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ORIGINAL ARTICLE
Clinical Safety and Diagnostic Value of the Gadolinium
Chelate Gadoterate Meglumine (Gd-DOTA)
Christoph U. Herborn, MD,* Elmar Honold, MD,† Michael Wolf,‡ Jörn Kemper, MD,§
Sonja Kinner, MD,¶ Gerhard Adam, MD,§ and Jörg Barkhausen, MD¶
Objective: The purpose of this study was to assess the diagnostic
value and safety of the contrast agent gadoterate meglumine
(Gd-DOTA, DOTAREM, Guerbet, Roissy CdG Cedex, France) in
the setting of a postmarketing surveillance study.
Materials and Methods: Between January 2004 and October 2005,
radiologists in 61 radiologic institutions were asked to document the
routine use of Gd-DOTA in a questionnaire. In addition to assessing
the image quality and diagnostic value of the contrast-enhanced
magnetic resonance imaging scans, we statistically evaluated and
analyzed demographic and safety data.
Results: A total of 24,308 patients were intravenously injected with
Gd-DOTA for various diagnostic examinations. The examination
allowed for establishing a diagnosis in ⬎99% of cases and image
quality was rated as “excellent” or “good” in 97.5% of all cases.
Adverse events were noted in only 0.4% of the examinations and
were mostly rated as minor, such as feeling of warmth or taste
alteration. There was one serious adverse event, albeit with complete
recovery.
Conclusion: This postmarketing surveillance study suggests diagnostic efficacy and a favorable clinical safety profile of Gd-DOTA in
clinical practice.
Key Words: magnetic resonance imaging, contrast material,
Gd-DOTA, safety profile
(Invest Radiol 2007;42: 58 – 62)
M
agnetic resonance imaging (MRI) is unique among
currently available imaging techniques in that there are
multiple parameters responsible for signal intensity that produce images with a rather high degree of soft-tissue contrast.
Thus, it was initially speculated that there would be no need
for contrast agents in MRI. However, its propensity to con-
Received July 19, 2006, and accepted for publication, after revision, September 17, 2006.
From the *Medical Prevention Center Hamburg; †Guerbet GmbH, Sulzbach;
‡Michael Wolf Information Systems, Püttlingen; §Department of Diagnostic and Interventional Radiology, University Medical Center HamburgEppendorf; and ¶Department of Diagnostic and Interventional Radiology
and Neuroradiology, University Hospital Essen, Germany.
Reprints: Christoph U. Herborn, MD, Medical Prevention Center Hamburg,
University Medical Center Hamburg-Eppendorf, Falkenried 88, 20251
Hamburg, Germany. E-mail: [email protected].
Copyright © 2006 by Lippincott Williams & Wilkins
ISSN: 0020-9996/07/4201-0058
58
trast material is far greater than that of x-ray computed
tomography (CT). In the early 1980s, it became apparent that
contrast enhancement substantially improved the sensitivity
and specificity of MRI scans. Accordingly, it has been demonstrated that MRI benefits vastly from paramagnetic contrast
media for the detection of blood– brain barrier disruptions as
well as for further characterization of parenchymal lesions
and lymph nodes. For example, many brain metastases can
only be visualized after contrast enhancement,1–5 and some
hepatic lesions can only be classified by the way in which
they take up contrast material.6 –12 In addition, contrast media
are essential for displaying the vascular system with fast
3-dimensional gradient-echo sequences.13–17 The development of new hardware together with advances in contrast
media design continue to drive the expansion of intravenous
contrast media applications.18
Currently, a variety of paramagnetic contrast agents are
used for a broad spectrum of clinical indications, including
gadoterate meglumine (Gd-DOTA, DOTAREM, Guerbet,
Roissy CdG Cedex, France), a paramagnetic extracellular
contrast agent used for enhancement of signal intensity in
MRI. The compound is approved for imaging cerebral and
spinal lesions with abnormal blood– brain barrier or anomalous vascularity as well as for body imaging. Gd-DOTA is a
very stable and hyperosmolar agent (1350 mosm/kg H2O)
with a gadolinium concentration of 0.5 mol/L, characterized
by r1 and r2 values (determined experimentally at 20°C and
a magnetic field strength of 1.0T) of 3.4 L (mmol ⫻ s)⫺1 and
4.8 L (mmol ⫻ s)⫺1, respectively. The aim of this large-scale
postmarketing surveillance study, which was conducted in
Germany, was to assess the diagnostic quality and safety of
intravenous injections of Gd-DOTA in patients who underwent routine MRI examinations.
MATERIALS AND METHODS
Patients
Demographic, clinical, imaging, and safety data from
patients who underwent routine MRI examinations with intravenous administration of Gd-DOTA were obtained from
board certified radiologists in 61 radiologic institutions
throughout Germany between January 2004 and October
2005. Enrollment in the study was possible up to 1000
patients per study site (mean 394.61; median 399.5; mode
400). According to the summary of product characteristics,
known allergies to gadoterate, meglumin, other Gd-drugs, or
Investigative Radiology • Volume 42, Number 1, January 2007
Investigative Radiology • Volume 42, Number 1, January 2007
severe renal impairment (ie, creatinine clearance less than 30
mL/min) were contraindications. Therefore, those patients
were not included in this study.
In view of the recommendations concerning observational studies issued by the German Federal Institute for
Drugs and Medical Devices (BfArM) in 199819 and in accordance with the definition of a “noninterventional trial” in
Article 2(c) of Directive 2001/20/EC,20 the decision to include a patient in this observational study was completely
independent of the decision to conduct an MRI examination,
ie, the patient underwent the MR examination irrespective of
the participation in this study. Gd-DOTA was to be used in
accordance with the local approved Summary of Product
Characteristics which is equivalent to the European package
insert.
Data Collection
Patient data were collected through the use of standardized questionnaires completed by the radiologist. Patients’
demographic data (age, sex, height, and weight, including
calculation of body mass index 关BMI兴, measured in kg/m2)
and the type of examination performed were recorded. In
addition, information was collected on the number and type
of relevant medical history, premedication administered; the
intravenous contrast medium injection (dose, amount, and
mode of administration, ie, manual/automated/single or repeated injection); subjective assessments of image quality
(excellent, ie, superb and completely homogenous signal
enhancement of target structures, evaluation possible with
high diagnostic confidence; good, ie, good signal enhancement of target structures, almost completely homogeneous,
evaluation possible with satisfactory diagnostic confidence;
mediocre, ie, moderate signal enhancement of target structures, but still inhomogeneous, evaluation possible with low
diagnostic confidence; bad, ie, low and inhomogenous signal
enhancement of target structures); very bad (ie, no signal
enhancement); and assessment of the diagnostic yield of the
examination (yes/no) stating the reasons when the answer
was “no.” Adverse events spontaneously reported from the
patient at any time were recorded as well as adverse events
that were observed by the MR technologist, nurse, or physician. Details of any adverse events (type, duration, necessity
of treatment, type of treatment) also were collected, including
information on outcome and any indication of whether the
examination had to be discontinued because of such events or
whether a return to normal health status was achieved, as well
as stating whether there was considered to be a causal
relationship to the contrast medium. Each patient was monitored about adverse reactions during and for approximately
30 – 60 minutes after the procedure.
Statistical Analyses
All data were typed in an electronic data sheet using
Visual Stats AWB (version 2002). Concomitant medication
was recorded, and adverse events were classified in accordance with World Health Organization Adverse Reaction
Terminology. Based on the data of the postmarketing surveillance study, statistical analysis was done with SPSS for
Windows using the ␹2 test according to Pearson. Whenever
© 2006 Lippincott Williams & Wilkins
Clinical Safety and Diagnostic Value of the Gd-DOTA
data were missing, the results were adjusted to 100% to allow
for comparison of percentages. A P value less than 0.05 was
considered statistically significant.
RESULTS
Patient Demographics
A total of 24,308 patients were included (10,924 men
关44.9%兴 and 13,327 women 关54.8%兴). The gender of 57
patients (0.2%) was not stated in the questionnaires. Patients
ranged in age from a few weeks to 103 years (mean, 51.8
years). A total of 4907 (20.2%) of the patients were classified
as having relevant medical history. The most common risk
factors were known allergies (including to iodinated contrast
material), arterial hypertension, coronary artery disease, and
asthma (Table 1).
Types of Examinations
In 13,668 patients (56.2%), the contrast-enhanced MRI
study was performed for neuroradiological purposes, body
MRI studies were performed in 2743 patients (11.3%), and
musculoskeletal MRI with contrast material enhancement
was performed in 28.8% (n ⫽ 7009).
Contrast Medium Injection
The Gd-DOTA contrast medium was injected manually
in a majority of cases (76.0%), whereas automated intravenous injection was performed in 24.0% of cases. Most of
patients received a single injection of Gd-DOTA (98%) and
the average dose was 0.1 mmol/kg. The injected volume of
Gd-DOTA per patient ranged from 0.6 mL in a newborn to 80
mL in an obese woman, the average volumes injected varied
with the type of examination and were bodyweight-adjusted.
For the entire study cohort, a mean volume of 15.8 mL of
Gd-DOTA was injected per examination. A mean dose of
0.1070 mmol/kg was intravenously injected (95% confidence
interval, 0.1067; 0.1074). Comparison of contrast medium
volumes and the patients’ weight with subdivision into patients with normal weight and those with overweight according to the conventional, age-related limits of the body
mass index (BMI) showed that patients with a BMI above
TABLE 1. The Number and Percentage of Relevant Medical
History of Patients Included in the Study of 24,308 Patients
Injected With Gd-DOTA
Medical History
Renal insufficiency
Impaired liver function
History of allergies
History of contrast material adverse event
Asthma
Coronary artery disease
Myocardial insufficiency
Arterial hypertension
Central nervous disorders
Others
Total
n
%
218
178
1829
190
298
620
366
1635
624
450
4907
0.9
0.7
7.5
0.8
1.2
2.6
1.5
6.7
2.6
1.9
20.2
59
Investigative Radiology • Volume 42, Number 1, January 2007
Herborn et al
25 received statistically significantly less contrast agent (P ⬍
0.001).
Subjective Assessment of Image Quality and
Diagnostic Yield
The question referring to the diagnostic yield was not
answered in 217 patients (0.9%). The remaining patients were
adjusted to 100%, of which a total of 23,993 (99.6%) were of
diagnostic quality and 98 (0.4%) were classified as nondiagnostic. Subjective assessment of the image quality was missing in 221 questionnaires (0.9%). The results of the remaining
99.1% of cases (again adjusted to 100%) are presented in
Table 2. Image quality was rated as “excellent” or “good” in
23,490 cases (97.5%). Image quality was statistically significantly worse in patients with overweight (BMI ⬎ 25) (P ⬍
0.001). Further analysis of the reasons given for rating image
quality as nondiagnostic revealed that technical problems
were the primary cause in only 16 of the 98 cases (0.1% of all
examinations). Movement and/or lack of cooperation from
the patient during the examination were involved in 58 cases
(0.2%) and, in 38 cases (0.2%), a detailed reason for the poor
image quality was not declared.
Adverse Events
Minor adverse events associated with Gd-DOTA occurred infrequently and included nausea, feeling of warmth,
and taste alteration. Adverse events were reported in a total of
94 patients (0.4%), and the most frequently occurring adverse
events are listed in Table 3. There were no statistically
significant differences between the subgroups of the study
population for any adverse event, except for patients with
liver disease. Those experienced nausea after injection statistically significantly more often than any other subgroup (P ⬍
0.001). Only one reaction led to discontinuation of the examination (0.004%), and all other examinations were routinely terminated. Twenty-four patients (25.5%) with adverse
reactions required further medical treatment of the adverse
event, including one who required hospitalization (1.1%).
Complete recovery was achieved in 58 patients who reported
adverse events (61.7%), 1 case (1.1%) was classified as
unknown outcome, and in 34 cases (36.2%) it was not stated
whether symptoms persisted. All documented subsequent
courses were uneventful. In 2 (2.1%) patients the experienced adverse events were classified as not related to the
administration of the contrast agent. In 63 (67%) patients,
these were considered to be most likely related to the injec-
TABLE 2. Image Quality Evaluation of Gd-DOTA-Enhanced
MRI Scans
Image Quality
Excellent
Very good
Mediocre
Bad
Very bad
Total
60
n
%
9866
13,624
558
36
3
24,087
41.0
56.6
2.3
0.1
⬍0.1
100
TABLE 3. Most Frequently Encountered Adverse Events in
94/24,308 (0.4%) Patients After the Injection of Gd-DOTA in
This Study
Adverse Event
n
%
Nausea
Vomiting
Feeling of warmth
Paraesthesia
Injection site pain
Pruritus
Urticaria
Taste alteration
Retching
Coughing
42
13
6
5
5
5
5
4
4
4
0.17
0.05
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
tion of the agent. In 29 cases (30.9%) the causal relationship
to Gd-DOTA was not mentioned.
In 1 of 24,308 patients (0.004%), a serious adverse
event occurred that was considered to be life-threatening.
This 65-year-old man with no known allergies underwent an
MRI examination with intravenous injection of 17 mL of
Gd-DOTA for assessment of cervicobrachalgia (pain in the
area of cervical vertebra spreading to the left arm) and
cervical myelopathy on May 17, 2004. His medical history
included alcohol and drug abuse (not specified further),
symptomatic transitory psychotic syndrome, coronary artery
disease with status post angioplasty, and stent implantation
into the of the left anterior descending coronary artery. He
also had a history of an occluded left-sided femoro-femoral
arterial bypass grafting, hypercholesterolaemia, and gastric
surgery (not specified further), and peripheral arterial occlusive disease was diagnosed in 1998, which had been treated
with phenprocoumon. The patient did not show effort angina,
arrhythmias, or known thyroid disorders. On the day of the
examination, he was treated with diazepam and a 50-mL
injection of NaCl (0.9%). Immediately after the Gd-DOTA
injection, he experienced anaphylactic shock associated with
nausea, eructation, pallor, perspiration, and convulsions. His
pulse decreased, and ventricular fibrillation was recognized.
He was immediately transferred to the intensive care unit
(ICU) of the hospital, where corrective treatment was initiated and resuscitation and intubation were performed. In the
ICU, the patient was diagnosed with an acute coronary
syndrome and, during conventional coronary angiography on
18 May 2004, 4 stents were successfully implanted in the
right coronary artery. After this intervention, the patient was
reported to be stable. The final outcome was favorable with
complete recovery. According to the hospital physician, an
anaphylactic reaction caused by the administration of contrast
medium seemed to be possible based upon the history (the
patient’s health status deteriorated immediately after the injection of Gd-DOTA with consecutive shock) but could not
be definitely established. It is most probable that the acute
symptoms were caused by an acute occlusion of the right
coronary artery caused by pre-existing coronary artery disease; however, the anaphylactic reaction to the contrast medium may have triggered this critical situation.
© 2006 Lippincott Williams & Wilkins
Investigative Radiology • Volume 42, Number 1, January 2007
DISCUSSION
This postmarketing surveillance study has provided the
largest analysis of tolerance, adverse reactions and diagnostic
yield with the use of Gd-DOTA since its introduction into
clinical practice. Overall, Gd-DOTA was shown to have a
favorable tolerability profile and it also permitted diagnostic
examinations in ⬎99% of injections. A single serious adverse
event was observed among ⬎24,000 injections and image
quality was rated as excellent or good in almost all cases
(97.5%).
Because a very high degree of soft-tissue contrast is an
inherent benefit of MRI, it might be anticipated that no
further benefit, in terms of both image quality and diagnostic
confidence, could be derived from the use of additional
contrast material. However, the use of paramagnetic contrast
agents has dramatically improved the diagnostic sensitivity
and specificity of MRI for evaluating diseases of the central
nervous system, parenchymal organs and especially the vascular system. Gd-DOTA was shown in this study to provide
a combination of both diagnostic information and diagnostic
confidence, while being generally well tolerated, in line with
other paramagnetic contrast agents. In view of this, the use of
Gd-DOTA-enhanced MRI should be considered among the
range of diagnostic first-line imaging strategies, according to
the suspected disease at hand.
Adverse events may be associated with the administration of any given medication in clinical practice. However, as
contrast media are always critical in this regard since the
majority of examinations are mere diagnostic procedures, one
must always outweigh the risks of the agent against the
benefits. Thus, any contrast material should be administered
cautiously, especially in patients with a known history of
allergy or asthma. In particular, attention should be focused
on patients who have a known history of reaction to a contrast
agent. In comparison with x-ray compounds, the number of
such events is exceptionally low for MRI contrast agents.21
Interestingly, patients with a history of adverse reaction to an
iodinated contrast agent also are at a slightly greater risk of
reacting to injection of a paramagnetic contrast agent. In
addition, MRI contrast agents in the doses used for MR
imaging lack the nephrotoxicity associated with iodinated
contrast media.22 A particular strength of this postmarketing
surveillance study was that it allowed data on tolerability to
be collected from a patient population that included a significant proportion of patients with risk factors for adverse
reactions to contrast agents.
The results of this analysis have been consistent with
the findings of previous studies of Gd-DOTA published by
other study groups that included fewer patients. For example,
in a study of 1038 patients, Oudkerk et al found that minor
adverse events occurred in 0.97% of patients after the injection of Gd-DOTA for MRI studies of the brain and the rest of
the body.23 Adverse events were reported in 17.3% of patients after the administration of Gd-DOTA in a study that
included only 300 unselected neurologic patients. The fact
that the frequency of adverse events in this postmarketing
surveillance study was lower than in this rather small clinical
study may have been at least partially due to the latter
© 2006 Lippincott Williams & Wilkins
Clinical Safety and Diagnostic Value of the Gd-DOTA
investigators being more cautious in their approach than the
investigators in routine clinical practice who collected the
data reported in the present study.
Safety studies that have provided a comparable degree
of patient exposure have been performed with other paramagnetic contrast agents such as gadopentetate dimeglumine (ie,
Gd-DTPA, Magnevist, Schering, Berlin, Germany), which
was the first paramagnetic MRI contrast agent to be marketed
in Europe and the United States in 1988.24 –28 Gd-DOTA has
been reported to be similarly well tolerated and both agents
have been shown to possess similar diagnostic efficacy.21
More recently, new contrast agents have become available
and been subject to safety evaluations in smaller preclinical
and clinical studies.29,30
The present study is not without its limitations. For
example, the use of questionnaires for data collection in a
postmarketing surveillance study limits the quality of the
results compared with study designs such as controlled clinical trials because the responses to the questions are affected
to some extent by the subjective assessment of the investigator. On the other hand, a surveillance study by questionnaire
allows for collection of data from a very large and truly
representative study population. Hence, it is possible to also
identify very rare events (such as one severe adverse event in
our population of over 24,000 patients). Indeed, in the present
study, the overall incidence of reported adverse events was
only 0.4%. The most significant limitation of this evaluation,
as with most multicenter studies of contrast agent safety, is a
consequence of the inevitable variability among different
investigators in relation to the responses of patients about
adverse reaction occurrences and how they are elicited. In
addition, adverse events which occurred later than 24 hours
after Gd-DOTA-enhanced MRI might have been missed as
investigators did not initiate the contact after that timepoint.
Thus, it seems likely that some mild adverse events may have
been underreported in this patient cohort. In addition, this
study might be different from previous surveys in methods of
eliciting adverse events. Finally, the use of subjective assessments of image quality may have introduced variability and
bias to the study.
In conclusion, the experience with Gd-DOTA compiled
in this postmarketing surveillance study in more than 24,000
patients, including a significant proportion of patients with
risk factors for adverse reaction to contrast agents, has demonstrated both the favorable clinical safety profile as well as
the excellent clinical efficacy of this contrast agent.
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