Although statins have been shown to prevent contrast-induced acute kidney injury in patients with acute coronary syndromes, the benefit of statins is not known for patients at high risk for nephropathy who undergo elective coronary angiography. Two hundred twenty consecutive statin-naive patients with chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m 2 ) who underwent elective coronary or peripheral angiography were randomly assigned to receive rosuvastatin (40 mg on admission, followed by 20 mg/day; n = 110) or no statin treatment (control group, n = 110). Contrast-induced acute kidney injury was defined by an absolute increase in serum creatinine of ≥0.5 mg/dl or a relative increase of ≥25% measured 48 or 72 hours after the procedure. Contrast-induced acute kidney injury occurred in 15 patients (7.2%), 9 (8.5%) in the control group and 6 (5.8%) in the rosuvastatin group (p = 0.44). The incidences of adverse cardiovascular and renal events (death, dialysis, myocardial infarction, stroke, or persistent renal damage) were similar between the two groups at follow-up. In conclusion, rosuvastatin did not reduce the risk for contrast-induced acute kidney injury or other clinically relevant outcomes in at-risk patients who underwent coronary and peripheral vascular angiography.
Although statins have been shown to prevent contrast-induced acute kidney injury (CI-AKI) in patients with acute coronary syndrome, the benefit of statins is not known for patients at high risk for nephropathy who undergo elective coronary angiography. The aim of this study was to establish the efficacy of short-term, high-dose rosuvastatin in decreasing the incidence of CI-AKI in patients at high-risk for nephropathy who undergo elective coronary angiography.
Methods
Consecutive patients who underwent clinically driven, nonemergent coronary angiography or peripheral angiography in our institution were eligible for study inclusion if their estimated glomerular filtration rate (eGFRs) were <60 ml/min/1.73 m 2 from a sample drawn the day before the planned procedure. The eGFR was calculated by applying the Levey-modified Modification of Diet in Renal Disease (MDRD) formula: (186.3 × serum creatinine [mg/dl] −1.154 ) × (age [years] −0.203 ) × (0.742 if female). Data were obtained at baseline, on the day of the angiography, between 48 and 72 hours after angiography, and at 1-year follow-up.
From May 2012 to November 2013, 2,542 patients naive to statins and scheduled for elective coronary angiography were considered eligible for the study. Patients with high-risk features warranting emergency coronary angiography, acute renal failure or end-stage renal failure requiring dialysis, eGFRs <30 and ≥60 ml/min/1.73 m 2 , histories of congestive heart failure or coronary artery disease, severe coronary occlusion to be treated by coronary artery bypass graft surgery or percutaneous coronary intervention (PCI) after coronary angiography, allergy to contrast media, contrast media administration within the previous 14 days, current statin treatment, contraindications to statin treatment, severe co-morbidities, or pregnancy and those who refused to provide consent were excluded from the study.
The day before the procedure, all patients were randomly assigned to the rosuvastatin or no-rosuvastatin (control group) arm. Randomization was performed in a 1:1 ratio with computer-generated random numbers.
There were 275 patients (9.2%) with eGFRs <60 ml/min/1.73 m 2 . Of those, 20 patients were receiving current statin treatment or had contraindications to statins, 10 had previous contrast administration or allergy to contrast media, 20 had eGFRs <30 ml/min/1.73 m 2 , and 5 refused to provide consent. Those patients were excluded from the study. Thus, 220 patients were enrolled in the study. We randomly assigned 110 patients to the rosuvastatin treatment arm and 110 to the control arm ( Figure 1 ). Written informed consent for the procedure was obtained from all patients, and the study protocol was approved by the local ethics committee.
Patients randomized to the rosuvastatin arm were given 40 mg of rosuvastatin <24 hours before coronary angiography and then received 20 mg/day for 2 days. The control group did not receive statin treatment. All patients received intravenous hydration with isotonic saline (1 ml/kg/h, 0.9% sodium chloride) for 12 hours before and 24 hours after contrast exposure, according to guideline recommendations. All diuretics and nonsteroidal anti-inflammatory drugs were routinely discontinued 24 hours before the procedure. Coronary angiography was performed by the femoral approach. A nonionic, low-osmolality contrast agent (Optiray [ioversol]; Tyco Healthcare, Pointe Claire, Quebec, Canada) was used in all patients.
The CI-AKI risk score was calculated using the validated score as specified by Mehran et al according to the following parameters: hypotension (5 points), intra-aortic balloon pump use (5 points), congestive heart failure (5 points), age >75 years (4 points), anemia (3 points), diabetes mellitus (3 points), serum creatinine >1.5 mg/dl (4 points), and amount of contrast volume used (1 for each 100 cm 3 ). Serum creatinine, blood urea nitrogen, cystatin C, sodium, and potassium were measured 1 day before the procedure, between 48 and 72 hours after angiography, and at 6-month and 1-year follow-up. For those patients who developed CI-AKI, we repeated the measurements at 5 and 10 days after the procedure and asked for a nephrology consult, if necessary.
While the primary end point of the study was the incidence of CI-AKI (defined by an increase in serum creatinine of ≥0.5 mg/dl or an absolute increase of ≥25% from baseline <48 or 72 hours after contrast exposure), the secondary end point was a composite outcome measure of death, nonfatal myocardial infarction, ischemic cerebrovascular accidents, and a decrease in eGFR of ≥25% or renal failure requiring dialysis at 12 months.
Assuming a 21% incidence of CI-AKI in the control group, a sample size of 210 (105 per treatment group) patients would be required to detect a 70% relative reduction in the incidence of CI-AKI by rosuvastatin with 80% power and the conventional 2-sided type 1 error of 5%. Data are reported as mean ± SD for continuous variables. Student’s t and nonparametric Mann-Whitney U tests were used to determine differences between values for normally and abnormally distributed variables, respectively. Categorical variables were reported as percentages and were analyzed either by the chi-square test or by Fisher’s exact test, as appropriate. Odds ratios and 95% confidence intervals assessing the risk for the primary end point according to potential confounding variables were assessed by logistic regression. Differences in survival curves between the groups were assessed using the log-rank test. A p value <0.05 (2 tailed) was considered statistically significant.
Results
Of the original 220 patients enrolled in our study, 208 (103 in the rosuvastatin group and 105 in the control group) completed the study ( Figure 1 ). Clinical and biochemical characteristics were well matched between the 2 groups ( Tables 1 and 2 ), including mean age, gender distribution, risk factors, and clinical presentations, and there were no significant differences between groups in preprocedural laboratory results and medications used before the procedure. For 65 of the included patients (35.3%), the volume of contrast administered was >140 ml, and the mean contrast volume was significantly different between the groups. The contrast volume administered to the rosuvastatin group was significantly higher than in the control group (139.2 ± 77.42 vs 117.71 ± 56.87 ml, respectively, p = 0.02). The rosuvastatin group also had higher contrast nephropathy risk scores than did the control group (9.32 ± 3.89 vs 7.67 ± 3.40, respectively, p <0.001). Logistic regression analysis was performed to evaluate the efficacy of statin treatment on CI-AKI, adjusting for various potential prognostic and confounding factors (gender, age, diabetes, hypertension, low-density lipoprotein cholesterol level, creatinine clearance at baseline, contrast volume, and CI-AKI risk score).
| Variable | Control group (n:105) | Rosuvastatin group (n:103) | P value |
|---|---|---|---|
| Age (years) | 67.7±8.9 | 67.5±8.9 | 0.87 |
| Men | 76(73.4%) | 66(64%) | 0.23 |
| Diabetes mellitus | 50(47.6%) | 53(51.4%) | 0.53 |
| Systemic hypertension | 92(87.6%) | 91(88.3%) | 0.72 |
| Total cholesterol (>200 mg/dl) | 37(35.2%) | 42(40.7%) | 0.37 |
| Active smoking | 27(25.7%) | 31(30%) | 0.45 |
| Heart failure | 9(8.6%) | 12(11.6%) | 0.44 |
| Previous myocardial infarction | 18(17.1%) | 12(11.6%) | 0.27 |
| Previous coronary intervention | 5(4.8%) | 6(5.8%) | 0.73 |
| Previous coronary bypass | 6(5.7%) | 4(3.8%) | 0.81 |
| Preprocedural medications | |||
| Angiotensin-converting enzyme inhibitors | 45(42.9%) | 55(53.3%) | 0.11 |
| Calcium channel blockers | 20(19%) | 17(16.5%) | 0.67 |
| Diuretics | 39(37.5%) | 34(33%) | 0.56 |
| Acetylsalicylic acid | 76(73.3%) | 66(64%) | 0.23 |
| Variable | Control group (n:105) | Rosuvastatin group (n:103) | P value |
|---|---|---|---|
| Baseline Creatinine (mg/ dL) | 1.4±0.5 | 1.3±0.4 | 0.10 |
| Baseline eGFR(ml/min/m 2 ) | 51.3±15.8 | 52.8±14 | 0.48 |
| Serum cystatin C (mg/dL) | 1.2±0.3 | 1.2±0.5 | 0.71 |
| Contrast (mL) | 117.7±56.8 | 139.2±77.4 | 0.02 |
| 48 h Creatinine (mg dL/dl) | 1.5±0.4 | 1.4±0.3 | 0.42 |
| 48 h eGFR(ml/min/m 2 ) | 47.6±10.0 | 47.3±8.7 | 0.80 |
| 24h Serum cystatin C (mg/dL) | 1.2±0 .3 | 1.2±0.4 | 0.93 |
| 1 y Creatinine (mg/ dL) | 1.4±0.5 | 1.3±0.4 | 0.20 |
| 1 y eGFR(ml/min/m 2 ) | 49.7±15.8 | 55.4±15.3 | 0.11 |
| Contrast nephropathy risk score ∗ (mean ± SD) | 7.7± 3.4 | 9.3± 3.9 | <0.001 |
| CI-AKI | 9(8.6%) | 6(5.8%) | 0.44 |
However, contrast volume and nephropathy risk score were not predictive of CI-AKI in performing logistic regression analysis of the study.
The primary end point (CI-AKI) occurred in 15 of the 208 patients (7.2%), which included 9 patients (8.5%) in the control group and 6 patients (5.8%) in the rosuvastatin group (p = 0.44).
For patients in the control group who experienced CI-AKI, the creatinine values returned to baseline levels in 3 patients by the fifth day and in 5 patients by the 10th day; it remained higher than baseline levels in 1 patient after 10 days. For those who experienced CI-AKI in the rosuvastatin group, creatinine levels returned to baseline for 3 patients by the fifth day and for 3 patients by the 10th day. A nephrology/hemodialysis consult was requested for the 1 patient who presented with higher creatinine levels than baseline on the 10th day, and it was determined that no dialysis was needed.
One-year clinical follow-up was completed for 200 of the 208 patients (96%). The incidence of the composite outcome of death, nonfatal myocardial infarction, ischemic cerebrovascular accidents, and a decrease in eGFR of ≥25% or renal failure requiring dialysis, as well as the incidence of the individual components of this composite outcome, was not statistically different between the rosuvastatin and control groups (20% in the rosuvastatin group vs 26% in the control group, p = 0.28) ( Table 3 , Figure 2 ).
| Outcomes | Rosuvastatin group | Control group | Relative Risk (95% CI) | P value |
|---|---|---|---|---|
| Primary end point, No. of events/total Contrast-induced acute kidney injury | 6/103 | 9/105 | 0.71 (0.25 -2.0) | 0.52 |
| Secondary end point, No. of events/total | 21/100 | 28/100 | 1.38(0.78-2.4) | 0.25 |
| eGFR baseline (ml/min/m 2 ) | 52.8±13.4 | 51.3±15.8 | 1.0(0.96-1.04) | 0.86 |
| Contrast nephropathy risk score ∗ | 9.3± 3.9 | 7.7± 3.4 | 1.0(0.91-1.11) | 0.90 |
| Contrast volume (ml) | 139.2±77.4 | 117.7±56.9 | 0.99(0.99-1.0) | 0.99 |
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