The NEPHRIC Trial

This prospective, randomized trial demonstrates the superiority of iodixanol to low-osmolar contrast media in preventing contrast-induced nephropathy.

By Adam Brodsky, MD, and Charles J. Davidson, MD
 

To view the figures and tables related to this article, please refer to the print version of our September issue, page 34.

The early contrast agents were ionic monomers that were very hypertonic compared to human serum (1,500 to 1,800 mOsm/kg). Second-generation contrast agents are either ionic dimers or nonionic monomers of iodinated benzene rings. They are considerably less hypertonic than their predecessors (600 to 850 mOsm/kg), and possess a 3:1 iodine-to-particle ratio. The latest-generation contrast agent, iodixanol, is a nonionic, dimeric structure that reduces osmolality to the level of human serum. This is achieved by creating an iodine-to-molecule ratio of 6:1, with solute added to achieve isomolarity.

PREVIOUS RESEARCH
The renal toxicity of iodinated contrast agents has been well described. Diabetes mellitus, baseline renal insufficiency, and the volume of contrast material used are the strongest predictors of contrast-induced nephropathy (CIN). The etiology of CIN is not entirely understood and is likely multifactorial. Renal vasoconstriction, ischemia, and/or direct toxic effects have been implicated. Patients with baseline impaired renal function are at particularly high risk for developing CIN.1 Previous studies have shown that nonionic low-osmolar contrast media (LOCM) are less likely to cause CIN than are high-osmolar ionic contrast media (HOCM) in patients with diabetes and/or baseline renal insufficiency.2,3 Animal models have suggested that renal blood flow is decreased with iodixanol as compared to LOCM,4,5 due to the increased viscosity. Whether the incidence of CIN could be further reduced by iso-osmolar contrast media is unknown.

Chalmers et al compared a nonionic LOCM (iohexol) with iodixanol (iso-osmolar) in patients undergoing peripheral and renal angiography and demonstrated that iodixanol was indeed associated with a lower incidence of CIN.6 However, this study was unblinded and the contrast dose used was small (50 to 60 mL). Nevertheless, it was the first trial suggesting that iso-osmolar contrast media could further reduce the risk of CIN compared to LOCM.

THE NEPHRIC STUDY
Design
Aspelin et al7 conducted a prospective, double-blinded, randomized, placebo-controlled trial comparing iodixanol to a nonionic LOCM (iohexol). The study involved 129 patients with diabetes and stable renal insufficiency (serum creatinine, 1.5 mg/dL to 3.5 mg/dL for men; 1.3 mg/dL to 3.5 mg/dL for women) presenting for coronary or aortofemoral angiography.7 The patients were randomized to receive either nonionic iso-osmolar (iodixanol) or nonionic low-osmolar contrast media (iohexol). The primary endpoint was the peak increase in serum creatinine within the 3 days after angiography. Secondary endpoints included an increase in creatinine of either >0.5 mg/dL or >1.0 mg/dL over the 3 days after angiography, as well as the absolute change in serum creatinine over the 7 days after angiography.

Results
Statistically significant differences were found for all primary and secondary endpoints (Figure 1, Table 1). The peak increase in creatinine over 3 days was 0.13 mg/dL for iodixanol versus 0.55 mg/dL for iohexol (P = .001). Using an increase in creatinine of 0.5 mg/dL as the definition of CIN, 3% of the iodixanol group versus 26% of the iohexol group suffered CIN (P = .002). Restricting the definition of CIN to an increase in creatinine of 1 mg/dL, the incidence of CIN was 0% in the iodixanol group and 15% in the iohexol group.

The baseline characteristics of the two groups were similar with respect to age, weight, body-mass index, baseline serum creatinine, hydration status, volume of contrast used, and milligrams of iodine used. However, the average duration of diabetes was noted to be significantly longer in the iohexol group (18 years vs 12.8 years). Whether the longer duration of diabetes predisposes one to CIN is uncertain. Whereas diabetes itself is a known risk factor for the development of CIN, the duration of diabetes as a specific risk factor has not been reported.

COMMENTARY
This is the first prospective randomized trial demonstrating the superiority of iodixanol to low-osmolar contrast media in the prevention of contrast-induced nephropathy. The benefit was demonstrated when both change in creatinine and an absolute increase of >0.5 mg/dL was evaluated. The salutary effect is an extension of strategies to prevent contrast-induced nephropathy, much as what was observed with earlier studies with low-osmolar nonionic contrast media.

This was primarily a trial of diagnostic angiograms rather than percutaneous coronary intervention (PCI) (17% rate of PCI in the iodixanol group vs 25% in the iohexol group). Although the contrast dose in this trial (mean dose, 163 mL) was much larger than the 50-mL to 60-mL dose in the Chalmers study,6 modern PCI techniques may require larger doses of contrast than the mean dose used in this study.

The use of N-acetylcysteine (NAC) was low in this study (6% in the iodixanol group vs 11% in the iohexol group). However, the data regarding the benefit of NAC have been contradictory. The potential benefit of using oral NAC in conjunction with iodixanol deserves further investigation. One study utilizing intravenous NAC suggested further benefit to intravenous NAC when used in combination with iodixanol.8 The Visipaque Angiography/Interventions with Laboratory Outcomes for Renal Insufficiency (VALOR) study is an ongoing, prospective, multicenter, randomized, double-blind trial comparing iodixanol with NAC to LOCM with NAC and should further elucidate this issue.

Although all patients in the study by Aspelin et al had diabetes and renal insufficiency, and therefore would be expected to have been using angiotensin-converting enzyme inhibitors (ACEI), the incidence of ACEI usage was not reported. In a retrospective analysis of patients undergoing PCI, 29% of patients who developed CIN were receiving ACEI versus 20% of those who did not develop CIN (P<.001).9 Although ACEI usage may simply have been a marker for a more ill population, it is possible that ACEIs, given their effect on the renal vasculature, might have a deleterious effect on the development of CIN.
The statistical significance reached in the primary endpoint and all secondary endpoints in this study speaks to the robustness of the differential impact on postprocedural renal function of iodixanol versus iohexol. The prognostic importance of a rise in serum creatinine has been evaluated in several studies. A previous retrospective analysis of 7,586 patients who had undergone PCI demonstrated that in the 254 (3.3%) who experienced CIN there was increased mortality during the index hospitalization, as well as at 5 years.9 However, the patients who developed CIN were also found to have higher rates of several other comorbidities, including congestive heart failure, diabetes, myocardial infarction within 24 hours of PCI, and peripheral vascular disease.

Two studies that have controlled for comorbid states have also shown higher mortality rates in patients with CIN. Levy et al published a retrospective matched-pairs cohort study showing higher mortality during the index hospitalization after controlling for comorbidities.10 Gruberg et al published a prospective observational cohort study showing higher mortality at 1 year for patients with CIN.11 Iakavou et al demonstrated that in females, the development of CIN (defined as a 25% increase in creatinine) was associated with a worse prognosis than in males undergoing PCI.12 Thus, although there are no prospective, randomized trials proving that lowering the incidence of CIN will result in improved outcomes, there are observational data to suggest the existence of an adverse relationship between outcomes and CIN.13
The study by Aspelin et al confirms the fact the iso-osmolar nonionic contrast agent iodixanol is less nephrotoxic than nonionic LOCM in patients with diabetes and renal insufficiency. The possibility of a synergistic relationship between iso-osmolar contrast media and NAC remains unclear. Although the causal relationship between CIN and poor patient outcomes remains to be prospectively evaluated, retrospective data strongly support this hypothesis. 

Adam Brodsky, MD, is from the Department of Medicine, Division of Cardiology at the Northwestern University Feinberg School of Medicine, Chicago, Illinois. He holds no financial interest in any product or manufacturer mentioned herein. Dr. Brodsky may be reached at (312) 926-5421; ambrodsky@mac.com.

Charles J. Davidson, MD, is from the Department of Medicine, Division of Cardiology at the Northwestern University Feinberg School of Medicine, Chicago, Illinois. He is a consultant for Amersham Health. Dr. Davidson may be reached at (312) 926-5421; cdavidso@nmh.org.

1. Davidson CJ, Hlatky M, Morris KG, et al. Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization: a prospective trial. Ann Intern Med. 1989;110:119-124.
2. Barrett BJ, Carlisle EJ. Meta-analysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology. 1993;188:171-178.
3. Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the Iohexol Cooperative Study. Kidney Int. 1995;47:254-261.
4. Lancelot E, Idee JM, Couturier V, et al. Influence of the viscosity of iodixanol on medullary and cortical blood flow in the rat kidney: a potential cause of nephrotoxicity. J Appl Toxicol. 1999;19:341-346.
5. Deray G, Bagnis C, Jacquiaud C, et at. Renal effects of low and isoosmolar contrast media on renal hemodynamics in a normal and ischemic dog kidney. Invest Radiol. 1999;34:1-4.
6. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol. 1999;72:701-703.
7. Aspelin P, Aubry P, Fransson S, et al. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348:491-499.
8. Baker CSR, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. JACC. 2003;41:2114-2118.
9. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002;105:2259-2264.
10. Levy EM, Viscoli CM, Horwitz RJ. The effect of acute renal failure on mortality: a cohort analysis. JAMA. 1996;275:1489-1494.
11. Gruberg L, Mintz G, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. JACC. 2000;36:1542-1548.
12. Iakovou I, Dangas G, Mehran R, et al. Impact of gender on the incidence and outcome of contrast-induced nephropathy after percutaneous coronary intervention. J Intervent Cardiol. 2003 15;18-22.
13. Lindsay J, Apple S, Pinnow EE, et al. Percutaneous coronary intervention associated nephropathy foreshadows increased risk of late adverse events in patients with normal baseline serum creatinine. CCI. 2003;59:338-343.

 

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