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Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary Angioplasty Focus on Comparative Effects of Contrast Media.

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Presentation on theme: "Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary Angioplasty Focus on Comparative Effects of Contrast Media."— Presentation transcript:

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2 Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary Angioplasty Focus on Comparative Effects of Contrast Media on Thrombosis Mitigation, Mortality, and Renal Function Evolving Science New Mechanisms Optimal Management Steven V. Manoukian, MD, FACC Program Chairman Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Medical Director, Cardiovascular Services | Clinical Services Group | Hospital Corporation of America (HCA) | Nashville, TN

3 Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program

4 Welcome and Program Overview Commercial Support: This program is sponsored by an independent educational grant from Guerbet, LLC

5 Program Educational Objectives As a result of this session, participants will be able to: Discuss the role that cardiovascular contrast media (CM) can play in thrombosis mitigation and renal preservation in the setting of PCI Discuss the role that cardiovascular contrast media (CM) can play in thrombosis mitigation and renal preservation in the setting of PCI Detail the physical, chemical, and biological propertiesionicity, molecular structure, and viscosityof contrast agents used in PCI and their potential impact on renal function, thrombosis, and patient safety Detail the physical, chemical, and biological propertiesionicity, molecular structure, and viscosityof contrast agents used in PCI and their potential impact on renal function, thrombosis, and patient safety Apply landmark trials, registry data, and observational studies to optimize selection of CM in patients undergoing PCI Apply landmark trials, registry data, and observational studies to optimize selection of CM in patients undergoing PCI Identify high-risk patients that may be appropriate candidates for specific CM shown to decrease risk of thrombotic events and/or renal dysfunction Identify high-risk patients that may be appropriate candidates for specific CM shown to decrease risk of thrombotic events and/or renal dysfunction Explain how ionic properties, viscosity, and other chemical features may affect renal function and coagulation in the setting of PCI Explain how ionic properties, viscosity, and other chemical features may affect renal function and coagulation in the setting of PCI

6 Program Faculty Steven V. Manoukian, MD, FACC Program Chairman Director, Cardiovascular Research Sarah Cannon Research Institute Centennial Heart Cardiovascular Consultants Consultants Medical Director Cardiovascular Services Clinical Services Group Hospital Corporation of America (HCA) Nashville, TN Frederick Feit, MD Associate Professor Department of Medicine Division of Cardiology New York University School of Medicine Member, NYU Cardiac Catheterization Associates Associates New York, NY USA Roxana Mehran, MD Director of Outcomes Research, Data Coordination and Analysis Center for Interventional Vascular Therapy New York-Presbyterian Hospital Columbia University Medical Center Associate Professor of Medicine Associate Professor of Medicine Division of Cardiology Columbia University College of Physicians and Surgeons Director of the Clinical Research, Data Coordination and Analysis Center at the Cardiovascular Research Foundation New York City, NY USA

7 Faculty COI Financial Disclosures Steven V. Manoukian, MD, FACC Consultant, Educational Grant, Research Support, and/or Employment: BMS, Guerbet LLC, sanofi-aventis, The Medicines Company Frederick Feit, MD Consultant: CV Therapeutics, The Medicines Company Shareholder: Eli Lilly, Johnson and Johnson, The Medicines Company Roxana Mehran, MD Clinical Research Support: sanofi-aventis, Bracco Educational Support: The Medicines Company, Boston Scientific, Abbott, Medtronic, and Cordis Consultant/Honoraria: TMC, BSC, Abbott, Medtronic, sanofi-aventis, Lilly/Diachi Sankyo, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, Regado

8 Contrast Induced Acute Kidney Injury Roxana Mehran, MD, FACC, FAHA, FSCAI, FESC Associate Professor of Medicine Columbia University Medical Center Joint Chief Scientific Officer Cardiovascular Research Foundation

9 How to Assess Renal Function? Abbreviated Modification of Diet in Renal Disease equations (MDRD) equation: (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 eGFR, ml/min/1.73 m 2 = 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-0.203) x (0.742 if female) x (1.210 if African American)

10 Major Causes of Acute Kidney Injury In Cardiac Patients 1)Contrast Induced Nephropathy (CIN) 2)AKI after Cardiopulmonary Bypass Procedures

11 Definition New onset or exacerbation of renal dysfunction after contrast administration in the absence of other causes: New onset or exacerbation of renal dysfunction after contrast administration in the absence of other causes: increase by > 25% or absolute of > 0.5 mg/dL Contrast-Induced AKI from baseline serum creatinine Occurs 24 to 48 hrs post–contrast exposure, with creatinine peaking 5 to 7 days later and normalizing within 7 to 10 days in most cases

12 275 consecutive patients undergoing PCI given the contrast agent ioxilan Jabara R, et al. Am J Cardiol. 2009;Epub ahead of print. Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in PCI Definitions Rise in SCr 0.5 mg/dl (n = 9) Decrease in eGFR 25% (n = 21) Rise in SCr 25% (n = 28) Composite of all 3 Definitions (n = 29) CIN3.3%7.6%* 10.2% # 10.5% 10.5% Conclusion: The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition. *P=0.37 vs. rise in SCr 0.5 mg/dl # P=0.02 vs. rise in SCr 0.5 mg/dl P=0.001 vs. rise in SCr 0.5 mg/dl P=0.001 vs. rise in SCr 0.5 mg/dl There were no deaths or cases requiring dialysis. Major and minor bleeding rates were 1.5% and 1.8%.

13 Risk Factors for the Development of Contrast-Induced AKI Fixed (non-modifiable) risk factors Modifiable risk factors Pre-existing renal failure Volume and type of contrast medium Diabetes mellitus Multiple contrast injections within 72 hours Advanced congestive heart failure Hemodynamic instability Reduced left ventricular ejection fraction Dehydration Acute myocardial infarction Anemia Cardiogenic shock Intra-aortic balloon pump Renal transplant Low serum albumin level (<35 g/L) Angiotensin converting enzyme inhibitors Diuretics Nephrotoxic drugs (nonsteroidal anti- inflammatory agents, antibiotics, cyclosporine, etc.)

14 Risk Score Risk of CIN Risk of Dialysis 57.5%0.04% 6 to 10 14.0%0.12% 11 to 16 26.1%1.09% 16 1657.3%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

15 Prognostic Impact of CKD and Contrast Induced AKI

16 Contrast-induced AKI: In-hospital Mortality % In-hospital Death P<0.001 McCullough et al. Am J Med 1997; 103-375

17 Contrast-Induced Nephropathy: Resource Utilization Endpoint (%) Patients P-value With CIN Without CIN Hospital length of stay (days) 9.6+7.2 3.2+6.4 <0.001 ICU length of stay (days) 2.3+4.4 0.6+1.8 <0.0001 Need for hemodialysis (%) 120<0.0001 Iakovou I et al, J Am Coll Cardiol. 2002;39:2A

18 Preventive Trials

19 Strategies Prevention of Contrast Induced Nephropathy

20 Solomon R et al, N Engl J Med 1994;331(21):1416-1420 A total of 78 patients with mean baseline SCR 2.1 mg/dl who underwent coronary angiography/PCI N=78 0.45% saline alone 12 hours before and 12 hours after angiography N=28 Saline plus mannitol * N=25 Primary endpoint: increase in the baseline SCr of at least 0.5 mg/dl within 48 hours after the injection of radiocontrast agents Furosemide* N=25 * Given before angiography Randomization Effects of Saline, Mannitol, and Furosemide

21 Effects of Saline, Mannitol, and Furosemide to Prevent Acute Decreases in Renal Function Induced by Radiocontrast Agents Solomon R et al, N Engl J Med 1994;331:1416-1420 P=0.02 for Saline vs. Furosemide group P=NS for Mannitol vs. Furosemide group

22 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)

23 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

24 Periprocedural Hydration Protocol In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with preserved LVEF: IV 0.9% NS at 1cc/kg/hr 12 hours prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with preserved LVEF: IV 0.9% NS at 1cc/kg/hr 12 hours prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients w/o baseline CRI and mild to moderate LV dysfunction: (LVEF 30% to 40%): IV 0.45%NS at 50 cc/hour 12 hrs prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients w/o baseline CRI and mild to moderate LV dysfunction: (LVEF 30% to 40%): IV 0.45%NS at 50 cc/hour 12 hrs prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients with baseline CRI and normal LVEF: IV 0.9% NS at 1 cc/kg/hour for 12 hours pre- and post- procedure In patients with baseline CRI and normal LVEF: IV 0.9% NS at 1 cc/kg/hour for 12 hours pre- and post- procedure In patients with baseline CRI and reduced LVEF: IV 0.45% NS at cc/cc replacement (urine output should be match to maintain euvolemic state) for 12 hours pre- and post-procedure In patients with baseline CRI and reduced LVEF: IV 0.45% NS at cc/cc replacement (urine output should be match to maintain euvolemic state) for 12 hours pre- and post-procedure Consider 2 main factors: Baseline CRI (Yes/No) LVEF (Preserved/Impaired)

25 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

26 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

27 REMEDIAL Trial Saline + NAC N=118 Bicarbonate + NAC N=117 Saline+AA+NAC N=116 7 excluded Pts with eGFR<40 N=393 Randomized N=351 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

28 REMEDIAL Trial: Results Saline + NAC N=111 Bicarbonate + NAC N=108 Saline + Ascorbic Acid + NAC N=107 P Value 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=0.019, P<0.01 vs. saline + NAC group Briguorio C. et al, Circulation 2007

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

30 MEENA p = 0.97 p = 0.82

31 Meta-Analysis Sodium Bicarbonate for the Prevention of CIN Brar et al. cJASN 2009

32 Meta-Analysis Study Flow 469 Citations Identified 168 from EMBASE 261 from MEDLINE 40 from Cochrane Library 8 Citations identified from conference proceedings 424 Citations excluded based on screening of titles or abstracts 53 identified for further review 14 articles included in meta-analysis (N=2,290) Brar et al. cJASN 2009 38 Citations excluded after full review 36 Design was not correct 1 Unusual protocol 1 Difference between groups in volume administered & NAC dose Dates: 1996 to 2008 Randomized Trials Number of Patents: 2,290

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34 Brar et al. cJASN 2009 Change in Renal Function Published Randomized Trials Harm Benefit No effect Creatinine Sodium Bicarbonate (mg/dL) Creatinine Sodium Bicarbonate (mg/dL) Creatinine Sodium Chloride (mg/dL) Creatinine Sodium Chloride (mg/dL) Brar Maioli Adolph Masuda Ozcan Merten Briguori -0.2 -0.1 0.0 0.1 0.2 0.20.10.0-0.1\-0.2 Improvement with Bicarb Deterioration with Chloride

35 Meta-Regression Understanding Sources of Heterogeneity Trial Size Smaller trials show greater benefit Small Study Effect Summary: Positive effect only observed in small trials 12.6% vs. 10.7% P=0.32 13.5% vs. 6.7% P=0.03 Large Trials N=2290 N=2290 RR 95% CI 0.850.62-1.17 0.500.27-0.93 Merten Criteria N=290 Small Trials Brar et al. cJASN 2009

36 Forest Plot High Quality Studies Brigouri, 20070.19 (0.04, 0.82) Chen, 20070.13 (0.02, 1.02) Kim, 20070.98 (0.42, 2.28) Ozcan, 20070.33 (0.11, 0.99) Shaikh, 20070.75 (0.39, 1.44) Brar, 20080.91 (0.56, 1.46) Maioli, 20080.87 (0.52, 1.44) Adolph, 20081.56 (0.27, 9.08) Overall 0.71 (0.49, 1.03) (I-squared =33.3%, p=0.163) Note: weights are from random effects analysis 0.1 1 10 FavorsBicarbonate FavorsSaline Quality Criteria Similar volumeSimilar volume PatientsPatients If NAC used, dose & route similar between groupsIf NAC used, dose & route similar between groups No early terminationNo early termination Summary: No overall benefit, but trend driven by studies with extreme treatment effects

37 The CONTRAST Trial Algorithm Primary endpoint Worsening renal insufficiency within 12-96 hours Fenoldopam Matching placebo Randomize Hydrate 1º prior to and 12 º after cath 300 patients at increased risk for contrast nephropathy undergoing PCI

38 CONTRAST STUDY: CIN SCr at both baseline and during the 96° post drug administration period were available and analyzed at the central lab in 283 of 315 randomized patients (90%). P=0.84 P=0.61 OR [95% CI] = 1.11 [0.79, 1.57] P=0.27 Stone GW, et al. JAMA-2003

39 CONTRAST: 30-Day Adverse Events 30-day incidence of death, MI or dialysis: With CIN12.2% With CIN12.2% Without CIN4.1% Without CIN4.1% P=NS for all p=0.02 Stone GW, et al. JAMA-2003

40 Targeted Renal Delivery

41 FEN-001 Trial Design Patients undergoing elective angiography Patients undergoing elective angiography Moderate CKD defined as CrCl 70 ml/min ( 80 ml/min if diabetic) Moderate CKD defined as CrCl 70 ml/min ( 80 ml/min if diabetic) Anticipated CM volume 80 cc Anticipated CM volume 80 cc Teirstein et al, Am J Cardiol 2006. N=33 IV Placebo (no drugs/no device) 2:1 Randomization IV FEN 0.1 -> 0.2 mcg/kg/min IR FEN 0.2 mcg/kg/min Index angiography +/- interventional procedure (+ contrast) IR = intra-renal IV = intravenous FEN = fenoldopam Washout x 1 hr

42 Glomerular Filtration Rate Teirstein et al, Am J Cardiol 2006. 5-fold GFR TRT vs IV Sustained GFR for 2+ hrs post d/c All data based on a Fenoldopam dose of 0.2 mcg/kg/min GFR Response to IV-FEN and TRT-FEN vs. Control 4.9% 23.6% 25.1% -9.7% 9.6% -14.0% -20% -10% 0% 10% 20% 30% 123 Study Period6 Percent Change in GFR from Baseline [%] IV FEN (n=22) TRT-FEN (n=22) Control Group (n=11) Pre-procedure (IV-FEN vs. Control) Procedure (TRT-FEN vs. Control) Post-Procedure (Active vs. Control) p=0.0007 p<0.05 p=NS

43 Be-RITe! Registry: Higher Dose More Effective (TRT-Fenoldopam patients only) Predicted values per Mehran et al, JACC 2004. CIN Incidence Stratified by TRT Dose 30.3% 3.7% 28.3% 27.7% 0% 10% 20% 30% 40% 50% 0.2 mcg/kg/min 0.4 mcg/kg/min CIN Incidence or Predicted Incidence [%] CIN IncidencePredicted n=33n=242 p=0.79 p<0.0001

44 Renal Protective Effects and the Prevention of Contrast- InducedcNephropathy by Atrial Natriuretic Peptide Both ANP(0.042 µg/kg/min) and Hydration (1.3 ml/kg/h of Ringer) infusions were initiated 4 to 6 h before the angiographic and continued for 48 h after 14 pts excluded 261 pts Randomized 126 pts ANP plus hydration 128 pts hydration Morikawa et al. J Am Coll Cardiol 2009;53:1040–6

45 Incidence on CIN in the ANP Group Compared with the Control Group P=0.015 P= 0.042 P=0.023 Incidence of CIN (%) Creatinine Creatinine >0.5 mg/dl Creatinine Creatinine >25% of baseline Creatinine Creatinine >0.5 mg/dl or >25% of baseline Morikawa et al. J Am Coll Cardiol 2009;53:1040–6

46 N-Acetylcysteine (NAC)

47 CIN: Effect of n-Acetylcysteine Prospective, randomized Prospective, randomized 83 high risk patients 83 high risk patients CrCl < 50 ml/min CrCl < 50 ml/min Diabetes 33% 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

48 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 substudy 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)

49 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

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

51 Effect of Nonionic Radiocontrast Agents on Occurrence of CIN in Patients with Mild-moderate CRI: Pooled Analysis of the Randomized Trials Significantly highest incidence of CIN with iohexol then two other agents Significantly highest incidence of CIN with iohexol then two other agents Difference between iopamidol and iodixanol was not statistically significant ( P=0.227 ) Difference between iopamidol and iodixanol was not statistically significant ( P=0.227 ) Incidence of CIN P value Iopamidol (Isovue) Low osmolar Iohexol (Omnipaque) Low osmolar Iodixanol (Visipaque) Iso-osmolar13.5%25.0%11.0% 0.0240.001 Sharma et al. Catheter Cardiovasc Interv 2005;65:386-393.

52 The ICON Trial: Protocol Patients With Chronic Renal Insufficiency to Undergo Angiography/PCI n=130 Ioxaglate (Hexabrix) Low-osmolar, ionic Iodixanol (Visipaque) Isoosmolar, non-ionic Primary Endpoint: Peak increase in the serum creatinine concentration between day 0 (when contrast medium was administered) and day 3 Mehran et al. TCT 2006

53 ICON Trial: Increase of Serum Creatinine from Baseline (Secondary Study End Point) IoxaglateN=74IodixanolN=71p 0.5 mg/dL 0.5 mg/dL 18.2 % 16.2 % 0.82 1 mg/dL 1 mg/dL 4.5 % 1.5 % 0.36 25% 25% 24.2 % 16.2 % 0.29 25% or 0.5 mg/dL 25% or 0.5 mg/dL 24.2 % 16.2 % 0.29 JACC Intv 2009

54 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

55 CARE p = 0.39 p = 0.44 p = 0.15

56 CARE p = 0.11 p = 0.37 p = 0.20 Diabetic Subgroup

57 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

58 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 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

59 Mechanism of Thrombosis Induction and Mitigation with Contrast Media Comparative Effects, Cautionary Notes and Implications for PCI Frederick Feit, MD, FACC Associate Professor of Medicine New York University School of Medicine Director, Interventional Cardiology New York University School of Medicine New York, NY

60 Thrombosis Induction and Mitigation with Contrast Media: Outline Thrombin generation, platelet activation and their interrelationship Thrombin generation, platelet activation and their interrelationship Contrast media: The basics Contrast media: The basics Experimental data exploring the interaction of differing contrast media and thrombosis in animals and humans Experimental data exploring the interaction of differing contrast media and thrombosis in animals and humans Potential relevance in clinical practice Potential relevance in clinical practice

61 XIIa, XIa IX IXa VIII, Ca Intrinsic System Extrinsic System Injury Tissue thromboplastin XXa Ca,V ProthrombinThrombin PlateletActivation FibrinogenFibrin XIIIXIIIa Mature Thrombus Extrinsic System Intrinsic System

62 Sites of Anti-thrombotic Drug Action Tissue factor Plasma clotting cascade Prothrombin Thrombin FibrinogenFibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thromboxane A 2 ADP AT AT Aspirin Ticlopidine Clopidogrel Prasugrel GPIIb/IIIa inhibitors Bivalirudin Hirudin Argatroban FactorXa Thrombo- lytics Aspirin Thrombolytics GPIIb/IIIa inhibitors LMWH Fondaparinux Heparin Ticlopidine Clopidogrel Prasugrel Bivalirudin Hirudin Argatroban

63 Anionbindingexosite Active catalytic site Fibrinogen Thrombin

64 Anion binding exosite Active catalytic site Active Fibrin Thrombin

65 The Platelet Collagen Activation Platelet GPIIb/IIIa GPIIb/IIIa ADPEPIThrombin Thromboxane Fibrinogen COX

66 Coagulation – The Real Story Complex interplay on the surface of platelets Collagen Tissue Factor Thrombin Platelet activation Prothrombin ADP TXA 2 Plasma Clotting cascade THROMBUS FibrinogenFibrin GP2b3a expression & platelet aggregation Xa Ca Va

67 Contrast Media: Preconceived Notions Ionic Contrast: What they used to use Ionic Contrast: What they used to use Nonionic Contrast: What we use now, because it has lower osmolality (the good stuff) Nonionic Contrast: What we use now, because it has lower osmolality (the good stuff) Visipaque: The really good stuff, both theoretically and confirmed by the COURT trial Visipaque: The really good stuff, both theoretically and confirmed by the COURT trial Hexabrix: I heard of that; I think its pretty good, too Hexabrix: I heard of that; I think its pretty good, too

68

69 Contrast Media: More Evolved Notions Ratio of iodine:osmotically active particles determines osmolality Ratio of iodine:osmotically active particles determines osmolality Ioxaglate (Hexabrix), an ionic dimer has lower osmolality than nonionic monomers Ioxaglate (Hexabrix), an ionic dimer has lower osmolality than nonionic monomers Iodixanol (Visipaque) a nonionic dimer is isoosmolar to plasma Iodixanol (Visipaque) a nonionic dimer is isoosmolar to plasma

70 Basic Structures of Contrast Media Voeltz MD, et al. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review

71 Contrast Media: Very Evolved Notions Ionic contrast: conjugation of the benzene ring structure (anion) with a non-radioopaque cation resulting in a water soluble compound. Ionic contrast: conjugation of the benzene ring structure (anion) with a non-radioopaque cation resulting in a water soluble compound. Ionic monomers dissociate in vivo resulting in an iodine:particle ratio of 3:2; for ionic dimers, 6:2 Ionic monomers dissociate in vivo resulting in an iodine:particle ratio of 3:2; for ionic dimers, 6:2 Nonionic monomers do not dissociate so I:p ratio is 3:1; for nonionic dimers, 6:1 Nonionic monomers do not dissociate so I:p ratio is 3:1; for nonionic dimers, 6:1

72 71 6 cPs 8 cPs 5-10 cPs 11 cPs Viscosity at 37 0 C Diatrizoate ioxaglate Ioxilan Iohexol Iopamidol Iopromide Ioversol Ioxilan Iohexol Iopamidol Iopromide Ioversol Iodixanol Name Monomer Dimer Monomer Dimer # Benz.Rings Ionicity Ionic Nonionic Osmolality (mOsm/kg) HOCM (>1,500) LOCM (280 – 1,000) 14 cPs 16 cPs 10-22 cPs 26 cPs Viscosity at 20°C Comparative Characteristics of Contrast Media: Molecular Structures

73 Classification and Osmolality Class Chemical Name Trade Name and Manufacturer Osmolality (mOsm/kg H 2 0) High-Osmolar(HOCM) Ionic Monomers Diatrizoate Hypaque ® (GEH) 2016 RenoCal-76 ® (B) 1870 MD-76 ® R (M) 1551 Iothalamate Conray ® (M) 1400 Low-Osmolar (LOCM) High-Viscosity (HVCM) Low-Viscosity (LVCM) Nonionic Dimer Iodoxinal Visipaque TM 320 (GEH) 290 Nonionic Monomers Iopromide Ultravist ® 370 (BR) 774 Iopamidol Isovue ® 370 (B) 796 Iohexol Omnipaque TM 350 (GEH) 844 Ioversol Optiray ® 350 (M) 792 Ioxilan Oxilan ® 350 (G) 695 Ionic Dimer Ioxaglate Hexabrix ® 320 (G-M) 600 Voeltz MD, et al. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review

74 Engelhart et al. Invest Radiol 1988;23:922-7 Methods: Patients Undergoing angiography 1.Blood drawn from 5F pigtail in aorta utilizing 50cc syringe 2.5ml blood injected in multiple 10cc syringes 3.2ml contrast drawn into syringe (no mixing) 4.Inject onto filter paper at 10, 30, 60, 90 min. to assess thrombus

75 Incubation of Blood with Contrast Engelhart et al. Invest Radiol 1988;23:922-7

76 Differential Effects of Contrast Media on Platelet Aggregation Heptinstall et al. British Journal of Haemotology 1998;103:1023-30 Iopamidol: directly induced platelet aggregation and potentiated that induced by ADP Iodixanol: potentiated aggregation induced by ADP Ioxaglate: inhibited aggregation induced by ADP ADP antagonists, but not ASA inhibited Iopamidol induced platelet aggregation indicating that this phenomenon is not mediated by TXA2 and is at least in part by TXA2 and is at least in part by ADP % Aggregation Platelet aggregation and P-selectin expression in hirudinized whole blood containing iopamidol, iodixanol, or ioxaglate in the absence (open histograms) or presence (thatched histograms) of AR- C66096 (10 umol/l). *

77 In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Methods: 1.Pooled human plasma mixed with saline control or contrast Iohexol (Omnipaque), or Iodixanol (Visipaque), or Ioxaglate (Hexabrix) to a final concentration of 60mg I/ml for aPTT and TT studies 2.Platelet studies performed using ELISA tests

78 In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 NaCL 9 g/lIodixanolIohexolIoxaglate TT (s) 19 ± 2 84 ± 10 110 ± 18 >500 APTT (s) 44 ± 2 74 ± 1 81 ± 2 303 ± 13 P <0.01

79 In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 30 min intubation PF4IU/ml5-HTNg/mlPDGF-ABPg/ml TXB 2 Ng/mlFpANg/ml Control786185695133>1500 Ioxaglate4318<186479 Iodixanol20950621734835 Iohexol144680118606255 Thrombin406113782642110614>1500

80 In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 PF4 P<0.001 IU/ml PF4 determinations (platelet factor 4) which represent platelet degranulation induced by contrast media mixed 1:1 with blood for 1 min (mean ± SD, n=4).

81 Corot et al: Conclusions Ioxaglate demonstrated the most powerful anticoagulant properties, followed by iohexol and Iodixanol Ioxaglate demonstrated the most powerful anticoagulant properties, followed by iohexol and Iodixanol Iohexol resulted in major platelet activation; iodixanol in less platelet activation, only with 30 minutes of incubation; ioxaglate did not activate platelets Iohexol resulted in major platelet activation; iodixanol in less platelet activation, only with 30 minutes of incubation; ioxaglate did not activate platelets

82 Differential Effects on Thrombus Formation Jones C et al. Thrombosis Research 2003;112:65-71 Methods: 1.Contrast agent added to blood collected from normal volunteers in ratio of either 20% or 50% 2.Mixed for 1 min. 3.Thrombi formed in vitro by adding 1ml recalcified blood/contrast to the chandler loop (45 cm long, 3 mm inner circumference) PVC tubing 4.Rotated at 37 rpm for 90 mins 5.Thrombus analyzed by immunofluorescence and weighed 6.Thrombolysis over 24 hours, both spontaneous and by tPA assessed, by weight of thrombus and measuring free FITC in supernatant (a product of lysis of FITC-labeled fibrinogen

83 Differential Effects on Thrombus Formation Jones C et al. Thrombosis Research 2003;112:65-71 Weight (mg) Saline20% ------ Ioxaglate-50%20% --- Iobexol---50%20%-- Iodixanol ----- 50%20% P<0.0005

84 Differential Effects on Platelet Degranulation Jones C et al. Thrombosis Research 2003;112:65-71 Percent Positive Saline50% ------ Ioxaglate-50%20% --- Iobexol---50%20%-- Iodixanol ----- 50%20% Percentage of platelets positive for P-selectin expression in the presence of CM P<0.02 P<0.03

85 Fibrinolysis: Spontaneous or with tPA Jones C et al. Thrombosis Research 2003;112:65-71 Weight (mg) Floresence (arbitrary U) Saline20%20%---- Iohexol--20%20%-- Iodixanol----20%20% tPA-+-+-+ Saline20%20%---- Iohexol--20%20%-- Iodixanol----20%20% tPA-+-+-+ P<0.02

86 Thrombus Histopathology Jones C et al. Thrombosis Research 2003;112:65-71 Head and tail regions of thrombi for Saline control (top), Iohexol (mid), Iodixanol (bot). Thrombi formed in the presence of either contrast had larger, more platelet-rich heads and much larger tails, composed of an open irregular meshwork of fibrinogen/fibrin enclosing large dense RBC areas and scattered WBC. Iohexol thrombi had larger heads than iodixanol thrombi, which had a much more irregular structure with areas of very strong fibrinogen antibody binding interspersed with WBC aggregates.

87 Differential Effects on Thrombus Formation Conclusions No thrombi formed from blood incubated with Ioxaglate No thrombi formed from blood incubated with Ioxaglate Thrombi formed with Iohexol or Iodixanol weighed >10x more than those formed with saline controls, had different structure and were more resistant to thrombolysis Thrombi formed with Iohexol or Iodixanol weighed >10x more than those formed with saline controls, had different structure and were more resistant to thrombolysis Iohexol, but neither Iodixanol nor Ioxaglate increased platelet degranulation Iohexol, but neither Iodixanol nor Ioxaglate increased platelet degranulation

88 Contrast Media: Mechanistic Assessment of Thrombin Generation Methods: 1.Pooled plasma from healthy donors to prepare PRP and PPP 2.Thrombograms obtained by mixing PPP or PRP with activator (TF for extrinsic system and kaolin for intrinsic system) plus ioxaglate, iodixanol, abciximab (as shown) 3.Thrombograms assessed by lag time (clotting time), peak height (maximal velocity of net thrombin production, area under the curve (endogenous thrombin potential) Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274

89 Thrombogram: Iodixanol vs. Ioxaglate Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274 Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274 Influence of the contrast media addition on the thrombogram in PPP and PRP. (a) In defibrinated PPP initiated with rTF. (b) In defibrinated PPP initiated with contact activator. (c) In PRP initiated only with CA 2+ control; iodixanol (5% v/v); ioxaglate (5%, v/v). Data represent median of four independent experimentscontrol; iodixanol (5% v/v); ioxaglate (5%, v/v). Data represent median of four independent experiments

90 Abciximab + Iodixanol or Ioxaglate Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274 Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274 Effect of abciximab on the thrombogram in PRP in the absence and presence of CM (5% v/v ). control; abciximab alone (40 ug mL -1 ); abciximab + iodixanol; abciximab + ioxaglate. Data represent median of three independent experiments

91 Al Dieri et al: Conclusions Ioxaglate is a potent inhibitor of thrombus formation in prp and ppp. Effects of iodixanol are to slightly enhance thrombin generation Ioxaglate is a potent inhibitor of thrombus formation in prp and ppp. Effects of iodixanol are to slightly enhance thrombin generation Ioxaglate amplifies the effect of abciximab Ioxaglate amplifies the effect of abciximab Ioxaglate inhibits activation of factors V and VIII (thrombograms not shown) and of platelets by thrombin Ioxaglate inhibits activation of factors V and VIII (thrombograms not shown) and of platelets by thrombin These data suggest that ioxaglate interferes with binding of substrates to exosite I of thrombin and inhibits thrombin generation via inhibition of thrombin-mediated feedback activation These data suggest that ioxaglate interferes with binding of substrates to exosite I of thrombin and inhibits thrombin generation via inhibition of thrombin-mediated feedback activation

92 Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates Methods: 1)Healthy baboons with chronic AV (femoral) shunts 2)PS 153 stent deployed at 10 atm in AV shunt 3)Labeled platelets used 4)Saline control or contrast (Iodixanol, Isovue, Ioxaglate) locally infused 5)The fluid mechanics and mass transfer characteristics of the infused contrast were modeled using computational fluid dynamics Markou et al. Thromb Haemost 2001;85:488-93

93 Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates Markou et al. Thromb Haemost 2001;85:488-93 Schematic of the local infusion system, stented segment, and expanded diameter chamber region of the thrombogenic device showing their relative placement in the A- V baboon shunt. The top panel shows an in-platelet image of platelet deposition on a control stent and within chamber region of flow recirculation.

94 Platelet Deposition in the Expanded Region Markou et al. Thromb Haemost 2001;85:488-93 Time course of platelet deposition within the chamber regions of expanded diameter (9.0 mm i.d.) exhibiting low shear blow flow recirculation and stasis. The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of 111 Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ± 1 SEM Time (min) Platelets Deposited x 10 -6 A B

95 Platelet Deposition in the Stented Region Markou et al. Thromb Haemost 2001;85:488-93 Time course of platelet deposition onto 4.0 mm i.d. metallic stents (Palmaz- Schatz) deployed into A-V shunts in baboons. The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of 111 Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ± 1 SEM Time (min) Platelets Deposited x 10 -6 A B

96 Fibrin Deposition on Stented Segment Markou et al. Thromb Haemost 2001;85:488-93 Fibrin (mg) 4 4 2 4 Deposition of fibrin on the stented segment Fibrin (mg) 7 The blood flow rate was 100 ml/mi. Fibrin deposition was determined by measuring the accumulation of 125 iodine-labeled fibrinogen. A) CME infusion rate = 0.1 ml/min. B. CME infusion rate = 0.3 ml/min. Values are mean ± 1 SEM

97 Photographs of Thrombus Formed in Stents 96. Markou et al. Thromb Haemost 2001;85:488-93

98 Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates Ioxaglate reduced both platelet and fibrin deposition on stents by 75-80% (p<0.005), while the non-ionic agents reduced platelet deposition by 52% (p<0.05) In the regions of low shear flow, only ioxaglate (0.3ml/min) reduced platelet deposition sgnificantly (by 52%; p<0.05) In this model, while all three agents were inherently antithrombotic, the most striking effects were seen with ioxaglate

99 Primary endpoint: In-Lab Thrombus All Comers PTCA IohexolIoxaglate Randomized Blinded UFH: 10,000 u IV Aspirin UFH: 10,000 u IV Aspirin Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105 All Comers PTCA Iohexol Ioxaglate Primary Endpoint: In-Lab Thrombus

100 Iohexol (Omnipaque) vs Ioxaglate (Hexabrix) For PTCA Coronary Angioplasty: In-Lab Thrombus P = 0.04 Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105

101 Primary endpoint: Thrombus During Angiography All Comers PTCA IohexolIoxaglate Randomized UFH: 10,000 u IV Aspirin UFH: 10,000 u IV Aspirin Esplugas et al. Am J Cardiol 1991;68:1020-4 All Comers PTCA Iohexol Ioxaglate Primary Endpoint: Thrombus During Angiography

102 Iohexol (Omnigraf) vs Ioxaglate (Hexabrix) For PTCA In-Lab Angiographic Thrombus P < 0.005 Esplugas et al. Am J Cardiol 1991;68:1020-4

103 All Comers PCI Patients IodixanolIoxaglate Sequential Design Enoxaparin 1 mg/kg SC Q12 h, or 0.5 mg/kg 5 min prior to PCI Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8 All Comers PCI Patients Iodixanol Ioxaglate Primary Endpoint: In-Hospitral MACE (cardiac death, MI, TVR, CVA, systemic embolic event) Secondary endpoint: Angiographic outcomes (large thrombus > 2 vessel d iameters) ASA, 250 mg PO OD, clopidogrel 300 mg PO >6h GP IIb/IIIa in 43% (operator discretion) (Peak anti Xa > 0.5 IU/ml in 97% of patients)

104 Le Feuvre et al: Intraprocedural Large Thrombus P < 0.0001 Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8 Iodixanol vs. Ioxaglate for PCI Stent in 91%

105 Thrombosis Induction and Mitigation with Contrast Media: Conclusions Data from in vitro studies and from animal models indicate significant differences in the effects of different contrast media on thrombin generation, thrombolysis and platelet activation. Data from in vitro studies and from animal models indicate significant differences in the effects of different contrast media on thrombin generation, thrombolysis and platelet activation. Among commonly used agents, the ionic dimer, Ioxaglate (Hexabrix) inhibits both thrombin generation and platelet activation Among commonly used agents, the ionic dimer, Ioxaglate (Hexabrix) inhibits both thrombin generation and platelet activation Non-ionic monomers activate platelets, enhance thrombin generation and inhibit thrombolysis Non-ionic monomers activate platelets, enhance thrombin generation and inhibit thrombolysis The non-ionic dimer, Iodixanol (Visipaque) has intermediate results The non-ionic dimer, Iodixanol (Visipaque) has intermediate results

106 Thrombosis Induction and Mitigation with Contrast Media: Conclusions There are some provocative clinical data, but are they relevant in the current era? Stay Tuned!

107 The Role of Contrast Media (CM) on Clinical Outcomes in Patients with STEMI and High-Risk ACS: The Evidence-Based Case for Risk-Directed Selection of CM in PCI The Journey from Clinical Trials to Choices for CM in the Cardiac Catheterization Laboratory: How Should Recent Evidence and Trials Affect Our Choices? Steven V. Manoukian, MD, FACC Program Chairman Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Medical Director, Cardiovascular Services | Clinical Services Group | Hospital Corporation of America (HCA) | Nashville, TN

108 Clots, Contrast Media, and Catheterization Outline PCI ischemic complications PCI ischemic complications Anticoagulation in PCI Anticoagulation in PCI Bleeding complications of PCI anticoagulation Bleeding complications of PCI anticoagulation Impact of PCI periprocedural MI Impact of PCI periprocedural MI Clinical trials of contrast media in PCI Clinical trials of contrast media in PCI Conclusions Conclusions

109 Ischemic Complications of PCI Lincoff AM et al. JAMA 2003;289:853-863. Stone GW et al. Lancet 2007;369:907-19. Stone GW et al. NEJM 2008;358:2218-30. 30-Day Event Rates Adapted from REPLACE-2, ACUITY-PCI, HORIZONS PCI Subset

110 EPILOG: 30-Day Primary Efficacy Endpoint EPILOG Investigators. NEJM 1997;336:1689-96. 0.120.100.080.060.040.020.01 0 5 10 15 20 25 30 Probability of Death, Myocardial Infarction, or Urgent Revascularization Days After Randomization P<0.001 Placebo Abciximab + standard-dose heparin Abciximab + low-dose heparin

111 EPILOG: 30-Day Individual Endpoints EPILOG Investigators. NEJM 1997;336:1689-96. Efficacy End Point Placebo + Standard- Dose Heparin (n=939) Abciximab + Low-Dose Heparin (n=935) P Value Abciximab + Standard- Dose Heparin (n=918) P Value No. of patients (%) No. patients (%) Composite 109 (11.7) 48 (5.2) <0.001 49 (5.4) <0.001 Death 7 (0.8) 3 (0.3) 0.21 4 (0.4) 0.39 Myocardial infarction 81 (8.7) 34 (3.7) <0.001 35 (3.8) <0.001 Q-wave Q-wave 7 (0.8) 4 (0.4) 0.36 4 (0.5) 0.38 Non-Q-wave Non-Q-wave 74 (7.9) 30 (3.2) <0.001 31 (3.4) <0.001 Large non-Q-wave (CK MB > 5 x control) 53 (5.6) 19 (2.0) <0.001 23 (2.5) <0.001 Small non-Q-wave (CK MB 3-5x control) 18 (1.9) 11 (1.2) 0.26 8 (0.9) 0.07 Non-Q-wave after hospitalization 3(0.03) 3(0.03)00.2500.25 Urgent revascularization 48 (5.2) 15 (1.6) <0.001 21 (2.3) 0.001 Repeated percutaneous intervention 35 (3.8) 11 (1.2) <0.001 14 (1.5) 0.003 Coronary-artery bypass grafting 16 (1.7) 4 (0.4) 0.007 8 (0.9) 0.11 Death or myocardial infarction 85 (9.1) 35 (3.8) <0.001 38 (4.2) <0.001

112 ACUITY: Early Composite Ischemia Stone GW et al. NEJM 2006;355:2203-16. Days After Randomization 0 5 10 15 20 25 30 35 151050 Bivalirudin alone, 8.0%, P=0.30 Bivalirudin + GP IIb/IIIa inhibitor, 7.9%, P=0.37 Heparin + GP IIb/IIIa inhibitor, 7.4%

113 ACUITY: Major Bleeding Stone GW et al. NEJM 2006;355:2203-16. Days After Randomization 0 5 10 15 20 25 30 35 151050 Heparin + GP IIb/IIIa inhibitor, 5.7% Bivalirudin + GP IIb/IIIa inhibitor, 5.3%, P=0.41 Bivalirudin alone, 3.1%, P<0.001

114 ACUITY: Major Bleeding and Mortality Manoukian SV et al. JACC 2007;49:1362-8. Long rank p Value: <0.0001 7.3% Patients with major bleeding Patients without major bleeding Percent Mortality Days After Randomization 0 5 10 15 20 25 30 35 8765432101.2%

115 ACUITY: Predictors of Major Bleeding Manoukian SV et al. JACC 2007;49:1362-8. Age > 75 years 1.64 (1.32-2.02) <0.0001 Female gender 1.92 (1.61-2.29) <0.0001 Diabetes 1.20 (1.00-1.44) 0.057 Hypertension 1.24 (1.01-1.52) 0.040 No prior PCI 1.32 (1.08-1.62) 0.006 Anemia 1.87 (1.54-2.28) <0.0001 Renal insufficiency 1.53 (1.24-1.90) <0.0001 Baseline ST-segment deviation > 1 mm 1.35 (1.13-1.61) 0.0008 Baseline cardiac biomarker elevation 1.43 (1.19-1.74) 0.0002 Heparin plus GPI vs bivalirudin monotherapy 1.95 (1.56-2.44) <0.0001 Odds Ratio ± 95% CI OR (95% CI) p value 0 1 2 3

116 Clinical Classification of MI Thygesen K et al. J Am Coll Cardiol 2007;50:2173-95. Type 1 Spontaneous myocardial infarction related to ischaemia due to primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection Type 2 Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension Type3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischaemia, accompanied by presumably new ST-elevation, or new LBB,B, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood Type 4a Myocardial infarction associated with PCI Type 4b Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy Type 5 Myocardial infarction associated with CABG

117 ACUITY: Periprocedural MI and Mortality 30-Day Event Rates, PCI Population Prasad A et al. J Am Coll Cardiol 2009;54:477-86. 30-day events (%) P<0.0001 P=0.27 P<0.0001 P=0.8 P<0.0001 P=0.41 P=0.0004

118 Age (> 75 years) 2.53 (2.01-3.18) <0.0001 Anemia 1.51 (1.22-1.86) 0.0002 Prior stroke 1.29 (1.04-1.60) 0.02 Male 1.53 (1.23-1.90) 0.0001 Diabetes 1.51 (1.25-1.82) <0.0001 Baseline CrCl <60 mL/min 1.43 (1.13-1.80) 0.003 Pre-randomization UFH 1.25 (1.02-1.54) 0.03 Prior MI 1.33 (1.09-1.61) 0.005 CKMB/troponin+ at baseline 1.70 (1.37-2.12) <0.0001 ECG changes at baseline 1.76 (1.45-2.13) <0.0001 30-day major bleed 3.03 (2.33-3.94) <0.0001 30-day revascularization 1.76 (1.16-2.67) 0.008 Periprocedural MI 1.30 (0.85-1.98) 0.22 Spontaneously occurring MI 7.49 (4.95-11.33) <0.0001 ACUITY: Periprocedural MI and 1-Year Mortality Prasad A et al. J Am Coll Cardiol 2009;54:477-86. PCI Population 0.1 110 HR ± 95% CI HR (95% CI) P-value

119 Periprocedural Troponin and Mortality Nienhuis NB et al. Catheter Cardiovasc Interv 2008;71:325-6. Meta-Analysis, n=15,581 FuchsCantorGrubergNallamothuRicciardiKiniNatarajanCavalliniOkmenShyuHermannKizerMillerPrasad All trials 1.35 (1.13-1.60) 0 2 4 6 8 10 12

120 What do the Vascular Biology and Clinical Trials Teach Us? The Impact of Cardiac Contrast Media on MACE End Points In ACS

121 Ioxaglate Characteristics: Thrombotic Risk and MACE Ioxaglate has been shown to reduce platelet accumulation in stents (in animals)* * The clinical significance of this data is not known. Markou CP et al, Thromb and Haemost, 2001, 85:488-493.

122 Fibrin forms mesh which encapsulates the clot Fibrinogen Thrombin helps convert another protein, fibrinogen, into fibrin Activated Platelets Aggregate and adhere to the exposed collagen on the vessel wall, forming the initial clot Collagen Activates Resting Platelets Thrombin Activates Resting Platelets Antithrombotic and Anticoagulant Properties of Ioxaglate So what happens? Vessel Injured Exposes endothelial proteins, including collagen R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274 Heptinstall et al. British Journal of Haemotology 1998;103:1023-30 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

123 Antithrombotic and Anticoagulant Properties of IoxaglateCollagen VWF INJURY Platelet Adhesion & Secretion Tissue Factor Coagulation Cascade Thrombin Haemostatic plug Vaso- constriction Blood Vessel Endothelium Subendothelium Dr Isobel Ford Coagulation Cascade Thrombin Fibrin Platelet aggregation Platelet adhesion and secretion Vaso- constriction

124 Antithrombotic and Anticoagulant Properties of Ioxaglate What are issues and concerns for interventional cardiologists? What are issues and concerns for interventional cardiologists? This process can lead to occlusion of the vessels, such as coronary arteries during PCI This process can lead to occlusion of the vessels, such as coronary arteries during PCI End point includes mortality End point includes mortality End point includes NSTEMI and STEMI End point includes NSTEMI and STEMI R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274 Heptinstall et al. British Journal of Haemotology 1998;103:1023-30 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

125 Antithrombotic and Anticoagulant Properties of Ioxaglate So what role does ioxaglate play? Collagen Activates Resting Platelets Vessel Injured Exposes endothelial proteins, including collagen Fibrinogen Thrombin helps convert another protein, fibrinogen, into fibrin Activated Platelets Aggregate and adhere to the exposed collagen on the vessel wall, forming the initial clot Fibrin forms mesh which encapsulates the clot Thrombin Activates Resting Platelets R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274 Heptinstall et al. British Journal of Haemotology 1998;103:1023-30 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

126 Antithrombotic and Anticoagulant Properties of Ioxaglate Interface of ioxaglate with thrombosis generation Ioxaglate, does not activate resting platelets, unlike nonionic monomers.Ioxaglate, does not activate resting platelets, unlike nonionic monomers. Doesnt direct platelets to change shape, release pro-coagulant mediators or to adhere to anything.Doesnt direct platelets to change shape, release pro-coagulant mediators or to adhere to anything. This prevents/delays formation of the platelet clot.This prevents/delays formation of the platelet clot. Ioxaglate inhibits the generation of thrombin, reducing the amount of thrombin: inhibits the formation of fibrin.Ioxaglate inhibits the generation of thrombin, reducing the amount of thrombin: inhibits the formation of fibrin. Mechanisms that may be responsible for preventing/delaying formation of the fibrin mesh.Mechanisms that may be responsible for preventing/delaying formation of the fibrin mesh. Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelet plug.Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelet plug. R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274 Heptinstall et al. British Journal of Haemotology 1998;103:1023-30 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

127 Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCA Grines CL et al. J Am Coll Cardiol 1996;27:1381-6. Baseline Demographic Characteristics Low Osmolar Ionic Contrast Media (n=106) Nonionic Contrast Media (n=105) Age (yr) (mean ± SD) 63.7 ± 12.7 61.9 ± 12 Male patients (%) 6462 Clinical history (%) Hypertension Hypertension51.950.5 Diabetes Diabetes24.521.0 Smoking Smoking56.667.6 Prior MI Prior MI40.639.1 Prior PTCA Prior PTCA15.117.1 Treatment history (%) Aspirin Aspirin68.961.0 Heparin Heparin53.859.1 Nitrates Nitrates67.066.7 Tissue plasminogen activator Tissue plasminogen activator3.88.6 Indication for PTCA, % Acute MI Acute MI44.440.9 Post-MI ischemia Post-MI ischemia33.933.4 Unstable angina Unstable angina21.725.7

128 Ioxaglate Significant reductions in: Significant reductions in: Ischemic complications acutely and at one month Ischemic complications acutely and at one month Decreased blood flow during PTCA Decreased blood flow during PTCA Recurrent ischemia with repeat catheterization Recurrent ischemia with repeat catheterization Repeat PTCA Repeat PTCA Angina Angina Risk of CABG Risk of CABG Authors: Strongly consider for unstable angina/MI PTCA. Authors: Strongly consider for unstable angina/MI PTCA. Grines CL et al. J Am Coll Cardiol 1996;27:1381-6. Conclusions Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCA

129 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Bertrand ME et al. Circulation 2000;101:131-136. Baseline Clinical Characteristics Iodixanol (Nonionic; n=697) Ioxaglate (Ionic; n=714) Age, y 61.6 ± 10.6 62.3 ± 10.2 Male, % 78.276.2 Weight, kg 75.9 ± 12.2 76.2 ± 12.4 Height, cm 168.2 ± 8.6 168.0 ± 8.6 Diabetes, % 20.215.8 Current smokers, % 23.222.1 Former smokers, % 35.036.3 Obesity, % 20.120.2 Family history of CAD, % 30.726.3 Prior MI, % 19.118.5 Prior PTCA, % 16.114.7 Prior CAG, % 7.16.7 History of allergy/hypersensitivity, % 4.75.7 Indication for PTCA, % Unstable angina Unstable angina51.949.3 Stable angina Stable angina38.340.1 Silent ischemia Silent ischemia9.510.1

130 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Bertrand ME et al. Circulation 2000;101:131-136. MACE at 2-Day Follow-Up Iodixanol (Nonionic; n=697) Ioxaglate (Ionic; n=714) p During hospital stay (2 days) 33 (4.7%) 28 (3.9%) 0.45 Death Death02N Stroke Stroke21NS Q-wave MI Q-wave MI33NS NQWMI NQWMI24170.24 CABG CABG11NS Re-PTCA Re-PTCA34NS

131 No significant difference in in-hospital MACE between ioxaglate and iodixanol. No significant difference in in-hospital MACE between ioxaglate and iodixanol. Conclusions Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Bertrand ME et al. Circulation 2000;101:131-136.

132 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Davidson CJ et al. Circulation 2000;101:2172-2177. Demographics Iodixanol (n=405) Ioxaglate (n=410) N%N% Average age, y 61±12 62±12 Male2806927066 Hypertension2405924961 Diabetes mellitus 1102711027 Current smoker 1293213733 Past smoker 2385925161 Previous MI 1423516841 Hyperlipidemia2496115763 Angina3538738393 Angina CHS class IV 2907231176 Family CAD history 2426024059 Prior intervention 1283213332

133 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Davidson CJ et al. Circulation 2000;101:2172-2177. Hospital Stay Primary Clinical Outcomes Iodixanol (n=405) Ioxaglate (n=410) P N%N% Emergent recatheterization 51.292.20.29 Repeat revascularization 41.082.900.25 In-hospital abrupt closure 30.7102.40.05 Stroke/TIA10.210.20.99 Thromboembolic event 20.54100.42 Cardiac death 51.210.20.10 Nonfatal MI 82.0184.40.05 Emergent CABG 20.53.070.66 Composite outcome 225.4399.50.027

134 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Davidson CJ et al. Circulation 2000;101:2172-2177. Events from Hospital Discharge to 30 Days Iodixanol (n=390) Ioxaglate (n=400) P N%N% Emergent recatheterization or revascularization 133.3123.00.79 Abrupt closure 0020.50.16 Stroke/TIA10.310.30.99 Thromboembolic event 0020.50.16 Cardiac death 0010.30.32 Nonfatal MI 10.310.30.99 Emergent CABG 10.310.30.99 Composite outcome 153.8153.80.94

135 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Davidson CJ et al. Circulation 2000;101:2172-2177. Angiographic and Procedural Outcome Iodixanol (n=400) Ioxaglate (n=396) P N%N% Abrupt closure 20.571.80.09 Prolonged no-reflow 30.830.80.99 Distal embolization 20.510.30.57 Side-branch occlusion 61.561.50.99 Development of moderate to large thrombus 0000-- Dissection184.5256.30.25 Unplanned IABP 41.071.80.37 Unplanned abciximab 297.3328.10.66 Procedural success 36992.234085.90.004 >20% absolute decrease >20% absolute decrease37593.935590.0--- <50% residual stenosis <50% residual stenosis38997.337994.9--- TIME-3 flow TIME-3 flow39799.339198.8--- Composite outcome 6917.38722.00.093

136 Conclusions Regarding Ionic Contrast Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Davidson CJ et al. Circulation 2000;101:2172-2177. Iodixanol, significant Iodixanol, significant Reduction in in-hospital adverse composite Reduction in in-hospital adverse composite Increase in angiographic success Increase in angiographic success

137 Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Scheller B et al. Eur Heart J 2001;22:385-91. n=3,990 Ioxaglate (Hexabrix ® 320)Dimer, ionic Iobitridol (Xenetix ® 350)Monomer, non-ionic Iomeprol (Imeron ® 400) Monomer, non-ionic Iopamidol (Solutrast ® 370)Monomer, non-ionic Iopromid (Ultravist ® 370)Monomer, non-ionic Ioversol (Optiray ® 350)Monomer, non-ionic Iodixanol (Visipaque ® 320)Dimer, non-ionic

138 Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Demographic Data, n=3,990 Scheller B et al. Eur Heart J 2001;22:385-91. Non-ionic CM Ioxaglatep N18082182 Gender (male) 76%74%NS Age 63.9 ± 10.3 years NS Diabetes18.9%17.2%NS Angina pectoris Angina pectoris CCS 0-I 22.8% CCS 0-I 26.4% NS CCS II 36.6% CCS II 37.5% CCS III 28.2% CCS III 25.3% CCS IV 12.5% CCS IV 10.9% Acute coronary syndrome 34.2%32.3%NS Unstable angina Unstable angina24.9%21.3% AMI AMI9.3%11.0% Known CM intolerance 4.1%4.3%

139 Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Scheller B et al. Eur Heart J 2001;22:385-91. Angiographic Data, n=3,990 Non-ionic CM Ioxaglatep N18082182 LVEF 55 ± 15.9% 54.8 ± 17.8% NS Vessels diseased Single vessel 26% Single vessel 28% NS Two vessel 35% Three vessel 39% Three vessel 37% Stented vessel LCA 1.4% LCA 1.2% NS LAD 35.5% LAD 34.4% NS CX 19.8% CX 26.4% <0.05 RCA 36.5% RCA 32.8% <0.05 ACB 6.7% ACB 5.2% NS Stented vessel localization Proximal 31.5% Proximal 28.8% NS

140 Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Scheller B et al. Eur Heart J 2001;22:385-91. Angiographic Data, n=3,990 Non-ionic CM Ioxaglatep Stented vessel localization Proximal 31.5% Proximal 28.8% NS Middle 60.5% Middle 62.2% Distal 8.0% Distal 9.0% Restenotic lesion 18.6%17.4%NS RFD 3.37 ± 0.43 mm 3.37 ± 0.81 mm NS MLD 0.68 ± 0.63 mm 0.67 ± 0.58 mm NS Diameter stenosis 79.7 ± 17.8% 80.1 ± 5.5% NS Volume of CME 280.9 ± 120.5 ml 257.8 ± 101.6 ml 0.001 Heparin dose 12901 ± 4640 IU 11938 ± 3914 IU 0.001 ReoPro®4.9%5.3%NS

141 Primary Endpoint: 12-Month Acute and Subacute Stent Occlusion n=3,990 Scheller B et al. Eur Heart J 2001;22:385-91. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting PatientsEvent Non-Ionic CM IoxaglateP AOS and SAT All patients n=3990 All patients n=3990 AOS 24/1808 (1.3%) 7/2182 (0.3%) 0.001 SAT 44/1808 (2.45)% 16/2182 (0.7%) 0.001 Restonosis All patients n=3990 All patients n=3990 Reangiography 968/1808 (53.5%) 1062/2182 (48.7%) 0.002 Restenosis 329/968 (34.0%) 296/1062 (27.8%) 0.003 Combined clinical end point (TLR, CABG, death) All patients n=3990 All patients n=3990 Combined 414/1808 (22.9%) 356/2182 (16.3%) 0.001 TLR 301/1808 (16.6%) 229/2182 (10.5%) 0.001 CABG 22/1808 (1.2%) 31/2182 (1.4%) NS Death 110/1808 (6.1%) 109/2182 (5.0%) 0.007

142 Multivariate Analysis of Acute and Subacute Stent Thrombosis Scheller B et al. Eur Heart J 2001;22:385-91. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Variable, n=3990 WaldP CME5.86810.0154 Age0.00130.9707 LVEF1.60270.2055 CAD1.53910.2147 CM side effect 0.13680.7115 ReoPro®0.14820.7003 Unstable AP 0.17420.6764 AMI2.10490.1468 CCS3.25120.0714 MLD2.72560.0988 Heparin1.98420.1589 Localization0.01080.9173 Vessel diameter 0.61860.4316

143 n=3,990 Ioxaglate, significant reductions in: Ioxaglate, significant reductions in: Acute stent thrombosis Acute stent thrombosis Subacute stent thrombosis Subacute stent thrombosis Reangiography Reangiography Restenosis Restenosis Target lesion revascularization Target lesion revascularization Death Death Scheller B et al. Eur Heart J 2001;22:385-91. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting

144 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Baseline Clinical Characteristics IodixanolIoxaglateP N231267 Age (y) 64 ± 12 63 ± 11 NS Male gender, n 189 (82) 211 (79) NS Diabetes mellitus, n 64 (28) 92 (34) NS Hypertension, n 121 (53) 133 (50) NS Smoking history, n 94 (41) 97 (36) NS LDL cholesterol > 3.3 mmol/l 162 (70) 184 (69) NS Family history of CAD, n 46 (20) 51 (19) NS Prior CABG, n 16 (7) 23 (9) NS Prior MI, n 46 (20) 63 (24) NS Chronic renal failure 35 (15) 44 (16) NS Statin treatment before PCI 120 (52) 136 (51) NS Prior left ventricular failure, n 29 (13) 27 (10) NS PCI for acute MI, n 57 (25) 74 (28) NS PCI for unstable angina, n 37 (16) 58 (22) NS PCI for silent myocardial ischemia, n 29 (13) 27 (10) NS

145 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Angiographic Baseline Characteristics and Procedural Data IodixanolIoxaglatep Volume of contrast media (ml) 267 ± 125 276 ± 120 NS Peak anti-Xa >0.5 IU/ml, n 224 (97) 259 (97) NS Peak anti-Xa > 1 IU/ml, n 67 (29) 72 (27) NS Intravenous antiplatelet therapy, n 99 (43) 112 (42) NS Planned, n Planned, n 88 (38) 93 (35) NS Rescue, n Rescue, n 11 (5) 19 (7) NS Bifurcation/ostial lesion, n 23 (10) 29 (11) NS Number of vessel PCI per patient One vessel, PCI, n One vessel, PCI, n 192 (83) 219 (82) NS Two vessel PCI, n Two vessel PCI, n 37 (16) 43 (16) Three vessel PCI, n Three vessel PCI, n 2 (1) 5 (2)

146 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Angiographic Baseline Characteristics and Procedural Data (continued) IodixanolIoxaglatep Treatment device Failure to cross the lesion, n Failure to cross the lesion, n 6 (3) 10 (4) NS Balloon, n Balloon, n 10 (4) 17 (6) NS Stent, n Stent, n 215 (93) 240 (90) NS Number of stent used per patient One stent, n One stent, n 143 (62) 162 (61) NS Two stents, n Two stents, n 47 (20) 54 (20) Three stents Three stents 16 (7) 15 (6) Four stents or more, n Four stents or more, n 9 (4) 9 (3) Direct stenting, n 159 (69) 187 (70) NS Drug eluting stent, n 69 (30) 72 (27) NS Use of intra-aortic balloon pump, n 16 (7) 11 (4) NS

147 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Clinical Events IodixanolIoxaglatep Procedural events Cardiac death, n Cardiac death, n 2 (0.8) 0NS Non fatal MI or reinfarction, n Non fatal MI or reinfarction, n 7 (3) 1 (0.3) 0.05 Emergency CABG, n Emergency CABG, n 1 (0.4) 0NS Stroke or systemic thromboembolic event, n Stroke or systemic thromboembolic event, n00NS In-hospital events Cardiac death, n Cardiac death, n 2 (0.8) 0NS Non fatal MI or reinfarction, n Non fatal MI or reinfarction, n7(3) 1 (0.3) 0.05 Emergency repeat PCI, n Emergency repeat PCI, n 3 (1.3) 0NS Emergency CABG, n Emergency CABG, n 1 (0.4) 0NS Stroke or systemic thromboembolic event, n Stroke or systemic thromboembolic event, n00NS Composite outcome, n Composite outcome, n 11 (4.8) 1 (0.3) 0.005

148 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Clinical Events (continued) IodixanolIoxaglatep 30-day events Cardiac death, n Cardiac death, n 3 (1.3) 0NS Non fatal MI or reinfarction, n Non fatal MI or reinfarction, n 7 (3) 1 (0.3) 0.05 Emergency repeat PCI, n Emergency repeat PCI, n 5 (2.2) 1 (0.3) NS Emergency CABG, n Emergency CABG, n 1 (0.4) 0NS Stroke or systemic thromboembolic event, n Stroke or systemic thromboembolic event, n00NS Composite outcome, n Composite outcome, n 14 (6) 2 (0.7) 0.002

149 Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8. Angiographic and Procedural Complications During or Immediately After PCI IodixanolIoxaglatep Appearance of a large thrombus, n 14 (6) 1 (0.3) 0.0001 Target vessel occlusion, n Target vessel occlusion, n 12 (5.2) 1 (0.3) 0.003 Side branch (> 2 mm) occlusion, n Side branch (> 2 mm) occlusion, n 2 (0.9) 1 (0.3) NS Composite endpoint, n 14 (6) 1 (0.3) 0.0001 Sustained ventricular arrhythmia 2 (0.9) 1 (0.3) NS Hypotension with intervention 4 (1.7) 4 (1.5) NS Renal failure requiring treatment 0 3 (1) 3 (1)NS Contrast induced nephropathy 2 (1) 7 (2.6) NS Large thrombus, largest dimension greater than two vessel diameters; Contrast induced nephropathy, > 0.5 mg/dl and/or 25% increase in creatinine levels from day 0 to day 3

150 Ioxaglate: Ioxaglate: Thrombus-related events significantly less likely. Thrombus-related events significantly less likely. In-hospital MACEIn-hospital MACE Large thrombusLarge thrombus Iodixanol: Iodixanol: Independent predictor of in-hospital MACE. Independent predictor of in-hospital MACE. Conclusions Regarding Ionic Contrast Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

151 Non-Ionic Contrast Prescribing Information Prescribing Information. Visipaque Omnipaque Oxilan Isovue Optiray Ultravist

152 Clots, Contrast Media, and Catheterization Conclusions In PCI, ischemic complications are associated with adverse outcomes In PCI, ischemic complications are associated with adverse outcomes Aggressive PCI anticoagulation regimens are effective in reducing ischemic events but increase bleeding complications Aggressive PCI anticoagulation regimens are effective in reducing ischemic events but increase bleeding complications Active decision-making with regard to the type of contrast media may: Active decision-making with regard to the type of contrast media may: Favorably impact rates of ischemic complications Favorably impact rates of ischemic complications Not adversely affect rates of bleeding complications Not adversely affect rates of bleeding complications Obviate the need for aggressive anticoagulation regimens Obviate the need for aggressive anticoagulation regimens Improve overall PCI outcomes Improve overall PCI outcomes


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