South Korea. d The affiliation of the author has changed from Seoul National University Hospital to

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1 Prevention of radiocontrast medium induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial a randomized controlled study Sang-Ho Jo, MD, a, b, d Bon-Kwon Koo, MD, a Jin-Shik Park, MD, a Hyun-Jae Kang, MD, a Young-Seok Cho, MD, c Yong-Jin Kim, MD, a Tae-Jin Youn, MD, c Woo-Young Chung, MD, c In-Ho Chae, MD, c Dong-Ju Choi, MD, c Dae-Won Sohn, MD, a Byung-Hee Oh, MD, a Young-Bae Park, MD, a Yun-Shik Choi, MD, a and Hyo-Soo Kim, MD a Seoul and Gyeonggi-do, South Korea Background Contrast media cause oxidative stress, which has been suggested as one possible mechanism responsible for contrast-induced nephropathy. Statins appear to have pleiotropic effects, including antioxidant properties. We investigated to determine whether simvastatin pretreatment reduces the risk of contrast-induced nephropathy in a high-risk population of patients with renal insufficiency undergoing coronary angiography. Methods We conducted a prospective, randomized, double-blind, placebo-controlled, 2-center trial, involving 247 consecutive patients with chronic renal insufficiency (calculated creatinine clearance 60 ml/min and/or serum creatinine 1.1 mg/dl) undergoing coronary angiography. Patients were randomized to simvastatin (n = 124; 160 mg total, 40 mg orally every 12 hours starting the evening before and ending the morning after the procedure) or placebo (n = 123). All patients received pre - and postprocedure hydration. The iso-osmolar contrast agent iodixanol was used for coronary angiography in all patients. Results There was no difference between simvastatin and placebo in mean peak increase in serum creatinine measured within 48 hours after coronary angiography, the primary study end point (0.002 ± vs ± mg/ml respectively, P =.559). The incidence of contrast-induced nephropathy, a secondary end point defined as increase of either 25% or 0.5 mg/dl in serum creatinine, was 2.5% in simvastatin-treated patients (3/118) and 3.4% in placebo-treated patients (4/118), a nonsignificant difference (P = 1.00). There were also no differences between the 2 groups in length of hospital stay or 1- and 6-month clinical outcomes. Conclusions Simvastatin pretreatment for short-term at high dose do not prevent renal function deterioration after administration of contrast medium in patients with baseline renal insufficiency undergoing coronary angiography. (Am Heart J 2008;155:499.e1-499.e8.) Contrast-induced nephropathy (CIN) remains one of the most important clinical complications associated with the intravascular administration of radiocontrast media. Contrast-induced nephropathy is the third leading cause of hospital-acquired acute renal failure, accounting for 12% of all cases. 1 Although the incidence of CIN is relatively low in patients with preserved renal function, patients with underlying renal insufficiency are at higher risk for developing CIN. 2-4 Although CIN is generally From the a Division of Cardiology, Department of Internal Medicine, Seoul National University College of Medicine/Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea, b Division of Cardiology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Gyeonggi-do, South Korea, and c Cardiovascular Center, Seoul National University Bundang Hospital, Gyeonggi-do, South Korea. d The affiliation of the author has changed from Seoul National University Hospital to Hallym University Sacred Heart Hospital since this work was completed. Clinical Trial Registration: Identifier: NCT This study was supported by a grant from the Innovative Research Institute for Cell Therapy, Department of Internal Medicine, Seoul National University/Cardiovascular Center, (A062260) and the Clinical Research Center for Ischemic Heart Disease, Seoul, Republic of Korea, (0412-CR ) sponsored by the Ministry of Health & Welfare, Republic of Korea. Submitted August 22, 2007; accepted November 20, Reprint requests: Hyo-Soo Kim, MD, PhD, Department of Internal Medicine, Seoul National University/Cardiovascular Center, National Research Laboratory for Cardiovascular Stem Cell, Seoul, South Korea. Bon-Kwon Koo, MD, PhD, Department of Internal Medicine, Seoul National University/Cardiovascular Center, National Research Laboratory for Cardiovascular Stem Cell, Seoul, South Korea. hyosoo@snu.ac.kr /$ - see front matter 2008, Mosby, Inc. All rights reserved. doi: /j.ahj

2 499.e2 Jo et al American Heart Journal March 2008 benign, resolving spontaneously in most instances, transient dialysis may be required in high-risk patients, and this is associated with poor clinical outcomes, including inhospital and 2-year mortality rates of 36% and 19%, respectively. 5,6 Given the potential clinical severity of CIN, there has been considerable interest in the development of preventative strategies to reduce the risk of contrastinduced renal deterioration in at-risk populations. Among these measures, pharmacologic prophylactic strategies based on antioxidant properties have received considerable attention in recent years, with studies of N- acetylcysteine (NAC), for example, widely reported, albeit with conflicting findings. 7,8 Although the exact mechanism responsible for the nephroprotective action of NAC reported in some studies remains unclear, it has been suggested that protection is mediated via antioxidant and vasodilatory effects. 8,9 Statins, drugs primarily associated with low-density lipoprotein cholesterol lowering effects, have recently been shown to possess pleiotropic effects that include antioxidant properties. 10,11 In the context of cardiovascular disease, nitric oxide derived oxidant species that promote atherogenesis are suppressed by statins. 12,13 A potential role for statins in CIN prevention is suggested by findings in animal models where statins prevent ischemic nephropathy by stabilizing the endothelium and acting as free radical scavengers. 14,15 More recently, 2 clinical studies have reported positive findings for the effect of statins on CIN prevention in patients undergoing coronary interventions. 16,17 These findings, however, remain tentative because of study limitations that include retrospective designs, heterogeneous patient populations, and significant differences in baseline risk factors between groups being compared. Given the potential roles of oxidative stress and free radical production in the pathophysiology of CIN and the antioxidant pleiotropic effect attributed to statins, we performed a prospective, randomized, placebo-controlled clinical trial, PROMISS, to determine the safety and efficacy of a simvastatin in preventing CIN in patients with renal insufficiency undergoing coronary angiography. Methods Study population The PROMISS trial was conducted in 2 national hospitals in Korea: Seoul National University Hospital, Seoul, Korea, and Seoul National University Bundang Hospital, Gyeonggi-do, Korea. A total of 3080 patients referred for coronary catheterization and/or coronary intervention were screened for eligibility from February 2005 through January Patients aged 19 years with creatinine clearance (CrCl) rates 60 ml/ min (calculated using the Cockcroft-Gault formula) 18 or baseline serum creatinine (SCr) 1.1 mg/dl measured before prehydration before coronary catheterization were considered to be eligible. The following exclusion criteria were used: pregnancy, lactation, prior contrast media administration within 7 days of study entry, emergent coronary angiography, acute renal failure, end-stage renal disease requiring dialysis, history of hypersensitivity reaction to contrast media, cardiogenic shock, pulmonary edema, multiple myeloma, mechanical ventilation, parenteral use of diuretics, use of NAC or ascorbic acid, and use of metformin or nonsteroidal anti-inflammatory drugs within 48 hours of the procedure. Importantly, all patients who were recent statin users (within 30 days before the procedure) were excluded. This study was approved by the institutional review board at our institution. Randomization Eligible patients were randomly assigned to receive simvastatin or placebo. Patients were randomized 1:1 by computergenerated permuted block of 6 patients to ensure balanced assignment of patients to each group. Both patients and investigators were blinded to study group assignment. Randomization codes were provided by the research nurse at Seoul National University Hospital Cardiovascular Center. Study protocol After study candidates were identified based on preliminary laboratory test results, Informed consent was obtained and eligible study patients were randomized. All patients were hydrated with intravenous half-isotonic saline at a rate of 1 mg/kg per hour for 12 hours before and 12 hours after coronary catheterization. Patients randomized to simvastatin received 40 mg every 12 hours for 2 days: twice before coronary angiography, starting the evening before the procedure and twice after coronary angiography, beginning the evening of the day of the procedure. A total of 160 mg of simvastatin was administered in four 40-mg doses. Patients randomized to placebo received control treatment every 12 hours, in parallel with the simvastatin group. Coronary angiography was conducted routinely, via femoral or radial approach. The iso-osmolar, nonionic contrast media iodixanol (Visipaque, 320 mg iodine/ml, GE Healthcare Korea, Seoul, Korea) was used exclusively, based on reported findings from randomized, controlled trials (involving similar populations to those under study here) demonstrating that iodixanol is associated with less nephrotoxicity than the low-osmolar contrast media iohexol and ioxaglate, respectively. 19,20 Serum creatinine was measured in the morning on the day before coronary angiography (day 1) and in the morning on days 1 and 2 after the procedure. Baseline SCr (day 1) was measured before initiating preprocedure hydration. The highest SCr value obtained between days 1 and 2 was used to calculate the change in SCr. Serum creatinine levels were determined in a blinded fashion by laboratory personnel. Analysis was performed using autoanalyzers located in the Department of Laboratory Medicine at Seoul National University Hospital and Seoul National University Bundang Hospital. Creatinine clearance was calculated from SCr values using the Cockcroft-Gault formula. 18 Study end points The measure of primary interest was the mean peak increase in SCr within 48 hours after administration of contrast agent. The peak increase is the maximum difference of SCr between baseline and within 48 hours after contrast administration.

3 American Heart Journal Volume 155, Number 3 Jo et al 499.e3 Figure 1 Progress of patients throughout the trial. A flow diagram is included to illustrate the number of patients originally referred, screened for eligibility, selected and randomized, and those finally included in the primary analysis. The secondary end point was the incidence of CIN, defined as a relative increase in baseline SCr of 25% and/or an absolute increase of 0.5 mg/dl ( 44.2 μmol/l) within 48 hours after contrast administration. In addition, subgroup analyses were performed according to the presence of severe renal impairment (defined as baseline CrCl b30 ml/min), concomitant diabetes, the use of 140 ml contrast media, reduced left ventricular systolic function (ejection fraction by echocardiography 40%), and advanced age ( 75 years). Length of hospital stay and a composite clinical outcome of death, myocardial infarction, revascularization, dialysis, and cerebral infarction occurring during hospitalization and 1- and 6-month posthospitalization were also analyzed. The periprocedural changes of serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and C-reactive protein (CRP) level were also analyzed in both groups. Statistical analysis The sample size was calculated assuming a maximum SCr differences (between baseline and within 48 hours after angiography) of 0.36 and 1.1 mg/dl in the statin and placebo groups, respectively, 16 resulting in a 0.74-mg/dL difference

4 499.e4 Jo et al American Heart Journal March 2008 Table I. Baseline patients characteristics Characteristic Simvastatin (n = 124) Placebo (n = 123) P Age (y) 65.0 ± ± Sex (male/female) 91/33 88/ Weight (kg) 64.9 ± ± BMI (kg/m 2 ) 24.5 ± ± LVEF (%) 56.0 ± ± Diabetes mellitus (n [%]) 35 (28.2) 29 (23.6).468 Hypertension (n [%]) 84 (67.7) 72 (58.5).148 Dyslipidemia (n [%]) 22 (17.7) 21 (17.1) 1.00 Current smoker (n [%]) 13 (10.5) 22 (17.9).104 SCr Baseline SCr, mg/dl ± ± mg/dL (n [%]) 28 (22.6) 16 (13.0).067 Baseline CrCl (ml/min) ± ± Total cholesterol ± ± LDL cholesterol ± ± CRP (mg/l) ± ± Medications (n [% of patients]) ACEI or ARB 42 (33.9) 53 (44.1).151 Nitrate 54 (43.5) 41 (33.3).117 Calcium-channel blocker 23 (18.5) 23 (18.7) 1.00 β-blocker 59 (47.6) 46 (37.4).123 Statin 0 (0) 0 (0) 1.00 PCI performed (n [%]) 38 (30.6) 33 (26.8).574 Contrast media administration Contrast agent dose (ml) ± ± Dose 140 ml (% [n/n ]) 54.4 (62/114) 61.8 (68/110).281 ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; PCI, percutaneous coronary intervention. Values are mean ± SD. To convert values for serum creatinine to micromoles per liter, multiply by To convert values for CrCl to milliliter per second, multiply by The sum of the n's (n = 224) does not equal the total number of patients (N = 247) in the intention-to-treat analysis because contrast media dose was not recorded for 23 patients. between the 2 treatments. Based on this assumption, the estimated standardized effect size was calculated as 0.37 (assuming an SD of 2 for the placebo group), with a study population of 98 patients per group providing a 2-sided significance level of 5% and 80% power. A sample size of 123 patients per group was planned, taking into account the likelihood of incomplete data collection, protocol violations, and patients lost at follow-up (estimated 20%, total). Baseline demographic and procedure-related characteristics were analyzed from the intention-to-treat population. Laboratory data, including follow-up SCr measurements, were analyzed from the per-protocol population. Continuous variables were expressed as means and SD, whereas categorical variables were expressed as absolute number and proportion of patients in a given category. Data were compared using the χ 2 test or Fisher exact test (categorical variables) and the Student t test (continuous variables). P values of b.05 were considered statistically significant. All statistical analyses were performed using SPSS software version 13.0 (SPSS, Inc, Chicago, IL). Results Patient population and baseline characteristics Between February 2005 and January 2006, a total of 3080 consecutive patients were screened. Among them, Table II. Changes in baseline SCr after administration of contrast agent SCr Simvastatin (n = 118) Placebo (n = 118) P Baseline ± ± Follow-up ± ± Absolute change ± ± To convert values for creatinine to micromoles per liter, multiply by patients with a basal CrCl 60 ml/min and/or a SCr 1.1 mg/dl were considered eligible for participation. Eight patients declined participation, 2 were excluded because of chronic dialysis, and 233 were excluded because they were on statin medication. Thus, 247 patients were randomized, 124 to receive simvastatin and 123 to receive placebo, and included in the intention-to-treat analyses (Figure 1). After exclusions in each group because of incomplete laboratory test results, 118 simvastatin-treated patients and 118 patients receiving placebo were included in the per-protocol analyses for follow-up SCr measurements (Figure 1). Baseline demographics and clinical characteristics were similar between the 2 groups, with no significant differences observed (Table I). Primary end point peak increase in SCr For patients receiving simvastatin, mean SCr increased from 1.286±0.418 mg/dl at baseline to a maximum of 1.288±0.445 mg/dl within 2 days of the contrast procedure; this change was not significant (P =.911). For patients receiving placebo, corresponding mean SCr levels were ± and ± mg/dl, respectively, with no difference between baseline and peak values (P =.426) (Table II). The maximum changes in SCr were not significantly different when the simvastatin and placebo groups were compared (0.002 ± vs ± mg/dl respectively, P =.559) (Table II and Figure 2). Secondary end point incidence of CIN Three patients in the simvastatin group (3/118, 2.5%) and 4 patients in the placebo group (4/118, 3.4%) had a baseline SCr increase of 25% or 0.5 mg/dl ( 44.2 μmol/l) within 2 days of contrast administration. There was no difference in CIN incidence between the 2 groups (P = 1.0, Fisher exact test) (Figure 3). Subgroup analyses A post hoc subgroup analysis of patients according to the presence of severe renal impairment (baseline CrCl b30 ml/min), concomitant diabetes, administration of a high dose of contrast media ( 140 ml), lower left ventricular ejection fraction ( 40%) in

5 American Heart Journal Volume 155, Number 3 Jo et al 499.e5 Figure 2 Changes in baseline SCr after contrast administration in coronary angiography: all patients. Baseline and postprocedural (within 48 hours after contrast administration) SCr values are shown for each of the patients in the simvastatin (n = 118) and placebo (n = 118) study arms, respectively. See Table II for additional details. echocardiography, and advanced age ( 75 years) demonstrated no differences in baseline SCr, absolute peak increases in SCr, or CIN incidence when simvastatinand placebo-treated groups were compared (Table III). Inhospital, 1-month, and 6-month clinical outcomes and length of hospital stay There was no difference between simvastatin and placebo in the inhospital and 1-month posthospital discharge clinical composite outcome of death, myocardial infarction, revascularization, cerebral infarction, and dialysis after contrast administration (simvastatin, 0/124, 0%, vs placebo, 1/123, 0.8%; P =.498, Fisher exact test). Only one patient, in the placebo group, required hemodialysis for renal failure 3 days after coronary angiography. There was also no difference between the 2 groups in the composite outcome at 6-month clinical follow-up (simvastatin, 3/124, 2.4%, vs placebo, 5/123, 4.1%; P =.500, Fisher exact test) or in length of hospital stay (simvastatin, 4.5 days, vs placebo, 5.1 days; P =.390). Changes in serum total cholesterol, LDL cholesterol, and CRP Postprocedural changes in total cholesterol, LDL cholesterol, and CRP levels were analyzed in those patients for whom baseline and follow-up measurements were available (75%-84% of all patients in each group, depending on the analyte) (Table IV). There was a significant decrease in mean total cholesterol and LDL cholesterol in the patients who received a total dose of 160 mg simvastatin over 2 days. In contrast, for patients who received placebo, there was no change in the mean level of either total cholesterol or LDL cholesterol. Mean CRP levels increased significantly 2 days postprocedure compared to baseline, in both the simvastatin and placebo groups (Table IV). Discussion Contrast-induced nephropathy prevention by antioxidants Oxidative stress is considered an important mechanism in the development of CIN, based on evidence indicating a role for reactive oxygen species in contrast-mediated renal injury. 6,7 The antioxidant NAC has been investigated extensively as an agent for CIN prevention. Representative findings have demonstrated an increased benefit of NAC added to prophylactic hydration alone 7 and, more recently, greater efficacy with increased NAC dosing (1200 vs 600 mg, twice daily), 21 consistent with the suggestion that the antioxidant effects of NAC are dose-dependent. 22 Ascorbic acid, another antioxidant, is easily available, well tolerated, and inexpensive. In one randomized, placebo-controlled, double-blind trial evaluating the use of ascorbic acid for CIN prevention in 231 patients undergoing coronary angiography, a 62% risk reduction was observed, in favor of ascorbic acid. 23 Statins for CIN prevention Two clinical studies have evaluated the potential utility of statins in CIN prevention. In one study, a retrospective case-control database review of 1002 patients with renal insufficiency (baseline SCr 1.5 mg/ dl) undergoing coronary angiography, the risk of CIN was reduced in statin-naive patients who were administered simvastatin or atorvastatin just 24 to 72 hours (43 hours, average) before cardiac catheterization; 63%

6 499.e6 Jo et al American Heart Journal March 2008 Figure 3 Table III. Subgroup analysis of differences between simvastatin and placebo in baseline SCr changes and CIN incidence Subgroups Simvastatin Placebo P Incidence of CIN. The secondary end point, the incidence of CIN defined as a 25% or 0.5 mg/dl increase in baseline SCr within 48 hours of contrast administration, is illustrated for the simvastatin and placebo study arms. of patients received only 2 doses of statin. Contrastinduced nephropathy (defined as a 50% increase in SCr) occurred in 17.2% of the 250 patients receiving statins and in 22.3% of the 758 patients in the control group (P =.028). 16 In the second study, based on percutaneous coronary intervention registry data for patients, those patients who were on statin therapy before their procedure had a lower incidence of both CIN and nephropathy requiring dialysis compared with patients who were not taking statins. The incidence of CIN (defined as a baseline SCr increase of 0.5 mg/dl) was 4.37% in the statin group versus 5.93% in controls (P b.001); the incidence of nephropathy requiring dialysis was 0.32% in the statin group and 0.49% in controls (P =.03). 17 Although these findings suggest that statin use initiated before PCI may reduce the risk of CIN, the results of this large registry study remain tentative because of lack of randomization and, therefore, the presence of significant heterogeneity with respect to baseline, clinical, and procedural risk factors for CIN (eg, myocardial infarction, cardiogenic shock, emergent PCI, cardiac arrest rates, LVEF) between the 2 groups being compared based on statin use alone. First prospective study on CIN and statin The findings described in this report based on a prospective randomized, double-blind, case-controlled, 2-center trial strongly argue against a role for statins, as represented by short-term simvastatin administration, in CIN prevention. Simvastatin failed to reduce peak increases in SCr or lower the incidence of CIN CrCl b30 ml/min (n) 8 5 Baseline SCr (0.955) (0.914).666 Peak increase SCr (0.293) (0.926).226 CIN (n [%]) 0 (0) 1 (20).385 CrCl 30 ml/min (n) Baseline SCr (0.194) (0.153).400 Peak increase SCr 0.001(0.153) (0.122).887 CIN (n [%]) 3 (2.7) 3 (2.7) 1.00 Diabetes (n) Baseline SCr (0.666) (0.474).670 Peak increase SCr (0.205) (0.434).994 CIN (n [%]) 2 (6.3) 3 (11.1).652 Nondiabetes (n) Baseline SCr (0.261) (0.320).659 Peak increase SCr (0.143) (0.119).222 CIN (n [%]) 1 (1.2) 1 (1.1) 1.0 Dose of CM 140 ml (n) Baseline SCr (0.428) (0.430).891 Peak increase SCr (0.146) (0.286).348 CIN (n [%]) 1 (1.7) 4 (6.0).369 Dose of CM b140 ml (n) Baseline SCr (0.436) (0.277).317 Peak increase SCr (0.192) (0.128).721 CIN (n [%]) 2 (4.1) 0 (0.0).498 LVEF 40% (n) Baseline SCr (0.242) (0.144).280 Peak increase SCr (0.132) (0.181).719 CIN (n [%]) 0 (0) 2 (18.2).476 LVEF N40% (n) Baseline SCr (0.458) (0.410).464 Peak increase SCr (0.174) (0.250).411 CIN (n [%]) 3 (3.3) 2 (2.2) 1.00 Age 75 y (n) Baseline SCr (0.430) (0.229).290 Peak increase SCr (0.181) (0.177) 1.0 CIN (n [%]) 1 (6.3) 1 (6.3) 1.0 Age b75 y (n) Baseline SCr (0.417) (0.382).675 Peak increase SCr (0.162) (0.238).537 CIN (n [%]) 2 (2.0) 3 (2.9).068 CM, Contrast media. SCr values in milligrams per deciliter are reported as mean (SD). To convert values for creatinine to micromoles per liter, multiply by Calculated by Fisher exact test. The sum of the patients in these 4 groups (n = 217) did not equal the total number of patients included in the per-protocol analysis (n = 236) because the contrast media dose was not measured for 19 patients. The sum of the patients in these 4 groups (n = 203) did not equal the total number of patients included in the per-protocol analysis (n = 236) because 33 patients did not undergo echocardiography.

7 American Heart Journal Volume 155, Number 3 Jo et al 499.e7 Table IV. Changes in total cholesterol, LDL, and CRP 2 days after contrast agent administration Total cholesterol (mg/dl) LDL (mg/dl) CRP (mg/l) Baseline Follow-up P Simvastatin ± ± b.001 (n = 92) Placebo (n = 96) ± ± Simvastatin ± ± b.001 (n = 88) Placebo ± ± (n = 93) Simvastatin 0.56 ± ± 1.25 b.001 (n = 90) Placebo 0.54 ± ± 1.79 b.001 (n = 99) Follow-up data for total cholesterol, LDL, and CRP measurements were not available for all patients. Only patients with both baseline and follow-up data were included in these analyses. compared to placebo in the renally compromised study population overall, as well as in subgroups at even higher risk because of significantly decreased kidney function, concomitant diabetes, decreased LVEF, advanced age, or use of a large dose of contrast agent during coronary angiography. Consistent with simvastatin's primary role as a cholesterol-lowering agent, significant reductions in mean total cholesterol and LDL cholesterol were observed with the high-dose short-term protocol for simvastatin administration used in this study. Although statins have also been reported to lead to reduction in CRP levels, within 24 hours in one recent study, 24 this was not observed here. Rather, the significant increase in baseline CRP levels 2 days postprocedure in both the simvastatin and placebo groups suggests an acutephase response prompted by some aspect of the angiographic intervention. Our decision to use simvastatin in a short-term protocol similar to those used in other studies investigating antioxidants for CIN prophylaxis 7,23 was guided by several lines of evidence. First, simvastatin is one of the most potent statins in terms of antioxidant effects. 25 Second, the antioxidant activity of statins, as reflected in improved vascular endothelial function, for example, has been shown to occur rapidly and in the absence of significant cholesterol reduction, within 24 hours of initiating statin therapy. 26 In our study, all patients received the nonionic isoosmolar contrast agent iodixanol, which has been shown in a number of reports, 19,20 including a recent individual patient data meta-analysis, 27 to reduce CIN incidence in high-risk populations such as the one studied here. Consistent with the low incidences of CIN associated with iodixanol use in previous reports, the incidence of CIN in the placebo arm of this trial was 3.4%. As far as we are aware, the PROMISS trial is the first prospective, randomized, double-blind, controlled study to evaluate the use of a statin for CIN prevention. Although one of the recognized pleiotropic effects of statin involves antioxidant activity, which could counteract mechanisms implicated in the pathophysiology of CIN, our findings indicate that simvastatin is unable to lower the basic risk of contrast-associated renal deterioration in patients with underlying renal insufficiency undergoing coronary angiography. Limitations This study has some limitations. One of the 2 criteria for the enrollment of patients in this study (baseline SCr 1.1 mg/dl) may include patient with normal or only mildly impaired renal function. This may explain the lower incidence of CIN in our study than that of previous retrospective study. 16 However, we consider all the patients in our study were at risk for developing CIN, reflecting a previous study that reported the steeply increasing CIN probability in the cutoff level of SCr of 1.1 to 1.2 mg/dl. 28 Second, the concerns that the duration of simvastatin use may be a too short to exert its antioxidant effect for preventing CIN may be raised. However, as stated before, the antioxidant property of statin may exert its effect within 24 hours, 26 and studies that investigated the efficacy of antioxidants (NAC, 7,21 ascorbic acid 23 ) for preventing CIN also use the methods of short-term use of those drugs. Moreover, the one retrospective trial evaluating the efficacy of statin used the similar protocol of short period of statin use as our study. 16 Third, in this study, the patients were followed for only 48 hours. Some publications have stated that SCr peaked at 3 days after administration of the contrast medium and returned to normal within 10 days after. 29 Therefore, this study may have missed the peak SCr levels of the enrolled patents. But, most patients who experience the CIN usually have their creatinine increased within 24 hours after contrast administration, 30 hence the missing patients may not be so much. Although the PROMISS trial has attained meaningful results in evaluating the simvastatin treatment effect in CIN prevention, we consider that this trial is underpowered and may be inconclusive in much higher-risk patient groups with more severely impaired renal function at baseline. Therefore, future trials need to be conducted in much larger patients group at high risk. Conclusions In contrast to reported retrospective studies, findings from this prospective, randomized, double-blind, placebo-controlled trial do not support a role for simvastatins as prophylactic agents in the prevention of CIN. The use of simvastatin solely for this purpose is

8 499.e8 Jo et al American Heart Journal March 2008 not recommended for patients with renal insufficiency undergoing contrast-enhanced procedures. We thank Joo-Yong Hahn, MD, Hae-Young Lee, MD, Jung-Won Suh, MD, Yong-Seok Kim, MD, Jae-Jin Kwak, MD, Seok-Jae Hwang, MD, Sook-Jin Lee, MD, Jung-Ju Sir, MD, and Hack-Lyoung Kim, MD, for their assistance in conducting this study and in data collection. References 1. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39: Morcos SK, Thomsen HS, Webb JA. Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol 1999;9: Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105: Gruberg L, Mintz GS, Mehran R, et al. 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