A Prospective, Randomized Trial to

Determine the Early and Late

Reactions After the Use of Iopamidol
340 (Niopam™) and Iobitriol

VOLUME: 16 PUBLICATION DATE: Dec 03 2004

Sidebars_in_article:
Issue Number:
12 (Dec 2004)
author(s):

Kunadian Vijayalakshmi, MBBS, MRCP, David Williams DCR(R), Robert A Wright,

MD, FRCP, James A Hall, MA, MD, FRCP, Alun A Harcombe, MD, MRCP, Nicholas J
Linker, MD, FRCP, FESC, Michael J Stewart, MD, FRCP, Adrian Davies, BSc, MB,
FRCP, Mark A de Belder, MA, MD, FRCP

Intravascular contrast is a prerequisite for modern invasive cardiology. The contrast

agents used for various procedures have become increasingly safe in recent years.
Compared to ionic agents, the modern non-ionic contrast agents are fairly well tolerated,
with a low incidence of serious adverse reactions.1,2 Serious adverse events associated
with contrast agent such as ventricular fibrillation do occur in a few patients. It is not
known whether the fibrillation threshold is different between these agents in clinical
practice. Patients continue to experience uncomfortable and distressing symptoms from
the administration of contrast. Non-ionic contrast agents can be associated with late
complications that may not be recognized as such.
The clinical differences between the non-ionic agents currently available have not been
fully elucidated. Iobitridol 350 (Xenetix®, Guerbet) is a new iodinated low-osmolality
contrast medium.3 The safety and efficacy of iobitridol 350 has been studied in patients
undergoing cranial CT, arteriography of the lower limbs, urography and digital
subtraction angiography.4–6 There are few randomized studies to determine the safety
and efficacy of iobitridol 350 over the other commonly used non-ionic agents during
cardiac catheterization.7,8 Hence, we investigated the differences between the 2 non-
ionic monomers iopamidol 340 (Niopam, Bracco, U.K., Ltd.) and iobitridol 350
(Xenetix) during cardiac catheterization.

Methods
Study group. Participating patients were selected from those undergoing elective
coronary angiography. Two-thousand and nineteen consecutive patients undergoing
cardiac catheterization in a regional cardiothoracic center between August 2002 and
November 2003 were enrolled in the study. Follow-up was terminated in December 2003.
The Local Research Ethics Committee and the Research and Development Committee of
our institution approved the study protocol. Prior to cardiac catheterization, all patients
were provided with an information sheet and consent for the study was obtained. Patients
were not routinely sedated prior to cardiac catheterization. The type of study performed
was dependent upon the clinical information required (Table 1).
Coronary angiography. Coronary angiography was performed from any arterial route
(femoral, brachial, radial) using standard 6 French Judkins diagnostic catheters (Cordis
Corporation, Cordis Europa N.V., The Netherlands). Left venticulography was performed
according to our cardiac catheterization laboratory protocol of a 36 ml bolus of contrast
agent injected at 12 ml/second. In order to reduce viscosity, all contrast agents were kept
in a contrast media warming cabinet for 24 hours prior to use. The temperature inside the
cabinet was maintained at 37ºC. Each week, one of the contrast agents was randomly
assigned for use that week. Patients who had received any contrast agent within the
previous week were excluded from the analysis.
Electrocardiographic changes. Electrocardiographic changes were recorded on monitor
leads by the cardiac catheterization laboratory physiologists either during or shortly after
contrast injection into the coronary arteries. For the purposes of this study, ventricular
ectopy and non-sustained ventricular tachycardia during left venticulography were not
recorded as a significant ECG change. However, non-sustained ventricular tachycardia
observed during any other studies was recorded. In this study, minor ST-T changes were
not recorded. Any change from the baseline rhythm observed on the monitor leads was
documented. More than a 10 beat drop in the heart rate was also recorded.
Early Reactions. Early reactions were recorded by the radiographers in the cardiac
catheterization laboratory and by the nurse in charge of the patient on the cardiology
ward after the patient left the cardiac catheterization laboratory. New medications started
the week before and the week after cardiac catheterization were recorded. For patients
undergoing left ventriculography and aortography, the radiographer asked the patient to
arbitrarily score heat sensation during left ventriculography/aortography on a score of 0
to 5, with 0 being “no awareness of heat” and 5 being “extremely hot.”
Late reactions. Following discharge from the hosptial, each patient was asked to
complete a simple questionnaire on which notes would be made of any adverse reactions
occurring within one week post-cardiac catheterization. Patients were also advised to
document any new medications prescribed and within that period by the general
practitioner. The analysis of patients with late skin reactions was confined to those with
reactions that had clearly started after hospital discharge and therefore were not a
continuation of, for example, an urticarial reaction that occurred in the catheterization
laboratory. Patients with skin eruptions occurring solely at the site of the arterial puncture
were also not included in this group for analysis because these could have been secondary
to either skin disinfectant or local dressings.
Data collection. Patient demographic data, the type of procedure performed and
reactions were recorded.
Statistical analysis. The SPSS statistical software package (version 10.1) was used to
perform all statistical calculations. Continuous variables are expressed as mean ±
standard deviation and percentages. The relationship between the continuous variables
(age, height, weight) was evaluated using an independent sample t-test. Chi-squared tests
[X2 (degrees of freedom = df), probability value] were used to compare the early and late
reactions between the two groups. Fisher’s Exact test was used to compare the
differences in ventricular fibrillation arrests between the two groups. In this context, only
the probability value is provided. For all tests, a value of p < 0.05 was considered
statistically significant.

Results
The type of study patients underwent is shown in Table 1. There were no significant
differences in the baseline characteristics between the two groups (Table 2). The groups
contain different numbers of patients because of the randomization process, which
assigned a particular contrast agent to be used during each week of the study. Although
the numbers of weeks assigned to each agent are the same, the number of patients are
different because of variation in the number of patients undergoing diagnostic procedures
each week.
Heat reactions. A total of 1,673 patients underwent either left ventriculography or
aortography or both. Of these, 1,421 patients (85%) experienced heat sensation. Out of
these, 1,400 patients (99%) had heat sensation as their sole symptom. Fourteen patients
(0.9%) were unable to score the resulting heat sensation, and the remaining patients were
able to score the heat sensation on a scale of 0–5 (Table 3). There was no significant
difference in the heat score between the two contrast agents [X2 = 3 (1df), p = 0.1].
Early non-heat reactions. Symptoms excluding heat sensation occurring during cardiac
catheterization and 24 hours after were common. Sixty-eight patients (3.3%) recorded
symptoms within 24 hours that could be attributed to the effects of contrast. Of these 35
(3.2%) had received iopamidol 340 (Niopam) and 33 (3.6%) had received iobitridol 350
(Xenetix). There were no significant differences between the two groups in the number of
patients who had any additional early symptoms [X2 = 0.2 (1df), p = 0.65] (Table 4).
Electrocardiographic changes. There was a significant difference in the overall
electrocardiographic changes between the two groups, [X2 = 11.1 (1df), p = < 0.01]. This
was mainly attributed to the occurrence of ventricular fibrillation arrests requiring direct
current cardioversion in the iobitridol 350 (Xenetix) group compared to the iopamidol
340 (Niopam) group, p = < 0.01. Analysis of coronary angiography of patients who
experienced cardiac arrest revealed that ventricular fibrillation was neither catheter-
induced nor related to ischemia. Electrocardiographic changes were recorded in a total of
32 (1.6%) patients. A drop in heart rate was noted in 8 (0.4%) patients. There was,
however, no significant difference in any other electrocardiographic changes between the
two groups (Table 5).
Late reactions. Overall, 1,370 patients (68%) returned the questionnaire; 732 (67%) of
these received iopamidol 340 (Niopam) and 638 (69%) of these received iobitridol 350
(Xenetix) 350 [X2 = 0.9 (1df), p = 0.4]. In total, 220 patients (16%) reported symptoms
within one week after they were discharged from the hospital. Symptoms reported by
patients afterdischarge from the hospital were more frequent in the iobitridol 350
(Xenetix) group (18.5%) compared to the iopamidol 340 (Niopam) group (13.9%), [X2 =
5.2 (1df), p = 0.02]. This is attributed to the fact that itching reported by patients after
discharge from the hospital was more frequent in the iobitridol 350 (Xenetix) group
(8.2%) compared to the iopamidol 340 (Niopam) group (5%), [X2 = 4.9 (1df), p = 0.03].
Other frequently reported symptoms relating to these contrast agents are shown in Tables
6a and b.

Discussion
Toxicity due to contrast agents is attributed to the four main components of contrast
agents: ionicity, osmolality, viscosity and chemotoxicity. Pain experienced by patients
during intra-arterial injection is due to the high osmolality of contrast agents. However,
reducing the osmolality of an agent can result in problems caused by increased viscosity.
This can cause the transfer of water across cell membranes, particularly in areas of slow-
flow.
Iobitridol 350 (Xenetix) is a new iodinated, low-osmolality contrast medium. It is a tri-
iodinated, non-ionic monomer agent containing 35% (350 mg/ml) iodine intended for
intravenous and intra-arterial injection. Its osmolality is 915 mosm/kg H2O at 37ºC and
its viscosity 10 mPa.s at 37ºC and 21 mPas at 20ºC. It belongs to the family of non-ionic
monomers and has a high level of hydrophilicity due to a novel conformational stability
that is thought to limit the risk of interaction with biologic media. Although the safety
and efficacy of iobitridol 350 (Xenetix) has been studied in various diagnostic
procedures,8 there are few randomized trials comparing its efficacy with other commonly
used non-ionic monomers in cardiac catheterization.
Lefevre et al.,7 in a randomized study of 90 patients undergoing cardiac catheterization,
compared iobitridol 350 with iohexol (Omnipaque®). They demonstrated the diagnostic
efficacy and safety of iobitridol 350 (Xenetix) in terms of its effects on clinical,
laboratory and electrocardiographic parameters which were comparable to those of the
non-ionic reference product (iohexol, Omnipaque).
In their study, rhythm disorders occurred in 21.7% of patients receiving iobitridol 350
(Xenetix), conduction disorders (transient incomplete left bundle branch block) in 2.2%
and repolarization disorders (isolated monomorphous ventricular extrasystoles, ST-
segment elevation) in 21.7% of patients. Electrocardiographic changes were evaluated on
the basis of a 12-lead electrocardiogram performed pre- and post-catheterization and just
prior to the first contrast injection. An ECG was performed before and after the first
injection and after the last injection for each coronary artery. Finally, an ECG was
performed before and after ventriculography. Other adverse events such as chest pain,
nausea, palpitations, hypotension and hypertension occurred in 8.8% of the patients.
However, in our study, only specific ECG changes observed on the monitor leads during
the procedure were evaluated. This will account for the lower incidence of
electrocardiographic changes observed in the current study. The adverse events in the
study by Lefevre et al. were reported during the examination or during the 24 hours
following the examination. Patients in our study were followed up on for a period of
seven days to identify late reactions that could potentially be attributed to the contrast
agents. Intracoronary injection of contrast media carries a risk of specific adverse effects.
Hypertonicity may produce sinus bradycardia, heart block, QRS or QT-interval
prolongation, decreased systolic pressure, and increased left ventricular end-diastolic
pressure. These effects may be exacerbated by the presence of calcium chelating agents
in ionic monomer agents. There is a risk of precipitating ventricular fibrillation. Patients
with cardiac disease do not tolerate hemodynamic stress well and are at increased risk of
pulmonary edema. The present study demonstrates a higher incidence of ventricular
fibrillation arrests requiring direct current cardioversion associated with the use of
iobitridol 350 (Xenetix).
In our previous study,9 2,001 patients undergoing diagnostic angiography were randomly
administered iopamidol 340 (Niopam), ioxaglate 320 (Hexabrix), or iodixanol 320
(Visipaque). A total of 738 patients received iopamidol 340 (Niopam). Early reactions
occurred in 65 patients (8.8%) who received iopamidol 340 (Niopam). Late reactions
occurred in 159 patients (21.5%) who received iopamidol 340 (Niopam). In this study,
76.7% of the patients returned the questionnaire. Left ventriculography and aortography
were performed in 1,869 patients (93.4%).
In our second study,10 2,108 patients were randomized to undergo iopamidol 340
(Niopam), iomeprol 350 (Iomeron), or iodixanol 320 (Visipaque). A total of 738 patients
received iopamidol 340 (Niopam). Early reactions occurred in 155 patients overall
(7.4%), with no differences between agents. Late reactions occurred in 124 (16.8%)
patients who received iopamidol 340 (Niopam). In this study, 72.5% of the patients
returned their questionnaire. Left ventriculography and aortography was performed in
1,970 patients (93%).
However, in our current study, early and late reactions occurred in 3.2% and 13.9% of the
patients receiving iopamidol 340 (Niopam), respectively. A number of differences
between this study and the previous two studies may explain the lower number of patients
experiencing early and late reactions to iopamidol 340 (Niopam). First, there were a
number of clinical differences between the studies. In this study, the patients were older,
heavier and there were more diabetic patients. Secondly, more patients were randomized
to iopamidol 340 (Niopam) in this study. Thirdly, left ventriculography and aortography
was performed in fewer patients (1,673/2,019; 82.9%) compared to our previous studies.
Fourthly, the questionnaire return rate was lower, at 68%. The average volume of contrast
media used in this study was lower (1.54 ± 0.6 ml/kg) compared to our first (1.79 ± 0.89)
and second (1.80 ± 0.77) studies. The reactions seen with these patients may be related to
the total volume of contrast received, as well as the use of the bolus injections required
for aortography or ventriculography.
Limitations. Patients in this study were not randomized individually to receive one of the
two contrast agents; in order to facilitate smooth running of the study, patients
undergoing cardiac catheterization during a particular week were randomized as a group
to receive a particular agent. However, there were no significant differences between the
patients in each of the two groups despite this method of randomization. Patients
admitted for diagnostic cardiac catheterization had blood tests prior to the procedure.
However, we did not routinely check the renal functions for these patients post-
procedure.
We did not see the patients with late contrast reactions, but collected information by way
of a patient questionnaire. It is likely that this method of data collection resulted in over-
reporting of minor symptoms that may or may not have been related to the contrast agent.
However, the equal response rates in the two groups do suggest that patients in each of
the groups interpreted their symptoms in a similar way. We did not predefine on the
questionnaire what sort of skin reaction patients should look for, but the reactions
described are very similar to our previous study, suggesting that this is a true
phenomenon following the use of contrast agents in cardiac catheterization.
We cannot exclude the possibility that our results regarding electrocardiographic changes
represents a chance finding, but if other studies were to confirm this, then it would appear
that different contrast agents have different fibrillatory thresholds.

Conclusion
Iobitridol 350 (Xenetix) was associated with more ECG changes during cardiac
catheterization, including a 0.8% incidence of ventricular fibrillation requiring direct
current cardioversion, not seen with iopamidol 340 (Niopam). After cardiac
catheterization, itching was more common in the iobitridol group (Xenetix) compared to
the iopamidol group (Niopam). Since iobitridol 350 caused more ventricular fibrillation
without any clear benefits, iopamidol 340 would appear to be a preferable contrast agent
for coronary angiography.

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