Early and Late Reactions Following the Use of Iopamidol 340, Iomeprol 350 and Iodixanol 320 in Cardiac Catheterization

The choice of contrast agent used in diagnostic cardiac catheterization might be considered relatively unimportant compared to decisions on arterial access, choice of catheters and potential technical pitfalls. However, the choice of contrast agent can have a significant bearing on the patient’s experience with the procedure. When cardiac catheterization was in its infancy, ionic monomeric contrast agents were used. These were associated with a relatively high incidence of early side effects, such as nausea and urticaria. Recently, ionic dimeric agents and nonionic dimeric and monomeric agents have been used. There is clear evidence to support the use of nonionic agents over the older ionic agents, not only in the reduction of minor side effects, but also in the reduction of serious adverse events.1,2 Therefore, ionic monomer agents have largely been replaced by nonionic monomer contrast agents, ionic dimers and more recently, nonionic dimers. However, in our experience, there are significant differences in tolerability between these more modern contrast agents. We believe that careful utilization of contrast agent can improve the patient’s experience with diagnostic cardiac catheterization, both during and soon after the procedure. Although the incidence of potentially serious problems such as the induction of ventricular fibrillation is very low, it is not known whether the fibrillation threshold differs between agents We recently reported a prospective, randomized trial comparing the early and late side effects of 3 commonly used contrast agents.3 In this study, we demonstrated an unacceptably high incidence of early unpleasant reactions following the use of ioxaglate 320 (Hexabrix®) in diagnostic cardiac catheterization. Other investigators have demonstrated a reduction in heat and pain sensation on contrast injection with the nonionic dimer agent iodixanol 320 (Visipaque®).4–6 There are a number of reports concerning the incidence of late reactions, including skin rashes, following the use of nonionic contrast agents. The incidences of such reactions vary between 8–71%.7,8 In our previous study, the incidence of late skin reactions following the use of iodixanol 320 (Visipaque®) was 12.2%. On the basis of our previous study, we no longer use ioxaglate 320 (Hexabrix®) for routine cardiac catheterization. However, we wished to further investigate the incidence of early and late skin reactions following the use of nonionic agents. Therefore, we designed this study, in which the nonionic dimer iodixanol 320 (Visipaque®, Amersham Health) and the nonionic monomer iopamidol 340 (Niopam®, Merck Pharmaceuticals), both of which were well-tolerated in the early phase of cardiac catheterization in our previous study, were compared to a new nonionic monomeric contrast agent, iomeprol 350 (Iomeron®, Bracco UK Ltd.). This latter agent is reported to have lower osmolality and viscosity and higher water solubility compared to other nonionic contrast media.9 Methods Study group. A total of 2,108 sequential patients undergoing cardiac catheterization in a regional cardiothoracic center between April 1998 and April 1999 were enrolled in the study, which was approved by the local Ethics Committee. Cardiac catheterization was performed by an operator who was blind to the contrast agent in use by suspension of the bottle in an opaque sleeve. Demographic data were collected for each patient entering the study. Patients with a history of previous allergy to contrast agents were treated according to our catheter laboratory policy with hydrocortisone and chlorpheniramine. Patients were not routinely sedated prior to cardiac catheterization. The type of study was dependent on the clinical information required (Table 1). Coronary angiography was performed from any arterial route using standard 6 French (Fr) catheters. Left ventriculography was performed according to our catheter laboratory protocol of a 36 ml bolus of contrast agent injected at 12 ml/second. Each week was randomly assigned as a week when one of the different contrast agents was used. Patients who had received any contrast agent within the previous week were excluded from analysis. Electrocardiographic changes. ECG changes were recorded by the catheter laboratory technicians either during or shortly after contrast injection into the coronary arteries on monitor leads, not by 12-lead electrocardiography. For the purposes of this study, ventricular ectopy during left ventriculography was not recorded as a significant ECG change. Early reactions. Early reactions were recorded by the nursing staff in the cardiac catheter laboratory, who were also blind to the contrast agent in use, and on the cardiology ward after the patient left the catheterization laboratory. New medication following cardiac catheterization was recorded. For patients undergoing left ventriculography, the operator asked the patient to arbitrarily score heat sensation during left ventriculography on a score of 0–5, with 0 signifying no awareness of heat and 5 signifying “extremely hot”. Late reactions. Each patient was asked to complete a simple questionnaire following discharge from hospital, on which any adverse reactions occurring within 1 week of the cardiac catheterization were recorded. Patients were also required to document any new medication commenced within that period by the general practitioner. Patients with skin reactions were contacted by telephone or received a further questionnaire in order to gain more information about the nature of the skin reaction. Skin reactions occurring in the groin alone were not included, since these could have been secondary to either skin disinfectant or local dressings. Statistical methods. Statistical tests for association (Chi-squared and Fisher’s Exact) were used to compare the incidences of early and late reactions between the groups. Results are presented as numbers and percentages of each group with their appropriate probability values. Results There were no significant differences in the baseline characteristics of the study groups (Table 2). The groups contain different numbers of patients due to 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 were the same, the numbers of patients are different because of variations in the numbers of patients undergoing diagnostic procedures each week. A total of 12.9% of patients had undergone previous cardiac catheterization, but there was no significant difference in the incidence of previous cardiac catheterization between the 3 groups. Only 6 patients in the whole study group were pre-treated with hydrocortisone and chlorpheniramine because of a previous possible allergic reaction to a contrast agent. Early reactions. Symptoms occurring within 24 hours of cardiac catheterization were common. A total of 1,511 patients (72%) recorded a symptom within 24 hours that could be attributed to the effects of contrast. Of these patients, a total of 429 (65% of those receiving this agent) had received iodixanol 320 (Visipaque®), a total of 554 (78% of those receiving this agent) had received iomeprol 350 (Iomeron®) and 528 (72% of those receiving this agent) had received iopamidol 340 (Niopam®) (p Heat reactions. Of the 1,933 patients in whom left ventriculography was performed, a total of 1,927 (99.7%) were able to score the resulting heat sensation on a scale of 0–5 (Table 3), the remaining 6 patients being unable to make a score. Seven patients did require sedation with morphine during cardiac catheterization for anxiety or chest pain and this may have made the heat score unreliable in those patients. Iopamidol 340 (Niopam®) and iomeprol 350 (Iomeron®) caused very similar heat sensation, but heat sensation was less intense with iodixanol 320 (Visipaque®) (p Non-heat reactions. The differences observed between the groups for total possible early adverse reactions were predominantly the result of a lower heat intensity score with iodixanol 320 (Visipaque®). When heat score during left ventriculography was excluded, the incidence of other reactions was relatively low. A total of 1,356 of the 1,511 patients (80.1%) with early symptoms experienced heat on left ventriculography as their sole symptom. One hundred and fifty-five patients experienced symptoms in addition to the heat sensation on left ventriculography (Table 4). Such symptoms were slightly more common in the group receiving iomeprol 350 (Iomeron®) (8.5%) compared to the groups receiving iodixanol 320 (Visipaque®) (6.9%) or iopamidol 340 (Niopam®) (6.6%), but the differences were not statistically significant (p = 0.35). The additional symptoms are shown in Table 4. Electrocardiographic changes (Table 5). Cardiac arrest due to ventricular fibrillation occurred in 4 patients (0.19%) following contrast injection into the right coronary artery. All 4 patients were successfully resuscitated. Electrocardiographic changes during injection of contrast into the coronary arteries occurred in 437 patients (20.7%), including the 4 patients mentioned above. There was a highly significant excess of electrocardiographic changes in the group receiving iomeprol 350 (Iomeron®) compared to the other 2 groups. Ventricular fibrillation was more common with iomeprol 350 (Iomeron®), but this was not statistically significant. Late reactions. A total of 1,528 patients (72.5%) returned the questionnaire; the return rates in each group were similar (Table 1). A total of 384 patients (18.2% of all patients in the study and 25.1% of all those who returned the questionnaire) reported symptoms following discharge from hospital. Symptoms following discharge were significantly more frequent among the group receiving iodixanol 320 (Visipaque®) compared to the groups receiving iomeprol 350 (Iomeron®) or iopamidol 340 (Niopam®) (p = 0.01). The most frequently reported symptoms are shown in Table 6. Skin reactions. The incidence of skin reactions of any kind and the incidence of itching were both significantly higher in the group receiving iodixanol 320 (Visipaque®) than in the groups receiving either iomeprol 350 (Iomeron®) or iopamidol 340 (Niopam®). Skin reactions of any kind and itching both occurred with an incidence of 10.4% in the iodixanol 320 (Visipaque®) group. The incidences in the other 2 groups were between 2.7% and 6.5%. There was no significant difference in the volume of contrast agent received by those patients with late skin reactions compared to those patients who did not have a late skin reaction [mean, 134 ml and 95% confidence interval (CI), 126–143 ml versus mean, 135 ml and 95% CI of 123–138 ml]. Similarly, there was no significant difference in the volume of iodixanol 320 (Visipaque®) received by those patients with late skin reactions compared to those patients receiving this agent who did not have a late skin reaction (mean of 134 ml and 95% CI of 125–143 ml versus mean of 137 ml and 95% CI of 130–144 ml). There were 21 patients (Group A) with a widespread, itchy macular rash, sometimes with skin peeling or flaking. The other 93 patients (Group B) had localized reactions, associated with blistering, skin peeling or skin flaking. Group B could be further subdivided into localized reactions that were confined solely to the palms, soles of the feet or face (class B1, n = 30) or other localized reactions (class B2, n = 63). As in our previous study, class B1 reactions were most troublesome of the late skin reactions due to their location and the fact that many were associated with blistering, skin peeling or skin flaking. B2 reactions occurred on the trunk or limbs and were milder, with only 14 patients describing blistering, peeling or flaking of the skin. All forms of late skin reaction were more common with iodixanol 320 (Visipaque®) (Table 6). Of the 114 patients with a late skin reaction unrelated to the groin, medical advice was sought from the general practitioner or by telephoning the cardiology ward by 25 patients (21.9%). Of these, nineteen received treatment with either oral antihistamines or topical emollients. No patient required treatment with oral or intravenous steroids and no patient was hospitalized because of a severe adverse skin reaction. Eighty-nine patients did not seek medical advice for the skin reaction, but 14 treated themselves with over-the-counter topical emollients. The duration of the rash was less than 14 days in 76% of cases, although 1 patient described a rash lasting almost 3 months. Study limitations. Patients in this study were not randomized individually to receive 1 of the 3 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. Nevertheless, there were no significant differences between the patients in each of the 3 groups despite this method of randomization. We did not see patients with late contrast reactions, but gathered information either by way of a patient questionnaire or over the telephone. It is likely that this method of data collection resulted in over-reporting of minor symptoms which may or may not have been related to the contrast agent. However, the equal response rates in the 3 groups does suggest that patients in each of the groups interpreted their symptoms in a similar manner. 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. Discussion This study demonstrates that the incidence of the early, unpleasant reactions to contrast media used in diagnostic cardiac catheterization is relatively low with all 3 of the nonionic agents in this study. However, the incidence of any early reaction attributable to contrast agent was 7.4% and this is probably higher than the risk quoted to patients. The incidence of early reactions for all 3 agents was comparable to the incidence observed for iopamidol 340 (Niopam®) and iodixanol 320 (Visipaque®) in our previous study,3 but significantly less than the incidence observed in the same study with the ionic dimer agent, ioxaglate 320 (Hexabrix®). In terms of early adverse reactions, we have not been able to confirm any superiority of iomeprol 350 (Iomeron®) over iopamidol 340 (Niopam®). Indeed, the incidence of any early reaction within 24 hours of cardiac catheterization was greatest with iomeprol 350 (Iomeron®), although the incidences of early unpleasant reactions, such as nausea, vomiting and urticaria, were low and comparable in the 3 groups. Published data comparing the use of any form of Iomeron® with any form of Niopam® are limited. In a review by Katayama et al.,10 a large number of clinical trials comparing these 2 agents were analyzed, but yielded under 1,000 patients. Only 1 study compared the use of the 2 agents in cardiac catheterization.11 From the pooled data, no clear differences between the 2 agents could be identified. Adverse events following intra-arterial injection occurred in 3.5% of those receiving Iomeron® and 2.6% of those receiving Niopam®. In our study, we also observed significantly more ECG changes with iomeprol 350 (Iomeron®) compared to the other 2 contrast agents. Given the lower scores for heat sensation during left ventriculography for iodixanol 320 (Visipaque®) in our study, there are grounds for suggesting that this agent is the best tolerated of the 3 agents in the early phase following cardiac catheterization. It is currently the least expensive of the 3 agents used in this study, the average price for contrast used per procedure being £20.27, £23.51 and £23.57 for iodixanol 320 (Visipaque®), iopamidol 340 (Niopam®) and iomeprol 350 (Iomeron®), respectively. It would be interesting to determine whether the early adverse effects of contrast agents are due to the total contrast load or the effect of a rapid bolus of contrast during the left ventriculogram or the aortogram. In our study, only 138 patients had neither a left ventriculogram nor an aortogram. Because of this and the overall low incidence of symptoms such as nausea or vomiting, it is not possible to draw a firm conclusion from our study. The use of the iomeprol 350 (Iomeron®) was also associated with a significant excess of ECG changes during contrast injection, although these were predominantly transient ST-segment and T-wave changes and did not result in important clinical sequelae. Although we did not formally assess image quality, we did not note any downgrade in image quality for any of the 3 agents and no study was of insufficient quality to be termed “nondiagnostic”. This study confirms our previous finding of an excess number of late skin reactions following the use of iodixanol 320 (Visipaque®). Skin reactions following the administration of iodixanol 320 (Visipaque®) were significantly more common than with either iomeprol 350 (Iomeron®) or iopamidol 340 (Niopam®). There was no difference between the groups in the incidence of new medication started in the week prior to and the week following cardiac catheterization, so it is unlikely that the excess skin reactions among patients receiving iodixanol 320 (Visipaque®) were related to the use of other drugs. Similarly, analysis suggests that the skin reactions were not related to the volume of contrast agent received. Although patients were not examined by us, the group with skin reactions within 24 hours of receiving iodixanol 320 (Visipaque®) could be further divided into 2 groups, namely, those with a diffuse, itchy, macular rash and those with a peeling reaction that was often confined to the face, hands or feet. The course of the skin reactions appears benign and we would not consider them to represent a contraindication to the use of iodixanol 320 (Visipaque®), although patients should be advised of this particular side effect. No contrast agent was free from either early or late adverse reactions. In this study, there appears to be a trade-off between early and late reactions, with iodixanol 320 (Visipaque®) being the best tolerated agent in the early phase, but having a higher incidence of late skin reactions. Iomeprol 350 (Iomeron®) and iopamidol 340 (Niopam®) had significantly lower incidences of late skin rash but iomeprol 350 (Iomeron®) was the least well tolerated agent in the early phase, with a greater chance of inducing nausea and vomiting and “allergic” type reactions. In conclusion, there remain significant differences between modern contrast agents used in diagnostic cardiac catheterization. These differences should be considered when selecting an agent and when obtaining informed patient consent for procedures.

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