Letter to the Editor

Dear Editor, I read with interest the article, The Role of Radiographic Contrast Media in Invasive Angiographic Procedures: Innocent Bystander or Important Player?, by Warren K. Laskey, MD, published in the February 2004 edition of Cath Lab Digest (Volume 12, Number 2). In this article, Dr. Laskey concludes that evidence is accumulating to support the use of the iso-osmolal nonionic agent, iodixanol, during…invasive procedures in truly high-risk patients. Dr. Laskey focuses on selected results from three clinical trials to support this conclusion. However, he ignores other data from these trials, as well as from other trials, that raise serious questions of the validity of this conclusion. Dr. Laskey cites the results of the VICC trial¹ as convincing evidence of the superior safety profile of iodixanol compared to other low osmolar contrast agents. What he neglects to say is that no significant difference in overall major adverse cardiac events (MACE) between iodixanol (Visipaque) and iopamidol (Isovue®) was observed during the entire (0-30 day) study period. While it is true that a higher incidence of procedural non-Q wave MIs (CK-MB 3 X ULN) was seen in the iopamidol group in the in-hospital period, this finding must be balanced against the greater overall incidence in the iodixanol group of emergency re-catheterizations (6.8% with iodixanol vs. 5.2% with iopamidol) and re-interventions (2.5% with iodixanol vs. 1% with iopamidol, p=0.05). Dr. Laskey also cites the incidence of MI at 0-30 days to suggest superiority for iodixanol. However, 30-day MI values for the two agents are significantly different only due to the inclusion of the previously mentioned in-hospital non-Q wave MIs; when these are subtracted, there is no difference in the incidence of MI between the two agents. Such selective presentation of the data does a disservice to the investigators who performed the study and the scientific community that depends on balanced and accurate information to make clinical decisions. In the COURT trial², iodixanol was compared to ioxaglate, an ionic low osmolar agent. These results cannot be used to support an advantage of iodixanol over nonionic low osmolar agents. Furthermore, in the COURT study there were consistently favorable results for iodixanol over ioxaglate, unlike the decidedly mixed but ultimately balanced results in the VICC trial. With regard to the established superior renal safety profile of iodixanol to which Dr. Laskey refers, he references only one small study, in which iodixanol was compared to iohexol.³ He cites the findings of the NEPHRIC study without mentioning the significantly longer duration of diabetes mellitus in the comparator group receiving iohexol, nor the slightly lower serum creatinine and higher creatinine clearance in the iodixanol group. To date, no study has been done to show that all low-osmolar, nonionic agents have a similar profile with respect to incidence of CIN. In the absence of such data, conclusions regarding any supposed benefit of iodixanol must be understood to apply only to iohexol, the agent studied in the NEPHRIC trial. Conspicuously absent from Dr. Laskey’s article was any reference to three recently published studies of contrast-induced nephrotoxicity (CIN) after iodixanol involving more than 290 patients that fail to confirm the extremely low CIN incidence reported for this agent in the NEPHRIC trial.^4-6 In the RAPPID study4, subjects with pre-existing renal dysfunction were randomized to receive IV N-acetylcysteine and iodixanol or IV hydration and iodixanol. The incidence of CIN (>25% increase in serum creatinine) in the iodixanol plus hydration group was 21%, much higher than the 3% incidence reported for the iodixanol group in NEPHRIC. In another trial,⁵ subjects with chronic renal insufficiency receiving iodixanol were randomized to receive oral N-acetylcysteine or placebo. The incidence of CIN (creatinine increase >0.5 mg/dL at 48 hours post-contrast) in patients receiving iodixanol without premedication was 12%. Finally, Stone recently published a randomized, double-blind, placebo-controlled study6 in 315 subjects with moderate to severe renal failure evaluating the efficacy of fenoldopam mesylate in preventing CIN; iodixanol was used in 10% of these subjects. CIN (creatinine increase >0.5 mg/dL) was seen in 33.3% of subjects receiving iodixanol, compared to 25.3% of subjects receiving other contrast agents. All three of these studies have been published since the one study cited by Dr. Laskey. To date, no investigator has reproduced the extremely low incidence of CIN after iodixanol in high risk patients that was seen in the NEPHRIC study. Dr. Laskey appropriately raises the issue of choice of iodinated contrast in high-risk patients undergoing invasive cardiac angiography procedures. This subject deserves a full presentation and discussion of all available data. Unfortunately, Dr. Laskey appears to have selected data to support his conclusion, rather than drawing conclusions from a robust literature review. In light of the substantial cost differential between iodixanol and the nonionic, low osmolar agents, physicians should carefully differentiate between the actual versus the perceived benefits of these agents. Judith H. Murphy, MD, FACC, FAHA Executive Director, Corporate Medical Planning and Management Bracco Diagnostics Inc. The author responds: Dr. Murphy and I would agree on one important point: evidence-based medicine must be exactly that. However, until full publication of the VICC trial, proper interpretation of this trial with co-primary endpoints must wait. Nevertheless, the difference in emergency re-cath rates (6.8% for iodixanol vs. 5.2% for iopamidol) was not only not even close to statistically significant (p=0.24) but surprisingly and unacceptably high in a study in which use of platelet GP IIb/IIIa antagonists approached 80%. Furthermore, the re-intervention rate in VICC (2.5% vs 1%) may not, in fact, be significant when corrected for multiple looks at the data (in-hospital/48 hr MACE and 30 day MACE). Finally, the studies cited by Dr Murphy (her references 4-6) do not, in fact, have as their primary end point the difference in CIN between iodixanol and a comparator; rather, these studies examine the effect of N-acetylcysteine on CIN (references 4-5) and the effect of fenoldapam on CIN (reference 6). Notably, a meta-analysis of sixteen iodixanol vs. comparator double-blind, randomized trials, presented at the most recent European Congress of Radiology meetings (Stacul F, et al.), supports the benefit of iodixanol in reducing the risk of CIN in high-risk patients undergoing angiography.