| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Neuroradiology, Center for Medical Imaging and Physiology, Lund
University Hospital, SE-221 85, Lund, Sweden.
2 Department of Internal Medicine, Lund University Hospital, SE-221 85, Lund,
Sweden.
3 Department of Diagnostic Radiology, University Hospital Essen, Hufelandstr.
55, DE-45122 Essen, Germany.
4 Radiology Service, VA North Texas Healthcare System, 4500 S. Lancaster Rd.,
Dallas, TX 75216.
5 Department of Radiology, The Brigham and Women's Hospital, 75 Francis St.,
Boston, MA 02115.
6 Institut für Röntgendiagnostik, Universität Würzburg,
DE-97080 Würzburg, Germany.
7 MR-Institute, University Hospital Graz, Auenbruggerplatz 9, AT-8036 GRAZ,
Austria.
Received April 29, 2002;
accepted after revision June 21, 2002.
The opinions and assertions contained herein are the private views of the
authors and are not to be construed as official or as representing the views
of the United States Department of Veterans Affairs.
Abstract
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
SUBJECTS AND METHODS. We enrolled in our study a total of 45 patients at six centers who had lower extremity deep venous thrombosis documented on radiographic venography. Forty-four patients received the study drug; 39 completed the study. Each patient received three sequential IV injections of feruglose at doses of 0.75, 1.25, and 3.0 mg Fe/kg body weight. MR venography at 1.5 T was repeated at three levels after each dose. Safety was evaluated.
RESULTS. The agreement between contrast-enhanced MR venography and radiographic venography with regard to deep venous thrombosis above the knee was zero at the lowest dose (0.75 mg Fe/kg body weight), 43% at the dose 2.0 mg Fe/kg body weight, and 49% at the dose 5.0 mg Fe/kg body weight. No significant difference was seen between the two highest doses. The highest cumulative dose provided the greatest diagnostic usefulness score. No serious adverse events occurred.
CONCLUSION. The two highest doses of feruglose showed the best agreement between contrast-enhanced MR venography and radiographic venography for deep venous thrombosis above the knee. The safety and tolerability of feruglose were confirmed.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
We report the results of a multicenter phase 2 study of dosage using Clariscan in patients with deep venous thrombosis. The aims of the study were to determine the optimal Clariscan dose for contrast-enhanced MR venography of the abdominopelvic and lower extremity veins and to evaluate safety and tolerability of Clariscan in patients with deep venous thrombosis.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
MR Imaging Technique
MR imaging was performed on 1.5-T scanners, using T1-weighted imaging
techniques with TE of less than 3 msec. The scanner used at the Lund site was
a 1.5-T unit (Magnetom Vision; Siemens, Erlangen, Germany). We used a
three-dimensional turbo fast low-angle shot MR angiography sequence (TR/TE,
6.8/2.1; flip angle, 25°; slab thickness, 128 mm). The matrix size was 200
x 512, the field of view was 338 x 450 mm, the effective partition
thickness was 3.2 mm (interpolated to 1.6 mm), and the acquisition time was 43
sec. The same sequence was used for the lower abdomen and pelvis, the upper
leg, and the lower leg. The sequence was thus performed three times after each
contrast medium injection.
MR venography was performed no sooner than 2 min after injection of the contrast medium to ensure a steady-state condition. Some centers used unenhanced MR venography to obtain subtraction images.
Original coronal images as well as postprocessing images (multiplanar reconstructions and maximum intensity projections) were used in each patient's evaluation.
Efficacy Analysis
The primary efficacy end point was the diagnostic accuracy of
Clariscan-enhanced MR venography versus radiographic venography for detection
of deep venous thrombosis above the knee (i.e., from the distal popliteal vein
to the inferior vena cava). Findings in a patient were considered evaluable
for efficacy if he or she had received all three doses of the study drug and
had undergone radiographic venography that showed at least one vessel above
the knee that was positive for thrombus and had undergone MR venography at
each dose. Patients with findings positive only for a thrombus below the knee
were added in the analysis of secondary end points. The primary efficacy end
point was evaluated in a randomized review of MR venograms by an independent
reviewer who was unaware of patient identification and clinical information.
Secondary end points were analyzed on the basis of evaluation by the
independent reviewer, on-site evaluation, or both.
The following venous groups were evaluated: inferior vena cava, iliac (common, internal, external), femoral (common, deep, proximal, distal), and popliteal (proximal, distal). If a vessel group contained at least one thrombus on radiographic venography and any vessel in the same group contained at least one thrombus on contrast-enhanced MR venography, the group was considered to be in agreement. If no vessels in a group contained thrombi on radiographic venography and no vessels in the same group contained thrombi on contrast-enhanced MR venography, the group was considered to be in agreement. If overall image quality for MR venography at a particular dose was inadequate for diagnostic purposes, that MR venogram was considered to be in disagreement with radiographic venography.
A patient's diagnosis was considered to be in agreement only if all vessel groups were in agreement. The diagnostic accuracy (proportion of patients whose findings on MR venography were in agreement with radiographic venography) was calculated for each dose.
The secondary efficacy end points included vessel-level sensitivity, specificity, and accuracy; positive predictive value and negative predictive value; diagnostic usefulness of each dose; quality of delineation; contrast index (signal intensity of region of interest/signal intensity of muscle); diagnostic evaluability; confidence in thrombus assessment; overall image quality; and signal intensity.
Safety
The patients were closely observed and questioned for any kind of adverse
event up to 72 hr after the administration of the study drug. Samples for
blood and serum chemistry, hematology, and urinalysis evaluation were obtained
at screening and at 1-2 hr before injection (baseline values). Blood and urine
samples also were obtained at 2, 24, and 72 hr after injection. Any value
greater than 80% of the span of the reference range or with a more than 40%
increase or decrease after administration was considered clinically
significant. A 12-lead ECG evaluation was conducted at 1-2 hr before injection
and at 2, 24, and 72 hr after injection. Vital signs were recorded before,
during, and after the injections. Physical examinations were performed at 1 hr
before injection, and 24 and 72 hr after injection.
Statistical Analysis
The statistical evaluation was performed using SAS software (SAS Institute,
Cary, NC). Missing values were treated as missing, and estimated values were
not substituted. Statistical tests used a 0.05 significance level and were
two-sided when applicable. Confidence intervals, both individual and
simultaneous, were at a 95% confidence level. The statistical analysis of the
primary efficacy and point included an omnibus test of dose differences
(Cochran-Mantel-Haenszel row means test), pairwise comparisons (using the
McNemar test, adjusted by the stepdown Bonferroni method performed only if the
omnibus test was significant), and a test of trend (Cochran-Mantel-Haenszel
correlation statistic) for the dose response. Accuracy, sensitivity,
specificity, positive predictive value, and negative predictive value on
vessel level were derived from the Lee-Dubin estimate for clustered binary
data [21].
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
|
Diagnostic usefulness was evaluated by the independent reviewer using scores ranging from 1 (high) to 3 (low). The highest cumulative dose (5.0 mg Fe/kg body weight) provided the greatest diagnostic usefulness (score of 1.13 vs 1.87 for 2.0 mg Fe/kg body weight and 3.00 for 0.75 mg Fe/kg body weight). The quality of vessel delineation was assessed by the independent reviewer on a vessel-by-vessel basis using an ordinal scale (0 = not diagnostic, 6 = excellent visualization). We identified a trend for greater delineation of vessels with increasing dose, with the best quality achieved at the highest dose (5.0 mg Fe/kg body weight). Overall, delineation was poorer in the vessels below the knee than elsewhere.
The contrast index for small to large vessels of the pelvis, thigh, and knee improved significantly (p < 0.01) for each higher dose of Clariscan. Vessel size also had a significant effect on the contrast index: large vessels provided the highest contrast indexes (p < 0.05).
Every MR venogram was graded as diagnostically evaluable or not evaluable by the independent reviewer. The diagnostic evaluability of the images above the knee was poor at the lowest dose, 3%. By comparison, 91% and 97% were diagnostic at 2.0 and 5.0 mg Fe/kg body weight doses, respectively. Fewer contrast-enhanced MR venograms were diagnostic below the knee (60% at 2.0 mg Fe/kg body weight vs 80% at 5.0 mg Fe/kg body weight) (Table 3).
|
More diagnostic examinations were possible using contrast-enhanced MR venography compared with radiographic venography for the inferior vena cava, common iliac, internal iliac (Fig. 1A), and deep femoral veins (Fig. 1B). For example, at the highest dose, the vena cava in 24 patients and the internal iliac in 26 patients were evaluable on MR venography but not on radiographic venography.
|
|
Every vessel was graded as high or low with respect to confidence in thrombus existence as assessed by the independent reviewer. We found an apparent trend toward increasing confidence in thrombus existence at higher doses. At the 5.0 mg Fe/kg body weight dose, all veins above the knee showed at least 90% confidence, except for the distal popliteal (75%) and the deep femoral (79%) veins. No more than 50% of patients were assessed with high confidence for the vessels below the knee.
Both the overall image quality (assessed as either adequate or inadequate for diagnostic purposes by the independent reviewer) and the signal intensity showed significantly higher values with the two higher doses compared with the lowest dose. No clear difference was seen between the two higher doses.
Safety
Eleven (25%) of 44 patients experienced 13 adverse events after the study
drug was injected. One adverse event (back pain) resulted in the patient's
withdrawal from the study. Of the 13 adverse events, 11 were of mild intensity
and two were of moderate intensity. The most common adverse events were fever
(7%) and thrombocytopenia (5%). Only one adverse event (thrombocytopenia) was
considered likely to be related to the study drug. Two adverse events required
treatment (one patient took two 500-mg paracetamol tablets for a mild
headache, and another patient took 4 mg of dimethindene orally for a mild
erythematous rash). Each patient recovered from the adverse event before
completion of the study. One patient died within 2 weeks of receiving the
study drug. The death was attributed to the patient's preexisting condition
(progression of malignant lymphoma). This patient reported thrombocytopenia as
an adverse event, which was ruled unrelated to the study drug.
Our study found no dose effects on clinical laboratory results and no trends over time for any laboratory parameter other than the expected changes in iron parameters resulting from physiologic mechanisms of iron transport and storage. Significant elevations over baseline of total iron plasma concentration were seen at 2 hr and of ferritin at 24 and 72 hr after study drug injection. No changes from baseline in vital signs, ECG results, or physical examination were judged clinically significant.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our study showed that the agreement between contrast-enhanced MR venography and radiographic venography with regard to deep venous thrombosis above the knee was zero at the lowest dose (0.75 mg Fe/kg body weight), 43% at the dose of 2.0 mg Fe/kg body weight, and 49% at the dose of 5.0 mg Fe/kg body weight. We found no significant difference between the two higher doses. The low patient agreement was largely the result of the strict patient-agreement criteria, in which agreement was reached only when findings for all four vessel groups (inferior vena cava, iliac, femoral, and popliteal) were in agreement between contrast-enhanced MR venography and radiographic venography. However, we did ascertain more diagnostic information (larger number of diagnostically evaluable vessels) on contrast-enhanced MR venography compared with radiographic venography regarding the inferior vena cava, common iliac, internal iliac, and deep femoral veins (Fig. 1A,1B,1C). The latter two are usually not visualized on radiographic venography. The sensitivity, specificity, and accuracy of contrast-enhanced MR venography compared with radiographic venography ranged from 66% to 76% for vessels above the knee and 21% to 58% for vessels below the knee (Table 2). Furthermore, fewer vessels were diagnostically evaluable below the knee (60% at 2 mg and 80% at 5 mg Fe/kg body weight) than above the knee (91% and 97%, respectively). Additional secondary efficacy variables, such as quality of delineation, diagnostic usefulness of each dose, and contrast index, had a tendency to perform better with the highest (5.0 mg Fe/kg body weight) dose and above the knee.
|
These results are unacceptably low for vessels below the knee. One negative factor was that the patients were examined in the supine position. Varying degrees of compression of the veins is likely to have been present, and this has most likely affected the diagnostic usefulness and agreement for this region. A technique for obtaining noncompression has been reported [12] and would perhaps have improved the results. However, simplicity and avoiding time-consuming maneuvers are crucial in the clinical setting and hence these possibilities are limited.
No serious adverse events occurred in this study. Two moderate and 11 mild adverse events were reported. The most common adverse events were fever (7%) and thrombocytopenia (5%). Only one of the adverse events (thrombocytopenia, not requiring treatment) was likely to be related to the study drug. These results confirm the favorable safety profile of Clariscan documented in prior studies [18, 22, 23].
Previous MR imaging studies without contrast medium injection that obtained axial spin-echo images [10], axial gradient-echo images [12], or two-dimensional time-of-flight MR venograms [5, 9] have reported high sensitivity and specificity (87-100%) for detection of thrombosis of the pelvic and lower extremity veins. However, these techniques are time-consuming, and motion artifacts can be created because the patient has difficulty remaining still. The iliac veins are vulnerable to in-plane saturation effects [13]. Contrast-enhanced MR venography of the lower extremities with gadolinium-based contrast agents has not been widely used [13]. Timing of the contrast material injection is necessary, and contrast administration has to be repeated to image more than one anatomic level.
Intravascular contrast agents such as Clariscan have several advantages. For example, the bolus transit time does not need to be determined, which simplifies the injection technique and avoids timing errors. Insufficient resolution is one of the major problems with contrast-enhanced MR angiography using extracellular contrast agents. Intravascular contrast agents allow longer scanning times than extracellular contrast agents because of their relatively long half-life in the blood [16, 19]. The longer scanning time permits increased matrix size with preserved or higher signal-to-noise ratio, thus improving the spatial resolution. We did not explore the full potential of Clariscan for maximizing resolution because our study design used three cumulative doses that were injected within a predefined time frame, thereby limiting the maximal scanning time of each dose. This limitation became obvious when we evaluated the vessels below the knee, which are small and lie closely together in pairs (Fig. 2). We think that a significant improvement in resolution would be possible if longer scanning times than those allowed in this study were used.
|
A third advantage of contrast-enhanced MR angiography using intravascular contrast agents is the possibility of scanning as many vascular regions as needed without a moving-table technique after administration of the contrast bolus. An obvious gain is the visualization of the pelvic and abdominal vessels (Fig. 1A) and the deep femoral vein (Fig. 1 B), compared with what can be depicted on radiographic venography. In addition, vessels with different flow velocities will be properly depicted. Furthermore, scanning for deep venous thrombosis and pulmonary embolism can be performed during a single MR angiographic session [14].
A drawback of contrast-enhanced MR venography using intravascular contrast agents is the need for postprocessing because the contrast agent is present in arteries as well as in veins. In some anatomic regions, such as below the knee, this limitation constituted a major problem in our study. Multiplanar reconstructions (Figs. 1C and 2) and maximum intensity projections (Figs. 1A and 1B) are necessary and were used. Improvements of these tools (e.g., in vessel separation) are being developed and will most certainly speed up the postprocessing phase as well as enable a maximal usage of the resolution. These improvements should have a considerable impact, especially in imaging the vessels below the knee. Apart from insufficient resolution, the major negative contributor to the intermediate agreement between contrast-enhanced MR venography and radiographic venography in our study was the use of strict patient agreement criteria (agreement between the two methods only when all four vessel groups of the patient were in agreement regarding the presence of thrombosis). Bearing this in mind, we believe that our results justify further clinical studies to assess the performance of Clariscan for contrast-enhanced MR venography of the abdominopelvic and lower extremity veins.
In conclusion, this study has shown that the diagnostic accuracy of Clariscan-enhanced MR venography to detect deep venous thrombosis above the knee was intermediate (for the two higher cumulative doses) primarily because of strict patient-agreement criteria. We detected no significant difference in this regard between the doses of 2.0 and 5.0 mg Fe/kg body weight for the primary efficacy end point. The highest dose gave somewhat better results for secondary end points of specificity, quality of delineation, and contrast index than the two lower doses. The study has confirmed the safety and tolerability of Clariscan in cumulative doses of 0.75, 2.0, and 5.0 mg Fe/kg body weight.
Further studies with higher spatial resolution and better postprocessing capabilities are necessary before contrast-enhanced MR venography with intravascular contrast agents can replace radiographic venography for the detection of deep venous thrombosis of the lower extremities.
Acknowledgments
We thank M. V. Knopp, Department of Radiology, German Cancer Research
Center, Heidelberg, Germany, for his participation as an investigator in this
study. Amersham Health, Oslo, Norway, is acknowledged for funding the study
and performing the statistical analyses.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Remy-Jardin, M. Pistolesi, L. R. Goodman, W. B. Gefter, A. Gottschalk, J. R. Mayo, and H. D. Sostman Management of Suspected Acute Pulmonary Embolism in the Era of CT Angiography: A Statement from the Fleischner Society Radiology, November 1, 2007; 245(2): 315 - 329. [Full Text] [PDF]
|
|
|
|
|
|
W. Li, J. Salanitri, S. Tutton, E. E. Dunkle, J. R. Schneider, J. A. Caprini, L. N. Pierchala, P. M. Jacobs, and R. R. Edelman Lower Extremity Deep Venous Thrombosis: Evaluation with Ferumoxytol-enhanced MR Imaging and Dual-Contrast Mechanism--Preliminary Experience Radiology, March 1, 2007; 242(3): 873 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kluge, W. Luboldt, and G. Bachmann Acute pulmonary embolism to the subsegmental level: diagnostic accuracy of three MRI techniques compared with 16-MDCT. Am. J. Roentgenol., July 1, 2006; 187(1): W7 - 14. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
