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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
Fibrin (mg)
1 0.5 0
H ex ab rix e e si pa q
m ni pa qu
sa lin
ue
Vi
Results
Saline
Iodixanol
Iohexol
Ioxaglate
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
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)
NS
2.0 %
1.3 %
NS
6.3 %
5.2 %
NS
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 !!
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
Final n=815
Heparin Discretionary Abciximab PCI Primary Endpoint: In-hosp Composite Thrombotic Events Secondary Endpoints: In-hosp and 30 day Clinical and Angio
COURT death/MI/UR
6.8%
4.4 (30)
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
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
Angiographic Outcomes
Abrupt closure No reflow Distal embolization Side branch occlusion Thrombus development TIMI-3 flow
(all p = ns)
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
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
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
16,3%
16,6%
p=0.077
5,0%
CABG
death
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 .
Conclusion 2
Limitations of this study
Lab success
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
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".
Comparative effects of ionic and non-ionic CM on a FeCl3-induced model of thrombosis in the rat
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
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.
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)
"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
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
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
Ionic contrast Bivalirudin Bivalirudin + ReoPro 395+/-144 (n=77) 460 +/- 189 (n=29)
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
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