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

2. 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)

3. Classification of iodinated contrast agents14 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 ( )
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 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)

4. 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"

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

6. Major Clinical Studies comparing ionic and non ionic contrast agents in cardiac applications ( )
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)

7. 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:

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

9. 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 ( )

10. 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 ( )

11. 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 ( )

12. 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,

13. 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,

14. 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 = ioxaglate = 2182
All other demographic data : NS differences between both groups
B. Scheller Eur Heart J (2001) 22,

15. 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,

16. 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,

17. 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,

18. 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

19. Non-ionic versus ionic CM on abrupt vessel closure and ischemic complications after angioplasty: a meta-analysis
p No.
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 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 Ionic Worse
Odds Ratio
Cucherat M et al. Am J Cardiol 1999; 84 (6A): 98P

20. 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.

21. 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:

22. 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:

23. 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:

24. 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:

25. 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:

26. 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:

27. 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:

28. 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:

29. 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

30. 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

31. 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

32. Baseline data (1) Iodixanol Ioxaglate p n 231 267 Age 64+/-12 63+/-11NS
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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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
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 p 857.

41. 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

42. 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 !

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

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