left and right common femoral artery. For both the MR angiographic and x-ray angiographic data, images of the left and right sides of each patient were interpreted separately, and the contralateral side was masked. The abdominal aorta, though present on images of both sides, was interpreted only on the images of the right side. Electronic calipers were used to calculate stenosis on MR angiographic images, and manual calipers were used to calculate stenosis on x-ray angiographic images. For both MR angiographic and x-ray angiographic data in each vessel, the reader first identified the most significant stenosis, and if it appeared to be greater than 10%, the reader measured the diameter of the normal vessel and of the stenotic vessel for the most significant stenosis in that vessel. This measurement thus provided the maximum stenosis for the vessel for comparison with the MR angiographic and x-ray angiographic data. The percentage of stenosis was then automatically calculated as 100 x [1 - (Dmin/Dnorm)], where Dmin is the minimum stenotic diameter and Dnorm is the normal vessel diameter. If an image of more than one vessel on a side was considered uninterpretable, images in that patient were considered uninterpretable, and no further analysis was performed.
Because of the inherent variability in determination of the percentage of stenosis from an angiogram, the average percentage of stenosis that was based on the interpretation of the two readers was considered the "standard of truth" or truth for the percentage of stenosis; a stenosis of 50% or greater determined from the x-ray angiogram was considered clinically significant disease for the purpose of these analyses.
Data Analyses
The primary effectiveness analysis was performed to test for a dose response for diagnostic effectiveness with ROC analysis (13). To construct the ROC curve, sensitivity and specificity were calculated by using successively increasing cutoffs from 0%–100% stenosis for defining a disease or no-disease diagnosis with MR angiography. In addition, to provide an estimate of sensitivity and specificity, a 50% cutoff for clinical disease (ie, matching the x-ray angiographic definition) was used.
The effectiveness analysis was based on the analysis of the data from the intent-to-treat population. This population was defined as patients who underwent x-ray angiography and nonenhanced MR angiography and received gadofosveset or placebo. That is, a patient was evaluated for effectiveness if the patient received the study drug and if at least one postcontrast MR angiographic image and an interpretable x-ray angiographic image were obtained. Because we followed an intent-to-treat principle, for the purposes of determination of the accuracy of MR angiography versus x-ray angiography, all uninterpretable MR angiographic images were considered inaccurate. That is, uninterpretable MR angiographic images of vessels that were significantly diseased were considered false-negative images, and uninterpretable images of vessels that were not significantly diseased were considered false-positive images.
The area under the ROC curve (AUC) was used for the primary analysis. The AUC for the gadofosveset-enhanced MR angiographic image was compared with that of the nonenhanced MR angiographic image at each dose by using the method of DeLong et al (13). The presence of a significant linear trend in the increase in the change in AUC as a function of dose was tested to assess the presence of a dose response for each reader independently.
In secondary analyses, the sensitivity, specificity, and proportion of uninterpretable MR angiographic images were tabulated for each MR angiographic image reader according to dose group. Because no statistical comparisons between individual doses were made for sensitivity, specificity, and accuracy, only point estimates, and not CIs, were computed. All analyses were performed independently for each MR angiographic image reader.
For safety data, continuous data were summarized by using descriptive statistics. Categorical variables were summarized by using counts and percentages. Any significance testing and determination of CIs were performed by using 
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Specificity.—The specificity of gadofosveset–enhanced MR angiography and that of nonenhanced MR angiography are shown in Figure 4. The change in specificity was estimated on the basis of the difference between the data obtained before and after administration of gadofosveset. As can be seen in Figure 4, specificity improved for all three readers up to and including the 0.03 mmol/kg dose. When compared with nonenhanced MR angiography, the lowest dose (0.005 mmol/kg) at gadofosveset-enhanced MR angiography had approximately the same specificity as did nonenhanced MR angiography, and it increased to a 15%–32% improvement across readers at the 0.03 mmol/kg dose. A similar range of improvement was seen for the 0.05 mmol/kg dose group. Absolute specificity improved slightly at 0.05 mmol/kg compared with 0.03 mmol/kg for two readers, but it declined slightly for one reader. Relative specificity (postcontrast specificity minus precontrast specificity) increased for two readers and decreased for the third reader. All three readers showed decreases in specificity at the 0.07 mmol/kg dose compared with the specificity observed at the 0.05 mmol/kg dose. The average improvement in specificity is shown in Figure 4.
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2 test) for both sides for one reader, and the data showed a strong trend for the other two readers (Fig 6). Figure 6 also provides the average percentage of uninterpretable images obtained with nonenhanced MR angiography, averaged across all readers and dose groups.
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Three of the nine serious adverse events were determined to be possibly or probably related to the study drug. The principal investigators rated one of these three treatment-related serious adverse events as mild, one as moderate, and one as severe. There was no dose-related trend in severe or serious adverse events. One patient developed urticaria on the anterior and posterior areas of the chest and on the abdominal areas approximately 1 hour after gadofosveset-enhanced MR angiography. The patient was treated with 50 mg of diphenhydramine administered intravenously. The urticaria resolved, and the patient was discharged 2 hours after the injection. This serious adverse event was rated as mild and was probably related to the drug, as indicated by the principal investigator.
One patient experienced chest pain 24 hours after MR angiography with gadofosveset. The pain resolved after treatment with sublingually administered nitroglycerin. The patient was hospitalized after the event for further observation. An electrocardiogram performed 2
hours after study drug administration showed a prolonged QT interval, which was present throughout the subsequent hospitalization. Laboratory evaluation results were normal, and a stress echocardiogram was negative for ischemia and demonstrated a normal resting left ventricular systolic function. In addition, a chest radiograph revealed a normal heart and mediastinum, with no cardiopulmonary disease. This serious adverse event was classified as moderate and possibly related to the study drug by the principal investigator.
One patient died 3 days after gadofosveset-enhanced MR angiography. The patient completed the MR angiographic procedure without complaints, and no adverse events were observed or reported at that time and through the 24-hour follow-up examination. The patient did not come for the 72–96-hour follow-up visit because of sudden death. The immediate cause of death was atherosclerotic cardiovascular disease; the manner of death was listed as natural causes, although the patient had a history of an abdominal aortic aneurysm that was approximately 7 cm in size. This serious adverse event was deemed as severe and possibly related to the study drug by the principal investigator.
There was no statistically significant dose-related trend in severe or serious adverse events. Specifically, there were no clinically important changes in physical examination results or electrocardiographic tracings, and there were no dose-related clinical laboratory adverse events. The only adverse event thought to be possibly dose related was paresthesia, which was typically mild, did not require intervention, and lasted less than 2 minutes. No events of paresthesia required treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Gadofosveset is a small-molecule contrast agent that bonds noncovalently to serum albumin. This property enhances the paramagnetic effectiveness of gadolinium and allows lower doses than are required with conventional MR imaging contrast agents. Protein binding also increases the intravascular residence time of the contrast agent (4). The result is extended imaging time, higher spatial resolution, and larger anatomic coverage. The route of clearance of gadofosveset is renal excretion, which is a desired route for MR imaging contrast agents. Given these properties, the current dose-ranging study was performed to determine whether the accuracy of diagnosis is improved with gadofosveset-enhanced MR angiography compared with nonenhanced MR angiography.
The accurate diagnosis of stenosis in the aortoiliac region often is impossible with nonenhanced MR angiography, primarily because the anatomy of the iliac arteries is more tortuous than that of other vessels in the legs (3,14,15). Furthermore, at nonenhanced MR angiography, poststenotic vessels can show decreased signal intensity because of intravoxel phase dispersion and nonuniform inflow enhancement, which can exaggerate the apparent degree of stenosis (16). These effects cause flow artifacts at nonenhanced MR angiography, and these artifacts can result in a substantial number of false-positive examinations (low specificity), as well as a lack of accuracy for stenosis measurement. As a result, both sensitivity and specificity of nonenhanced MR angiography can be affected, and a large number of uninterpretable images are produced in daily practice. As shown in this study, at doses of 0.03 mmol/kg and higher, gadofosveset-enhanced MR angiography effectively eliminated the problem of nondiagnostic images obtained in the aortoiliac region. Of note, researchers of other studies commonly exclude uninterpretable images from effectiveness analysis. The effects of uninterpretable images were included in this study.
The diagnostic performance of gadofosveset-enhanced MR angiography with the 0.005 mmol/kg dose was not significantly better than it was with the placebo, and therefore that dose was not considered clinically useful. At all doses of 0.01 mmol/kg and higher, significant improvement in performance was demonstrated compared with the performance of nonenhanced MR angiography for all readers. However, gadofosveset-enhanced MR angiography at the 0.03 mmol/kg dose performed better than it did at the 0.01 mmol/kg dose in several ways. For example, the percentage of uninterpretable images obtained at the 0.01 mmol/kg dose, though better than those obtained with nonenhanced MR angiography, was still substantial. Since uninterpretable images can be a substantial clinical burden, the 0.01 mmol/kg dose does not appear to be clinically optimal. Also, all three readers showed an increase in absolute specificity and sensitivity for interpretation of images obtained at the 0.03 mmol/kg dose compared with those obtained at the 0.01 mmol/kg dose. Two of three readers showed an increase in specificity and sensitivity improvement for the 0.03 mmol/kg dose compared with these values at the 0.01 mmol/kg dose. The 0.05 mmol/kg dose was not significantly better than the 0.03 mmol/kg dose in the AUC improvement, nor did the uninterpretable rate improve at this higher dose. While absolute sensitivity improved for all three readers, the sensitivity compared with that of nonenhanced MR angiography decreased for two of these readers. Specificity was essentially the same when the 0.03 and 0.05 mmol/kg doses were compared. Thus, the higher 0.05 mmol/kg dose, while creating MR angiograms with higher signal intensity, did not appear clinically justified on the basis of diagnostic effectiveness. The highest dose, 0.07 mmol/kg, showed a significant decrease in specificity (all readers), sensitivity (all readers), and AUC (all readers), and this effect likely reflected the effect of background enhancement on the readers’ ability to detect significant vascular disease in the aortoiliac region.
The safety and tolerance profile of gadofosveset was adequately demonstrated in these patients who had or were suspected of having peripheral arterial occlusive disease. Three serious adverse events occurred that were judged to be possibly or probably related to gadofosveset administration. No dose-related trend was observed in severe or serious adverse events. The only individual dose-related adverse event was paresthesia. None of the episodes of paresthesia required intervention, and the majority lasted less than 2 minutes.
Several potential limitations of this study were observed. First, with the design of this study, we used a blinded reading of MR angiographic and x-ray angiographic images without any other patient information being available to the readers. Although this design is a good method for minimization of bias in the evaluation of the diagnostic performance of the MR angiographic procedure alone, it does not reflect the typical clinical use of an imaging test. Despite the somewhat artificial nature of the blinded reading design, however, very good agreement with x-ray angiographic findings was achieved in this trial.
Second, although assessment of the degree of the most significant stenosis in a vessel is a critical component of the angiographic assessment of occlusive disease, it does not capture the full complexity of the diagnostic evaluation in patients who have this disease. Physiologic and functional performance measures (eg, pressure gradient measurements, exercise performance) often play a key role in determination of the proper treatment of patients with vascular disease. However, the methods used in this study provide a rigorous and statistically valid comparison with x-ray angiography, which is considered to be the standard of care for evaluation of the anatomic characteristics of peripheral arterial disease.
Third, no explicit comparison with existing gadolinium-based contrast agents was performed, nor was a direct comparison performed in this study to determine the added benefit of steady-state images in addition to the dynamic images. However, the absence of such a comparison clearly does not affect the dose response of gadofosveset for MR angiography, which was the primary purpose of this study. Future studies will be required to quantify the potential advantages of gadofosveset compared with existing first-pass contrast agents.
Finally, it is broadly accepted that the x-ray angiography standard of reference itself has certain limitations, and this acceptance makes complete concordance between MR angiography and x-ray angiography unlikely. These limitations include the projectional nature of x-ray angiography compared with three-dimensional MR angiographic data, catheter- and vasospasm-related overestimation of disease that may occur in catheter-based digital subtraction angiography, and interreader variability of the standard of reference. The absence of any mechanism for synchronization of the bolus arterial phase with the center of the k space at MR angiography is a potential limitation of this study. Some of the difficulty in a comparison of MR angiography with a two-dimensional standard of reference was addressed in this study by using the average of two independent readers who were blinded to findings at x-ray angiography for comparison with the individual readers who were blinded to findings at MR angiography. In this study, there was good, but not perfect, agreement (approximately 92%) between the two readers at x-ray angiography. Thus, the 87% and 91% average accuracy obtained at the 0.03 mmol/kg and 0.05 mmol/kg doses, respectively, appears to approach the maximum achievable agreement when three-dimensional MR angiography is compared with two-dimensional x-ray angiography.
In conclusion, the accuracy of the gadofosveset-enhanced MR angiographic examination was, on average, approximately 88% for the three blinded readers at the 0.03 mmol/kg dose. Side effects from the gadofosveset-enhanced MR angiographic examination at this dose were generally mild and transient. The safety and effectiveness data indicate that 0.03 mmol/kg is the clinical dose for gadofosveset-enhanced MR angiography of the aortoiliac region.
Gadofosveset principal investigators and enrolling centers: Pierre Perreault, MD, CHUM-Hospital St Luc, Montreal, Quebec, Canada; Mark Edelman, MD, Rush North Shore Medical Center, Skokie, Ill; Richard A. Baum, MD, and Emile R. Mohler III, MD, University of Pennsylvania Hospital, Philadelphia; Joseph Rapp, MD, VAMC, San Francisco, Calif; Alison Spouge, MD, London Health Science Centre, London, Ontario, Canada; Stephen Quinn, MD, Oregon Cardiovascular Teachings, Eugene; John Corson, MD, University of Iowa Hospitals and Clinics, Iowa City; Jeffrey H. Maki, MD, Puget Sound VA Medical Center, Seattle, Wash; Martin Leon, MD, Lenox Hill Hospital, New York, NY; Yaron Sternbach, MD, University of Rochester Medical Center, NY; Randy Guzman, MD, St Boniface General Hospital, Winnipeg, Manitoba, Canada; Roy Fujitani, MD, UCI College of Medicine, Orange, Calif; Christopher Morris, MD, University of Vermont, Burlington; Timothy Goertzen, MD, University of Nebraska, Omaha; Rodney Raabe, MD, the Heart Institute of Spokane, Wash; Robert Anton, MD, Citrus Memorial Hospital, Inverness, Fla; Pamela Nurenberg, MD, University of Texas Southwest Medical Center, Dallas; Barry Stein, MD, Hartford Hospital, Conn; Robert Feldman, MD, Mediquest, Ocala, Fla; Daniel Link, MD, University of California, Sacramento.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, E.R.M.; study concepts, all authors; study design, E.K.Y., R.M.W.; literature research, E.R.M., K.S., R.M.W., R.A.B.; clinical studies, E.R.M., P.P., R.A.B., M.A.E.; data acquisition, R.M.W., K.S.; data analysis/interpretation, all authors; statistical analysis, R.M.W.; manuscript preparation and definition of intellectual content, E.R.M., R.M.W., K.S.; manuscript editing, revision/review, and final version approval, all authors
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