This prospective, randomized, double-blind study was performed to compare the incidence of contrast-induced nephropathy (CIN) after the administration of the iso-osmolar contrast medium iodixanol to the low-osmolar contrast medium iopromide during coronary angiography in patients with impaired renal function. Patients with creatinine clearance (CrCl) <60 ml/min who underwent coronary angiography and/or percutaneous coronary intervention were randomized to receive either iodixanol (n = 215) or iopromide (n = 205). The primary study end point was the incidence of CIN, which was defined as an absolute increase in serum creatinine (SCr) ≥0.5 mg/dl (44.2 mol/L) or a relative increase ≥25% compared to baseline SCr. The secondary end points were the proportion of patients with increases in SCr ≥0.5 mg/dl, the proportion with SCr increases ≥1.0 mg/dl (88.4 mol/L), and the peak increase in SCr. Age, the presence of diabetes mellitus, mean baseline SCr, CrCl, the use of N-acetylcysteine, contrast volume, and the predicted risk score for CIN were similar in the 2 groups. CIN developed in 39 patients (9.3%); there was no significant difference between the iodixanol and iopromide groups (10.7% and 7.8%, respectively; absolute difference 2.9%, 95% confidence interval −3.1% to 8.9%, p = 0.394). The proportions of patients with SCr increases ≥0.5 mg/dl (6.5% vs 6.3%) and ≥1.0 mg/dl (2.8% vs 2.9%) were similar in the 2 groups. There was a tendency for more patients with relative increases ≥25% (10.2% vs 6.8%) and greater peak increases in SCr (0.037 ± 0.375 vs 0.029 ± 0.351 mg/dl) to be in the iodixanol group, but these differences were not statistically significant. In conclusion, the incidences of CIN after coronary angiography did not significantly differ between the iodixanol and iopromide groups in patients with impaired renal function.
In this study, the incidence of contrast-induced nephropathy (CIN), a serious complication of coronary angiography (CAG) and percutaneous coronary intervention, was compared between 2 nonionic contrast media, the iso-osmolar contrast media (IOCM) iodixanol (Visipaque; GE Healthcare, Milwaukee, Wisconsin) (dimer, 320 mg I/ml, 290 mosmol/kg H 2 O) and the low-osmolar contrast media (LOCM) iopromide (Ultravist; Bayer AG, Leverkusen, Germany) (monomer, 300 mg I/ml, 607 mosmol/kg H 2 O) in patients with impaired renal function.
Methods
Consecutive patients scheduled for CAG were screened from February 2009 through May 2010 regardless of percutaneous coronary intervention. Patients aged >19 years with creatinine clearance (CrCl) <60 ml/min were eligible for enrollment. The exclusion criteria were pregnancy, lactation, having received contrast media <7 days before the procedure, emergent CAG in which sufficient preprocedural hydration was unavailable, acute renal failure, end-stage renal disease requiring dialysis, history of hypersensitivity reaction to contrast media, cardiogenic shock, pulmonary edema, and mechanical ventilator support. Use of metformin and nonsteroidal anti-inflammatory drugs or parenteral use of diuretics was discontinued within 48 hours of the procedure.
The patients were randomized by the permuted block randomization method to receive iodixanol or iopromide. Patients and investigators were blinded regarding assignment. CAG was performed according to standard protocols using the radial or femoral approach. Patients received intravenous normal saline at a rate of 1 ml/kg/hour ≥8 hours before and after CAG. The use of N-acetylcysteine was allowed at the attending physician’s discretion. If N-acetylcysteine was to be used, it was given orally at a dose of 1,200 mg twice daily on the day before and the day of administration of the contrast agent (a total of 2 days). The predictive risk score of CIN was assessed on the basis of the patient’s clinical and laboratory findings, as previously proposed. In brief, 8 variables were assigned weighted integers: hypotension (5), intra-aortic balloon pump (5), congestive heart failure (5), age >75 years (4), anemia (3), diabetes (3), volume of contrast (1 for each 100 ml), and glomerular filtration rate (2 for 40 to 60 mg/min/1.73 m 2 , 4 for 20 to 40 mg/min/1.73 m 2 , and 6 for <20 ml/min/1.73 m 2 ); the sum of the integers was the total risk score.
Serum creatinine (SCr) was measured on the day before CAG (day −1) before the start of preprocedural hydration, and CrCl was estimated using the Cockcroft-Gault formula. SCr was also measured on days 1 and 2 after the procedure, and the higher SCr level was used to calculate the change in SCr.
The primary study end point was the development of CIN, which was defined as an absolute increase in SCr ≥0.5 mg/dl (44.2 mol/L) or a relative increase of ≥25% after CAG compared to baseline SCr. The secondary study end points were the proportion of patients with increases in SCr ≥0.5 mg/dl (44.2 mol/L), the proportion with SCr increases ≥1.0 mg/dl (88.4 mol/L), and the peak increase in SCr. In addition, subgroup analysis was performed according to gender, age (<65 vs ≥65 years), the presence of severe renal impairment (defined as baseline CrCl <45 ml/min), diabetes, left ventricular systolic dysfunction (the presence of regional wall motion abnormality or a left ventricular ejection fraction by echocardiography <40%), N-acetylcysteine use, and CIN risk score. In addition, safety outcomes, including periprocedural thromboembolic events (acute stent thrombosis, Q-wave infarction, pulmonary embolism, and ischemic stroke) and 1-month major adverse cardiovascular events (the composite of death, myocardial infarction, revascularization, and cerebral infarction), were reported. The study fully complied with the Declaration of Helsinki and was approved by the institutional review board of Seoul National University Bundang Hospital (Seongnam, Kyeongi-do, South Korea). All patients provided written informed consent.
On the basis of the results of the Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix in Patients With Renal Insufficiency Undergoing Coronary Angiography (RECOVER) study, it was predicted that iodixanol would reduce the frequency of CIN as much as 50% compared to iopromide, assuming CIN incidences of 8% and 17% in the iodixanol and iopromide groups, respectively. This required an estimated sample size of 420 patients (210 in each group) to achieve 80% power and a 2-sided α error of 5%. All data are presented as percentages or as mean ± SD. Comparisons of baseline data were performed using the chi-square test or Fisher’s exact test (categorical variables) and Student’s t -test (continuous variables) as appropriate. Results with 2-sided p values <0.05 were considered statistically significant. Statistical analyses were performed with R version 2.9.2 (R Development Core Team, Vienna, Austria)
Results
Among the 429 patients, 218 received iodixanol and 211 received iopromide ( Figure 1 ). Nine patients were excluded because of inappropriate inclusion or insufficient SCr follow-up; the final group available for analysis included 420 patients, 215 in the iodixanol group and 205 in the iopromide group.
The baseline characteristics of the 2 groups were similar, as listed in Table 1 . CIN developed in 39 patients (9.3%), of whom 23 (10.7%) were in the iodixanol group and 16 (7.8%) in the iopromide group (absolute difference 2.9%, 95% confidence interval −3.1% to 8.9%, p = 0.394; relative risk 1.37, 95% confidence interval 0.66 to 2.82, p = 0.290). The proportion of patients with SCr increases ≥0.5 and 1.0 mg/dl were similar in the 2 groups. There was a tendency for more patients with relative increases ≥25% and greater peak increases in SCr to be in the iodixanol group, but this difference was without statistical significance ( Figure 2 , Table 2 ). No interaction was found in the subgroup analysis performed according to gender, age ≥65 years, CrCl <45 ml/min, diabetes, left ventricular systolic dysfunction, N-acetylcysteine use, and CIN risk score ( Figure 3 ).
| Variable ⁎ | Total | Iodixanol | Iopromide |
|---|---|---|---|
| (n = 420) | (n = 215) | (n = 205) | |
| Baseline characteristics | |||
| Age (years) | 71.5 ± 8.5 | 71.1 ± 8.7 | 71.9 ± 8.2 |
| Women | 194 (46%) | 105 (49%) | 89 (43%) |
| Creatinine (mg/dl) | 1.39 ± 0.62 | 1.37 ± 0.60 | 1.41 ± 0.65 |
| CrCl (ml/min) | 42.1 ± 12.0 | 42.1 ± 11.8 | 42.1 ± 12.2 |
| CrCl <45 ml/min | 226 (54%) | 119 (55%) | 107 (52%) |
| Body mass index (kg/m 2 ) | 23.8 ± 3.1 | 23.7 ± 3.1 | 23.9 ± 3.0 |
| Cholesterol (mg/dl) | 171.4 ± 43.1 | 173.8 ± 42.6 | 168.8 ± 43.6 |
| Glycosylated hemoglobin (%) | 6.85 ± 1.45 | 6.91 ± 1.63 | 6.80 ± 1.29 |
| Uric acid (mg/dl) | 6.51 ± 2.01 | 6.43 ± 2.03 | 6.59 ± 2.00 |
| Hemoglobin (mg/dl) | 12.2 ± 1.8 | 12.2 ± 1.7 | 12.3 ± 1.9 |
| High-sensitivity C-reactive protein (mg/dl) | 1.27 ± 2.91 | 1.10 ± 2.45 | 1.45 ± 3.33 |
| Ejection fraction (%) | 55.4 ± 13.5 | 55.7 ± 12.7 | 55.2 ± 14.3 |
| Left ventricular dysfunction † | 120 (29%) | 62 (29%) | 58 (28%) |
| Diabetes mellitus | 194 (46%) | 94 (44%) | 100 (49%) |
| Hypertension | 321 (76%) | 163 (76%) | 158 (77%) |
| Dyslipidemia | 123 (29%) | 57 (27%) | 66 (32%) |
| Previous percutaneous coronary intervention | 80 (19%) | 41 (19%) | 39 (19%) |
| Previous coronary bypass | 22 (5.2%) | 11 (5.1%) | 11 (5.4%) |
| Previous myocardial infarction | 44 (10.5%) | 21 (9.8%) | 23 (11.2%) |
| Previous heart failure | 21 (5.0%) | 10 (4.7%) | 11 (5.4%) |
| Previous stroke | 43 (10.2%) | 25 (11.6%) | 18 (8.8%) |
| Previous peripheral artery disease | 21 (5.0%) | 10 (4.7%) | 11 (5.4%) |
| Smoking | 199 (47%) | 98 (46%) | 101 (49%) |
| Medications | |||
| Statins | 212 (51%) | 100 (47%) | 112 (55%) |
| β blockers | 172 (41%) | 88 (41%) | 84 (41%) |
| Angiotensin-converting enzyme inhibitors | 123 (29%) | 61 (28%) | 62 (30%) |
| Angiotensin receptor blockers | 124 (30%) | 62 (29%) | 62 (30%) |
| Nitrates | 176 (42%) | 93 (43%) | 83 (41%) |
| Nicorandil | 59 (14%) | 32 (15%) | 27 (13%) |
| Calcium channel blockers | 187 (45%) | 90 (42%) | 97 (47%) |
| N-acetylcysteine | 260 (62%) | 137 (64%) | 123 (60%) |
| Procedural information | |||
| Percutaneous coronary intervention | 189 (45%) | 93 (43%) | 96 (47%) |
| Contrast media volume | 175.6 ± 123.0 | 172.3 ± 119.1 | 179.0 ± 127.2 |
| Contrast media >140 ml | 206 (49%) | 103 (48%) | 103 (50%) |
| Predictive CIN risk score | 10.3 ± 4.5 | 10.2 ± 4.5 | 10.4 ± 4.5 |
| CIN risk score >10 | 185 (44%) | 93 (43%) | 92 (45%) |
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