CardioContrastWRAP: A Leading Investigator,
First Person Clinical Report®
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
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 isoosmolar 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
Characteristics of Contrast Media
►Physical Characteristics
Molecular Structure
Osmolality
Viscosity
Ionicity
►Patient Safety
Thrombotic Risk & MACE
Renal Tolerance
►Indications & Packaging
3
Comparative Characteristics of Contrast Media:
Molecular Structures
Osmolality
(mOsm/kg)
HOCM
(>1,500)
Ionicity
Ionic
Ionic
# Benz.Rings
Monomer
Dimer
LOCM
(280 – 1,000)
Nonionic
Monomer
Ioxilan
Dimer
Name
Diatrizoate
ioxaglate
Iohexol
Iopamidol
Iopromide
Ioversol
Iodixanol
Viscosity
at 370C
6 cPs
8 cPs
5-10 cPs
11 cPs
4
Viscosity
at 20°C
14 cPs
16 cPs
10-22 cPs
26 cPs
Comparative Characteristics of Contrast Media:
Viscosity
► A unique profile within the concentration range of 320 to 370 mgI/mL. (1)
(1) Data on file at Guerbet LLC.
5
Comparative Characteristics of Contrast Media:
Viscosity
(2) Data on File. Guerbet LLC.
6
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)
(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.
7
Contrast Media Ionicity (Ionic Dimer)
► 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)
* The clinical significance of this data is not known.
(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.
8
Physical Characteristics:
Dimeric, Ionic Molecular Structure of Ioxaglate
Antithrombotic/Anticoagulant Properties
Ioxaglate Characteristics:
Thrombotic Risk and MACE
► Ioxaglate has been shown to reduce platelet
accumulation in stents (in animals)*.(13)
* The clinical significance of this data is not known.
(13) Markou CP et al, Thromb and Haemost, 2001, 85:488-493.
10
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► So what happens?
Vessel Injured
Exposes endothelial proteins,
including Collagen.
Collagen
Thrombin
Activates Resting
Platelets
Activates Resting
Platelets
Activated Platelets
Aggregate & adhere to the
exposed Collagen on the
vessel wall forming the initial
clot
Fibrin forms Mesh which
encapsulates the Clot
Fibrinogen
Thrombin helps convert
another protein,
Fibrinogen, into Fibrin
Antithrombotic and Anticoagulant
Properties of Ioxaglate
Blood Vessel
Endothelium
Subendothelium
Collagen
INJURY
VWF
Vasoconstriction
Platelet Adhesion
& Secretion
Tissue
Factor
Coagulation Cascade
Thrombin
Platelet aggregation
Dr Isobel Ford
Haemostatic plug
Fibrin
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► 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
► So what role does ioxaglate play?
Vessel Injured
Exposes endothelial proteins,
including Collagen.
Collagen
Thrombin
Activates Resting
Platelets
Activates Resting
Platelets
Activated Platelets
Aggregate & adhere to the
exposed Collagen on the
vessel wall forming the initial
clot
Fibrin forms Mesh which
encapsulates the Clot
Fibrinogen
Thrombin helps convert
another protein,
Fibrinogen, into Fibrin
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► 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 binds w/thrombin, preventing it from activating platelets;
therefore preventing/delaying the formation of the platelet plug.
• 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.
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► 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.
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
Antithrombotic and Anticoagulant
Properties of Ioxaglate
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
► 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
► 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
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)
(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.
21
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► 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 PCICV-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
(CONTINUED) 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
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
C. Le Feuvre et al. Catheter Cardiovasc Intervention, 2006, 67:852-858. (CONTINUED)
23
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► 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
Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.
24
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.
Liss P et al. Kidney International, 2006, 70:1811-1817
25
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 ioxaglatetreated 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.
Liss P et al. Kidney International, 2006, 70:1811-1817
26
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
Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
27
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
Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
28
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)
(16) Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
(17) Liss P et al. Kidney International, 2006, 70:1811-1817
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