1. CARE Cardiac Angiography in REnally impaired patients: A comparison between Iodixanol (Visipaque) and Iopamidol (Isovue) in high risk patients for contrast induced nephropathy

2. CARE 1. Largest prospective randomized comparison trial of low- osmolar vs iso-osmolar CM. 2. High risk patients 1. eGFR <60 ml/min 2. Cardiac catheterization 3. Complimentary preventative strategies 1. Volume expansion with bicarbonate (all centers) 2. Double dose NAC (some centers) 4. Rigorous statistical approach 1. Multiple definitions of CIN 2. Prospective randomized double blind design 3. Single laboratory performing serum creatinine analysis 4. Analysis by time post CM of follow-up serum creatinine 5. Prospectively defined subgroups – diabetes, NAC

3. CARE Inclusion criteria Inclusion criteria Age >18 years Age >18 years Documented eGFR >20 and 20 and <60 ml/min/1.73m 2 from a SCr obtained w/i 72 h of enrollment Scheduled for cardiac angiography Scheduled for cardiac angiography Willing to receive periprocedure prophylaxis per protocol Willing to receive periprocedure prophylaxis per protocol IV sodium bicarbonate IV sodium bicarbonate NAC (by center) NAC (by center) Exclusion criteria Pregnant or lactating female Hx of sensitivity to I-dye NYHA IV CHF Hyperthroidism Unstable renal function or on dialysis Contrast dye w/i 7 days prior to 72 h post Loop diuretics w/i 24 h pre or post CM administration Receiving NSAIDs, aminoglycosides, or other renally toxic medications Planned used of adenosine or dipyridamole during angiography 25 Centers in North America

4. CARE-Clinical and Procedural Characteristics of Study Patients Characteristic Iopamidol (204) Iodixanol (210) P value Age (yr) 72.9 ± 9.0 70.5 ± 9.9 0.04 Gender M/F (%) 68/3260/400.15 Weight (kg) 82.7 ±17.7 86.7 ± 20.6 0.03 SCr t (mg/dl) 1.46 ± 0.36 1.44 ± 0.41 0.64 eGFR* ( ml/min/1.73m 2 ) 49.3 ±11.6 50.2 ±13.0 0.45 Diabetes (%) 38.243.80.27 PCI (%) 39.739.00.92 Volume of CM (ml) 133.7 ±74.4 136.4 ±71.6 0.70 Time of post CM SCr (h) 45-71 hours (%) 45-71 hours (%) 72-96 hours (%) 72-96 hours (%) >96 hours (%) >96 hours (%)83.3%13.2%3.5%83.3%13.8%2.9%0.94 t SCr at baseline * By abbreviated MDRD formula

5. Results: Total Group n=414 Definition of CIN Iopamidol(n=204)Iodixanol(n=210) 95% CI of difference (Iop-Iod) P-value ≥0.5 mg/dl  SCr 4.4%6.7% -6.7, 2.1 0.39 ≥25%  SCr 9.8%12.4% -8.6, 3.5 0.44 ≥ 25%  eGFR 5.9%10.0% -9.3, 1.1 0.15

6. Results: Diabetes SubGroup n=170 Definition of CIN Iopamidol(n=78)Iodixanol(n=92) 95% CI of difference (Iop – Iod) P-value ≥0.5 mg/dl  SCr 5.1%13.0% -16.4, 0.5 0.39 ≥25%  SCr 10.3%15.2% -14.9, 5.0 0.44 ≥ 25%  eGFR 6.4%13.0% -15.4, 2.1 0.15

7. Results: PCI n=163 Definition of CIN Iopamidol(81)Iodixanol(82) P value ≥ 0.5 mg/dl  SCr 2.5%7.3%0.28 ≥ 25%  SCr 4.9%14.6%0.06 ≥ 25%  eGFR 1.2%12.2%0.01

8. Results: NAC n=168 Definition of CIN Iopamidol(79)Iodixanol(89) P value ≥ 0.5 mg/dl  SCr 1.3%6.7%0.12 ≥ 25%  SCr 11.4%12.4%1.0 ≥ 25%  eGFR 5.1%9.0%0.38

9. Results Mean change in peak SCr GroupIopamidolIodixanol P value Total (n=414) 0.07 ± 0.22 0.12 ± 0.23 0.03 Diabetes (n=170) 0.07 ± 0.26 0.16 ± 0.27 0.01 NAC (n=168) 0.05 ± 0.20 0.10 ± 0.22 0.19

10. CARE Conclusion There was no difference in the incidence of CIN between iopamidol (low osmolar CM) and iodixanol (iso-osmolar CM). There was no difference in the incidence of CIN between iopamidol (low osmolar CM) and iodixanol (iso-osmolar CM). No difference in total group with CKD No difference in total group with CKD No difference in those with both diabetes and CKD No difference in those with both diabetes and CKD No difference in those who underwent PCI No difference in those who underwent PCI No difference in those who received NAC No difference in those who received NAC

11. CARE Conclusion Iopamidol was associated with a significantly smaller mean increase in serum creatinine compared to iodixanol. Iopamidol was associated with a significantly smaller mean increase in serum creatinine compared to iodixanol. For total group For total group For those with diabetes For those with diabetes

12. CARE-Implications Osmolality alone is not the sole determinant of CIN. Osmolality alone is not the sole determinant of CIN. Iopamidol osmolality is 796 Iopamidol osmolality is 796 Iodixanol osmolality is 290 Iodixanol osmolality is 290 Prior studies suggesting less CIN with iso-osmolal CM may be the result of comparisons: Prior studies suggesting less CIN with iso-osmolal CM may be the result of comparisons: CM agents having different renal toxicity. CM agents having different renal toxicity. NEPHRIC: comparator=iohexol NEPHRIC: comparator=iohexol RECOVER: comparator=ioxaglate RECOVER: comparator=ioxaglate Different patient populations Different patient populations Different definitions of renal insufficiency and CIN. Different definitions of renal insufficiency and CIN.

13. CARE – Comparison with other prospective randomized trials Low osmolal (osmolality)Iso-osmolal(osmolality)Condition Statistical result Iohexol (844) Iodixanol (290) Coronary, CKD (SCr* 3.1), 35% DM No difference 1 Iohexol (844) Iodixanol (290) Coronary, CKD (SCr 1.5), 100% DM Iodixanol superior to iohexol 2 Ioversol (792) Iodixanol (290) Coronary, CKD (SCr 2.0), 52% DM No difference 3 Iopamidol (796) Iodixanol (290) MDCT, CKD (SCr 1.6) No difference 4 Iopamidol (796) Iodixanol (290) Coronary, CKD (SCr 1.45), 41% DM No difference 5 Ioxaglate (600) Iodixanol (290) Coronary, CKD (SCr 1.34, 48% DM Iodixanol superior to ioxaglate 6 1 Chalmer and Jackson, BJR 1999 4 Barrett et al (IMPACT), Invest Rad 2006 2 Aspelin et al (NEPHRIC), NEJM 2003 5 Solomon et al (CARE), TCT 2006 3 Rudnick et al, (VALOR), ASN 2005 6 Jo et al (RECOVER), JACC 2006 *SCr: serum creatinine (mg/dl)

14. Acknowledgements CARE was sponsored by Bracco Diagnostics, Inc CARE was sponsored by Bracco Diagnostics, Inc CARE investigators: CARE investigators: R. Applegate – Winston Salem, NC B. Barrett - St. Johns, NL J.B. Cavender – Birmingham, AL S. Doucet – Montreal, QC J. Ducas – Winnipeg, MT J.T. Eagan – Birmingham, AL T. Fischell – Kalamazoo, MI J. Gelormini – Buffalo, NY R. Katholi – Springfield, IL R. Kipperman – Oklahoma City, OK M. Labinaz – Ottawa, ON J.R. Laird – Washington, DC E. Mahmud – San Diego, CA R.G. McKay – Hartford, CT A.E. Moreyra – New Brunswick, NJ M. K. Natarajan – Hamilton, ON K. Niazi – Atlanta, GA J.S. Reiner – Washington, DC E. Rivera – Amarillo, TX S.K. Sharma – New York, NY R.J. Solomon – Burlington, VT C.S. Staniloae – New York, NY M.E. Stillabower – Newark, DE C. Walker – Houma, LA I.R. Weinstein – Orlando, FL