Response to Letters Regarding Article, “Cardiac Angiography in REnally Impaired Patients (CARE) Study: A Randomized Double-Blind Trial of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease”
We thank the responding authors for their comments on our study,1 which deal primarily with trial design. The timing of postcontrast creatinine sampling is a limitation of all trials on this topic. The CARE trial is unique because it is the first trial in which the exact timing of the postcontrast samples was reported and because 83% of the single postcontrast samples were collected during a time period when most cases of contrast-enhanced nephropathy (CIN) are known to occur (ie, 2 to 3 days after contrast administration). Few patients had samples taken beyond 71 hours, and it is very likely that the critical increases in serum creatinine observed at day 4 or 5 were already present at day 2 or 3 after contrast. We do not believe that any bias was introduced by measurements at these later time points or that the rates observed for these small numbers of patients are meaningful.
The prophylaxis used in CARE may have affected the overall incidence of CIN, but not whether possible differences between the 2 contrast agents exist. We believe that the jury is still out on whether N-acetylcysteine, bicarbonate, or their combination is effective as prophylaxis. Using a protocol similar to that described by Merten et al2 (for bicarbonate alone) and Briguori et al3 (for the combination of N-acetylcysteine and bicarbonate), we could not replicate their findings in this larger group of patients. The results from CARE should encourage caution in the use of these strategies.
Both letters question the severity of risk of the population studied in CARE. We believe that this is a population at high risk for CIN. Large numbers of patients had diabetes mellitus (n=170), underwent percutaneous coronary intervention (n=163), received >50 g iodine (n=146), or had a glomerular filtration rate <40 mL/min (n=114). Patients in the iodixanol group who underwent percutaneous coronary intervention or received a high dose of contrast were younger, and patients with diabetes mellitus received less contrast volume (all P<0.05). By all definitions of CIN, no differences existed between the 2 agents in these high-risk subgroups. Although the lack of a statistical difference between the 2 contrast agents is not synonymous with “equivalency,” the relatively tight confidence intervals support the assertion that a clinically significant difference between the agents does not exist for patients similar to those who were enrolled in CARE.
We agree with Drs Anselmino and Biondi-Zoccai that the results in the subgroup with diabetes mellitus need validation. This is important, because a previous trial in patients with diabetes and renal insufficiency (NEPHRIC; Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media) found that iso-osmolar iodixanol was superior to low-osmolar iohexol. The difference in results between CARE and NEPHRIC may relate to the contrast agent chosen for comparison. In both trials, iodixanol induced a similar mean change in serum creatinine (0.16 and 0.13 mg/dL, respectively), but the change was 0.07 mg/dL for iopamidol and 0.55 mg/dL for iohexol. CIN rates for the low-osmolar agents, iopamidol and iohexol, were 5% and 26%, respectively, by the CIN definition reported in NEPHRIC. These data argue against an effect of osmolality on the incidence of CIN in high-risk patient groups.
Dr Solomon is a consultant to Tyco-Mallinckrodt and Bracco Diagnostics. The remaining authors report no conflicts.
Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS, Katholi RE, Gelormini JL, Labinaz M, Moreyra AE; Investigators of the CARE Study. Cardiac Angiography in REnally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation. 2007; 115: 3189–3196.
Briguori C, Airoldi F, D’Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A. Renal insufficiency following contrast media administration trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 2007; 115: 1211–1217.