1. SlideCAST Resource Contrast Media for Cardiovascular Angiography and PCI— Molecular Characteristics and Antithrombotic Effects: Implications for Interventional Cardiology Presented by Steven V. Manoukian, MD, FACC, FSCAI Director, Cardiovascular Research Sarah Cannon Research Institute Medical Director for Cardiology Services Clinical Services Group Hospital Corporation of America (HCA) Nashville, Tennessee 1 CardioContrastWRAP: A Leading Investigator, First Person Clinical Report®

2. Program Overview: CardioContrastWRAP 1.Welcome to CardioContrastWRAP: A Leading Investigator, First Person Clinical Report® 2.Overview of clinical issues in selecting CM for PCI: risk of thrombosis, CIN, and need for risk stratification 3.Overview of CM agents used in cardiology: ionic vs nonionic, hypo-osmolar for iso- osmolar agents; product characteristics and comparisons 4.Detailed review of product characteristics: ionicity, viscosity, osmolality 5.Thrombosis cascade in acute, ischemic heart disease: clinical implications 6.Effects of ionic, dimeric CM agents (ioxaglate) on thrombosis, platelets, and anticoagulation 7.Pivotal studies evaluating MACE and thrombosis risk using different CM 8.Implications of CM selection for clinical practice and risk stratification 9.Renal issues in PCI: CIN, predictive risk scores, prevention measures 10.Comparative studies evaluating risk of CIN in patients on ioxaglate vs. iodixanol 11.Summary and conclusions: Selecting CM for PCI 2

3. Characteristics of Contrast Media ► Physical Characteristics  Molecular Structure  Osmolality  Viscosity  Ionicity ►Patient Safety  Thrombotic Risk & MACE  Renal Tolerance ► Indications & Packaging 3

4. 4 6 cPs 8 cPs 5-10 cPs 11 cPs Viscosity at 37 0 C Diatrizoate ioxaglateioxaglate Ioxilan Iohexol Iopamidol Iopromide IoversolIoxilan 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

5. Comparative Characteristics of Contrast Media: Viscosity ► A unique profile within the concentration range of 320 to 370 mgI/mL. (1) 5 (1) Data on file at Guerbet LLC.

6. Comparative Characteristics of Contrast Media: Viscosity 6 (2) Data on File. Guerbet LLC.

7. Advantages of Low Viscosity CM ► Allows for easy injection through small diameter catheters. (3, 4) ► Provides better flow through small blood vessels and capillaries. (5) ► Allows for increased flow rate and lowered injection pressures. (3, 6) ► Facilitates a minimally invasive approach to interventional procedures. (3) 7 (3) Voeltz M et al, J Invasive Card, 2007. (4) Roth R et al, Cathet Cardiovasc Diag, 1991, 22:290-294. (5) Dawson P et al, 1999. (6) Eloy R et al, Clin Mater, 1991, 7:89-197.

8. Contrast Media Ionicity (Ionic Dimer) 8 ►Provides the antithrombotic and anticoagulant properties of an ionic contrast medium.*  No direct platelet activation. (7)  Acts against thrombin formation. (8, 9, 10)  Inhibits the formation of fibrin. (9, 11)  Inhibits blood coagulation, in vitro, more than non-ionic CM. (12)  Synergistic effects with abciximab. (7) (7) Al Dieri R et al, J of Thombosis and Hemostasis, 2003, 1:269-274. (8) Ing jj et al, Radiology, 1989, 172:345-348. (9) Kopko PM et al, Radiology, 1990, 174:459-461. (10) Fareed J et al, Radiology, 1990, 174:321-325. (11) Corot C et al, Blood Coagulation and Fibrinolysis, 1996, 7:602-608. (12) Ioxaglate Package Insert, Data on File. Guerbet LLC. * The clinical significance of this data is not known.

9. Physical Characteristics: Dimeric, Ionic Molecular Structure of Ioxaglate Antithrombotic/Anticoagulant Properties

10. Ioxaglate Characteristics: Thrombotic Risk and MACE ► Ioxaglate has been shown to reduce platelet accumulation in stents (in animals)*. (13) 10 * The clinical significance of this data is not known. (13) Markou CP et al, Thromb and Haemost, 2001, 85:488-493.

11. Antithrombotic and Anticoagulant Properties of Ioxaglate ► So what happens?

12. Collagen VWF INJURY Platelet Adhesion & Secretion Platelet aggregation Tissue Factor Coagulation Cascade Thrombin Fibrin Haemostatic plug Vaso- constriction Blood Vessel Endothelium Subendothelium Dr Isobel Ford Antithrombotic and Anticoagulant Properties of Ioxaglate

13. ► What are issues and concerns for interventional cardiologists?  This process can lead to occlusion of the vessels, such as coronary arteries during PCI  End point includes mortality  End point includes NSTEMI and STEMI Antithrombotic and Anticoagulant Properties of Ioxaglate

14. ► So what role does ioxaglate play? Antithrombotic and Anticoagulant Properties of Ioxaglate

15. ► Interface of ioxaglate with thrombosis generation: Ioxaglate, does not activate resting platelets, unlike nonionic monomers. Doesn’t direct platelets to change shape, release pro-coagulant mediators or to adhere to anything. This prevents/delays formation of the platelet clot. 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. Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelet plug. Antithrombotic and Anticoagulant Properties of Ioxaglate

16. ► Studies to be consulted: Resting Platelet Activation S Heptinstall et al. British Journal of Heamtology. 1998 N Chronos et al. Circulation. 1993 L Melton et al. Acad Rad.1995 JM Idee & C Corot. Fundam Clin Pharmacol. 1999 Inhibition of Thrombin and Fibrin Li and Gabriel. Acad Rad. 1997 JJ Ing et al. Radiology. 1989. PM Kopko et al. Radiology. 1990 J Fareed et al. Radiology. 1990 C Corot et al. Blood Coag and Fibrinolysis. 1996 R Al Dieri et al. Journal of Thrombosis and Hemostasis. 2003 CP Markou et al. Thrombo and Heamost. 2001. Antithrombotic and Anticoagulant Properties of Ioxaglate

17. Mechanism: Antithrombotic and Anticoagulant Properties Al Dieri, et. al., JOURNAL OF THROMBOSIS AND HEMOSTASIS, 2002 IONIC DIMER: Provides the antithrombotic and anticoagulant properties of an ionic contrast medium. Although precise clinical significance is not fully elucidated, ionic dimer ioxaglate has:  No direct platelet activation. (7)  Acts against thrombin formation. (8, 9, 10)  Inhibits the formation of fibrin. (9, 11)  Inhibits blood coagulation, in vitro, more than non-ionic CM. (12)  Synergistic effects with abciximab. (7) 17

18. Key Clinical Studies Grines C et al. J Am Coll Cardiol, 1996; 27:1381-1386 Le Feuvre C et al. Catheter Cardiovascular Intervention, 2006, 67:852-858. Antithrombotic and Anticoagulant Properties of Ioxaglate

19. ► GRINES STUDY, JACC, 1996 Randomized trial with 211 patients with AMI or UA undergoing coronary angioplasty (PCI), comparing ionic, low osmolar, ionic (ioxaglate) with nonionic low-osmolar (iohexol) 106 patients received, ioxaglate and 105 received iohexol End points monitored for 30 days Patients receiving ionic CM agent, ioxaglate, were significantly less likely to experience decreased blood flow during the procedure (8.1% for ioxaglate vs 17.8% for iohexol, p=0.04) Following procedure, residual stenosis, vessel patency, moderate to large thrombus and use of adjunctive thrombolytic therapy were similar in both groups 19 Antithrombotic and Anticoagulant Properties of Ioxaglate

20. ► GRINES STUDY (continued), JACC, 1996 HOWEVER, patients receiving ionic CM ioxaglate had fewer recurrent ischemic events requiring repeat catheterization: 3.0% for ioxaglate cohort, 11.4% for iohexol cohort (p=0.02) AND, patients receiving ionic CM ioxaglate had need for fewer repeat angioplasty during the hospital stay: 1.0% for the ioxaglate cohort, 5.8% for iohexol cohort (p=0.06) IN ADDITION: One month after angioplasty for acute ischemic syndromes, the group treated with an ionic, low-osmolar contrast agent, ioxaglate demonstrated fewer symptoms of angina (8.5% vs 20%); angina at rest (1.4% vs 11.8%); and a reduced need for bypass surgery (0% vs. 5.9%) compared to nonionic CM. 20 Antithrombotic and Anticoagulant Properties of Ioxaglate

21. Summary of Grines Study Thrombotic Risk and MACE ► “In patients with unstable ischemic syndromes undergoing coronary angioplasty, the use of ionic low osmolar contrast media (ioxaglate) reduces the risk of ischemic complications acutely and at 1 month after the procedure. And therefore, low osmolar, ionic contrast media should be strongly considered when performing interventions in patients with UA or MI. (14) 21 (14) Grines C et al. J Am Coll Cardiol, 1996; 27:1381-1386 (15) Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.

22. ► Antithrombotic and Anticoagulant Properties of Ioxaglate CLAUDE LE FEUVRE STUDY Catheterization and CV Interventions: 2006 PROSPECTIVE SINGLE-CENTER STUDY EVALUATING 498 CONSECUTIVE PATIENTS to assess cardiac events after LOW OSMOLAR IONIC (ioxaglate) CM vs isomolar nonionic (iodixanol) Evaluation of these TWO contrast media in the CURRENT PCI- CV-IC SETTING, i.e. against the backdrop of clopidogrel, UFH or LMWH, direct stenting, and DES. 231 patients received iodixanol and 267 received ioxaglate Baseline and procedural characteristics were matched in both groups 22 Antithrombotic and Anticoagulant Properties of Ioxaglate (CONTINUED) Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.

23. ► CLAUDE LE FEUVRE STUDY: Catheterization and CV Intervention: 2006 A peak anti-Xa level of >0.5 IU/ml was achieved in 97% of patients in both groups GP IIb/IIIa inhibitors were used in 42% of patients Coronary stenting was accomplished in 91% of patients Direct stenting in 70%; DES in 28% of patients RESULTS In-hospital MACE was more frequent in iodixanol patients as compared with those receiving ioxaglate: 4.8% MACE events in the iodixanol group and 0.3% in ioxaglate (p<0.0005) Primary driver of MACE events was the appearance of a large thrombus during PCI, observed in 6% of those using iodixanol vs 0.3% in those using ioxaglate (p<0.0001) Le Feuvre 23 Antithrombotic and Anticoagulant Properties of Ioxaglate C. Le Feuvre et al. Catheter Cardiovasc Intervention, 2006, 67:852-858. (CONTINUED)

24. ► CLAUDE LE FEUVRE STUDY: Catheterization and CV Interventions, 2006 MULTIVARIATE ANALYSIS: PREDICTORS OF MACE INCLUDED: —Use of nonionic isomolar iodixanol —Number of stents used —Ballon dilatation before stenting CONCLUSION IN A STUDY REFLECTING CURRENT PCI PRACTICES, THROMBUS-RELATED EVENTS ARE MORE FREQUENT WITH THE ISOMOLAR NONIONIC DIMER CM, IODIXANOL, THAN WITH THE LOW OSMOLAR IONIC AGENT, IOXAGLATE 24 Antithrombotic and Anticoagulant Properties of Ioxaglate Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.

25. Renal Studies: CIN Liss Study in Kidney International ►Swedish Coronary Angiography and Angioplasty Registry ►Total of 57,925 patients between 2000 and 2003 ►45,485 patients treated with iso-osmolar CM iodixanol ►12,440 subjects treated with ionic low-osmolar ioxaglate ►Incidence of clinically significant renal failure was greatest for patients receiving iso-osmolar CM iodixanol (1.7%) ►Incidence of clinically significant renal failure was significantly lower in ioxaglate (0.8%, p<0.001) ►Odds ratio for acquiring CIN was greater for iodixanol than for ioxaglate: OR was 1 for iodixanol vs. 0.48 for ioxaglate. 25 Liss P et al. Kidney International, 2006, 70:1811-1817

26. Renal Studies ►In subsets of patients with diabetics or previous renal failure, OR remained higher in greater in iodixanol groups. ►During study period, hospitals switching CM to iodixanol experienced a doubling in clinically significant renal failure after cardiac procedures. ►Dialysis was required in 0.2% of patients receiving iodixanol, which was significantly higher (p< 0.01) than for ioxaglate- treated patients (0.1%). ►CONCLUSION: In this Swedish Registry study, risk of developing renal failure, and need for dialysis, in patients undergoing coronary procedures was higher in patients who received iodixanol than those receiving ioxaglate. 26 Liss P et al. Kidney International, 2006, 70:1811-1817

27. ICON STUDY: 2009 ►ICON (Ionic vs non-ionic contrast to obviate worsening Nephropathy after angioplasty in chronic renal failure patients) ►Randomized, prospective double-blind multicenter study ►Compared nephrotoxicity of nonionic iso-osmolar CM iodixanol vs ionic, low-osmolar CM ioxaglate in patients with CRF undergoing angioplasty ►146 patients randomly assigned to iodixanol (n=72) or ioxaglate (n=74) ►Baseline characteristics matched, and predicted risk score for CIN was 11.9 for iodixanol and 11.8 for ioxaglate. ►N-acetylcysteine use was 70% and 73%, respectively 27 Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.

28. ICON STUDY-MEHRAN-JACC INT 2009 ►PRIMARY END POINT was median peak increase in serum creatinine from day 0-3 after angiography. ►Patients received active CIN protection with hydration and adjunctive medications ►The primary end points did NOT differ significantly between iodixanol and ioxaglate: —Median peak increase 0.09 for iodixanol vs 0.15 for ioxaglate —Peak increase of SCr > 0.5 mg/dl was 15.9% for iodixanol vs 18.2% for ioxaglate CONCLUSION: Use of non-ionic, iso-osmolar CM iodixanol does NOT reduce renal deterioration in patients with renal impairment compared with ionic low-osmolar ioxaglate 28 Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.

29. Two Renal Studies: Conclusions ► “In high-risk patients undergoing coronary angiographic procedures, use of the nonionic iso-osmolar CM Iodixanol does not reduce renal deterioration in patients with renal impairment, compared with the ionic low-osmolar CM ioxaglate.” (16) ► “The risk of developing renal failure has been shown to be lower with ioxaglate than with the iso-osmolar contrast medium iodixanol acutely and at 1 month.” (17) 29 (16) Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421. (17) Liss P et al. Kidney International, 2006, 70:1811-1817