Iodinated Contrast Media and Contrast-Induced Nephropathy:<br />
Is There a Preferred Cost-Effective Agent?

At the time they were introduced in 1988, the nonionic contrast agents were significantly more expensive than the previously available agents due to substantial development expenses and higher manufacturing costs. However, the improved safety and tolerability of the newer agents was generally considered to warrant the additional expenditure. Over time, the acquisition costs of the nonionic monomer agents declined from approximately $1.00 per mL in 1990 to $0.25–0.30 per mL today. This reduction in costs is attributable to the fact that the development costs of these agents were recouped long ago, and the rise of group purchasing organizations in the late 1990s significantly increased price pressure on all manufacturers of medical supplies and drugs, including contrast media.
The first dimeric agent (essentially 2 tri-iodinated molecules joined together, hence a ratio of 6 iodine atoms to 1 molecule in solution) was introduced in 1985. This agent, ioxaglate, was a low-osmolar agent (600 mOsmol/kg) but was ionic, with 1 negative charge per contrast molecule. Ioxaglate was preferred by a number of cardiology practices since it combined the presumed anticoagulant properties of an ionic agent with the low osmolality of the nonionic agents. However, a series of studies subsequently showed that the rate of postprocedure complications was not lowered with the use of ioxaglate, while allergic reactions and nausea were significantly higher with this agent.^1–3
The introduction in 1996 of a second dimeric contrast agent, iodixanol, was expected to reduce contrast media reactions further. As formulated, this agent is isotonic to human plasma (290 mOsmol/kg) and, unlike ioxaglate, is nonionic. The reduction in osmolality provided by iodixanol versus the existing nonionic agents was not as dramatic as the reduction achieved with the development of the nonionic monomers, but still promised to further improve tolerability. As a new and presumably superior agent, in 1996, iodixanol was priced at a significant premium to the low-osmolar contrast agents ($1.20 per mL versus about $0.50 per mL for the low-osmolar monomers).
Due to the increased cost of iodixanol, the agent was not widely used until the publication of a series of clinical studies that suggested iodixanol might be safer and better tolerated compared with several of the existing low-osmolar agents. In 2000, the COURT study suggested that outcomes in percutaneous coronary intervention (PCI) patients were significantly improved versus ioxaglate, the other dimeric agent.⁴ This finding was controversial, since a concurrent publication, the VIP trial, did not show superiority with iodixanol.⁵ In fact, a more recent trial (published in 2006 in the era of stenting and aggressive antiplatelet therapy) actually demonstrated superior outcomes with ioxaglate rather than iodixanol.⁶ Nevertheless, after publication of the COURT study, a number of cardiology practices switched from ioxaglate to iodixanol.
In 2003, a European study on contrast nephropathy (the NEPHRIC study) was published by Aspelin and colleagues.⁷ This study compared outcomes in 129 renally impaired angiography patients with diabetes randomized to iodixanol or to the nonionic monomer agent iohexol. In this study, the rate of contrast-induced nephropathy (CIN, defined as an increase in serum creatine of 0.5 mg/dL over prestudy levels) was 26% with the nonionic monomer and 3% with iodixanol. In addition, 6 patients in the iohexol group developed acute renal failure, while none did in the iodixanol group. The NEPHRIC study provided a rationale for additional cardiology practices to switch to iodixanol, either selectively for their renally impaired patients, or for all of their patients.
Since the NEPHRIC study, several analyses of the rates of CIN after the use of iodixanol or other agents have been published, including one by our group.^8,9 Overall, these analyses show that the low rate of CIN after iodixanol in the NEPHRIC study has not been reproducible, and further suggest that the rate of CIN may be higher among some lowosmolar agents (e.g., iohexol) than other low-osmolar agents (e.g., iopamidol).
A recent meta-analysis of studies conducted by the manufacturer of iodixanol suggested that this agent was better tolerated than a group of low-osmolar comparator agents.¹⁰ However, this analysis was flawed in that it did not evaluate the low-osmolar agents individually, and 87% of patients in the low-osmolar comparator group received either iohexol or ioxaglate for their procedures. In fact, in the one study cited in this analysis in which iodixanol was compared to iopamidol in 144 patients, CIN occurred only after iodixanol administration.¹¹ A recent analysis of drug safety databases maintained by the U.S. Food and Drug Administration revealed that certain contrast agents, such as iohexol and iodixanol, show a higher relative reporting rate for renal adverse events than other widely used agents, such as iopamidol.¹² Using accepted drug safety signaling methodology, the authors found a signal for increased renal adverse events for iodixanol and iohexol, but not for iopamidol. This report was followed by an analysis of outcomes from a registry of over 55,000 patients undergoing angiography in Sweden, which showed that patients receiving iodixanol for their cardiology procedure were twice as likely to experience clinically significant acute renal failure as those receiving the low-osmolar agent ioxaglate.¹³ In addition, the rate of postprocedure dialysis doubled in patients receiving iodixanol.
To evaluate whether iodixanol provides a general benefit over all other low-osmolar agents in renally impaired patients, a number of prospective clinical studies have been conducted in recent years, the results of which are just emerging. In general, these studies show that the same benefit for iodixanol over iohexol cannot be demonstrated when iodixanol is compared to other nonionic low-osmolar agents. In 2005, Brigouri and colleagues reported that CIN rates were not significantly different when patients with chronic renal insufficiency were randomized to iodixanol or the low-osmolar nonionic agent iobitridol for their angiography procedures (2.7 vs. 3.5%, respectively, p = 1.0).¹⁴ In a recently published study from Korea, the RECOVER study, iodixanol was compared to the ionic dimer ioxaglate.¹⁵ In this study a significant reduction in the incidence of CIN was shown with iodixanol, but only when the two endpoints, serum creatine increases ≥ 0.5 mg/dL or 25% from baseline, were combined. Another recent study, ICON, failed to demonstrate a benefit with iodixanol over ioxaglate in renally impaired cardiac angiography patients. A preliminary report on this trial indicated that postprocedure increases in serum creatine were similar in the two populations (p = 0.08), and no differences were noted between the two groups with respect to renal failure or 30-day outcomes.¹⁶ Given the conflicting results of studies with these two contrast agents, it is unclear whether a true benefit exists with the use of iodixanol over ioxaglate in renally impaired patients. However, since ioxaglate is an ionic, dimeric contrast agent, findings of studies involving this agent cannot be generalized to nonionic monomeric agents such as iopamidol or iopromide.
Barrett and colleagues recently reported data from 153 patients with chronic kidney disease randomly assigned to receive iodixanol or iopamidol for contrast-enhanced computed tomography (CT).¹⁷ In this trial, the rate of CIN in patients undergoing CT was similarly low, whether they were given iodixanol or iopamidol for their procedure (2.6% iodixanol vs. 0% iopamidol, p = 0.2). Most recently, the largest study conducted to date comparing iodixanol with a low-osmolar agent in high-risk patients undergoing coronary angiography has failed to demonstrate a benefit with iodixanol over iopamidol in renally impaired cardiac angiography patients. In the CARE study, 414 patients with chronic kidney disease were randomized to iodixanol or iopamidol for their cardiac angiography procedure.¹⁸ Rates of CIN were comparable after use of the two agents (serum creatine increase ≥ 0.5 mg/dL, 6.7% for iodixanol and 4.4% for iopamidol, p = 0.39; serum creatine increase ≥ 2 5 % from baseline, 12.4% for iodixanol and 9.4% for iopamidol, p = 0.44). Even in the subset of patient with diabetes, which included 170 patients versus 129 in the NEPHRIC study, rates of CIN were comparable (serum creatine increase ≥ 0.5 mg/dL, 13.0% for iodixanol and 5.1% for iopamidol, p = 0.12; serum creatine increase ≥ 25% from baseline, 15.2% for iodixanol and 10.3% for iopamidol, p = 0.37).
Following the publication of the NEPHRIC study, Aspelin and colleagues published an analysis suggesting that, based on the incidence of clinically relevant renal failure in patients receiving iohexol in that study, iodixanol was more cost-effective than the low-osmolar agent in high-risk angiography patients.¹⁹ If a similar approach was applied to the data recently published by Solomon and Liss, the results might indicate the opposite.^12,13 What seems clear is that even in high-risk patients iodixanol is not better tolerated than all low-osmolar agents. Iopamidol in particular has a well demonstrated safety profile in renally impaired patients which is at least equivalent to that of iodixanol.
Pricing for nonionic contrast media varies by institution and depends on factors such as the size of the contract, the mix of products being purchased and membership in a particular group purchasing organization. Table 1 models the effect of cost differences between the low-osmolar contrast agent iopamidol ( Isovue^®-370, Bracco Diagnostics, Princeton, New Jersey) and the isotonic contrast agent iodixanol (Visipaque^™- 320, GE Healthcare, Inc., Princeton, New Jersey) using publicly available and calculated prices for these agents. Contrast media prices are bracketed on the high end by manufacturers’ list prices and on the low end by Federal Supply Schedule (FSS) prices, which are federally mandated “best-customer prices” that must be offered to large government purchasers such as Veterans Administration hospitals. According to the manufacturers, the current list price for a box of ten 200 mL bottles of Visipaque-320 is $1968.65 ($0.98/mL), while the list price for ten 200 mL bottles of Isovue-370 is $1,650.00 ($ 0.82/ mL).²⁰ At these prices, 2000 mL of Visipaque costs approximately 20% more ($315.00) than a comparable amount of Isovue. Given the 14% increase in iodine per mL contained in Isovue-370 versus Visipaque-320, 1 gram of iodine purchased as Visipaque-320 would cost $3.08, while the same gram of iodine purchased as Isovue-370 would cost $2.23.
On the low end, the Federal Supply Schedule (FSS) price for Isovue (10 units of 200 mL bottles) works out to $0.11/mL, while that for a comparable purchase of Visipaque is over three times as much ($0.40/mL).²¹ These prices, which are only available to large government purchasers, represent the highest available discounts from manufacturers on their products (87% off the list price for Isovue and 57% off the list price for Visipaque). Most contrast media users pay something in between the list price and the FSS price. If one takes the average between the list and FSS prices for these two agents, one can see that, at $0.69/mL, Visipaque-320 would cost approximately 50% more than Isovue-370, at $0.47/mL. In general, the discounts negotiated by large hospitals or group purchasing organizations represent approximately 50–75% off the list price for low-osmolar agents such as Isovue and 25–35% off the list price for Visipaque. Given the 19% difference in list pricing, this means that for most hospitals, the cost of using Visipaque is approximately two to three times the price of a comparable low-osmolar agent. Given the approximately 2 million invasive cardiac procedures performed annually in the U.S., the exclusive use of Visipaque could cost the health care system more that $300 million a year.
Given the lack of difference in clinically relevant outcomes between iodixanol and certain other nonionic agents and the substantial differences in acquisition costs, the use of iopamidol or a low-osmolar agent other than iohexol may be recommended at this time. Since 2004, over 35,000 patients at our cardiac catheterization laboratory have received Isovue-370 for their procedure. Given the roughly 10,000 catheterizations performed annually at our institution, and an average contrast agent volume of 200 mL per exam, the potential annualized cost savings of using Isovue instead of Visipaque amounts to approximately $630,000 (Table 1). In practice, this means that over the 3 years we have been using Isovue for our cardiac angiography patients, our institution has saved almost 2 million dollars versus what we would have paid had we been using iodixanol during that time. As the late United States Senator Everett Dirkson reputedly once said: “…a million here and a million there, and pretty soon you’re talking real money”.