1. Contrast Induced Nephropathy: Predictors, Prevention, and Management Columbia University Medical Center Cardiovascular Research Foundation Roxana Mehran, MD

2. Disclosures: Research Grant to CRF: Tyco, Guerbert Consultant/ Advisory Board: FlowMedica

3. Cardiorenal Risk CardiacDiseaseRenalDisease Acute Renal Failure and Death in the Cardiac Patient Myocardial Infarction, Heart Failure, Arrhythmias, and Cardiac Death in the Renal Patient

4. How to Assess Renal Function? Abbreviated Modification of Diet in Renal Disease equations (MDRD) equation: eGFR, ml/min/1.73 m 2 = 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-0.203x (0.742 if female) x (1.210 if African American) (140- age) x Body Weight [kg]* Creatinine Clearance, ml/min = * Multiple by 0.8 in female Cockcroft-Gault equation: Serum Creatinine mg/dL] x 72

5. Predictors of All-Cause Mortality to 7 Years BARI Trial + Registry Szczech L. et al., Circulation 2002; 105:2253-8. RR 95% CI P CKD (baseline Cr > 1.5 mg/dl) 2.311.63-3.28<0.001 Sex, female vs. male 0.910.75-1.100.32 Race, black vs. non-black 1.401.04-1.890.028 Age, y 1.051.04-1.06<0.001 Diabetes mellitus Oral hypoglycemics Oral hypoglycemics1.631.29-2.06<0.001 Insulin Insulin1.801.26-2.58<0.001 PTCS vs. CABG 1.040.87-1.250.67 Interaction between PTCA and insulin-treated diabetics 1.731.11-2.690.02 Smoking history Prior tobacco use Prior tobacco use1.301.06-1.590.01 Tobacco use at baseline Tobacco use at baseline1.821.42-2.33<0.001

6. Risk Factors for CIN Patient-related Risk Factors Renal insufficiency Renal insufficiency Diabetes mellitus with renal insufficiency Diabetes mellitus with renal insufficiency Age Age Volume depletion Volume depletion Hypotension Hypotension Low cardiac output Low cardiac output Class IV CHF Class IV CHF Other nephrotoxins Other nephrotoxins Renal transplant Renal transplant Hypoalbuminemia (<35 g/l) Hypoalbuminemia (<35 g/l) Procedure-related Risk Factors Multiple contrast media injection within 72 hrs Multiple contrast media injection within 72 hrs Intra-arterial injection site Intra-arterial injection site High volume of contrast media High volume of contrast media High osmolality of contrast media High osmolality of contrast media

7. Risk Score Risk of CIN Risk of Dialysis ≤ 5 7.5%0.04% 6 to 10 14.0%0.12% 11 to 16 26.1%1.09% ≥ 16 57.3%12.6% Mehran et al. JACC 2004;44:1393-1399. Hypotension IABP CHF Age >75 years Anemia Diabetes Contrast media volume Risk Factors 5 5 5 4 3 3 Integer Score 1 for each 100 cc 3 Scheme to Define CIN Risk Score Serum creatinine > 1.5mg/dl 4 eGFR <60ml/min/1.73 m 2 2 for 40 – 60 4 for 20 – 40 6 for < 20 eGFR < 60ml/min/1.73 m 2 = 186 x (SCr) -1.154 x (Age) -0.203 X (0.742 if female) x (1.210 if African American) Calculate OR

8. Prognostic significance of the proposed risk score for CIN extended to prediction of 1-year mortality. (Red bars = development dataset; blue bars = validation dataset.) CIN Risk Score & 1-year Mortality Risk Groups: Risk Score: ≤56 to 1011 to 15≥16 Mehran et al. JACC 2004;44:1393-1399.

9. Preventive Trials

10. Hydration

11. Optimal Hydration Regimen Mueller et al Arch Intern Med 2002 1937 Patients Screened 317 Ineligible or No Consent 685 for Primary End Point Analysis 698 for Primary End Point Analysis 1620 Randomized 809 Received 0.9% Saline 124 Excluded From Primary End Point Analysis Repeat Catheterization (n=78) Incomplete Data (n=46) 811 Received 0.45% Sodium Chloride 113 Excluded From Primary End Point Analysis Repeat Catheterization (n=59) Incomplete Data (n=53) Bypass Grafting (n=1)

12. Optimal Hydration 0.9% NS vs 0.45% NS P=.35 0 1 2 3 CNMortalityVascular Incidence, % 0.9% Saline 0.45% Sodium Chloride P=.93 P=.04 Mueller et al Arch Intern Med 2002

13. Prevention of CIN with Sodium Bicarbonate Merten GJ et al. JAMA, 2004;291:2328-2334 Patients With Baseline Serum Creatinine >1.8 mg/dl who Underwent Contrast Exposure (Iopamidol in All) N=137 Sodium Chloride Hydration (154 mEq/L of Sodium Chloride) N=68 Sodium Bicarbonate Hydration (154 mEq/L of Sodium Bicarbonate) N=69 Primary endpoint: increase in serum creatinine ≥25% within 2 days post-exposure

14. Prevention of CIN with Sodium Bicarbonate: Results EndpointsSodiumChlorideN=59 Sodium Bicarbonate N=60 P value Incidence of CIN (%) 13.6%1.7%0.02 Incidence of CIN (↑SCr 0.5 mg/dL) 11.9%1.7%0.03 Merten GJ et al. JAMA, 2004;291:2328-2334

15. REMEDIAL Trial Saline + NAC N=118 Bicarbonate + NAC N=117 Saline+AA+NAC N=116 7 excluded Pts with eGFR<40 N=393 Pts with eGFR<40 N=393 Randomized N=351 Randomized N=351 Excluded N=42 Excluded N=42 NAC = N-acetylcysteine, AA = ascorbic acid 9 excluded 107 included into analysis 108 included into analysis 111 included into analysis Briguorio C. et al, Circulation 2007

16. REMEDIAL Trial: Results Saline + NAC Bicarbonate + NAC Saline + Ascorbic Acid + NAC P Value N=111N=108N=107 Serum creatinine increase by ≥25% 11 (9.9%)2 (1.9%)*10 (10.3%)0.010 Serum creatinine increase by ≥0.5 mg/dL 12 (10.8%)1 (0.9%)†12 (11.2%)0.026 eGFR decrease by ≥25% 10 (9.2%)1 (0.9%)†10 (10.3%)0.018 P=0.019P<0.01 *P=0.019, †P<0.01 vs. saline + NAC group Briguorio C. et al, Circulation 2007

17. MEENA Design DESIGN: Prospective, randomized, parallel-group, single-center clinical evaluation of two hydration strategies for patients undergoing coronary angiography OBJECTIVE: To compare the incidence of CIN between periprocedural hydration with sodium bicarbonate vs. sodium chloride (0.9%, normal saline) PRIMARY ENDPOINT: Decrease in estimated GFR by ≥ 25% within 4 days of coronary angiography DESIGN: Prospective, randomized, parallel-group, single-center clinical evaluation of two hydration strategies for patients undergoing coronary angiography OBJECTIVE: To compare the incidence of CIN between periprocedural hydration with sodium bicarbonate vs. sodium chloride (0.9%, normal saline) PRIMARY ENDPOINT: Decrease in estimated GFR by ≥ 25% within 4 days of coronary angiography 353 patients enrolled between January 2006 and January 2007 236 patients assigned to sodium chloride 178 patients assigned to sodium bicarbonate 156 evaluable patient Brar, S et. al., i2/ACC 2007 147 evaluable patient 22 excluded 28 excluded Hydration Protocol 3 mL/kg for 1 hr before the procedure 1.5 mL/kg during and for 4hrs post- procedure Hydration Protocol 3 mL/kg for 1 hr before the procedure 1.5 mL/kg during and for 4hrs post- procedure

18. MEENA p = 0.97 p = 0.82

19. Sodium Bicarbonate StudyN (Saline, Bicarb) Procedure Baseline Function (mL/min/ 1.73m2) Fluid protocol CIN rate (%) p RANDOMIZED RANDOMIZED Brar353 (175, 178) Cardiac4848SalineBicarbonate13.613.50.97 Briguori219 (108, 111) Cardiac Peripheral 3235SalineBicarbonate9.91.90.02 Merten119 (59, 60) Cardiac Peripheral 4541SalineBicarbonate13.71.70.02 Masuda*59 (29, 30) Emergency cardiac 3940SalineBicarbonate3570.01 NON-RANDOMIZED NON-RANDOMIZED CARE414 (246, 168) Cardiac5050Bicarbonate(-NAC)Bicarbonate(+NAC)10.611.9NS

20. N-ACETYLCYSTEINE (NAC)

21. CIN: Effect of n-Acetylcysteine Prospective, randomized Prospective, randomized 83 high risk patients 83 high risk patients  CrCl < 50 ml/min  Diabetes 33% IV CONTRAST for CT (75 ml of Low Osmolar CM) IV CONTRAST for CT (75 ml of Low Osmolar CM) n-AC 600 bid x 2 days pre- n-AC 600 bid x 2 days pre- CIN definition: creatinine increase of 0.5 mg/dl CIN definition: creatinine increase of 0.5 mg/dl Hydration with 0.45% @ 1 ml/kg/h x 24 h Hydration with 0.45% @ 1 ml/kg/h x 24 h Tepel NEJM 2000 p= 0.01

22. N- acetylcysteine (NAC) and Contrast-induced Nephropathy: a Meta-analysis of 13 Randomized Placebo Controlled Trials Zagler et al. Am Heart J 2006;151:140-145. 1892 pts. undergoing coronary angiography 1892 pts. undergoing coronary angiography All hydrated w/ IV fluids and low-osm nonionic CM All hydrated w/ IV fluids and low-osm nonionic CM impaired renal function (> 1.2 mg/dL) impaired renal function (> 1.2 mg/dL) treated with NAC oral or intravenously treated with NAC oral or intravenously CIN defined as increase in creatinine ≥0.5 mg/dL or ≥25% from baseline to 48 hrs. CIN defined as increase in creatinine ≥0.5 mg/dL or ≥25% from baseline to 48 hrs. 4 of 13 trials reported statistically significant reduction in CIN after NAC 4 of 13 trials reported statistically significant reduction in CIN after NAC overall nonsignificant 32% reduction in the risk for CIN after overall nonsignificant 32% reduction in the risk for CIN after NAC (combined RR 0.68, 95% CI 0.46-1.01) NAC (combined RR 0.68, 95% CI 0.46-1.01)

23. Zagler et al. Am Heart J 2006;151:140-145. Relative Risk for Developing CIN after NAC Risk Ratio (Random) 95% Cl 0.1110 Favors treatment Favors control 0.20.525 RR (Random) 95% Cl Control n/N NAC n/N Study or substury Review: Acetylcysteine and CIN Comparison: 01 NAC on CIN Outcome: 01 CIN Total events: 124 (NAC), 162 (Control) Test for heterogenety: Ch=27.54 (P0.005), 1 2 =56.4% Test for overall effect: Z=1.88 (P=0.05) Allaqaband et al8/456/401.19 (0.45, 3.12) Briguori et al 6/9210/910.59 (0.23, 1.57) Diaz-Sandoval et al 2/2513/290.18 (0.04, 0.72) Durham et al10/389/411.20 (0.55, 2.63) Goldenberg et al 4/413/391.27 (0.30, 5.31) Gomes et al 8/788/781.00 (0.40, 2.53) Kay et al4/10212/980.32 (0.11, 0.96) Nguyen-Ho et al9/9519/850.42 (0.20, 0.89) Oldemeyer 4/493/471.28 (0.30, 5.41) Pate et al57/23850/2391.14 (0.82, 1.60) RAPIDO 2/418/39 0.24 (0.05, 1.05) Shyu 2/6015/610.14 (0.03, 0.57) Fung et al8/466/451.30 (0.49, 3.46) Total: (95% Cl)9509320.68 (0.46, 1.02)

24. Meta-analysis: High vs. Low Osm Contrast Media 39 Trials - 5146 patients 39 Trials - 5146 patients CIN > 0.5 mg/dl CIN > 0.5 mg/dl CIN in 7% of all patients CIN in 7% of all patients CIN in 30% of CRI patients CIN in 30% of CRI patients For CRI, NNT=8 (treat 8 to prevent 1 CIN case) For CRI, NNT=8 (treat 8 to prevent 1 CIN case) Low osmolal group included Ioxaglate (Hexabrix); Iodixanol (Visipaque) not studied Low osmolal group included Ioxaglate (Hexabrix); Iodixanol (Visipaque) not studied Barrett and Carlisle J Am Soc Nephrol 92;

25. The NEPHRIC Study Nephrotoxicity in High-risk Patients a Double Blind Randomized Multicentre Study of Iso-osmolar and Low-osmolar Non-ionic Contrast Media

26. NEPHRIC Study: Protocol Randomized, double blind, prospective, multicenter Randomized, double blind, prospective, multicenter Primary endpoint: peak increase in serum creatinine concentration @ 3 days after angiography Primary endpoint: peak increase in serum creatinine concentration @ 3 days after angiography Patients with diabetes and serum creatinine 1.5-3.5 mg/dl who underwent coronary or aortofemoral angiography Iso-osmolar, non-ionic Iodixanol [Visipaque] N=64 Mean Contrast Volume = 163 ml PTCA – 17% Low-osmolar, non-ionic Iohexol [Omnipaque] N=65 Mean Contrast Volume = 162 ml PTCA – 25% Aspelin P et al, NEJM, 2003; 348: 491-499

27. Primary Endpoint – Peak Increase in Scr from Baseline to Day 3 (µmol/l) p=0.002 Iodixanol Iodixanol (Visipaque) Iohexol Iohexol (Omnipaque) n=62n=64 Mean 11.2 ±19.7 41.5 ± 68.6 Minimum - 19.0 - 21.0 Max74.0331.0

28. RECOVER Trial – Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix in Patients With Renal Insufficiency Undergoing Coronary Angiography Jo et al. JACC 2006; 48:924-30 Prospective, randomized trial 300 patients with CrCl ≤ 60 ml/min 149 pts. (135 pts. included in primary analysis) ioxaglate 151 pts. (140 pts. included in primary analysis) iodixanol Primary endpoint – Incidence of CIN Increase in SCr ≥ 25% or ≥ 0.5 mg/dl

29. RECOVER Trial – Incidence of CIN Jo et al. JACC 2006; 48:924-30 P=0.021 N=300

30. ICON Trial Patients with chronic renal insufficiency undergoing PCI with at least 150cc of contrast volume Patients with chronic renal insufficiency undergoing PCI with at least 150cc of contrast volume IoxaglateN=74IoxaglateN=74IodixanolN=71IodixanolN=71 N=130 P=0.26 Incidence of CIN Mehran R. et al, Transcatheter Cardiovascular Therapeutics. 2006.

31. Renal Failure in Patients Undergoing Coronary Procedures using Iso-osmolar or Low-osmolar Contrast Media Liss et al. Kidney International 2006 Contrast media (CM) CM properties N Time period Iodixanol iso-osmolar, nonionic, 45 485 2000-2003 Ioxaglate low-osmolar, nonionic, 12 440 2000-2003 Swedish Coronary Angiography and Angioplasty Registry Swedish Hospital Discharge Registry

32. Rehospitalization with Renal Failure as a Primary Diagnosis Liss et al. Kidney International 2006 P<0.001P<0.001 P<0.001P<0.001 P=0.022P=0.022

33. Start of Dialysis after Coronary Angiography or PCI Liss et al. Kidney International 2006 P=0.098P=0.098 P=0.010P=0.010 P=0.009P=0.009

34. 1-year Follow-up Liss et al. Kidney International 2006 * Groups differ in time period !CM N of pts iodixanol 54 616 ioxaglate 24 479 * iohexol 6 854 6 854 Renal failure Iodixanol Iohexol Ioxaglate f Time (years) % 6 5 4 3 2 1 0 0123456789101112

35. CARE Design DESIGN: Prospective, randomized, double-blind, parallel-group, multi-center clinical evaluation ipamidol-370 and iodixanol-320 OBJECTIVE: To compare the incidence of CIN between iopamidol-370 and iodixanol-320 PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration DESIGN: Prospective, randomized, double-blind, parallel-group, multi-center clinical evaluation ipamidol-370 and iodixanol-320 OBJECTIVE: To compare the incidence of CIN between iopamidol-370 and iodixanol-320 PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration 482 patients enrolled between July 2005 and June 2006 in 25 clinical site in North America 14 patients withdrew consent 468 assigned to a treatment arm 236 patients assigned to Iodixanol-320 230 patients assigned to Iopamidol-370 204 evaluable patient Solomon, RJ et. al., Circulation 115, 3189 (2007) 210 evaluable patient 26 excluded

36. CARE p = 0.39 p = 0.44 p = 0.15

37. CARE p = 0.11 p = 0.37 p = 0.20 Diabetic Subgroup

38. Conclusions (1) CRI is one of the most important independent predictors of poor outcome post PCI CRI is one of the most important independent predictors of poor outcome post PCI CIN remains a frequent source of acute renal failure and is associated with increased morbidity and mortality, and higher resource utilization CIN remains a frequent source of acute renal failure and is associated with increased morbidity and mortality, and higher resource utilization Several factors predispose patients to CIN Several factors predispose patients to CIN Preventive measures pre procedure, as well as careful post procedure management should be routine in all patients Preventive measures pre procedure, as well as careful post procedure management should be routine in all patients

39. Conclusions (2) Conclusions (2) Hydration pre-PCI (12 hours recommended) Hydration pre-PCI (12 hours recommended) D/C nephrotoxic drugs (NSAIDS, antibiotics, etc) D/C nephrotoxic drugs (NSAIDS, antibiotics, etc) Role of n-acetylcysteine is disputable Role of n-acetylcysteine is disputable No Role for IV Fenoldopam No Role for IV Fenoldopam Sodium bicarbonate may be useful, but need more definitive data Sodium bicarbonate may be useful, but need more definitive data Limit contrast agent volume Limit contrast agent volume Low-osmolar agents are better than high-osmolar Low-osmolar agents are better than high-osmolar  Within non-ionic contrast, the data are contradictory Role of local drug delivery for prevention of CIN requires further investigation Role of local drug delivery for prevention of CIN requires further investigation Role of Cooling Therapy is being examined: COOL CIN Study Role of Cooling Therapy is being examined: COOL CIN Study