Online Appendix for the following August 15 JACC article
TITLE: A Meta-Analysis of the Renal Safety of Isosmolar Iodixanol Compared to LowOsmolar Contrast Media
AUTHORS: Peter A. McCullough, MD, MPH, FACC, Department of Medicine,
Divisions of Cardiology and Preventive Medicine, William Beaumont Hospital, Royal
Oak, Michigan, Michel E. Bertrand, MD, FACC, 2Division of Cardiology, University of
Lille, Lille, France, Jeffrey A. Brinker, MD, FACC, 3Division of Cardiology, The Johns
Hopkins Medical Institutions, Baltimore, Maryland, Fulvio Stacul, MD, Institute of
Radiology, University of Trieste, Trieste, Italy
APPENDIX
Previously Unpublished Trials Included in the Meta-Analysis
1. A Single-Center, Randomized, Double-blind Comparative Phase III Study in Patients
Undergoing Cardioangiography With Iodixanol 320 mg I/ml or Iohexol 350 mg I/ml
This single-center, randomized, double-blind comparative Phase III study was conducted
at the National Hospital (Rikshospitaler) in Oslo, Norway, between April 1994 and June
1995. A total of 50 cardioangiography patients with normal renal function (25 per group)
were recruited and followed for 7 days after the procedure. The primary objectives of the
study were to examine the degree of prolonged renal enhancement and adverse events
associated with iodixanol-320 and iohexol-350.
Few differences were found between the 2 treatment groups throughout the study. Mean
patient age was 60.4 ± 7.8 years and 60.9 ± 8.2 years for the iodixanol and iohexol
groups, respectively. Patients in the iodixanol group received a mean contrast volume of
124.4 ± 42 ml compared to a mean contrast volume of 119.2 ± 33.2 ml in the iohexol
group. Fewer patients reported injection discomfort with iodixanol than with iohexol
(11% vs. 24%), although the numbers of patients reporting adverse events were similar (6
and 7, respectively). Baseline Cr concentrations were 1.14 ± 0.20 mg/dl and 1.16 mg/dl
± 0.14 mg/dl, respectively. Serum Cr one day after the procedure increased by 0.05 ±
0.09 mg/dl in the iodixanol group and by 0.05 ± 0.09 mg/dl in the iohexol group. No
statistical difference was found in any parameter of renal function 1, 3, or 7 days after
angiography. Computed tomography one day after the procedure demonstrated greater
retention of iodixanol than iohexol in the renal cortex (14.19 ± 5.35 HU vs. 8.54 ± 5.14
HU) and medulla (8.99 ± 4.03 HU vs. 5.35 ± 3.11 HU) that resolved within 48 hours. No
correlation between maximum renal enhancement at 24 hours and parameters of renal
function was observed.
The conclusion of this study was that cardioangiography with iodixanol can be performed
in patients with normal renal function without long-term effects on glomerular and
tubular renal function parameters, and with minor transient retention of CM. This study
was not published because larger trials with similar clinical findings were published
previously (Table 1).
2. A Randomized, Double-blind Comparative Phase III Study of the Efficacy and Safety
of Iodixanol Versus Iohexol for Visceral Arteriography, Peripheral Arteriography and/or
Aortography
This randomized, double-blind comparative Phase III study was conducted between June
1991 and June 1992 at 2 centers, the University of Minnesota, Minneapolis, MN, and the
University of California at Los Angeles, Los Angeles, California. A total of 110 patients
with baseline Cr values below 2.00 mg/dl were enrolled and followed for 3 days. Fiftysix of the patients underwent visceral arteriography, and 54 of the patients underwent
peripheral arteriography. The objective of the study was to compare the efficacy (vessel
visualization) and safety of iodixanol 320 mg I/ml and iohexol 350 mg I/ml.
Few differences were observed between the baseline characteristics or outcomes of the
patients given iodixanol (n = 27) versus iohexol (n = 29) for visceral arteriography. Mean
patient age was 44 ± 17 years in the iodixanol group and 48 ± 16 years in the iohexol
group. In the iodixanol and iohexol groups, the mean volumes of contrast administered
were 107 ± 52 ml (given in 3.3 ± 2.4 injections) and 106 ± 56 ml (given in 3.2 ± 2.2
injections), respectively. Both iodixanol and iohexol provided diagnostic visualization in
all patients, and no significant differences were observed overall. However, iodixanol
provided a greater number of “excellent” visualizations of the kidney than iohexol (100%
vs. 71%, p = 0.01). No significant differences in the incidence of adverse events were
noted (3 events for iodixanol and 5 for iohexol), although less injection discomfort was
reported for iodixanol than iohexol (26% vs. 41%, respectively). One patient in each
group experienced a clinically relevant increase in Cr during the study. The patient in the
iodixanol group had undergone kidney transplant and had elevated Cr values at baseline
(1.90 mg/dl).
Similarly, few differences were observed between the baseline characteristics or
outcomes of the patients given iodixanol (n = 28) versus iohexol (n = 26) for peripheral
arteriography. Mean patient age was 66 ± 14 years in the iodixanol group and 62 ± 14
years in the iohexol group. In the iodixanol and iohexol groups, the mean volumes of
contrast administered were 147 ± 44 ml (given in 4.4 ± 1.5 injections) and 151 ± 45 ml
(given in 5.0 ± 2.8 injections), respectively. Both iodixanol and iohexol provided
diagnostic visualization except in 1 patient with an occluded graft (iohexol group). No
significant differences in overall efficacy were observed. Furthermore, no significant
differences in the incidence of adverse events were noted (3 events for iodixanol and 2
for iohexol), although less injection discomfort was reported for iodixanol than iohexol
(50% vs. 88%, respectively, p = 0.003). No statistically significant differences in Cr and
other laboratory parameters of clinical interest were noted, although one diabetic patient
in the iodixanol group experienced elevated Cr at baseline (2.20 mg/dl) and at all followup visits, with a peak value of 2.90 mg/dl 3 days post-procedure.
The results of this Phase III trial demonstrated that iodixanol injected intra-arterially was
well tolerated and provided excellent visualization of visceral and peripheral vessels.
Similar results were obtained and published in later studies, hence this study was not
published (Table 1).