Adverse Reactions of Low Osmolar Non-Ionic and Ionic Contrast Media When Used Together or Separately During Percutaneous Coronary Intervention

Results: With respect to the “follow on” group, allergic reactions occurred in 9 of 150 patients (6.0%) who received the combination of ioxaglate and iopromide versus 1 of 93 (1.1%) who only received iopromide ( p = 0.094). There was no difference with respect to MACE [6 (4.0%) ioxaglate and iopromide versus 4 (4.3%) iopromide alone, p = 1.00]. In the “planned” group, 7 of 165 patients (4.2%) receiving ioxaglate had an allergic reaction as opposed 0.0% (0 of 124 patients) in the iopromide group ( p = 0.021). All contrast reactions were mild. The incidence of a MACE was similar in both groups [1 (0.6%) ioxaglate versus 2 (1.6%) iopromide, p = 0.579]. The incidence of allergic reactions was similar if ioxaglate was used alone or in combination with iopromide ( p = 0.478). Conclusions: Whilst combining ionic and non-ionic contrast agents in the same procedure was not associated with any more adverse reactions than using an ionic contrast agent alone, the ionic contrast agent ioxaglate was associated with the majority of allergic reactions. With respect to choice of contrast agent, using the non-ionic agent iopromide alone for coronary intervention is associated with the lowest risk of an adverse event. Keywords Ioxaglate Iopromide Angioplasty Complications Introduction Contrast media are essential components of the performance of percutaneous coronary intervention (PCI), but their contribution to complications occurring during these procedures has been debated. Non-ionic low osmolar contrast agents have been shown to decrease the incidence of adverse reactions associated with diagnostic procedures when compared to high osmolar ionic compounds. 1–4 Allergic reactions also appear to occur more frequently in patients receiving low osmolarity ionic compounds when compared to non-ionic compounds. 5,6 Studies in vitro have shown that non-ionic low osmolar agents have less inherent anticoagulant activity than ionic agents. 7,8 A few randomised clinical trials have supported the conclusion that the ionic low osmolar compound ioxaglate is associated with fewer ischaemic complications of coronary intervention than are non-ionic agents. 9,10 Based on the perceived better tolerability and cheaper cost of non-ionic agents in our environment, our laboratory routinely uses these compounds for diagnostic angiography and reserves the ionic agent, ioxaglate, for percutaneous coronary interventions. This policy meant that many patients who “followed on” from their diagnostic procedures to coronary interventions received two different classes of agents in rapid succession during the same procedure. Due to a lack of data concerning the safety of “mixing” different classes of contrast agents, we sought to determine whether this practice resulted in more adverse clinical events than would a policy of continuing the same type of contrast agent. In order to establish a baseline risk of adverse reactions, we ascertained the incidence of such events in patients undergoing “planned” percutaneous coronary intervention that received exclusively either ioxaglate or iopromide (the non-ionic agent). Materials and Methods Study Population All 532 patients who underwent PCI from January 2001 to February 2002 in our institution were included in the study. We performed a retrospective analysis of our prospective, observational percutaneous coronary intervention database. Three operators using standard techniques performed all coronary interventions during the study period and patients’ details were prospectively entered into our database. It is our policy for patients to receive at least 300 mg of aspirin within 24 h of the procedure and to continue on 100–150 mg daily after the intervention. Intracoronary stent implantations were performed using standard techniques of high-pressure balloon inflations and patients generally received a loading dose of 300 mg of clopidogrel (if not previously on it) and 75 mg daily thereafter for 4 weeks. Heparin was administered as a weight-adjusted dose. Patients routinely had blood drawn for creatine kinase (CK) enzyme (and MB isoenzyme) the morning after the procedure and more frequently if there was a reason to suspect an adverse cardiac event. Data on the occurrence of thrombotic stent occlusion (TSO), emergency target vessel revascularisation (TVR) and periprocedural myocardial infarction (MI) are routinely collected in our institution prospectively and entered into our database. In addition, the occurrence of allergic reactions is noted and routinely entered into our database. As is the policy of our institution, all patients undergoing diagnostic coronary angiography received the low osmolar non-ionic monomer contrast agent iopromide (Ultravist, Schering, Berlin, Germany). During coronary intervention the choice of contrast medium was at the discretion of the operator and all patients received either the low osmolar ionic dimer compound ioxaglate (Hexabrix, Guerbet, Paris, France) or iopromide. For the purpose of this study we divided patients into two groups. The first group comprised patients who underwent diagnostic coronary angiography and “follow on” coronary intervention, which was defined as unplanned percutaneous coronary intervention directly after the diagnostic angiogram. All patients received iopromide during the diagnostic procedure and either iopromide or ioxaglate during the coronary intervention. The second group of patients had their diagnostic angiogram (using iopromide) performed some time before their “planned” percutaneous coronary intervention. This group was divided into two subgroups based on whether or not they received iopromide or ioxaglate during their coronary intervention. Finally, we compared the incidence of allergic reactions in patients who received ioxaglate alone or in combination with iopromide. Procedural Variables The number of attempted lesions, stent usage, fluoroscopy time, volume of contrast media used and use of glycoprotein IIb/IIIa antagonists were recorded for each patient. Study Endpoints The primary endpoint was the development of an allergic reaction requiring treatment with H1 and H2 antagonists, corticosteroids or catecholamines. Allergic reactions could include cutaneous manifestations of urticaria with or without pruritus, erythema, maculopapular rash, conjunctival symptoms and facial or peripheral angioneurotic oedema. This data was obtained from the database and where necessary correlations were obtained from the clinical record. The secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and urgent target vessel revascularisation at 30 days. Urgent TVR was defined as the occurrence of emergency coronary bypass surgery or repeat PCI of the treated vessel for recurrent ischaemia within 30 days of the initial procedure. Non-fatal myocardial infarction was defined as an increase in the creatine kinase concentration to three times the upper limit of normal with a concomitant rise in the CK–MB isoenzyme above the upper limit of normal or the appearance of new Q waves after the procedure. If a patient reached more than one cardiac endpoint, only the most severe endpoint was counted as a major adverse cardiac event (MACE) for the final analysis. Thrombotic stent occlusion was defined as angiographically proven total occlusion (TIMI flow <2), or flow-limiting thrombus formation inside the stent within 30 days after initially successful stenting. Statistical Analysis All values are reported as mean ± one standard deviation unless otherwise stated. Categorical variables are compared with χ 2 -test or Fischer's exact test as appropriate. Continuous variables with a normal distribution are compared with unpaired Student's t -test and continuous variables not normally distributed are compared with the Mann–Whitney Wilcoxon test. Statistical analysis was performed using SPSS for Windows (version 10). Statistical significance was defined as a two-tailed p value of <0.05. Results During the study period there were 243 patients who had “follow on” PCI. Of these 93 received iopromide alone and 150 received ioxaglate in addition to iopromide. There were 289 patients who had “planned” PCI. Of these 165 received exclusively ioxaglate and 124 received iopromide alone. The baseline clinical characteristics of the patients who underwent “follow on PCI” are presented in Table 1 and those who underwent “planned” PCI are presented in Table 2 . In the “follow on” cohort, there was one patient in the iopromide and ioxaglate group and no patient in the iopromide group with known previous iodine allergy. In the “planned” cohort there was one patient in each group with a known previous iodine allergy. All patients with a known iodine allergy were treated prior to their procedure with dexamethasone, promethazine hydrochloride and ranitidine. Primary Endpoint FOLLOW ON GROUP As shown in Table 3 , there were 9 (6.0%) allergic reactions in patients who received the combination of iopromide and ioxaglate as opposed to 1 (1.1%) in patients who only received iopromide ( p = 0.09). PLANNED GROUP Table 4 reveals that there were 7 (4.2%) allergic reactions in patients who received ioxaglate alone as opposed to no reactions in patients who only received iopromide ( p = 0.02). The allergic reactions in both groups were predominantly urticaria, which generally occurred on the upper torso. All of these reactions were mild, occurring within one hour of the procedure and all responded to standard therapy according to our laboratory protocol, which included 200 mg intravenous hydrocortisone, 12.5 mg intramuscular promethazine hydrochloride and 50 mg intravenous ranitidine. No more profound reactions necessitating the use of catecholamines or fluid resuscitation were documented and no reactions to our knowledge occurred after hospital discharge. PATIENTS RECEIVING ANY IOXAGLATE As previously described, there were 9 (6.0%) allergic reactions in patients receiving both ioxaglate and iopromide and 7 (4.2%) reactions in patients who exclusively received ioxaglate. This difference was not statistically significant ( p = 0.48). Secondary Endpoints Cardiac events occurring up until day 30 for the “follow on” group are also shown in Table 3 . A major adverse cardiac event occurred in six patients (4.0%) in the group of patients receiving iopromide and ioxaglate and in four (4.3%) patients receiving only iopromide ( p = 1.00). Cardiac events occurring up until day 30 in the “planned” group of patients receiving exclusively iopromide or ioxaglate are shown in Table 4 . A major adverse cardiac event occurred in one patient (0.6%) in the group of patients receiving ioxaglate alone and in two (1.6%) patients receiving only iopromide ( p = 0.58). Discussion We have demonstrated a higher incidence of allergic reaction in patients receiving ioxaglate than those that received iopromide. Our results are consistent with previous studies which have shown a higher rate of allergic adverse reaction in patients receiving ioxaglate compared with those receiving a variety of other non-ionic contrast media. 5,11–14 With regard to the direct comparison of ioxaglate and iopromide in patients undergoing coronary angiography, there was a study by Neiss et al., 15 which showed no significant difference in terms of tolerability between ioxaglate and iopromide although the study was limited to 20 patients. Our study is unique in that it specifically addresses the incidence of allergic reactions in patients who receive both an ionic and non-ionic contrast agent during the same procedure. We have demonstrated that combining agents appears to be no worse than using ioxaglate alone, but is associated with more allergic reactions than when using iopromide alone. Whether the use of ioxaglate reduces the risk of an adverse cardiac event during coronary intervention cannot be answered by our small non-randomised study. Whilst the reactions observed in our study where generally mild it has implications for future investigations requiring the use of contrast media. All patients who had a reaction will be considered to have had an allergic reaction to a contrast agent, which may delay or preclude future investigations or require the use of premedication regimens. The exact pathophysiology of allergic reactions induced by contrast agents is not well defined although it has been well documented that contrast media cause mediator release from mast cells or basophils in humans. 16–19 The responsible mechanisms are believed to include a direct effect of contrast agents on effector cells 16–19 and an indirect effect via the activation of complement 16,17,19,20 which in turn causes mast cell activation. 17 We are unaware of any mechanistic studies to determine why allergic reactions occur more frequently in patients receiving ionic rather than non-ionic contrast agents although in the in vitro study by Assem et al., 19 ioxaglate was reported to cause more histamine release than did low osmolar non-ionic agents. Although non-ionic contrast media appear to be associated with a reduced incidence of allergic reactions, it has been suggested that these potential benefits may be offset by a higher incidence of thrombotic complications when compared to ionic agents. In vitro studies reveal that both types of contrast media display anticoagulant and antiplatelet properties, however, ionic contrast agents appear to display more favourable effects. 7,8,21 There are a number of clinical, anatomical (coronary anatomy, lesion morphology), pharmacological (use of thienopyridines, aspirin, glycoprotein IIb/IIIa inhibitors and heparin dosage) and technical factors (stents) that may affect the incidences of major ischaemic events after PCI. In addition there have been a number of randomised and non-randomised trials comparing non-ionic and ionic contrast media in patients undergoing coronary angiography and PCI. A number of these trials showed that surrogate endpoints, such as the incidences of abrupt closure, coronary thrombosis or platelet deposition on guide wires, were less frequent with ionic contrast agents. 10,22,23 In terms of direct comparison of ioxaglate and iopromide, there has been a small study of patients undergoing abdominal and femoral angiography, 24 which looked at a number of haemostatic parameters in vivo. The authors found that both agents caused activation of the coagulation system and platelets and there was no difference in the degree of activation between the two agents. The small study of patients undergoing coronary angiography by Neiss et al., 15 did not specifically address thrombotic complications of contrast use. When it comes to clinically more relevant major adverse events there are conflicting data concerning the use of ioxaglate in coronary interventions. In a number of randomised 9,10 and non-randomised trials, 25 the use of ioxaglate was associated with a reduction in thrombotic events after percutaneous coronary intervention. In a large non-randomised trial by Scheller et al., 25 the authors found a higher rate of both acute and subacute stent occlusion in patients receiving non-ionic contrast agents when compared to ioxaglate. They also found a lower incidence of the combined clinical endpoint of target lesion revascularisation, coronary artery bypass surgery and death in the group who received ioxaglate (16.3% versus 22.9%, p = 0.001). Whilst a large study of nearly 4000 patients, this study is limited by its non-randomised nature, the use of six different non-ionic contrast agents and slight differences between the groups compared. Of note we found no difference in the rate of thrombotic stent occlusion between our groups although our study is too small to draw any definite conclusions with this respect to this endpoint. In contrast, a number of trials have shown no difference between ionic or non-ionic contrast media 5,14,26,27 with respect to major ischaemic events. In the largest randomised trial published to date, Schrader et al. 5 evaluated the outcomes of 2000 patients undergoing PCI. Patients received either iomeprol (non-ionic) or ioxaglate (ionic) according to a randomised double-blind protocol. The frequency of re-occlusions necessitating repeat angioplasty and the rate of major ischaemic complications including emergency bypass surgery and myocardial infarction were not significantly different in either group. The authors of this study concluded that the observed in vitro differences between non-ionic and ionic contrast media seem to be insignificant under clinical conditions. More recently, two large multicentre studies of patients undergoing PCI have compared the isosmolar non-ionic dimer iodixanol to ioxaglate. 14,27 In the study by Davidson et al., 27 there was a low incidence of in-hospital adverse events in both groups, and the iodixanol cohort actually experienced the primary composite clinical outcomes less frequently than the ioxaglate group (5.4% versus 9.5%, respectively; p = 0.027). In the larger study by Bertrand et al., 14 there was no difference in 2 day or 1 month major adverse cardiac events in either group. These studies suggest that, using contemporary techniques, non-ionic agents may potentially be safer (or at least no worse), than ionic agents. The data presented in our study, whilst non-randomised, support the conclusions that there is no apparent major advantage of using ioxaglate over iopromide with respect to a reduction in major ischaemic complications of percutaneous coronary intervention. Study Limitations Our study has a number of limitations inherent in retrospective observational reports. Patients in this study were not randomised either to the use of contrast agent or as to whether they would have “follow on” PCI or “planned” PCI. The diagnosis of an allergic reaction is rather subjective and open to bias, however, it has always been our policy to document such events prospectively at the time of the percutaneous coronary intervention. In addition, our observations are only applicable to the index hospital admission and we may have missed late reactions. The ionic and non-ionic monomers appear to induce late onset allergy-like reactions with equal frequency 28 and therefore would have potentially affected both groups equally. Notably, this type of reaction is considered to be rarely life-threatening as opposed to acute reactions and is possibly of less clinical relevance. It is also possible that allergic reactions were related to other medications although the timing is more likely to reflect the choice of contrast agent. We routinely perform a creatine kinase measurement the morning after a percutaneous coronary intervention and more frequently if there is clinical suspicion of an adverse cardiac event. It is possible, however, that we may have missed small rises in creatine kinase, which may have influenced the number of myocardial infarcts diagnosed. Whilst our study groups were well matched in the “follow on” group, there were some significant differences in the “planned” PCI cohort. There was a higher dose of contrast utilised in the iopromide group, however, we documented more allergic reactions in the ioxaglate group. As this is a retrospective study we did not collect data on other potential adverse events related to contrast use such nausea and vomiting, renal failure and other potentially thromboembolic events including stroke or systemic infarction, which may have impacted on our results. Conclusions Whilst combining ionic and non-ionic contrast agents in the same procedure was not associated with any more adverse reactions than using an ionic contrast agent alone, the ionic contrast agent ioxaglate was associated with the majority of allergic reactions. With respect to choice of contrast agent, using the non-ionic agent iopromide alone for coronary intervention is associated with the lowest risk of an adverse event. References 1 M.A. Bettman C.B. Higgins Comparison of an ionic with a non-ionic contrast agent for cardiac angiography: results of a multicenter trial Invest Radiol 20 1985 70 74 2 G.L. Wolf R.L. Arenson A.P. 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