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 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 = 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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