Washington, DC - Two new studies have shown that there is no benefit to treating coronary angiography or PCI patients with an iso-osmolar contrast agent. In these latest studies, there was no difference in the incidence of contrast-induced nephropathy in patients treated with iodixanol, an iso-osmolar, nonionic contrast agent, or those treated a low-molecular contrast agent.

The studies, Cardiac Angiography in Renally Impaired Patients (CARE), led by Dr Richard Solomon (University of Vermont College of Medicine, Burlington), and Ionic Versus Nonionic Contrast to Obviate Worsening of Nephropathy After Angioplasty in Chronic Renal Failure Patients (ICON), led by Dr Roxanna Mehran (Columbia University, New York, NY), were both presented here during the late-breaking clinical-trials session at the TCT 2006 annual meeting.

"Based on the data that we now have, including the data that were presented by Dr Mehran, low-osmolar contrast agents, which are generally less expensive than iso-osmolar contrast agents, can be safely used in high-risk patients when those patients receive some volume and possibly some antioxidant therapy," concluded Solomon. "As long as you give a patient volume and use a low-osmolar agent, you are just as safe as when you use an iso-osmolar agent."

Results from the ICON trial

Dr Roxanna Mehran

Presenting the ICON results first to the media, Mehran noted that contrast-induced nephropathy continues to be a significant concern for radiologists and cardiologists. It usually occurs 24 to 48 hours after contrast exposure, with creatinine levels peaking five to seven days later and normalizing within seven to 10 days. While levels often return to normal, elevated contrast-induced nephropathy is a leading cause of iatrogenic renal failure, morbidity, and mortality after coronary angiography, particularly in those with preexisting renal disease, said Mehran.

"There is no question that patients with heart disease have renal disease, and vice versa, and we need to look at this overlap of disease processes and be able to deal with the complications," said Mehran.

For this reason, investigators sought to determine the nephrotoxic potential of iodixanol, an iso-osmolar, nonionic contrast media, and ioxaglate, an ionic contrast agent with low osmolality that is less viscous than iodixanol, in complex patients with comorbid disease. Previous studies have suggested that iso-osmolar agents might be beneficial in reducing the risk of nephropathy, while others have hypothesized that a less viscous agent, such as ioxaglate, might also reduce the risk. In the ICON study, contrast-induced nephropathy was defined as new-onset or exacerbation of renal dysfunction following contrast administration in the absence of other causes, resulting in a relative 25% increase or an absolute 0.5-mg/dL increase in serum creatinine levels from baseline.

Overall, 74 patients with renal insufficiency undergoing angiography were randomized to ioxaglate, and 71 patients were randomized to iodixanol. Patients were quite sick, said Mehran, with 45% having diabetes mellitus and 87% having hypertension. All patients had stable renal function, defined as two consecutive serum creatinine measurements within 15% of each other and within 1.5 to 3.0 mg/dL. All subjects were well hydrated, said Mehran, receiving approximately 3.7 L of fluid. The use of N-acetyl-cysteine was left to the discretion of the investigator. The primary end point was the peak increase in serum creatinine out to day three.

Compared with ioxaglate, iodixanol did not significantly reduce the increase in serum creatinine levels after coronary catheterization or PCI, said Mehran. There was no significant difference between the two agents at any time, nor was there any difference between the two agents when other definitions of contrast nephropathy were used. Also, in-hospital and 30-day outcomes did not differ between the two agents. The rate of contrast nephropathy in this population with either contrast media was 18% to 20%, despite excellent hydration, noted Mehran.

"I think that this is such an important problem, because no matter how hard we try to treat patients, this risk continues to stay," said Mehran. "It's important because 20% of our patients [in this study] were exposed to this complication. Hydration is a must, and right now there are some trials ongoing that look at local drug delivery into the renal artery to try to prevent this complication . . . but there are no real good answers right now."

CARE also attempts to tackle the issue

In the second study presented during the late-breaking clinical-trials session, the CARE investigators randomized 414 high-risk patients with an estimated glomerular filtration rate <60 mL/min and undergoing coronary angiography to iodixanol, the iso-osmolar agent, or iopamidol, a low-osmolar contrast agent. Using multiple definitions of chronic induced nephropathy, Solomon and colleagues sought to determine, like Mehran, whether the low-osmolar agent was as effective as the more expensive iso-osmolar contrast media.

All patients underwent complementary preventive strategies, including volume expansion with sodium bicarbonate and the use of a double dose of N-acetyl-cysteine that was left to the discretion of the operators. The contrast agents were administered intra-arterially, noted Solomon, as delivery via this route is thought to be associated with a lower incidence of nephropathy.

Investigators found that there was no difference in the incidence of contrast-induced nephropathy in patients treated with iopamidol or iodixanol. Looking only at patients who underwent PCI or those with diabetes mellitus, investigators also found no difference in the incidence of nephropathy among those treated with the different agents, although there were trends favoring the low-osmolality agent. In addition, there was no difference in contrast-induced nephropathy among those who received N-acetyl-cysteine. Iopamidol was associated with a significantly smaller mean increase in serum creatinine levels when compared with iodixanol.

CARE: Results (n=414)        

Definition of contrast-induced nephropathy	Iopamidol (n=204)	Iodixanol (n=210)	p
>0.5-mg/dL increase in serum creatinine (%)	4.4	6.7	0.39
>25% increase in serum creatinine (%)	9.8	12.4	0.44
>25% decrease in the estimated glomerular filtration rate creatinine (%)	5.9	10.0	0.15

CARE: Mean change in peak serum creatinine levels (mg/dL)

Group	Iopamidol	Iodixanol	p
Total population (n=414)	0.07	0.12	0.03
Diabetes population (n=170)	0.07	0.16	0.01
N-acetyl-cysteine-treated population (n=168)	0.05	0.10	0.19

In 2003, the NEPHRIC trial showed that iodixanol was superior to iohexol in patients with chronic kidney disease and diabetes mellitus. This led many to believe that the newer iso-osmolar agents were superior to those with low osmolality. Solomon noted that the study included only patients with diabetes mellitus, and none had volume expansion before treatment, possibly affecting the results. These early trials included many different patient populations and tested different agents against each other, leading to disparate results across various trials. The implications from CARE, as well as ICON, are clear, however.

"Osmolality is not the sole determinant of contrast-induced nephropathy, no matter how it was defined," Solomon concluded.

Many confusing studies to date

Commenting on the results of the studies, discussant Dr Cindy Grines (William Beaumont Hospital, Royal Oak, MI) noted that clinicians remain interested in serum creatinine increases as even small increases trend toward higher mortality that is more significant over time. Moreover, the data haven't always been clear, despite previous head-to-head comparisons.

"It's been very difficult to sort through all of these trials because of differences in design, different patient populations, different volumes of contrast agents administered, and totally different types of procedures," said Grines. "There were also huge differences in hydration protocols that would make comparisons difficult. And most of the studies have been negative to date."

With the presentation of both studies, Grines said the data suggest that any low-osmolar contrast agent is acceptable in patients undergoing catheterization or PCI as long as they're adequately hydrated. However, Grines questioned whether the surrogate end point, the transient change in serum creatinine levels, is an acceptable end point or whether larger trials are needed to make this conclusion about the equivalence of both agents.