Download Magnetic Resonance Angiography Using the Intravascular Contrast

Reference Section
Magnetic Resonance Angiography Using the Intravascular
Contrast Agent Vasovist ®
a report by
Mathias Goyen
University Medical Centre Hamburg
Atherosclerosis is a generalised disease and
contributes to cardiac death, stroke, limb loss and a
range of other illnesses. Disease in the major arteries,
including the infra-renal abdominal aorta, internal
iliac arteries, renal arteries and peripheral vasculature,
remains a major cause of morbidity and mortality.
For example, the prevalence of disease in the infrarenal abdominal aorta ranges from less than 3% in 60year-old patients to 20% in 75-year-old patients,1,2
and the incidence increases with increasing age.
Other forms of vascular disease such as renal artery
stenosis present additional manifestations, including
hypertension and renal failure. As the average age of
the population increases, the burden of vascular
disease is anticipated to increase.
Until recently, X-ray angiography (XRA) requiring
arterial catheterisation and the use of substantial
volumes of iodinated contrast agent was the clinical
standard practice when a detailed image of the
vasculature was required. However, less invasive
imaging techniques using X-ray computed
tomography (CT) or magnetic resonance imaging
(MRI) have been developed. These imaging
methods, either without exogenous contrast agents
(MRI only) or with exogenous contrast agents (both
CT and MRI) have become increasingly popular
over the past few years as data have suggested that
their accuracy, in some clinical settings, might
approach that of the accepted standard diagnostic
method, catheter XRA using iodinated dye.3–5
MRI is a safe, non-invasive and widely available
imaging technique that has experienced rapid growth
over the past decade. Enhancement of MR images
with exogenous contrast agents such as chelates of
gadolinium or iron has become standard clinical
practice in many settings. Such contrast agents
provide technical benefits, including improved image
quality, and clinical benefits, such as improved
sensitivity and specificity for disease. Magnetic
resonance angiography (MRA), a more recent
development in MRI, uses tailored acquisition
sequences to highlight blood flow and is widely used
to assist in the management of patients with vascular
diseases, especially in the brain. In many vascular
EUROPEAN CARDIOVASCULAR DISEASE 2006
beds like peripheral vessels, however, non-contrast
MRA is not used routinely in clinical practice due to
shortcomings of unenhanced MRA and/or the
limitations of currently available MR contrast agents.
What is Vasovist®?
MS-325 is the product development code for the
drug product containing trisodium gadolinium
(international non-proprietary name: gadofosveset)
as the active substance. Vasovist® injection is
composed of an aqueous solution (244mg/ml,
0.25mmol/litre) of drug substance, gadofosveset
trisodium, and a small amount of ligand excipient,
fosveset, to ensure minimal free gadolinium in
solution. The drug substance consists of a stable
gadolinium diethylenetriaminepentaacetic acid
(Gd-DTPA) chelate substituted with a
diphenylcyclohexylphosphate group. Vasovist ®
injection is a clear, colourless to slightly yellow
solution in which the pH has been adjusted from
6.5 to 8.0. The density is 1.12g/ml and the
osmolality ranges from 700–950mOsm/Kg at
37ºC. The viscosity of Vasovist® injection ranges
from 2.7 to 3.3cps at 20ºC. The molecular formula
is C33H40GdN3Na3O15P and the molecular weight
for the anhydrous form is 957.86.
Mathias Goyen is Chief
Communication Officer (CCO) at the
University Medical Center in
Hamburg, Germany. He was
previously Assistant Professor of
Radiology at the Department of
Diagnostic and Interventional
Radiology at the University Hospital
Essen, Germany. Dr Goyen has
edited four books and
authored many peer-reviewed
articles in the field of magnetic
resonance angiography. He
completed his medical studies in
Bochum, Germany and Basel,
Switzerland and his residency
training in radiology at the
University Hospital Essen, Germany
Vasovist® is administered either by a hand or
power injector to deliver a dose of 0.03mmol/kg in
25–30 seconds.
Overview of the Clinical Development
Programme
Prior to approval in the EU, Vasovist® underwent
extensive evaluation of the safety and efficacy of the
drug. The clinical development programme for
efficacy included two phase II studies and four phase
III studies. In phase II studies, approximately 300
patients were evaluated to define optimal dose for
MRA. The optimal dose for MRA was found to be
0.03mmol/kg. The clinical effectiveness of Vasovist®
was demonstrated through analysis of efficacy data of
672 patients who were included in four adequate and
well-controlled phase III studies. Vascular beds
1
Reference Section
Figure 1: Vasovist ®-enhanced f-p 3D-CE-MRA of the Carotid and Calf Arteries
with 1mm 3 Isotropic Voxel Sizes
intravenous bolus injection. The overall rate and
experience of adverse events was comparable with
placebo and was similar to that reported in clinical
trials for other Gd chelates.
Clinical Applications of
Vasovist®-enhanced MR Angiography
Due to the use of parallel acquisition techniques with an acceleration factor of three, scan time is only 12 seconds for the
carotids. Due to the high relaxivity of the contrast agents, high vessel-to-background contrast is achieved despite the small
contrast media volume of less than 8ml and the reduction of signal-to-noise ratio by PAT acceleration. Source: Stefan O
Schoenberg, Department of Clinical Radiology, University Hospitals – Grosshadern, Munich, Germany.
representative of areas of turbulent blood flow
(aortoiliac occlusive disease) to an organ (renal artery
disease) and slow flow (pedal arterial disease) were
studied. In all of these studies, the fundamental
methodology was the same.
Summary of Efficacy Results of Four
Phase III Studies
Vasovist® reduced the rate of uninterpretability
significantly and improved the diagnostic confidence.
Fewer than 2.3% were uninterpretable for Vasovist®enhanced MR angiography, versus approximately
16% for two-dimensional time of flight. For
comparison, 2.8% of the vessels were deemed
uninterpretable on XRA. For all readers in all
studies, the vascular surgeon readers agreed with
XRA more often when using Vasovist®-enhanced
MRA than when using pre-contrast MRA (range of
improvements: 1–36%). For six of the eight readers,
the improvement was substantial (>15%) and
statistically significant (p<0.001).
Safety Data for Vasovist®
Safety data in 767 patients (505 males and 262
females) receiving 0.03mmol/kg bw dose are
reported. There were no clinically significant trends
found in adverse events, laboratory assays, vital signs,
ECG, or oxygen saturation. Vasovist® has a good
safety profile and can be safely administered as an
2
Diagnostic accuracy of 3-D contrast-enhanced MR
angiography (3D-CE-MRA) is a result of temporal
and spatial resolution, anatomic coverage and
acquisition time. For first-pass 3D-CE-MRA (f-p
3D-CE-MRA) with standard extracellular Gdchelates this relationship is in conflict with the transit
time of the contrast agent and the breath hold
capacity of the patient. Representative clinical
examples are the assessment of carotid, renal and
peripheral arteries. In all three vessel territories
maximum spatial resolution is required for exact
detection and grading of atherosclerotic stenoses. For
the carotid arteries, the North American
Symptomatic Carotid Endarterectomy Trial
(NASCET) criteria require accurate definition of a
70% stenosis as a threshold for surgical
endatherectomy. With regard to the renal arteries, a
large multicentre study has shown relatively
moderate results for stenosis grading if voxel sizes
greater than 3mm3 were used for f-p 3D-CE-MRA
while a recent study has shown good correlation to
digital subtraction angiography using isotropic voxel
sizes of less than 1mm3 and non-intravascular Gdchelates.8,9 The same study could also demonstrate
that cross-sectional measurements of area stenosis are
feasible if sufficient spatial resolution is used.9 On the
other hand, high temporal resolution is also desirable
for f-p 3D-CE-MRA for a number of reasons – in
the carotid artery, delayed inflow and collateral flow
can be visualised in the case of a haemodynamically
significant stenosis, whereas retrograde flow can be
appreciated in subclavian steal syndrome. For the
renal arteries, disturbing overlay of enhancing renal
parenchyma on small intrarenal branches can be
effectively avoided allowing better visualisation of
diseases involving the distal renal arteries, such as in
fibromuscular dysplasia.10 For the peripheral arteries,
critical ischaemia with inflammatory changes often
results in substantial venous overlay prior to sufficient
arterial enhancement. Here, the so-called hybrid
approach often represents the only way to overcome
this diagnostic limitation.11 This includes either a
selective high-resolution f-p 3D-CE-MRA of the
calves after a test-bolus measurement or a timeresolved f-p 3D-CE-MRA preceding the moving
table-MRA of the pelvis and thighs.11
Any technical development overcoming this
limitation of multiple measurements with different
demands for temporal and spatial resolution would
EUROPEAN CARDIOVASCULAR DISEASE 2006
Magnetic Resonance Angiography Using the Intravascular Contrast Agent Vasovist ®
Figure 2: High-resolution Pulmonary MR Angiogram
Acquired in the Steady-state Phase after
Application of Vasovist ®
a reasonable scan time of approximately 5 minutes.12
Due to the absence of motion artefacts in the
peripheral arteries, exquisite image quality can be
achieved allowing for visual artery–vein separation
despite the close proximity of theses vessels.
Artery–vein separation can be further enhanced by the
use of semi-automated software, which is currently
under preparation by different vendors.
The add-on of the high-resolution s-s 3D-CE-MRA
represents a valuable problem-solving tool in
combination with the imaging during first pass.
While the acquisition scheme of f-p 3D-CE-MRA
can be adapted to meet the requirements for fast
time-resolved imaging, the target area of interest is
revisited during the s-s 3D-CE-MRA and imaged
with maximum resolution.
Other Potential Indications –
Off-label Use
be desirable. Intravascular contrast agents such as
Vasovist® that are both bolus-applicable and remain
in the vessels in the steady state have the potential to
integrate these different diagnostic requirements
within one single comprehensive scan. A recent
study has shown that high-resolution f-p 3D-CEMRA with Vasovist® allows data sets to be acquired
with an isotropic spatial resolution of 1mm3 in the
carotid arteries with acquisition times of only 12
seconds.12 These acquisitions were accelerated by the
use of parallel acquisition techniques (PAT) with
acceleration factors of up to three. While PAT allow
for higher spatial resolution at no increase in scan
time, they decrease the signal-to-noise ratio at least
by the square root of the acceleration factor. Thus,
MR contrast agents with high relaxivity are required.
Due to the strong protein binding, the relaxivity of
Vasovist® is relatively high resulting in good image
quality for f-p 3D-CE-MRA even for small total
volumes, despite higher acceleration of acquisition
by PAT. Figure 1 shows an example of f-p 3D-CEMRA of the carotid and calf arteries.
In addition to the use of this combined firstpass/steady-state approach for the labelled
indications, one can envision further applications
beyond one single field of view. With the
introduction of whole-body MRI scanners with
multiple independent rf-channels and inbuilt coil
systems for large anatomic coverage this approach
becomes attractive for assessment of the entire
vasculature by a combination of multi-station f-p
3D-CE-MRA and s-s 3D-CE-MRA. This shifts
the focus of MRA away from solely displaying
vascular anatomy to a more disease-specific
imaging approach. One example includes the
systemic assessment of atherosclerotic disease,
which has been shown as an arising application for
screening of cardiovascular risk factors in
preliminary studies.13,14 This systemic angiographic
assessment is also of high interest for patients with
vasculitis such as Takayasu arteritis that manifests in
multiple different locations. Here, the combination
of f-p 3D-CE-MRA of the carotid and renal
arteries in combination with high-resolution
assessment of the inflammatory stenoses could
improve the overall diagnostic work-up of the
patients and replace a more time-intensive multistep multi-modality approach.
After acquisition of MRA images in the first pass, any
of the three vessel territories can easily be revisited for
high-resolution 3D-CE-MRA in the steady-state
phase (s-s 3D-CE-MRA). Initially, there were
concerns with regard to the presence of venous overlay
on the s-s 3D-CE-MRA data sets, particularly for
arteries with small vessel calibre and close-by coursing
veins such as in the distal calves. However, with today’s
optimised surface coils and the use of PAT, isotropic
voxel sizes of less than 100µm3 can now be acquired in
Lastly, intravascular contrast agents enable the
combined systemic assessment of arteries and veins,
which is of particular interest for detection of lowerleg venous thrombosis complicated by pulmonary
embolism.15 Figure 2 shows a high-resolution s-s 3DCE-MRA of the pulmonary vascular bed, acquired
in one breath hold of approximately 35 seconds at a
spatial resolution of 1mm3 using a PAT acceleration
factor of three. In the steady state, it also would be
feasible to use two sagittally-oriented 3-D slabs, each
An acceleration factor of three was used for parallel imaging resulting in an overall
scan time of 35 seconds for the entire data set with 1mm3 isotropic spatial
resolution. Source: Stefan O Schoenberg, Department of Clinical Radiology,
University Hospitals – Grosshadern, Munich, Germany.
EUROPEAN CARDIOVASCULAR DISEASE 2006
3
Reference Section
covering one lung separately, for further reduction of
scan time without sacrificing spatial resolution.16
Conclusion
Vasovist®-enhanced MRA is safe and well-tolerated
in patients with vascular disease, effective for the
detection of vascular stenosis and aneurysms,
significantly more accurate – both more sensitive
and specific – than non-contrast MRA for the
diagnosis of vascular stenoses and similar to
conventional angiography for the overall
characterisation of vascular disease, without the need
for catheterisation. ■
References
1. Criqui M H et al., “The prevalence of peripheral arterial disease in a defined population”, Circulation (1985);71:
pp. 510–515.
2. Vogt M T et al., “Lower extremity arterial disease and the aging process: a review”, J Clin Epidemiol (1992);45:
pp. 529–542.
3. Rieker O et al., “CT angiography versus intraarterial digital subtraction angiography for assessment of aortoiliac occlusive
disease”, AJR Am J Roentgenol (1997);169: pp. 1,133–1,138.
4. Tan K T et al., “Magnetic resonance angiography for the diagnosis of renal artery stenosis: a meta-analysis”, Clin Radiol
(2002);57: pp. 617–624.
5. Grist T, “MRA of the abdominal aorta and lower extremities”, J Magn Reson Imaging (2000);11: pp. 32–43.
6. Rapp J H, Wolff S D, Quinn S F et al., “Aortoiliac occlusive disease in patients with known or suspected peripheral
vascular disease: safety and efficacy of gadofosveset-enhanced MR angiography—multicenter comparative phase III study”,
Radiology (2005);236: pp. 71–78.
7. Goyen M, Edelman M, Perreault P et al., “ MR angiography of aortoiliac occlusive disease: a phase III study of the safety
and effectiveness of the blood-pool contrast agent MS-325”, Radiology (2005);236: pp. 825–833.
8. Vasbinder G B et al., “Accuracy of computed tomographic angiography and magnetic resonance angiography for diagnosing
renal artery stenosis”, Ann Intern Med (2004);141: pp. 674–682.
9. Schoenberg S O, Rieger J R, Weber C H et al., “High-spatial-resolution MR-angiography of renal arteries with integrated
parallel acquisitions: comparison with digital subtraction angiography and US”, Radiology (2005);236: pp. 687–698.
10. Schoenberg S O et al., “Renal arteries: optimization of three-dimensional gadolinium-enhanced MR angiography with
bolus-timing-independent fast multiphase acquisition in a single breath hold”, Radiology (1999);211: pp. 667–679.
11. Meissner O A, Rieger J, Weber C et al., “Critical limb ischaemia: hybrid-MR angiography compared with DSA”,
Radiology (2005);235: pp. 308–318.
12. Nikolaou K, Schoenberg S O, Hartmann M, Chamberlin P, Reiser M F, “Ultra-high-resolution whole-body MRA using
parallel imaging on a 32-channel MR system and intravascular contrast agents: protocol optimization for clinical
applications”, Eur Radiol (2005); (Suppl): p. 340.
13. Herborn C U et al., “Peripheral vasculature: whole-body MR angiography with midfemoral venous compression—initial
experience”, Radiology (2004);230: pp. 872–878.
14. Kramer H, Schoenberg S O, Nikolaou K et al., “Cardiovascular screening with parallel imaging techniques and a wholebody MR imager”, Radiology (2005);236: pp. 300–310.
15. Ruehm SG et al., “Pelvic and lower extremity veins: contrast-enhanced three-dimensional MR venography with a dedicated
vascular coil-initial experience”, Radiology (2000);215: pp. 421–427.
16. Oudkerk M et al., “Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary
angiography for the diagnosis of pulmonary embolism: a prospective study”, Lancet (2002);359: pp. 1,643–1,647.
4
EUROPEAN CARDIOVASCULAR DISEASE 2006