Letters to the Editor

In response to: W.C. Kang, et al, Vol. 16, No. 12, pp. 725–726 Successful Management of a Resistant, Focal Calcified Lesion Following Direct Coronary Stenting with a Cutting Balloon I would like to commend Kang, et al for their innovative approach described in the above-mentioned article. Two important cautionary notes should be emphasized regarding the application of this technique. First, the use of a cutting balloon within a stent that is not fully expanded (as opposed to its use in the treatment of in-stent restenosis) poses the risk of the cutting balloon blades becoming caught in the underexpanded stent struts. Second, the pressures used for the inflation of the cutting balloon exceeded the rated burst pressure. The risk of balloon rupture increases once the rated burst pressure is exceeded. If the cutting balloon bursts, not only is there the risk of focal arterial perforation by a pinhole jet, but there is a significant risk that the deformed cutting balloon will now be entrapped within the underexpanded stent. Either of these complications may result in additional otherwise unnecessary procedures, including coronary artery bypass surgery, and also exposes the patient to increased risk. Again, the authors’ case illustrates important maneuvers available to the interventionalist for the treatment of focal calcified lesions following direct coronary artery stenting; however, a greater emphasis and discussion regarding the potential complications of their strategy are warranted. Respectfully, Robert S. Dieter, MD, RVT Director of Vascular Medicine Cardiovascular Medicine Medical College of Wisconsin In response to: K. Vijayalakshmi, et al, Vol. 16, No. 12, pp. 707–711 A Prospective, Randomized Trial to Determine the Early and Late Reactions After the Use of Iopamidol 340 (Niopam™) and Iobitridol 350 (Xenetix^®) in Cardiac Catheterization We read with interest and surprise the paper by Vijayalakshmi et al¹ comparing two low-osmolar, non-ionic contrast media (CM), namely, iopamidol 340 mgI/ml (Niopam 340) and iobitridol 350 mgI/ml (Xenetix 350), with respect to their early and late adverse reactions. We take the utmost care with the safety of our products and would therefore like to make several comments on this study. Non-ionic monomeric CM have long been recognized as having a good cardiac tolerance² and, to our knowledge, there have been no studies showing clinically-relevant differences between them. All modern low-osmolar CM are highly hydrophilic molecules, lack calcium-binding additives in their formulation, have very low protein binding (1–3%), and both iobitridol and iopamidol are no exceptions in this respect.³ The iobitridol molecule has been designed in order to obtain a hydrophilic sphere stable enough to prevent the unveiling of hydrophobic zones potentially able to elicit hydrophobic interactions with their biological environment.⁴ This concept has been validated by X-ray crystallographic studies in the presence of elastase,⁵ histological,⁶ and intracellular imaging by secondary ion mass spectrometry studies.⁷ The authors justify their interest in iobitridol by its novelty. In fact, this molecule was launched about ten years ago and has, since then, been approved and used extensively in more than 60 countries for both cardiological and radiological procedures. It can be estimated that more than 16 million procedures have been conducted with this molecule worldwide. The authors report a higher incidence of delayed reactions (> 24 hours to 7 days) with iobitridol (18.5% vs. 13.9% for iopamidol). This surprising result deserves several comments. First, it is worth noting that this difference is essentially related to a difference in the incidence of itching (iobitridol: 8.2% vs. 5.0% for iopamidol). Interestingly, the incidence in skin rash was similar for both CM (iobitridol: 2.4% vs. 2.5% for iopamidol). Types of skin rash also did not differ, as shown in their table 6b. It does not seem exaggerated to state that skin rash is clinically more worrying than itching. Furthermore, the same team has already published two large-scale studies comparing early and late reactions induced by low-osmolar CM (ioxaglate, iopamidol, iomeprol and the non-ionic iso-osmolar CM iodixanol).^8,9 In both studies, the iso-osmolar CM iodixanol induced significantly more late skin rashes than its competitors (12.2 and 10.4% vs. 2.7–4.3%). Second, there is important variability in both early and late reactions from one study to another for the same compound (iopamidol 340) in the same institution and in patients undergoing the same diagnostic procedures (for early reactions, the incidence varies from 3.2% in this study¹ to 8.8%,⁸ and for late reactions, the incidence varies from 13.9% in this study¹ to 21.5%⁸). The authors explain this important discrepancy by the administration of a lower volume of CM in the present study.¹ This explanation is not valid when it comes to allergy-like reactions, which are not dose-dependent.^10,11 In a Japanese survey on more than 300,000 patients, the incidence of allergy-like reactions was actually lower in patients receiving more than 80 ml than in those receiving a lower volume.¹² Interestingly, in a survey of more than 61,000 patients receiving iobitridol for diagnostic procedures,¹³ a similar trend was noted, with a higher incidence of adverse events in patients receiving a low (14 delayed reactions were noted in 12.4% of 2,370 patients who received a non-ionic monomeric CM for computed tomography (CT). However, it is worth noting that, in this same study, 10.3% of a group who underwent CT without CM injection also reported delayed reactions. This would raise questions as to the reliability of patient testimony. Concomitant treatment by beta-blockers has been shown to be associated with increased risk of bronchospasm.¹⁵ It can be supposed that treatment with beta-blockers is quite frequent in the type of population enrolled in such studies. Unfortunately, the associated treatments are not described in this manuscript. The authors also report more ECG changes and notably more ventricular fibrillation (VF) with iobitridol than with iopamidol. Although data generated from post-marketing spontaneous reporting cannot be compared with the context of a randomized clinical trial, the occurrence of 7 cases of VF in patients injected with iobitridol versus none in those injected with iopamidol during the course of diagnostic cardiac procedures in the study of Vijayalakshmi et al.¹ is surprising to us when considering the amount of experience gathered to date in the knowledge of iobitridol’s safety profile. It is very difficult to establish a relationship between a drug and an adverse event. The maximum available information around the occurrence of the event and patient characteristics need to be taken into account, and this has led to the construction of complex algorithms for pharmacovigilance surveillance. The occurrence of these 7 cases of VF might be explained by other non-reported missing factors such as biology disorders or co-medication that played the role of confounding factors, and in our opinion, more details about the 7 patients involved should be provided before any firm conclusion can be drawn regarding the responsibility of iobitridol. The safety profile of iobitridol in the post-marketing setting is characterized mainly by the reporting of allergic-like reactions, as is the case with all other CM of this class. The rate of adverse reactions in that uncontrolled, biased setting, driven by spontaneous reporting, is in the range of “very rare” to cases per million. Most cardiac disorders reported to us have mainly been a consequence of these reactions and remain exceptional. Cardiac disorders not linked to allergic-like reactions have been very exceptionally notified and did not generate any signal with respect to ventricular rhythm disorders. All iodinated contrast media, including iopamidol, can lengthen the QT interval and possibly induce subsequent ventricular rhythm disorders.^16,17 Also, co-treatment with amiodarone has been shown to induce QT prolongation following cardiac catheterization with the non-ionic monomer iohexol.¹⁸ The responsibility of the procedure itself, although excluded by the authors, still remains a potentially strong confounding factor, as suggested by a large, retrospective analysis.¹⁹ In conclusion, we attach particular importance to the safety of the compounds we market. Iobitridol has been extensively used for more than 10 years in more than 16 million procedures. This interesting study would, in our opinion, benefit from a thorough discussion of all potential confounding factors which may interfere with the assessment of the compound’s responsibility. Emmanuelle Pinès, MDGuerbet, Pharmacovigilance Department Philippe Zamia, PhD Guerbet, Biostatistics Department Jean-Marc Idée, MS, PharmDGuerbet, Research Department Roissy, France (See references below) In response to: K. Vijayalakshmi, et al, Vol. 16, No. 12, pp. 707–711 A Prospective, Randomized Trial to Determine the Early and Late Reactions After the Use of Iopamidol 340 (Niopam™) and Iobitridol 350 (Xenetix^®) in Cardiac Catheterization In a randomized, double-blind trial aimed at determining the early and late reactions after use of iopamidol and iobitridol in cardiac catheterization, Vijayalakshmi et al¹ have found a significant difference favoring iopamidol (0% vs 0.76% ; p = 0.01) in the occurrence of ventricular fibrillation (VF) requiring cardioversion. A 0.11% rate of VF has previously been reported with iopamidol in cardioangiography,² but the equivalent did not yet exist for iobitridol. Aside from a clinically negligible excess of self-reported late itching, this finding could be very important from a clinical angle and deserves a more critical approach than that which has been exposed in their paper. Even if the double-blind procedure is generally difficult to ensure in clinical trials comparing contrast media, the reality of the difference on this hard end point is not questionable. On the other hand, what could be questionable is the validity of the randomization on a weekly basis. As stated by the authors, the randomization process is responsible for the different number of patients in each group (1,093 randomized for iopamidol and 926 for iobitridol). We must question ourselves on the reasons for and consequences of this disequilibrium which could have influenced the quality of the procedure (choice of the operators, availability for teaching, schedule for more or less complex procedures, especially when combined with peripheral angiography...). Technical factors (catheter positioning in the coronary arteries, ventricle crossing, catheter size, pressure damping…), rather than chemical considerations, have generally been recognized as responsible for ventricular arrhythmias during cardiac angiography.³ Even with 7 cases of VF in patients receiving iobitridol versus none in those receiving iopamidol, Vijayalakshmi et al should have clearly explained that the former cannot be definitively considered as soley responsible for these arrhythmias. The statement that ventricular fibrillation was neither catheter-induced nor related to ischemia cannot be accepted as an argument. Neither the time of occurrence of VF in the course of the procedure (ventricle crossing, coronary artery intubation, injection…), nor the criteria for catheter-induced cardiac arrest are described. Moreover, electrocardiographic changes were recorded on monitor leads either during, or shortly after, contrast injection, and minor ST-T changes could not be taken into account. Due to the lack of relevant information on the cardiac status of the patients, the causes and clinical significance of these arrhythmias are impossible to determine. Were patients with acute coronary syndromes included in the study? What about left ventricular ejection fraction or renal function? What about diuretics, blood potassium and baseline repolarization? What about standard treatment of coronary insufficiency such as beta-blockers, ACE inhibitors, or even statins? The reference to the rate of rhythm disorders in our 1996 paper⁴ wrongly suggests that there is an electrophysiologic substratum for the occurrence of ventricular fibrillation in this new study. However, we were unable to demonstrate any significant difference in ECG tolerance with another low-osmolality, non-ionic contrast media (iohexol) at that time due to the limited number of patients studied (90). The lack of description of the prognosis of these patients suggests that they all recovered. This is in agreement with the report by the PAMI investigators, who recently demonstrated that even in very high-risk patients (primary PTCA), ventricular fibrillation in the catheterization laboratory (4.1% of procedures) does not influence PCI success or prognosis.⁵ As stated by the authors, a play of chance cannot be disregarded. For a better understanding of what occurred in this series, detailed case reports are warranted, as well as a comparison with the data of post-marketing surveys. Jean-Louis Gayet, MD and Thierry Lefèvre, MD Cardiologist & Private Consultant Institut Hospitalier Jacques Cartier Colombes, France Massy, France

(References for Letter from Emmanuelle Pinès, MD, et al.) 1. Vijayalakshmi K, Williams D, Wright RA, et al. A prospective, randomized trial to determine the early and late reactions after the use of iopamidol 340 (Niopam) and iobitridol 350 (Xenetix) in cardiac catheterization. J Invas Cardiol 2004;16:707–711. 2. Hirshfeld JW. Cardiovascular effects of iodinated contrast agents. Am J Cardiol 1990;66:9F–17F. 3. Krause W, Schneider PW. Chemistry of X-ray contrast agents. In: Krause W (ed). Contrast Media. Topics in Current Chemistry. Springer Verlag, Heidelberg, 2002;222:151–171. 4. Meyer D, Fouchet M-H, Petta M, et al. Stabilization of the hydrophilic sphere of iobitridol, an iodinated agent, as revealed by experimental and computational investigations. Pharm Res 1995;12:1583–1591. 5. Prangé T, Neuman A, Corot C, et al. Study of the complex between the contrast agent iobitridol (Xenetix) and elastase (PPE): a model for hydrophobic site protection in drug-protein interactions. Pharm Res 1997;14:1713–1717. 6. Beaufils H, Idée J-M, Berthommier C, et al. Iobitridol, a new non-ionic low-osmolality contrast agent, and iohexol. Impact on renal histology in the rat. Invest Radiol 1995;30:33–39. 7. Larras-Regard E, Mony M-C. Intracellular imaging of iodinated contrast media in rat kidney by SIMS (IMS 4F). In: Lareau R, Gillen G, (eds). Secondary Ion Mass Spectrometry, SIMS XI. John Wiley and Sons, 1998, pp135–138. 8. Sutton AGC, Finn P, Grech ED, et al. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J 2001;141:677–683. 9. Sutton AGC, Finn P, Campbell PG, et al. Early and late reactions after the use of iopamidol 340, iomeprol 350 and iodixanol 320 in cardiac catheterization. J Invas Cardiol 2003;15:133–138. 10. Eloy R, Corot C, Belleville J. Contrast media for angiography: Physicochemical properties, pharmacokinetics and biocompatibility. Clin Mat 1991;7:89–197. 11. Ansell G. Complications of intravascular iodinated contrast media. In: Ansell G, Bettmann MA, Kaufman JA, Wilkins RA (eds). Complications in Diagnostic Imaging and Interventional Radiology. Blackwell Science Inc.: Boston, 1996, pp245–300. 12. Katayama H, Yamaguchi K, Kozuka T, et al. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1990;175:621–628. 13. Petersein J, Peters CR, Wolf M, et al. Results of the safety and efficacy of iobitridol in more than 61,000 patients. Eur Radiol 2003;13:2006–2011. 14. Yasuda R, Munechika H. Delayed adverse reactions to non-ionic monomeric contrast-enhanced media. Invest Radiol 1998;33:1–5. 15. Lang D, Alpern MB, Visintainer PF, et al. Elevated risk of anaphylactoid reaction from radiographic contrast media is associated with both b-blocker exposure and cardiovascular disorders. Arch Intern Med 1993;153:2033–2040. 16. Mitsumori M, Hayakawa K, Soga T, et al. Effects of contrast media on the RR and QT interval during coronary angiography. Acta Radiol 1991;32:120–123. 17. Petersen R, McKay CR, Kawanishi DT, et al. Double-blind comparison of the clinical, hemodynamic, and electrocardiographic effects of sodium meglumine ioxaglate or iohexol during diagnostic cardiac catheterization. Angiology 1992;43:765–780. 18. Goernig M, Kirmeier T, Krack A, et al. Iohexol contrast medium induces QT prolongation in amiodarone patients. Br J Clin Pharmacol 2004;58:96–98. 19. Armstrong SJ, Murphy KP, Wilde P, et al. Ventricular fibrillation in coronary angiography: What is the role of contrast medium? Eur Heart J 1989;10:892–895. (References for Letter from Jean-Louis- Gayet, MD and Thierry Lefèvre, MD) 1. Vijayalakshmi K, Williams D, Wright R, et al. A prospective, randomized trial to determine the early and late reactions after the use of iopamidol 340 (Niopam™) and iobitridol 350 (Xenetix®) in cardiac catheterization. J Invas Cardiol 2004;16:707–711. 2. Ballerini L, Barbaresi F, Binaghi G, et al. Iopamidol in cardioangiography: A retrospective, multicenter study. Part I. Adult patients. Int J Card Imaging 1992;8:35–43. 3. Armstrong SJ, Murphy KP, Wilde P, et al. Ventricular fibrillation in coronary angiography: What is the role of contrast medium? Eur Heart J 1989;10:892–895. 4. Lefevre T, Funck F, Aliot E, et al. Safety and efficacy of the new iodinated nonionic low-osmolality contrast medium Iobitridol (Xenetix) in coronary and ventricular angiography. Acta Radiol Suppl 1996;400:75–80. 5. Mehta RH, Harjai KJ, Grines L, et al. Sustained ventricular tachycardia or fibrillation in the cardiac catheterization laboratory among patients receiving primary percutaneous coronary intervention: Incidence, predictors, and outcomes. J Am Coll Cardiol 2004;43:1765–1772.