HEXABRIX Philippe HAVARD Hexabrix : Focus on clinical studies in interventional cardiology J-P Barraud

Clinical studies in interventional cardiology Focus usually on efficacy and safety (adverse events) of Devices: hundreds ! Drugs: many, including contrast media Strategies In different patient groups Acute coronary syndrome Unstable angina Stable angina Etc… Over different periods of time During the procedure During hospital stay Within 1 year or more …. Are based on results of : Randomized control trials (mono or multicentric) Registries (general or specific)

Classification of iodinated contrast agents 14 15 10-20 26 Diatrizoate Iothalamate Ioxaglate Iohexol Iopamidol Ioversol Iopromide Ioxilan Iodixanol Monomer Dimer Ionicity Ionic Non-ionic # Benzene Osmolality (mOsm/kg) Chemical Name High (>1500) Iso (280) Low (600-1000) The first human contrast angiogram is said to have taken place in 1919 and employed potassium iodide to opacify the veins of an upper extremity. Subsequently, a variety of other agents were utilized, each accompanied with considerable toxic potential. Selectan, the 1st organic iodide was introduced in 1929 and was followed by a number of modified compounds (eg Uroselectin, Diodrast). In the 1950's agents containing a fully substituted benzene ring containing 3 molecules of iodine was introduced. Since then, a variety of agents have followed that differ in several categories. Osmolality is the ratio of iodine molecules to osmotically active particles in the contrast agent. High osmolar agents have 3 iodine atoms for every 2 osmotically active agents (the cation and anion). Contrast agents in this group have >1500 mOsm/kg. Low osmolar contrast agents have osmolalities in the 600-1000 mOsm/kg range. This is achieved either by 6 iodine atoms per 2 osmotically active particles or by 3 iodine atoms per 1 osmotically active group. Efforts to further reduce osmolality lead to a class of contrast agents with 6 iodine atoms per 1 osmotically active group. After addition of sodium and calcium to the compound, this class possesses an osmolality of 290 mOsm/kg. The ionicity refers to the compound containing an ionizable group. All high osmolar contrast agents are ionic. However, the low osmolar agents can be either ionic or nonionic. The iso-osmolar contrast agents are currently nonionic. Further, the chemical structure of the commercial contrast agent contains either one or two benzene rings. Monomeric contrast agents contain one benzene ring whereas the dimeric contrast agents contain two benzene rings. Finally, the viscosity of the contrast agents differs according to its chemical structure and formulation with the iso-osmolar contrast agents having the highest viscosity. Viscosity (mPa.s) (20°C)

FDA recommendation Regulatory Authorities require the manufacturers of non-ionic contrast media to print each package insert with the following: "Non-ionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing non-ionic contrast media"

(One of) the cardiologists‘ nightmare The formation of thrombus during Angioplasties/ stenting procedures. Thrombo-embolic complications

Major Clinical Studies comparing ionic and non ionic contrast agents in cardiac applications (1990-2006) Lefevre, J Inv Card ‘98 (n=773) Qureshi, AJC ‘97 (n=30) Le Feuvre CCI ‘06 (n= 498) Scheller, EHJ ‘01 (n=3,990) Batchelor, AJC ‘00 (n=454) Chevalier, ACC ‘99 (n=1,713) Aguirre, JACC ‘95 (n=1930) Grines, JACC ‘96 (n=211 Bertrand, Circ ‘00 (n=1,411) Piessens, CCD ‘93 (n=500) Schrader, JACC ‘99 (n=2,000) Bertrand, Circ ‘92 (n=64) Malekianpour, AHJ ‘98 (n=210) Esplugas, AJC ‘91 (n=100) Davidson, Circ ‘00 (n=856) Lembo, AJC ‘91 (n=913) Gasperetti, JACC ‘91 (n=124) Favors Nonionic Neutral Favors Ionic Sutton, CCD ‘02 (n=618) There have been numerous clinical studies, with various study designs, comparing contrast media for percutaneous coronary interventions. This slide lists the major studies presented in the last decade. Overall, most study results have favored ionic contrast media over nonionics, however, several studies have shown no difference between agents, and only one recently reported clinical trial favored a nonionic contrast media. Fleisch, ACC ‘99 (n=1179)

Low Osmolar Ionic vs. Nonionic Contrast Media in Patients with Myocardial Infarction or Unstable Angina undergoing PTCA Grines C et al J Am Coll Cardiol 1996; 27: 1381-1386

Ionic vs. Non ionic Contrast Medium during PTCA for Acute Myocardial Infarction (GUSTO IIb) Batchelor WB et al. Am J Cardiol 2000; 85: 692-697

Impact of ionic (ioxaglate: Hexabrix) and non ionic (ioversol) LOCM on PTCA (1) Study design: Prospective, double-blind, randomized study 2870 consecutive patients (Bern university hospital, Switzerland) End-points: Any cardiac complications Death MI Repeat PTCA Number of stented patients Number of patients who received ReoPro (abciximab = GpIIa IIIb inhibitor) Fleisch M et al. J Am Coll Cardiol 1999; 33:(suppl A), 85 A (1188-92)

Impact of ionic (ioxaglate: Hexabrix) and non-ionic (ioversol) LOCM on PTCA (2) Results: 1179 PTCA 542 stented patients Note: * = statistically significant difference Fleisch M et al. J Am Coll Cardiol 1999; 33:(supplA),85 A (1188-92)

Conclusions Use of ioxaglate for PTCA is associated with Impact of ionic (ioxaglate) and non ionic (ioversol) LOCM on PTCA: related complications Conclusions Use of ioxaglate for PTCA is associated with A reduced risk of cardiac complications: thrombotic coronary artery occlusions, MI, repeat-PTCA Reduced use of stents (especially in the group of at risk patients) ReoPro (abciximab = anti GpIIb/IIIa) Fleisch M et al. J Am Coll Cardiol 1999; 33:(suppl A), 85 A (1188-92)

Contrast Media and Risk Reduction of Stents Occlusion Study design prospective, inclusion period 4.5 years coronary angiography with non ionic CM interventional procedure with stent implantation with ioxaglate in 1,808 patients or a non ionic (6 types) in 2,182 patients. Primary end point acute (< 72 hrs) and subacute (< 30 days) stent thrombosis Secondary end point combined clinical endpoint: death, CABG, target lesion revascularization (TLR) Scheller B. et al. Eur Heart J (2001) 22, 385-391

Acute Stent Occlusion (AOS) Coronary Stenting, ASA (aspirin) + Ticlopidine n=3,990 pts P = 0.001 Scheller B. et al. Eur Heart J (2001) 22, 385-391

Acute coronary syndrome Patients Demographics Acute coronary syndrome 34,2% 32,3% 24,9% 21,3% 9,3% 11,0% 0% 10% 20% 30% 40% Acute Coronary Syndrom Unstable angina Acute MI nonionic Ioxaglate ns # patients : nonionic CM = 1808 ioxaglate = 2182 All other demographic data : NS differences between both groups B. Scheller Eur Heart J (2001) 22, 385-391

Primary endpoint 4% 3% 2% 1% 0% Acute Stent Thrombosis 1,3% 0,3% 2,4% 0,7% 0% 1% 2% 3% 4% Acute Stent Thrombosis Subacute Stent Thrombosis nonionic Ioxaglate p=0.001 B. Scheller Eur Heart J (2001) 22, 385-391

Combined endpoint 12 months follow-up 22,9% 16,3% 16,6% 10,5% 1,2% 1,4% 6,1% 5,0% 0% 5% 10% 15% 20% 25% combined TLR CABG death nonionic Ioxaglate p=0.001 p=0.077 ns B. Scheller Eur Heart J (2001) 22, 385-391

Conclusion When ioxaglate was used  significant reduction of: Acute and subacute stent thrombosis Target lesion revascularization (TLR) « A possible explanation of this finding could be the inhibitory effect of ioxaglate on thrombin, which plays an important role in the process of in-stent restenosis due to its mitogenic potential on smooth muscle cells ». The number of patients with clinical symptoms or positive noninvasive tests within 6 months was lower in the group receiving Ioxaglate, as reflected in the decreased need for repeat angiography. In these selected patients, binary restenosis rate was significantly reduced with the use of Ioxaglate. A possible explanation for this finding could be the inhibitory effects of Ioxaglate on thrombin, which plays an important role in the process of instent restenosis due to its mitogenic potential on smooth muscle cells. But, our study is limited concerning the restenosis rate because only 52 % of the patients underwent reangiography. A prospective randomized trial with respect to restenosis rate in relation to different contrast agents is needed. B. Scheller Eur Heart J (2001) 22, 385-391

Only randomized clinical trials from 1990 to 1999 Non-ionic versus ionic CM on abrupt vessel closure and ischemic complications after angioplasty: a meta-analysis Only randomized clinical trials from 1990 to 1999 Total of 6176 patients Ioxaglate versus non-ionic monomer: 4490 patients Ioxaglate versus non-ionic dimer (Visipaque): 2226 patients Cucherat M et al. Am J Cardiol 1999; 84 (6A): 98P

Non-ionic versus ionic CM on abrupt vessel closure and ischemic complications after angioplasty: a meta-analysis p No. 0.10 5567 0.03 3341 0.60 2226 0.78 Ionic vs. Nonionic Overall 0.68 Ionic vs. Nonionic Monomer 1.18 Ionic vs. Nonionic Dimer A recent meta-analysis pooling data from all legitimate randomized clinical trials published in the literature from 1985-2000 used a fixed effects model to compare the clinical outcomes between ionic and nonionic contrast media, overall, and separately for the nonionic monomers and dimers. The results of this meta-analysis are shown here for the hard endpoint of abrupt closure. Overall, ionic agents were associated with a 22% reduction in risk compared with non-ionic media. However, heterogeneity did exist, such that the greatest difference in outcome observed between ionic contrast media and the nonionic monomers, where a statistically significant 32 % risk reduction was found. Interestingly, no significant difference in the risk of abrupt closure could be shown between ionic contrast media and nonionic dimers. Ionic Better 1 Ionic Worse Odds Ratio Cucherat M et al. Am J Cardiol 1999; 84 (6A): 98P

Non-ionic versus ionic CM on abrupt vessel closure and ischemic complications after angioplasty: a meta-analysis CONCLUSIONS ioxaglate vs nonionic monomers A reduction by 32 % of abrupt closure in patients population who received ioxaglate compared to non-ionics. ioxaglate vs non-ionic dimer : iodixanol (Visipaque) Results of 2 trials (COURT and VIP) seem to be discordant, preventing any clear conclusion.

To compare angiographic outcomes between the 2 contrast media The COURT Study Objectives To compare in-hospital and 30 day MACE in Acute Coronary Syndrome patients receiving ioxaglate vs. iodixanol for PCI To compare angiographic outcomes between the 2 contrast media Methods Study patients: Unstable Angina Pectoris (UAP) or Myocardial Infarct (MI) requiring PCI Timeframe: May 97-July 98 “Double-blind”, randomized trial Davidson, et al. Circulation 2000; 101: 2172-2177

COURT: Study Design 41 Non-evaluable excluded from analysis *Not intention-to-treat (13 U.S. sites) 856 ACS Patients Iodixanol n=405 Ioxaglate n=410 Final n=815 Heparin Discretionary Abciximab PCI Primary Endpoint: In-hosp Composite “Thrombotic Events” Secondary Endpoints: In-hosp and 30 day Clinical and Angio Davidson, et al. Circulation 2000; 101: 2172-2177

COURT: Sample Size and Power Minimum Sample Size Required (assuming  = 0.05, 1 -   0.90) Control Event Rate Active Treament Event Rate (RRR) Minimum Sample Size Required IIb/IIIa Trials 15% 11% (25) ~5000 9% (45) ~1300 COURT 1º Endpoint 9.5% 7.1% (25) ~5200 5.5% (42) ~2000 COURT death/MI/UR 6.8% 4.4 (30) ~5500 Davidson, et al. Circulation 2000; 101: 2172-2177

COURT: Endpoint Selection Traditional MACE: Death/MI/Urgent Rev: Standard used in antithrombotic trials COURT MACE: Any of the following: Stroke/Transient ischemic attack (TIA = ministroke) Arterial systemic thromboembolic event Emergent Recatheterization Any repeat revascularization Urgent CABG Abrupt Closure Cardiac Death Nonfatal MI Davidson, et al. Circulation 2000; 101: 2172-2177

COURT Trial Adjudicated Results Iodixanol Ioxaglate N % p-Value Emergency recath/ revasc 9 2.2 16 3.9 NS Abrupt closure 3 0.7 10 2.4 Stroke / TIA 1 0.2 Thromboembolic event 2 0.5 4 1.0 Cardiac death 5 0.0 0.10 Non-fatal MI 8 2.0 18 4.4 Emergency CABG Composite outcome 21 5.2 39 9.5 0.03 Composite outcome (30d) 13 Traditional MACE 4.6 Primary Clinical Outcomes Davidson, et al. Circulation 2000; 101: 2172-2177

COURT Trial Angio Core Lab Iodixanol (n=405) Ioxaglate (n=410) Abrupt closure 1 (0.3) 4 (1.0) No reflow 3 (0.8) Distal embolization 2 (0.5) Side branch occlusion 6 (1.5) 6 (1.6) Thrombus development TIMI-3 flow 99% Angiographic Outcomes (all p = ns) No Apparent Difference In Thrombus Davidson, et al. Circulation 2000; 101: 2172-2177

COURT: Primary Treatment Device Iodixanol (n=405) Ioxaglate (n=410) Balloon 248 (61) 244 (60) Stent 127 128 Rotablator 24 23 Laser/DCA 3 12* Abciximab 171 (42) 174 (42) *Debulking procedures more often performed in Ioxaglate group Davidson, et al. Circulation 2000; 101: 2172-2177

COURT Study: Conclusions First and only Randomized Control Trial to show improved clinical outcomes with a nonionic CM vs. ionic CM. Significant reduction in 7 component 1º endpoint favoring Iodixanol. Limitations Lack of intention to treat design Statistical power Relevance of endpoint selection Mortality paradox Statistical robustness lacking Suboptimal PTCA in Ioxaglate group may provide more plausible explanation for differences in outcome Davidson, et al. Circulation 2000; 101: 2172-2177

Published in Catheterization and Cardiovascular Interventions (2006) Cardiac Events After Low Osmolar Ionic and Isosmolar Non-ionic Contrast Media Utilization in the Current Era of Coronary Angioplasty Claude Le Feuvre, Anne Batisse, Jean P. Collet, Jean P. Batisse, Rémy Choussat, Farzin Beygui, Gérard Helft, Gilles Montalescot and Jean P Metzger Cardiology Department, Pitié-Salpêtrière Hospital, Paris Le Feuvre et al. Cardiac Catheter Intervent. 2006

Hexabrix® versus Visipaque® in PCI Prospective, monocentric study, all patients undergoing Percutaneous Coronary Interventions (PCI) for 6 months Monthly allocation of Visipaque 320 (iodixanol) in months 1, 3, 5 or Hexabrix® 320 (ioxaglate) in months 2, 4, 6 Inclusion of 498 consecutive patients Aspirin + clopidogrel for all patients + low molecular weight heparin enoxaparin (Lovenox) (1 mg/kg BID SC or bolus of 0.5 mg/g just before PCI) Direct stenting or use of GPIIb/IIIa inhibitors left at the discretion of the operator Le Feuvre et al. Cardiac Catheter Intervent. 2006

Hexabrix® versus Visipaque in PCI: (2) Primary endpoint: cumulative rate of major adverse cardiac events (MACE) during the hospital stay: Cardiac death Recurrent non fatal acute MI Emergency CABG or repeat PCI Stroke or systemic thromboembolic events Secondary endpoint: cumulative rate of composite angiographic or procedural complications during or immediately after PCI Clinical outcomes assessed: At hospital discharge And by telephone at 30 days Le Feuvre et al. Cardiac Catheter Intervent. 2006

Baseline data (1) Iodixanol Ioxaglate p n 231 267 Age 64+/-12 63+/-11 NS Male 189 (82%) 211 (79%) Diabetes mellitus 64 (28%) 92 (34%) Hypertension 121 (53%) 133 (50%) Smoking history 94 (41%) 97 (36%) LDL cholesterol >3,3 mmol/l 162 (70%) 184 (69%) Family history of CAD 46 (20%) 51 (19%) Le Feuvre et al. Cardiac Catheter Intervent. 2006

Baseline data (2) Iodixanol Ioxaglate p n 231 267 Prior CABG 16 (7%) 23 (9%) NS Prior MI 46 (20%) 63 (24%) Prior left ventricular failure 29 (13%) 27 (10%) PCI for acute MI 57 (25%) 74 (28%) PCI for unstable angina 37 (16%) 58 (22%) PCI for silent myocardial ischaemia Le Feuvre et al. Cardiac Catheter Intervent. 2006

Baseline angiographic data Iodixanol Ioxaglate p Volume of contrast medium (ml) 267+/-125 276+/-120 NS Peak antiXa > 0,5 UI/ml 224 (97%) 259 (97%) Anti Gp IIb/IIIa 99 (43%) 112 (42%) One vessel PCI 192 (83%) 219 (82%) Two vessels PCI 37 (16%) 43 (16%) Three vessels PCI 2 (1%) 5 (2%) Failure to cross the lesion 6 (3%) 10 (4%) Use of intra-aortic balloon pump 16 (7%) 11 (4%) Le Feuvre et al. Cardiac Catheter Intervent. 2006

Baseline angiographic data (2) Iodixanol Ioxaglate p Balloon 10 (4%) 17 (6%) NS Stent 215 (93%) 240 (90%) One stent / patient 143 (63%) 162 (61%) Two stents / patient 47 (20%) 54 (20%) Three stents / patient 16 (7%) 15 (6%) >/4 stents / patient 9 (4%) 9 (3%) Direct stenting 159 (69%) 187 (70%) Drug eluting stent 69 (30%) 72 (27%) Le Feuvre et al. Cardiac Catheter Intervent. 2006

Results: Primary endpoint and clinical outcome Iodixanol (Visipaque®) Ioxaglate (Hexabrix®) p In-hospital outcome n (%) Cardiac death 2 (0.8%) NS Non fatal MI or re-infarction 7 (3%) 1 (0.3%) 0.05 Emergency repeat PCI 3 (1.3%) Emergency CABG 1 (0.4%) Stroke or systemic thromboembolic event Composite outcome: PRIMARY ENDPOINT 11 (4.8%) 0.005 30-day outcome n (%) Non fatal MI or reinfarction 4 (1.7%) Composite outcome: CLINICAL OUTCOME 13 (5.6%) 0.002 Le Feuvre et al. Cardiac Catheter Intervent. 2006

Results: Angiographic and procedural complications during or immediately after PCI Iodixanol 6 Ioxaglate 5 4 % 3 2 1 Large thrombus Target vessel occlusion Le Feuvre C et al. Catheter cardiovasc Intervention 2006

Results: Angiographic and procedural complications during or immediately after PCI (2) Iodixanol Ioxaglate p Large thrombus (>2 vessel Ø) 14 (6%) 1 (0,3%) 0,0001 Target vessel occlusion 12 (5,2%) 0,003 Side branch occlusion (>2 mm) 2 (0,9%) NS Composite: MAIN SECONDARY ENDPOINT Sustained ventricular arrhythmia Hypotension with intervention 4 (1,7%) 4 (1,5%) Renal failure requiring treatment 3 (1%) Le Feuvre et al. Cardiac Catheter Intervent. 2006

Independent predictors of in-hospital MACE (multivariate analysis) Hexabrix® versus Visipaque in PCI: Le Feuvre et al. Catheter Cardiovasc intervention 2006 Independent predictors of in-hospital MACE (multivariate analysis) Use of Visipaque Bifurcation/ostial lesion Higher number of stents used Balloon dilation before stenting Le Feuvre et al. Cardiac Catheter Intervent. 2006

COURT (2000) versus Le Feuvre et al COURT (2000) versus Le Feuvre et al. (2006): Similar criteria but different environment ! COURT Le Feuvre et al Type of study Prospective, multicentric Prospective, monocentric Number of patients 856 498 Year of enrollment 1997-98 2004 MACE Cardiac death, perprocedural nonfatal MI, unplanned CABG, repeat PCI for documented ischemic ECG change, stroke, abrupt closure of target vessel, systemic arterial thromboembolic event Cardiac death, recurrent nonfatal acute MI, emergency CABG, repeat PCI for documented ischemic ECG change, stroke or systemic thromboembolic event anti-coagulant Standard UFH Lovenox (enoxaparin: Low Molecular Weight Heparin) Direct stenting 31% 70% Drug-eluting stent 28% Anti-GPIIb/IIIa 42% 43% Davidson et al. (COURT) Circulation 2000; Le Feuvre et al. Cardiac Catheter Intervent. 2006 p 857.

Conclusion «In our study reflecting the current era of PCI, thrombus-related events are more frequent with the iso-osmolar non-ionic dimer iodixanol (Visipaque) than with the low osmolar ionic agent ioxaglate (Hexabrix®)» Le Feuvre et al. Cardiac Catheter Intervent. 2006, p 852

Summary The environment of the cathlab has changed from the late 90s to 2008 The late 90s: Devices: PTCA Anti thrombotic drugs: UFH Anti platelet drugs: aspirin 2008: Devices: stents, including 73% Drug eluting stents in the US (Source: GW Stone, EuroPCR08) Anri thrombotics: UFH, LMWH, bivalirudin, fondaparinux Anti platelet drugs: aspirin, clopidogrel, GpIIb IIIa inhibitors The use of Hexabrix is still associated with good safety !

Main message  Hexabrix® poster on the Guerbet booth at EuroPCR 07 and EuroPCR 08

Explanations of these results will be Reviewed during a future session . Thank you for your attention !