Iodixanol Tied to Higher Renal Failure Rates, Study Says

By Jane Salodof MacNeil

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NICE, FRANCE -- A study of 77,000 Swedish cardiac patients found rates of renal failure were about twice as high following the use of iodixanol, an iso-osmolar contrast medium promoted as less toxic to the kidneys than competing low-osmolar products, reported Pontus B. Persson, M.D., Ph.D., at the annual meeting of the Cardiovascular and Interventional Radiological Society of Europe.

"From these data we conclude there is absolutely no indication that iodixanol is less harmful for kidney function than ioxaglate or iohexol," Dr. Persson said.

"Actually, the contrary may be the case, but further studies are required to test if the contrary really may hold true," concluded Dr. Persson, a renal physiologist at Humboldt University's Campus Charité Mitte in Berlin.

Dr. Persson and colleagues in Sweden compared patients in the Swedish Coronary Angiography and Angioplasty Registry to rehospitalizations with a diagnosis of renal failure in a Swedish hospital discharge register. The follow-up stretched as long as 12-14 years after percutaneous coronary interventions (PCI) and coronary angiography.

Within 1 year of coronary angiography or PCI, 70 of 5,728 patients given iohexol (Omnipaque) and 291 of 24,577 patients given ioxaglate (Hexabrix) returned to a hospital with a renal failure diagnosis, Dr. Persson said. For both agents the proportion was 1.2%. Among 47,543 patients for whom iodixanol (Visipaque) was used, rehospitalization with renal failure was about twice as common: 1,108 patients or 2.3%. The difference was statistically significant.

With attribution of a hazard ratio of 1 to the diagnosis of primary or secondary renal failure with iodixanol, the investigators calculated hazard ratios of 0.84 for iohexol and 0.77 for ioxaglate. Dr. Persson said these varied only slightly in subgroup analyses for patients with and without a prior history of renal failure.

As two-thirds of the Swedish market is using iodixanol, said Dr. Persson, the investigators also did a subgroup analysis of patients treated during the last 4 years to rule out a "time effect" on the findings. "Again the data are rather clear," he said. "Again we see a much higher risk for developing renal failure in the iodixanol group."

In an interview at the meeting, he said iodixanol is gaining a large share of the global market because it is thought to be less harmful to the kidneys. Low-osmolar contrast media were developed, he said, in an attempt to reduce significant side effects with the first generation of high-osmolar media. As the low-osmolar media were much better tolerated, biotechnology companies attempted to reduce the osmolarity even further.

The strategy did not make sense to Dr. Persson for two reasons. First, he did not believe osmolarity was a problem. "Actually we [have been] giving diuretics with high osmolarity for decades, and nothing has happened," he said.

Second, in reducing osmolarity, he maintained the new products increased the viscosity, "so it's more like syrup and not like water." Dr. Persson said the higher viscosity can cause severe damage to the kidney because it clots the tubules. As a result of the changes, he contended, "Those contrast media that today are thought to be [safer] for the kidney lead to a twofold higher increase in renal failure diagnosis."

Representatives of iodixanol's parent company, GE Healthcare Ltd. in Buckinghamshire, England, disputed Dr. Persson's findings in an interview with this newspaper after attending his presentation.

European medical director Hervé Lemaignen, M.D., and brand manager Pamela McCord questioned whether nephropathy diagnosed long after use of iodixanol could be attributed to the dye.

They emphasized that the evidence in support of iodixanol being less neurotoxic comes from a randomized, double-blind, prospective, multicenter study (N. Engl. J. Med. 2003;348:491-9). It found serum creatinine levels increased significantly less 3 days after angiography with iodixanol, compared with iohexol.

Dr. Persson said creatinine levels are only a surrogate measure for renal damage, and contended that the published study was flawed because the patients in the iohexol group had diabetes a mean of 18 years and thus likely had more kidney damage than the iodixanol group for whom the mean duration of diabetes was only 12.8 years.

The GE Healthcare officials stated in turn that Dr. Persson's study was flawed, as the original database did not specify which contrast medium was used. "What they did was send out a questionnaire asking, "Which contrast medium did you use in this year in your hospital?" So it is stretching it quite a little bit," Ms. McCord said.

Dr. Lemaignen also challenged Dr. Persson's argument that increased viscosity makes iodixanol harmful to the kidneys. It is more viscous in the vial, he said, but becomes thinner when mixed with blood.

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