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Contrast Media |
1 From the Department of Diagnostic and Interventional Radiology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany (M.G.); Rush North Shore Medical Center, Skokie, Ill (M.E.); Hôpital St Luc, Montreal, Quebec, Canada (P.P.); London Health Sciences Center, London, Ontario, Canada (E.O.); Hospital Italiano, Buenos Aires, Argentina (H.B.); Royal Adelaide Hospital, Adelaide, Australia (J.T.); University of Florida/Shands-Jacksonville, Jacksonville, Fla (D.S.); University of Iowa Hospital and Clinics, Iowa City, Iowa (M.S.); University of Pennsylvania School of Medicine, Philadelphia, Pa (E.R.M.); St Luke's Medical Center, Milwaukee, Wis (R.B.); Brigham and Women's Hospital, Boston, Mass (E.K.Y.); Berlex Laboratories, Montville, NJ (K.S.); and EPIX Medical, Cambridge, Mass (R.M.W.). Received May 30, 2004; revision requested June 8; revision received September 9; accepted December 16. Address correspondence to M.G., University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany (e-mail: mathias{at}goyen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: Study was approved by institutional review boards of participating institutions, and required national approvals were obtained. Study protocol conformed to Good Clinical Practice guidelines, and informed patient consent was obtained. Patients with known or suspected peripheral vascular disease received 0.03 mmol/kg MS-325 for aortoiliac MR angiography. They were also examined with conventional angiography. MS-325–enhanced MR was evaluated for safety and effectiveness. Along with unenhanced two-dimensional time-of-flight MR angiography, it was compared with conventional angiography for presence of vascular stenosis. Student t tests were used to identify significant improvement in diagnostic sensitivity, specificity, and accuracy, as well as quantitative characterization of stenoses by three blinded readers. Correlations between readers of conventional angiograms were calculated and compared with MR results.
RESULTS: In 174 patients, MS-325–enhanced MR angiography showed significant improvement (P 
.001) in sensitivity, specificity, and accuracy for diagnosis of clinically significant (
50%) stenosis, compared with unenhanced MR. For all readers, areas under the receiver operating characteristic curve for both quantitative and qualitative measures of significant disease increased (P < .001) for MS-325–enhanced MR compared with time-of-flight MR. All readers also expressed higher confidence in diagnosis (P < .001) and found fewer images uninterpretable with MS-325 enhancement. All measures of interpretation accuracy approached corresponding measures of correlation between readers of conventional angiograms. Incidence of severe and serious adverse events with MS-325 was low. No patients were withdrawn from study due to adverse events or abnormalities in laboratory results. There were no clinically important trends in findings at hematology, blood chemistry, urinalysis, electrocardiography, or physical examination.
CONCLUSION: MR angiography with MS-325 provides significant improvement in effectiveness over unenhanced MR (and minimal and transient side effects) at a dose of 0.03 mmol/kg and was safe and effective for MR evaluation of patients with aortoiliac occlusive disease.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Currently, newer MR contrast media are being developed. Among them is MS-325 (gadofosveset trisodium) (EPIX Medical, Cambridge, Mass; Schering, Berlin, Germany; and Berlex Laboratories, Montville NJ), an investigational blood-pool contrast agent for MR imaging that binds strongly but reversibly to human serum albumin in the plasma (14,15). Because of this albumin binding, MS-325 exhibits a prolonged plasma elimination half-life and increased relaxivity. These properties may be particularly useful for contrast-enhanced three-dimensional MR angiography. With prolonged T1 shortening of blood (16), MR angiographic resolution and anatomic coverage could be improved, since a longer imaging window is available after a single injection. This is a potential advantage over extracellular agents, for which only a short imaging window is available because of rapid extravasation.
Phase I investigations demonstrated that MS-325 was safe and well tolerated at doses up to and including the maximum dose tested of 0.05 mmol per kilogram of body weight and also showed that MS-325–enhanced MR angiography of the carotid and peripheral arteries in healthy volunteers yielded better results than unenhanced MR angiography (16). In a phase II clinical trial, MS-325–enhanced MR angiography of aortoiliac runoff vessels was evaluated in 238 patients with known or suspected peripheral arterial disease, at doses up to 0.07 mmol/kg and with conventional angiography used as the reference standard. The results demonstrated that of all doses used, 0.03 mmol/kg was the most appropriate for detecting vascular disease (17). Thus, the current multicenter, phase III trial was conducted to evaluate prospectively the safety and effectiveness of MS-325–enhanced aortoiliac MR angiography at a dose of 0.03 mmol/kg.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Patient Population
The primary inclusion criterion for this phase III trial was known or suspected aortoiliac arterial disease. Conventional angiography was scheduled between 3 and 30 days before or after MR angiography enhanced with MS-325. Exclusion criteria included contraindication to MR imaging (eg, pacemaker, aneurysm clip); allergy to gadolinium-based contrast agents; hip replacement, aortoiliac graft or iliac stent placement on both sides; and history of severe renal impairment, renal transplantation, hemodialysis, or peritoneal dialysis. All patients were at least 18 years of age.
Contrast Agent
MS-325 (gadofosveset trisodium) is a gadolinium-based small molecule (975.77 Da) that binds reversibly to human serum albumin. It resides principally in the blood pool and exhibits a serum half-life of 2–3 hours (15). In plasma, MS-325 has been shown to have a relaxivity six to 10 times that of gadopentetate dimeglumine, depending on its concentration (14).
Each patient received a single 0.03-mmol/kg bolus injection of MS-325. The appropriate weight-based volume of MS-325 (0.12 mL/kg) was administered over 25 seconds, which corresponds to half of a typical dynamic image acquisition time. Injections were given either by hand or with a power injector. In all cases, the intravenous bolus was immediately followed by a 30-mL normal saline flush at 1 mL/sec.
MR Angiography
The MR systems operated at a magnetic field strength of 1.5 T with Food and Drug Administration–approved hardware and software. Phased-array coils were used for radiofrequency transmit and receive. In consultation with the Food and Drug Administration, noncontrast MR angiography was selected as a comparator to prove the required effectiveness of MS-325–enhanced MR angiography. Before MS-325 administration, noncontrast (baseline) MR angiograms of the vascular region were obtained according to the preferred sequence of each institution or that recommended by the MR system vendor. These were consistently spoiled gradient-echo time-of-flight (TOF) protocols; specific parameter choices varied among sites. Typical protocols used short repetition time, sequential gradient-echo scanning, with parameters in the following range: 33/2–4 (repetition time msec/echo time msec); flip angle, 30°–60°. Acquisition times were typically between 4 and 8 minutes.
After the baseline angiograms were obtained, a subtraction mask was obtained at the same imaging parameters as specified for the arterial-phase ("dynamic") images. Both dynamic and steady-state MS-325–enhanced MR angiograms were acquired. One of three methods was employed to determine the interval from the start of MS-325 administration to the start of MR imaging for the arterial-phase MR angiograms: (a) sites with commercially available automated timing sequences could use those; (b) sites could use an empiric delay for aortoiliac occlusive disease, based on the patient's weight (<60 kg, 45-second delay; >60 kg, 35-second delay) or medical history; or (c) sites could administer an intravenous timing bolus (10% of the dose) to determine the optimal imaging time for each patient. MS-325–enhanced MR angiography of dynamic and steady-state time points was then performed according to the image sequences provided in the protocol. Steady-state images began within 15 minutes of MS-325 administration.
Postcontrast aortoiliac MR angiography at both dynamic and steady-state time points were performed with a three-dimensional spoiled gradient-echo technique. All images were acquired as a coronal slab, with a field of view of 330 x 440 mm. Dynamic images were acquired with 192 x 512 in-plane resolution (144–192 phase-encode steps) and with 22–32 partitions interpolated to 44–64 sections (<4 mm acquired, <2 mm reconstructed). The parameters were as follows: 1.7-3/6.6–10.25; flip angle, 20–25°; and acquisition time, 40–50 seconds. Steady-state images were acquired with 385 x 512 in-plane resolution (307–385 phase encode steps) and 56–64 partitions, interpolated to 112–128 sections (1.8–1.95 mm acquired, 0.900–0.975 mm reconstructed), at the following parameters: 2-3/7.4-28; flip angle, 20–30°; acquisition time, 6–8 minutes. Steady-state images were fat suppressed, with one saturation pulse per repetition time.
Conventional Angiography
Conventional angiography was performed according to accepted institutional standards within 30 days of MR angiography for comparison, but not within 3 days, to separate the safety monitoring periods. Imaging of the aortoiliac vessels in the following two views was required: left anterior oblique and right anterior oblique, with an image intensifier matrix of at least 1024 x 1024 or cut films. Additional views were obtained if medically required.
Safety Evaluation
Safety data were monitored in all patients. A brief medical history was obtained, and physical examination was performed before administration of the contrast agent. Vital signs (blood pressure, pulse, temperature, and respiratory rate) and electrocardiographic (ECG) recordings were obtained, and clinical laboratory evaluations (including hematologic evaluation, serum chemistry, urinalysis, prothrombin time, partial thromboplastin time, and direct and indirect bilirubin levels) were performed before and injection of contrast agent and until 72–96 hours afterward. In addition, the injection site, adverse events, and concomitant medications were continuously recorded throughout the study period until 72–96 hours after injection of contrast agent.
All patients were closely monitored during administration of MS-325 and throughout the study for the occurrence of adverse events. An adverse event was defined as any untoward medical occurrence in a patient regardless of causal relationship with the study drug. A treatment-emergent adverse event was one that occurred after contrast material administration and within the defined monitoring period. Because adverse events were recorded only from the point of MS-325 administration onward, all those noted during this study are considered treatment emergent.
Any signs and symptoms experienced by the patient from the time of MS-325 administration through the 72–96 hour follow-up (or later if deemed necessary by the investigator) were recorded on a case report form. In addition to the nature of the adverse event, its onset, duration, intensity, relation to study drug, and outcome were recorded. Any treatment employed to alleviate the adverse event was recorded on the concomitant medication case report form page, including the generic name, dose, units, form, route, and frequency of any administered drugs. If no adverse events were observed, this was also noted.
All adverse events were assessed by the principal investigators (M.G., M.E., P.P., E.O., H.B., J.T., D.S., M.S., E.R.M., R.B.) and assigned an intensity score on the following standard scale: mild, experience that was minor and did not cause marked discomfort to subject or change in activities of daily living; moderate, experience was of low-level inconvenience to the subject, who was able to continue with activities of daily living; severe, experience that markedly interfered with activities of daily living. For all adverse events, the principal investigator also judged the likely relationship to the study drug (unlikely to be related, possibly related, or probably related). All study monitoring and reporting of adverse events followed Good Clinical Practice guidelines.
Effectiveness Evaluation
This multicenter trial included a prospectively designed protocol for the blinded reading of image data. The blinded readings were conducted by three independent readers with 6, 9, and 8 years of experience (acknowledgments: E.H., M.T., N.V.) for the MR angiograms and three additional independent readers with 7, 19, and 10 years of experience (acknowledgments: L.B., P.O., M.B.) for the conventional angiograms. All readers were board-certified blinded radiologists who had no other involvement in the trial. All image readers were blinded to patient clinical information and, therefore, provided a controlled and nonbiased assessment of the effectiveness of the diagnostic imaging procedure alone. Seven vessel segments were evaluated: the infrarenal aorta, left and right common iliac arteries, left and right external iliac arteries, and left and right common femoral arteries.
We defined clinically significant stenosis as any occlusion of at least 50%. The first two blinded readers examined all the conventional angiograms for all patients. When they disagreed regarding the presence of clinically significant stenosis, the third radiologist (the adjudicator) independently read the images (without being given the results from the first two readers) and acted as the adjudicator to resolve the discrepancy and made the final determination as to the presence or absence of disease in a given vessel. This adjudicated result provided the standard of reference, which represents a agreement between at least two readers of conventional angiograms.
Readers of conventional and MR angiograms first determined if the images were interpretable. It was noted and recorded if the image was uninterpretable, that is, insufficient for the diagnosis of any vessel. Before quantitative measurement of stenosis, the blinded readers of MR angiograms made qualitative assessments. Readers were asked to rate their first impression of the presence of significant disease in each vessel and their confidence in this impression. They ranks these first impressions on a five-point scale (1, definitely no disease; 2, likely no disease; 3, indeterminate; 4, likely disease; and 5, definitely disease) (18). Diagnostic confidence was also rated on a five-point scale (1, not confident; 2, somewhat not confident; 3, uncertain; 4, somewhat confident; and 5, very confident). This score was recorded and could not be changed after the quantitative analysis. The readers of conventional and MR angiograms then measured the degree of maximum stenosis (most severe in the case of multiple stenoses) in each vessel to assess the presence or absence of disease in that vessel. The normal vessel width and the most stenosed width was measured with digital calipers on a computer workstation (ProVision; Algotec, Duluth, Ga). The quantitative measurement and the location of the stenosis were recorded. Finally, the presence of aneurysm or dissection was noted for each vessel segment.
The readers of MR angiograms were presented with patient data twice. First they were given the TOF images, including subtraction images and maximum intensity projections. The second data set included the dynamic images, subtraction images with maximum intensity projections, and steady-state images with maximum intensity projections. The data from all patients were randomized so that the readers did not see TOF and contrast-enhanced images in any proximity or in any particular order.
Statistical Methods
The primary effectiveness analysis was based on the results from the blinded readings. For each reader, the sensitivity, specificity, and accuracy for the diagnosis at MS-325–enhanced MR angiography was compared with those at noncontrast MR angiography, with the conventional angiographic results used as the standard of reference. Sensitivity was defined as the percentage of clinically significant stenoses correctly identified on the MR angiograms. Specificity was defined as the percentage of MR vessels correctly identified as not having clinically significant stenosis. Accuracy was defined as the percentage of correct diagnoses (true-positive and true-negative diagnoses). According to an intent-to-treat methodology, all vessels that were not interpretable at MR angiography were considered inaccurate for the purposes of estimating sensitivity, specificity and accuracy. That is, if the vessel was diagnosed as diseased at conventional angiography, it was counted as a false-negative, and if it was diagnosed as not significantly diseased at conventional angiography, it was counted as a false-positive finding. Statistical significance for this primary analysis was assessed by using a cluster-corrected McNemar test, which eliminates bias caused by potential correlation among the vessels of a given patient (19).
A vessel-weighted and patient-weighted analysis of sensitivity, specificity, and accuracy was also performed on the MR angiographic diagnoses determined by individual investigators on-site. The rate of interpretability of conventional and MR angiograms (TOF and MS-325 enhanced) was calculated for each reader. The mean ± standard deviation of the confidence of diagnosis rating was also calculated for each reader for images acquired before and after contrast material administration, and a Student t test was performed to compare the results.
In addition, each reader's quantitative diagnoses were used to construct a receiver operating characteristic (ROC) curve to compare the overall diagnostic effectiveness of contrast-enhanced and noncontrast MR angiography. The ROC curves were constructed by plotting sensitivity versus 1 minus specificity, where each of 10 values on the curve was defined parametrically based on 11 threshold degrees of stenosis considered to indicate a positive diagnosis of disease (ie, thresholds of 0%–100% stenosis, in 10% increments). ROC curves were also constructed according to qualitative diagnostic standards, whereby five qualitative measures of disease state were each separately considered as a positive diagnostic threshold.
In addition to a comparison of binary diagnosis, several additional secondary effectiveness parameters were analyzed. MR and conventional angiograms were compared with regard to their agreement for the location of each stenosis, absolute differences in the measured percentage of stenosis by vessel, and percentages of uninterpretable images indicated by each reader.
To evaluate the consistency of the readers' diagnoses for conventional angiography, the results from each reader of conventional angiograms were analyzed with the other reader's diagnosis used as the reference standard. The agreement between readers of conventional angiograms was assessed by computing the mean sensitivity, specificity, and accuracy of interpretation for each compared with the other. The measurements were calculated in the same way for the MR angiographic measures, where uninterpretable images were categorized as providing a false diagnosis.
For safety data, counts and percentages of adverse events were tabulated. Also noted were changes in vital signs, laboratory results, physical examination findings, or ECG measurements. For ECG recordings, changes from baseline for the PR interval, QRS complex, QT interval, QTc interval, and ST segment were summarized by means of descriptive statistics and interpreted by an independent cardiologist. All changes were compared with zero by means of the Student t test (at P < .05). All analyses were performed with SAS v8.2 software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Safety Results
Sixty-nine of 178 patients (38.8%) reported 131 adverse events. Of these, 41 (23.0% of the 178) reported 63 adverse events that were considered possibly or probably related to the study drug by the investigator. The most common related events were paresthesia (eight patients, 4.5%), pruritis not otherwise specified (eight patients, 4.5%), hyperglycemia not otherwise specified (five patients, 2.8%), burning sensation not otherwise specified (four patients, 2.2%), and nausea (four patients, 2.2%). One serious adverse event was reported in the study. It was reported as an anaphylactoid reaction, which the investigator deemed mild in severity and probably related to the study drug. This serious adverse event had a duration of approximately 3 minutes, and the patient was treated, recovered, and completed the study, including MR angiography. In this study, 124 of 131 adverse events (94.7%) were rated mild or moderate in intensity, 75% (98 events) occurred within 2 hours after MS-325 injection, and 79% (103 events) resolved within 2 hours of onset. No patients died, and none were withdrawn from the study because of adverse events or abnormalities in laboratory results.
There were no clinically important changes in laboratory values, nor were important trends discerned in any changes from baseline in the vital signs, pulse oximetry data, or injection site examinations for the safety population. No clinically important trends were evident in the changes from baseline in any ECG parameters for the safety population. Furthermore, no ECG changes were considered clinically important by individual investigators.
Effectiveness Results
Figure 1 is a maximum intensity projection image of a typical MR angiogram, providing anatomic visualization similar to that of a conventional angiographic projection. The results of the primary effectiveness analysis, based on analysis of all images, are shown in Table 1. For the primary effectiveness analysis, all three blinded readers demonstrated significant improvement (P < .001) in diagnostic accuracy for MS-325–enhanced MR angiograms compared with noncontrast MR angiograms, with conventional angiograms used as the standard of reference (Table 1). In addition, each reader showed significant improvements (P .001) in both sensitivity and specificity. Among three blinded readers, the accuracy for MS-325–enhanced MR angiography ranged from 80.3% to 87.6%, while that for noncontrast MR angiography ranged from 68.4% to 74.5%. Absolute improvements in sensitivity, specificity, and accuracy ranged from 21.9% to 30.8%, from 8.5% to 11.9%, and from 10.5% to 13.1%, respectively. Compared with two-dimensional TOF MR angiography, there was a large decrease in the percentage of uninterpretable images for the blinded readers of MS-325–enhanced MR angiograms. Results are summarized in Table 2. Of the vessels interpretable at conventional angiography and included for comparison, fewer than 2.3% were uninterpretable at MS-325 MR angiography, versus approximately 16% for noncontrast MR angiography. For comparison, 2.8% of the vessels were deemed uninterpretable on the conventional angiograms reviewed as the standard of reference. The most common cause of uninterpretable noncontrast images was inadequate vessel contrast.
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Because a dissection was found in the arteries of only two patients, no conclusions can be drawn regarding dissections. However, 15 aneurysms in 14 patients were found with conventional angiography. All three readers of MR angiograms showed excellent sensitivity (93%–100%), specificity (93%–97%), and accuracy (93%–97%) for MS-325–enhanced MR angiography in the detection of aneurysms. On average, the sensitivity, specificity, and accuracy were 29%, 12%, and 12% higher, respectively, than for noncontrast MR angiography.
Table 5 summarizes the agreement between blinded readers A and B of conventional angiograms for the presence or absence of clinically significant (>50%) stenoses in all vessels. Overall, the readers' respective assessments agreed in approximately 90% of vessels. The sensitivity and specificity of conventional angiography in replicating its own results were assessed by computing the sensitivity and specificity for each reader of conventional angiograms when the other was held as the standard of reference.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The design of this study provided a number of features and analyses to help characterize MS-325–enhanced MR angiography compared with both noncontrast MR angiography and conventional angiography. Diagnostic effectiveness was assessed by means of both quantitative (primary) and qualitative interpretations. In addition to that assessment, an absolute comparison was also performed on a vessel-by-vessel and lesion-by-lesion basis, allowing a more precise comparison of MS-325–enhanced MR angiography with conventional angiography. The use of multiple readers of conventional angiograms generated a consensus that was superior to any individual reader's interpretation. The MR and conventional angiographic results were compared for analyses for which few comparisons are reported in the literature, such as those for absolute differences and location matches. Since two readers interpreted all conventional angiograms, a comparison between them was also available to set the MR angiographic results in the context of interreader variability.
The location match analysis revealed large differences between noncontrast and contrast-enhanced MR angiography. For detecting clinically significant (50%) stenoses, which best represents the intended clinical use of MS-325, there was excellent agreement between the locations on MS-325–enhanced MR angiograms and on the conventional angiograms. The poorer agreement between noncontrast MR angiograms and conventional angiograms reflected not only an increased number of uninterpretable images but also a large number of stenoses marked in different portions of the vessels on noncontrast MR angiograms.
The results of this study provide substantial evidence of improved diagnosis and patient management with the use of MS-325–enhanced MR angiography rather than noncontrast MR angiography. The problems of noncontrast MR angiographic techniques in the aortoiliac region are widely recognized: flow voids from turbulent vortices, artifacts from pulsatile flow, and the risk of patient motion artifacts, which is inherent to the longer imaging times required for noncontrast MR angiography (20–22). These problems are overcome with the use of MS-325–enhanced MR angiography, as indicated by the high diagnostic accuracy achieved with that technique (mean accuracy for the three blinded readers, 83.7%). The agreement between the two readers of conventional angiograms was approximately 90%, which is consistent with values reported in the literature (23). Therefore, the MS-325–enhanced MR angiographic results approach the level of agreement for conventional angiography.
Furthermore, the comparison of MS-325–enhanced MR angiography with conventional angiography for the location of clinically significant stenoses (50%) showed an average agreement of 92% for this study, only slightly lower than the agreement between the two readers of conventional angiograms for the locations of the same stenoses (approximately 96%), which demonstrates that the readers of conventional and MR angiograms were interpreting the same stenoses to make their diagnoses. In addition, there was a mean difference of approximately 17% between the percentage of stenosis for the three readers of MR angiograms and the average percentage for readers of conventional angiograms. This result compares favorably with the difference between the two readers of conventional angiograms for the measured percentage of stenosis (16%). Overall, there was a very high degree of agreement between the MS-325–enhanced MR angiographic measurements of vascular disease (diagnosis, localization and quantitation) relative to the agreement between the individual readers of conventional angiograms.
Perhaps the most important factor that elevates these quantitative measures of performance virtually to the level of the conventional angiographic standard is that MS-325 effectively eliminates the problem of uninterpretability. TOF and phase-contrast MR imaging all have limitations that reduce contrast in certain structures and certain flow patterns (21). MS-325 eliminates these limitations by creating a contrast mode inherent to the blood. Thus, averaged over the readers in this study, the number of uninterpretable vessels decreased from 16.1% for noncontrast MR angiography to 2.3% for MS-325 MR angiography, even lower than the 2.8% of vessels that were uninterpretable on conventional angiograms. The convergence of MR angiographic accuracy versus conventional angiographic accuracy in several quantitative measures to the corresponding value of agreement between readers of conventional angiograms is strong evidence that the error rate in MS-325–enhanced MR angiography might reflect the systematic error inherent to angiography in general.
A potential role of a blood-pool contrast agent such as MS-325 is the imaging of multiple vascular beds after a single injection of contrast agent. Since atherosclerotic disease is a systemic process, it is useful, for example, to couple aortoiliac MR angiography with imaging of the runoff arteries (24). With contrast-enhanced MR angiography with extracellular contrast agents, imaging speed is frequently the overriding factor in establishing the protocol. The current approach to three-dimensional contrast-enhanced MR angiography is to use increasingly shorter values of repetition and echo times, typically found only on advanced 1.5-T MR systems (25,26). Short imaging times also allow lower doses of contrast agent, but the duration of peak arterial enhancement is extremely brief, typically a few seconds. With the use of MS-325 during steady-state conditions, imaging speed may no longer need to be the primary factor in the design of MR angiographic protocols. Consequently, MR protocols could invest more time to acquire high-resolution images that are difficult or impossible to obtain with extracellular contrast agents. The steady-state contrast would allow for imaging of multiple beds, all at higher resolution than has been possible in the past.
There are several limitations to the very specific evaluation of MR angiograms that we used. Stenoses were graded on a percentage basis, without consideration of any hemodynamic information. Doppler ultrasonographic or pressure gradient measurements may be available in the clinical setting. A pure morphologic assessment is rarely the means of clinical diagnosis. While 50% stenosis is an established criterion for significant vascular disease (27–30), the percentage stenosis provides a limited view compared with a physician's typical examination and diagnosis. Moreover, a study such as ours cannot perfectly reflect actual clinical practice. A purely blinded reading of the data does not take into account the patient's medical history, disposition, or symptoms, as would be considered by a physician. In addition, clinical angiography of the aortoiliac region often includes angiography of the extremities. This concomitant knowledge could guide reading and lead to a different diagnosis. While the same lack of concomitant knowledge lends some systematic error to the conventional angiographic data used for the standard of reference, the errors introduced may be dissimilar between the two modalities.
We have also accepted the assumption that the standard of reference was improved by using the consensus of two reader results. With these limitations on the process of comparison, it was shown that MS-325–enhanced MR angiography performed similarly to conventional angiography. Finally, the specific advantages of steady-state blood-pool MR angiography were not compared with those of dynamic MS-325–enhanced MR angiography. The latter is comparable to the use of MR angiography with extracellular fraction contrast agents, which are frequently used with regulatory approval in Europe and without Food and Drug Administration approval for MR angiography in the United States.
Previous studies have amassed strong evidence as to the safety and tolerability of MS-325 administered as a 0.03 mmol/kg bolus in patients with peripheral vascular disease (16,17). In general, the side-effect profile generated here was similar to that seen in these previous studies, including both the overall rate of adverse events, as well as the most common such events observed. Moreover, the side effect profile was similar to that for other gadolinium-based contrast agents (12). Using a protocol similar to ours, Perreault et al (17) found a 24% rate of adverse events reported in the placebo population and rated as possibly or probably related to the study drug, compared with the 23% rate seen in our study. There was no evidence of any particular patient profile or trait that resulted in an increased risk to any particular side effect after administration of MS-325, including adverse events, vital signs, clinical laboratory results, physical examination findings, or ECG parameters. The data in total, including individual patient outcomes (all adverse events resolved, no interventions were required), support the conclusion that there is no substantive safety concern related to MS-325 administration. MS-325 may offer an option for contrast enhancement that approaches the effectiveness of conventional angiography without the established safety concerns posed by nephrotoxic effects of iodine (13) and x-ray radiation exposure.
We conclude that MS-325–enhanced MR angiography is safe and well tolerated in patients with peripheral vascular disease, effective for the detection of vascular stenosis and aneurysms, significantly more accurate (both more sensitive and specific) than noncontrast MR angiography for the diagnosis of vascular stenoses, and similar to conventional angiography for the overall characterization of vascular disease in the aortoiliac region, without the need for catheterization.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: ECG = electrocardiography • ROC = receiver operating characteristic • TOF = time of flight
E.K.Y. is a consultant and shareholder in EPIX Medical. See Materials and Methods for pertinent disclosures.
Author contributions: Guarantors of integrity of entire study, M.G., E.K.Y., K.S., R.M.W.; study concepts and design, E.K.Y., K.S., R.M.W.; literature research, M.G., E.K.Y., K.S., R.M.W.; clinical studies, all authors; data acquisition, M.G., M.E., P.P., E.O., H.B., J.T., D.S., M.S., E.R.M., R.B.; data analysis/interpretation, M.G., E.K.Y., K.S., R.M.W.; statistical analysis, K.S., R.M.W.; manuscript preparation and definition of intellectual content, M.G., K.S., R.M.W.; manuscript editing, M.G., E.K.Y., K.S., R.M.W.; manuscript revision/review and final version approval, all authors
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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