HEXABRIX (2) HEXABRIX SIGNIFICANT STUDIES

T. Peyroux February 2005

Comparative effects on thrombotic material on angioplasty devices

Lefevre T et al. Arch Mal Cur 1994; 87: 225-223

Thrombotic material deposit on angioplasty devices

Lefevre T et al. Arch Mal Cur 1994; 87: 225-223

A comparative primates study (1)

Baboon AV stent thromb model (n=14) CM infusion: 0.1 and 0.3ml/min Ioxaglate Iodixanol Iohexol In-situ Thrombus Assessment gross Radiolabeled platelets and fibrin scanning EM
Markou et al, Thromb Haemost 2001;85:488-93

A comparative primates study (2)

A comparative primates study (3) Stent / 0.3 ml/min

2 1.5

Fibrin (mg)

1 0.5 0
H ex ab rix e e si pa q

m ni pa qu

sa lin

ue

Vi

A comparative primates study (4)

Results

Saline

Iodixanol

Iohexol

Ioxaglate

70% reduction in thrombus (both platelet and fibrin deposition)

Flow Direction I = 0.3ml/min

Saline

Iodixanol

Iohexol

Ioxaglate

Low

High

Magnification

Impact of ionic (ioxaglate) and nonionic (ioversol) low osmolar contrast media on PTCA
Study design: Prospective, double-blind, randomized study 2870 consecutive patients. End-points : Any cardiac complications Death MI Repeat PTCA # of stented patients # of patients who received ReoPro.
Fleisch M et al J Am Coll Cardiol 1999; 33:(supplA),85 A (1188-92)

Impact of ionic (ioxaglate) and nonionic (ioversol) low osmolar contrast media on PTCA
Results: 1179 PTCA 542 stented patients

Fleisch M et al J Am Coll Cardiol 1999; 33:(supplA),85 A (1188-92)

Impact of ionic (ioxaglate) and nonionic (ioversol) low osmolar contrast media on PTCA. Related complications.
CONCLUSIONS Use of ioxaglate for PTCA is associated with A reduced risk of cardiac complications : thrombotic coronary artery occlusions, MI, re-PTCA Reduced use of stents (especially in the group of risk patients) and ReoPro.
Fleisch M et al J Am Coll Cardiol 1999; 33:(supplA),85 A (1188-92)

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (1)

Double blind randomized study. Inclusion criteria: subjects with ischemic syndromes (stable or unstable) or silent ischemia scheduled to undergo PTCA, including optional implantation of stent. Exclusion: Acute MI subjects (< 7 days after occurrence of symptoms). 1541 analysed patients.

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (2)

Objectives: Primary objective: to assess the influence of the contrast medium factor (Visipaque vs Hexabrix 320) and other factors as predictors for the occurence of major clinical complications in subjects undergoing PTCA. Secondary objective : to evaluate the overall safety profile of the 2 contrast media.

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (3)

Follow-up end-points: In hospital (2 days after the PTCA) : death, stroke, MI (Q-Wave and non Q-Wave), CABG and re-PTCA. 1 month after the PTCA (by telephone only) 1 month follow-up: Takes into account only major cardiac adverse events requiring patient rehospitalization. no evaluation of possible delayed reactions.

VIP Study (Visipaque In PTCA) (4) Results

MACE: death, stroke, Q-wave MI, non-Q-wave MI, CABG, RePTCA
Iodixanol N = 697 MACE 2-day followup Rehospitalization on 1 month follow-up MACE 1 month follow-up 4.7 % Ioxaglate N = 714 4.7 % p-Value

NS

2.0 %

1.3 %

NS

6.3 %

5.2 %

NS

Bertrand, et al. Circulation 2000; 101: 131-6

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (5)

Other comments: no evaluation of the renal function 136 patients have experienced 159 severe adverse events : --> 78 patients with Visipaque --> 58 patients with Hexabrix. Country was a major predictor of MACE => This higlights differences of procedures among the 5 countries No significant statistical difference in the MACE rate does not mean the products are equivalent

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (6)

Dissections and abrupt closure were also predictors of MACE and severe kind of lesion was borderline Procedure related dissections were slighly less important in the Visipaque group => This is operator dependant ! More hypersensitivity in the Hexabrix group but only 1 patient out of 197 had vomiting sideeffects. These are minor and occur before patients discharge vs delayed reactions with Visipaque.

VIP STUDY (EUROPE) VISIPAQUE VS HEXABRIX (7)

Last but not least : the majority of quoted references in the introduction and conclusion refer to pre and clinical studies which are positive for Hexabrix !!

The COURT Study

Objectives

To compare in-hospital and 30 day MACE in ACS patients receiving ioxaglate vs. iodixanol for PCI To compare angiographic outcomes between the 2 CM
Methods

Study patients: UAP or 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 Iodixanol n=405 n=405

Ioxaglate Ioxaglate n=410 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 IIb/IIIa Trials COURT 1 Endpoint 15% 9.5% Active Treament Event Rate (RRR) Minimum Sample Size Required ~5000 ~1300 ~5200 ~2000 ~5500

11% (25) 9% (45) 7.1% (25) 5.5% (42)

COURT death/MI/UR

6.8%

4.4 (30)

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/TIA 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
Primary Clinical Outcomes
Emergency recath/ revasc Abrupt closure Stroke / TIA Thromboembolic event Cardiac death Non-fatal MI Emergency CABG Composite outcome Composite outcome (30d) Traditional MACE N 9 3 1 2 5 8 2 21 % 2.2 0.7 0.2 0.5 0.7 2.0 0.5 5.2 9 2.2

Ioxaglate
N 16 10 1 4 1 18 3 39 % 3.9 2.4 0.2 1.0 0.0 4.4 0.7 9.5 13 4.6 p-Value NS NS NS NS 0.10 NS NS 0.03 NS NS

Davidson, et al. Circulation 2000; 101: 2172-2177

COURT Trial Angio Core Lab

Angiographic Outcomes
Abrupt closure No reflow Distal embolization Side branch occlusion Thrombus development TIMI-3 flow

Iodixanol (n=405) 1 (0.3) 3 (0.8) 2 (0.5) 6 (1.5) 0 99%

Ioxaglate (n=410) 4 (1.0) 3 (0.8) 1 (0.3) 6 (1.6) 0 99%

No Apparent Difference In Thrombus

(all p = ns)

Davidson, et al. Circulation 2000; 101: 2172-2177

COURT: Primary Treatment Device

Iodixanol (n=405) Ioxaglate (n=410)

Balloon Stent Rotablator Laser/DCA Abciximab

248 (61) 127 24 3 171 (42)

244 (60) 128 23 12* 174 (42)

*Debulking procedures more often performed in Ioxaglate group

Davidson, et al. Circulation 2000; 101: 2172-2177

COURT Study: Conclusions

First and only RCT to show improved clinical outcomes with a nonionic CM vs. ionic CM. Significant reduction in 7 component 1 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

Our counter-attack
Versus the COURT trial: Only trial showing Visipaques superiority Highlight all the flows Detail Hexabrix experience:
Reduction of stent thrombosis (Scheller) Reduction of abrupt closures (Cucherats metaanalysis) Decades of experience

less thrombo-embolic events.

Contrast media and risk reduction of stents occlusions

Study design
prospective, inclusion period 4.5 years coronary angiography with nonionic CM interventional procedure with stent implantation

Primary end point

acute (< 72 hrs) and subacute (< 30 days) stent thrombosis

Secondary end point

combined clinical endpoint (death, CABG, TLR)
B. Scheller Eur Heart J (2001) 22, 385-391

Patients Demographics
Acute coronary syndrome
# patients : nonionic CM = 1808 ioxaglate = 2182 40% 30% 20% 10% 0%
34,2%
ns

32,3%

nonionic ns

Ioxaglate

24,9% 21,3%
ns

9,3% 11,0%

Acute MI Acute Coronary unstable angina Syndrom All other demographic data : NS between both groups
B. Scheller Eur Heart J (2001) 22, 385-391

Primary endpoint
4% 3% 2% 1% 0%
p=0.001 nonionic Ioxaglate

2,4%

p=0.001

1,3% 0,7% 0,3%

Acute Stent Thrombosis Subacute Stent Thrombosis

B. Scheller Eur Heart J (2001) 22, 385-391

Combined endpoint 12 months follow-up

25% 20% 15%
10,5% 22,9%
p=0.001 p=0.001 nonionic Ioxaglate

16,3%

16,6%

10% 5% 0% combined TLR

ns

p=0.077

6,1% 1,2% 1,4%

5,0%

CABG

death

B. Scheller Eur Heart J (2001) 22, 385-391

Conclusion 1

When ioxaglate was used significant reduction of: Acute and subacute stent thrombosis Target lesion revascularization 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 .

B. Scheller Eur Heart J (2001) 22, 385-391

Conclusion 2
Limitations of this study

no double blind randomization no routine reangiography

Largest comparative study ionic vs nonionic LOCM n = 3990 Focusing on coronary stenting
B. Scheller Eur Heart J (2001) 22, 385-391

A significant reduction in bail-out stenting

A randomised trial of 618 patients
Sub-group of pts with ACS or acute MI: composite outcome in 17.2% of pts receiving Hexabrix vs. 24.8% of patients receiving Visipaque (p = 0.17). For all patients:

Visipaque 320 n = 307 pts

Hexabrix 320 n = 311 pts

Lab success

96.7% 6.8% 8.1% 4.6% 2.0% 17.9%

93.9% 3.2% 5.5% 3.2% 0.6% 14.8%

0.09 0.05 0.19 0.39 0.15 0.29

Bailout stent ReoPro MI Death in hospital Combined endpoint

Sutton et al. Cath Cardiovasc Diagn 2002; 57: 346-352

Nonionic vs. Ionic Contrast Media on Abrupt Vessel Closure and Ischemic Complications after Angioplasty: a Metaanalysis
Only randomized clinical trials from 1990 to 1999 Total of 6176 patients ioxaglate vs. nonionic monomer: 4490 patients ioxaglate vs. nonionic dimer: 2226 patients
Cucherat M et al. Am J Cardiol 1999; 84 (6A): 98P

Nonionic vs. Ionic Contrast Media on Abrupt Vessel Closure and Ischemic Complications after Angioplasty: a Metaanalysis
p No. 5567

Ionic vs. Nonionic Overall Ionic vs. Nonionic Monomer Ionic vs. Nonionic Dimer Ionic Better
0.6 8

0.7 8

0.10

0.03

3341

1. 18

0.60

2226

1 Odds Ratio

Ionic Worse

Cucherat M et al. Am J Cardiol 1999; 84 (6A): 98P

Nonionic vs. Ionic Contrast Media on Abrupt Vessel Closure and Ischemic Complications after Angioplasty: a Metaanalysis CONCLUSIONS ioxaglate vs nonionic monomers A reduction by 32 % of abrupt closure in patients
population who received ioxaglate compared to nonionics.

ioxaglate vs nonionic dimer : iodixanol Results of 2 trials (COURT and VIP) seem to be
discordant, preventing any clear conclusion.

Hexabrix specific clotting properties have been acknowledged by MOH in different countries. (North America and Europe)

FDA RECOMMENDATION

Regulatory Authorities require the manufacturers of Nonionic contrast media to print on every package insert the following :
" Nonionic

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 nonionic contrast media".

Extract of Hexabrix SPC in the Netherlands

It has been demonstrated in vitro that Hexabrix 320 exerts a stronger anticoagulant effect than low-osmolar, non-ionic contrast media. With use of the latter substances, cases have been reported in which in vitro blood clots occurred in catheters or syringes. It has also been demonstrated that Hexabrix 320 induced no platelet activity (no release of pro-coagulant factors) and inhibits the platelet aggregation, in contrast to non-ionic contrast media.

Contrast media and co-medications

Clopidogrel GPIIb IIIa Bivalirudin

Comparative effects of ionic and non-ionic CM on a FeCl3-induced model of thrombosis in the rat

Carotid artery Ultrasonic flow probe

Deposit of a filter paper soaked in FeCl3 applied to the ventral surface of carotid artery, distal to an ultrasonic flow probe Ide et al Am J Cardiol 2001;88:116G and Investigative Radiology 2003; 38: 34-43

The combination of inactive doses of ioxaglate and clopidogrel increased TTO vs. control groups.
50

*
Time To Occlusion (min) 40

30

20

10

0
GA Saline GA Ioxaglate GA Iohexol Clopidogrel Saline Clopidogrel Ioxaglate Clopidogrel Iohexol

Ide et al Am J Cardiol 2001;88:116G and Investigative Radiology 2003. 38: 34-43

GPIIb IIIa inhibitors (antiplatelet drugs)

GPIIb/IIIa inhibitors (antiplatelet drugs)

ReoPro (abciximab)

The 1st agent introduced into the market-place. Well-known as the reference. Molecule owned by Centocor (J&J). Commercialized by Centocor and Eli Lilly. Very expensive (around 1300 US$/patient dose).
Aggrastat (tirofiban)

Recently introduced into the market. Molecule owned and sold by Merck. Cost around 600 US$/patient dose.
Integrilin (eptifibatide)

Launched simultaneously as Aggrastat. Molecule owned and sold by Schering-Plough. Cost around 600 US$/patient dose.

Why do cardiologists inject GPIIb IIIa inhibitors to their patients ?

Placebo versus ReoPro

Placebo versus Integrilin

Placebo versus Aggrastat

Anticoagulant and antiplatelet effect of an ionic iodinated contrast medium, but not of a non-ionic one
In-vitro study Methodology : to measure thrombin generation in platelet rich plasma (PRP)

successively mixed with one of 3 solutions control ioxaglate (Hexabrix) iodixanol (Visipaque) mixed or not with ReoPro.
R. Al Dieri et al. Am J Cardiol 2000; 86 (suppl. 8A): 100 i (TCT-260) R. Al Dieri et al. Journal of Thrombosis and Haemostasis 2003, 1:269:274

Anticoagulant and antiplatelet effect of an ionic iodinated contrast medium, but not of a non-ionic one.
Results : Ioxaglate Inhibits Thrombin Generation in Platelet Rich Plasma Much More than Iodixanol

R. Al Dieri et al. Am J Cardiol 2000; 86 (suppl. 8A): 100 i (TCT-260) R. Al Dieri et al. Journal of Thrombosis and Haemostasis 2003, 1:269:274

Anticoagulant and antiplatelet effect of an ionic iodinated contrast medium, but not of a non-ionic one.

"ioxaglate strongly boosts the effect of the GPIIb IIIa inhibitor (abciximab) whereas iodixanol does not."
R. Al Dieri et al. Am J Cardiol 2000; 86 (suppl. 8A): 100 i (TCT-260) R. Al Dieri et al. Journal of Thrombosis and Haemostasis 2003, 1:269:274

EPIC TRIAL
Multicentric study : 60 investigating centers Total : 1930 patients
Placebo Outcome
Post-PTCA thrombus (%) Q-wave MI (%)+ Emergent CABG (%)+ Death (%)+

c7E3Fab
Non-ionic Ionic (n=380) (n=505) Non-Ionic (n=788)

Ionic (n=257)

17 1.6 2.7 0.4

18 3.2 4.5 1.6

15 0.2 2.0 0.4

15 1.4 2.5 1.4

+in-hospital;MI=myocardial infa rction;CABG=coronary bypass surgery

"After controlling for c7E3Fab randomization by logistic regression, ionic contrast agents were associated with a lower probability of Q-wave MI (odds ratio: 0.32;p=0.012) and death (odds ratio:0.27;p=0.016)."
F.V. Aguirre et al. Impact of nonionic contrast media on post-PTCA ischemic complications : results from the EPIC Trial JACC 1995, suppl - abstract 901-14

EPIC TRIAL - Comments

Despite of its limitations (post-hoc study - secondary analysis) The EPIC Trial :
suggests that the combined use of ionic contrast media and abciximab reduce major cardiac complications. may confirm in-vitro studies which suggest a potentialisation of Hexabrix and ReoPro's effects.

CONCLUSION
Abciximab is not "a miracle-drug" due to the variability of its effects observed in different studies. Nonionic monomers activate platelets (which release granules activating platelets) and do not influence thrombin generation. Iodixanol delays platelet activation. => In this case, cardiologists would only be relying on ReoPro's effects.
ON THE CONTRARY

ioxaglate inhibits thrombin formation and platelet activation. abciximab only has a potent effect upon GPIIb IIIa receptors located on the platelets' surface. => we may suggest that : ioxaglate's and abciximab's effects may be fully complementary the combined use of these 2 drugs may be the best insurance against thrombo-embolic complications.

Bivalirudin
Is a direct inhibitor of thrombin Seems to generate less bleeding than heparin Was registered by the FDA in December 2000 for PCI Commercial name: Angiomax Manufactured and sold by the Medicines Company, Cambridge MA - USA

A sub-analysis of Replace I (1)

Objective
To define the potential impact of the combination:

Contrast agents GpIIbIIIa Heparin / bivalirudin On ACTduring PCI

Methodology
All patients randomized to receive unfractioned heparin or bivalirudin Use of ionic/non-ionic based on operators preference Use of adjunctive GpIIbIIIa inhibitors was discretionnary

J.P. Reginelli at al JACC 2002;vol.39n5 p49 nll48.5

A sub-analysis of Replace I (2)

Results
1033 patients undergoing PCI in the REPLACE I trial. Analysis restricted to 798 patients recorded at the time of stent deployment. Clinical patients characteristics were similar Use of ionic contrast associated with ACT prolongation in patients receiving both abciximab and bivalirudin 80 % of the patients received ReoPro.

J.P. Reginelli at al JACC 2002;vol.39n5 p49 nll48.5

A sub-analysis of Replace I (3)

Measure of ACT (in seconds) at the time of stent deployment

Ionic contrast Bivalirudin Bivalirudin + ReoPro 395+/-144 (n=77) 460 +/- 189 (n=29)

Non ionic contrast 359+/- 82 (n = 319) 348 +/- 71 (n=305)

P value NS 0.01

This study demonstrates a potentialisation on ACT of ionic contrast combined with bivalirudin and ReoPro
J.P. Reginelli at al JACC 2002;vol.39n5 p49 nll48.5

Contrast Media and Stents

80 % of stented patients Bare metal stents New drug eluting stents (DES) Other avenues

New DES
Coated with Sirolimus or Paclitaxel Significant reduction of in-stent thrombosis by anti-proliferative drugs coated on the stent. 2 leading-companies : Cordis (J&J) and Boston Scientific.

Other avenues

Heparin coated stents Stents with thinner struts