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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, FSCAIDirector, Cardiovascular ResearchSarah Cannon Research Institute
Medical Director for Cardiology ServicesClinical Services Group
Hospital Corporation of America (HCA)Nashville, Tennessee
1
CardioContrastWRAP: A Leading Investigator, First Person Clinical Report®
Program Overview: CardioContrastWRAPProgram 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 iso-osmolar 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 MediaCharacteristics of Contrast Media
►Physical CharacteristicsMolecular Structure OsmolalityViscosityIonicity
►Patient SafetyThrombotic Risk & MACERenal Tolerance
►Indications & Packaging
3
4
6 cPs6 cPs 8 cPs8 cPs 5-10 cPs5-10 cPs 11 cPs11 cPsViscosityat 370C
Viscosityat 370C
DiatrizoateDiatrizoate ioxaglateioxaglateioxaglateioxaglateIoxilanIoxilanIohexol
IopamidolIopromideIoversol
IoxilanIoxilanIohexol
IopamidolIopromideIoversol
IodixanolIodixanolNameName
MonomerMonomer DimerDimer MonomerMonomer DimerDimer# Benz.Rings# Benz.Rings
IonicityIonicity IonicIonic IonicIonic NonionicNonionic
Osmolality(mOsm/kg)Osmolality(mOsm/kg)
HOCM(>1,500)HOCM
(>1,500)LOCM
(280 – 1,000)LOCM
(280 – 1,000)
14 cPs14 cPs 16 cPs16 cPs 10-22 cPs10-22 cPs 26 cPs26 cPsViscosityat 20°C
Viscosityat 20°C
Comparative Characteristics of Contrast Media: Molecular Structures
Comparative Characteristics of Contrast Media: Molecular Structures
Comparative Characteristics of Contrast Media: Viscosity
Comparative Characteristics of Contrast Media: Viscosity
► A unique profile within the concentration range of 320 to 370 mgI/mL. (1)
5(1) Data on file at Guerbet LLC.
Comparative Characteristics of Contrast Media: Viscosity
Comparative Characteristics of Contrast Media: Viscosity
6(2) Data on File. Guerbet LLC.
Advantages of Low Viscosity CMAdvantages 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)
7
(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.
Contrast Media Ionicity (Ionic Dimer)Contrast Media Ionicity (Ionic Dimer)
8
► 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)
(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.
* The clinical significance of this data is not known.
Physical Characteristics:Dimeric, Ionic Molecular Structure of Ioxaglate
Antithrombotic/Anticoagulant Properties
Physical Characteristics:Dimeric, Ionic Molecular Structure of Ioxaglate
Antithrombotic/Anticoagulant Properties
Ioxaglate Characteristics:Thrombotic Risk and MACEIoxaglate Characteristics:
Thrombotic Risk and MACE
► Ioxaglate has been shown to reduce platelet accumulation in stents (in animals)*.(13)
10
* The clinical significance of this data is not known.
(13) Markou CP et al, Thromb and Haemost, 2001, 85:488-493.
Collagen
Activates Resting Platelets
Thrombin
Activates Resting Platelets
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
► So what happens?
Fibrinogen
Thrombin helps convert another protein,
Fibrinogen, into Fibrin
Fibrin forms Mesh which encapsulates the Clot
Vessel Injured
Exposes endothelial proteins, including Collagen.
Activated PlateletsAggregate & adhere to the exposed Collagen on the
vessel wall forming the initial clot
Collagen VWFINJURY
Platelet Adhesion& Secretion
Platelet aggregation
Tissue Factor
Coagulation Cascade
Thrombin
Fibrin
Haemostatic plug
Vaso-constriction
Blood VesselEndothelium
Subendothelium
Dr Isobel Ford
Antithrombotic and Anticoagulant Properties of Ioxaglate
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
Antithrombotic and Anticoagulant Properties of Ioxaglate
Activated PlateletsAggregate & adhere to the exposed Collagen on the
vessel wall forming the initial clot
Collagen
Activates Resting Platelets
Thrombin
Activates Resting Platelets
► So what role does ioxaglate play?
Fibrinogen
Thrombin helps convert another protein,
Fibrinogen, into Fibrin
Fibrin forms Mesh which encapsulates the Clot
Vessel Injured
Exposes endothelial proteins, including Collagen.
Antithrombotic and Anticoagulant Properties of Ioxaglate
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 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.
• Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelet plug.
Antithrombotic and Anticoagulant Properties of Ioxaglate
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.
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
Mechanism: Antithrombotic and Anticoagulant PropertiesMechanism: 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
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
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
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
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
Summary of Grines Study Thrombotic Risk and MACE
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)
21
(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.
► 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 PCI-CV-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
22
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
(CONTINUED) Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.
► 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
23
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
C. Le Feuvre et al. Catheter Cardiovasc Intervention, 2006, 67:852-858. (CONTINUED)
► 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
24
Antithrombotic and Anticoagulant Properties of Ioxaglate
Antithrombotic and Anticoagulant Properties of Ioxaglate
Le Feuvre C et al. Catheter Cardiovasc Intervention, 2006, 67:852-858.
Renal Studies: CINRenal 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.
25Liss P et al. Kidney International, 2006, 70:1811-1817
Renal StudiesRenal 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 ioxaglate-treated 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.
26Liss P et al. Kidney International, 2006, 70:1811-1817
ICON STUDY: 2009ICON 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
27Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
ICON STUDY-MEHRAN-JACC INT2009
ICON STUDY-MEHRAN-JACC INT2009
► 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
28Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
Two Renal Studies: ConclusionsTwo 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)
29
(16) Mehran R et al. JACC Cardiovasc Interv, 2009, 5:451-421.
(17) Liss P et al. Kidney International, 2006, 70:1811-1817