clots, contrast media, and catheterization maximizing patient safety and outcomes in coronary...
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Clots, Clots, Contrast MediaContrast Media,, andand Catheterization Catheterization
Maximizing Patient Safety and Outcomes Maximizing Patient Safety and Outcomes in Coronary Angioplastyin Coronary Angioplasty
Focus on Comparative Effects of Contrast Media on Focus on Comparative Effects of Contrast Media on Thrombosis Mitigation, Mortality, and Renal FunctionThrombosis Mitigation, Mortality, and Renal Function
Evolving Science Evolving Science ●● New Mechanisms New Mechanisms ●● Optimal ManagementOptimal Management
Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCProgram ChairmanProgram Chairman
Director, Cardiovascular Research | Sarah Cannon Research Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Institute | Centennial Heart Cardiovascular Consultants |
Medical Director, Cardiovascular Services | Clinical ServicesMedical Director, Cardiovascular Services | Clinical ServicesGroup | Hospital Corporation of America (HCA) | Nashville, TNGroup | Hospital Corporation of America (HCA) | Nashville, TN
Welcome and Program OverviewWelcome and Program Overview
CME-accredited symposium CME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC
Mission statement: Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management
Processes: Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies
COI: COI: Full faculty disclosures provided in syllabus and at the Full faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program
Welcome and Program OverviewWelcome and Program Overview
Commercial Support: Commercial Support: This program is sponsored by This program is sponsored by an independent educational grant from Guerbet, LLCan independent educational grant from Guerbet, LLC
Program Educational ObjectivesProgram Educational ObjectivesAs a result of this session, participants will be able to:As a result of this session, participants will be able to: ► Discuss the role that cardiovascular contrast media (CM) can play in Discuss the role that cardiovascular contrast media (CM) can play in
thrombosis mitigation and renal preservation in the setting of PCIthrombosis mitigation and renal preservation in the setting of PCI
► Detail the physical, chemical, and biological properties—ionicity, Detail the physical, chemical, and biological properties—ionicity, molecular structure, and viscosity—of contrast agents used in PCI and molecular structure, and viscosity—of contrast agents used in PCI and their potential impact on renal function, thrombosis, and patient safetytheir potential impact on renal function, thrombosis, and patient safety
► Apply landmark trials, registry data, and observational studies to optimize Apply landmark trials, registry data, and observational studies to optimize selection of CM in patients undergoing PCIselection of CM in patients undergoing PCI
► Identify high-risk patients that may be appropriate candidates for specific Identify high-risk patients that may be appropriate candidates for specific CM shown to decrease risk of thrombotic events and/or renal dysfunctionCM shown to decrease risk of thrombotic events and/or renal dysfunction
► Explain how ionic properties, viscosity, and other chemical features may Explain how ionic properties, viscosity, and other chemical features may affect renal function and coagulation in the setting of PCIaffect renal function and coagulation in the setting of PCI
Program FacultyProgram Faculty
Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCProgram ChairmanProgram ChairmanDirector, Cardiovascular ResearchDirector, Cardiovascular ResearchSarah Cannon Research Institute Sarah Cannon Research Institute Centennial Heart Cardiovascular Centennial Heart Cardiovascular Consultants Consultants Medical DirectorMedical DirectorCardiovascular ServicesCardiovascular ServicesClinical Services GroupClinical Services GroupHospital Corporation of America (HCA) Hospital Corporation of America (HCA) Nashville, TNNashville, TN
Frederick Feit, MDFrederick Feit, MDAssociate Professor Associate Professor Department of MedicineDepartment of MedicineDivision of CardiologyDivision of CardiologyNew York University School of MedicineNew York University School of MedicineMember, NYU Cardiac CatheterizationMember, NYU Cardiac Catheterization Associates Associates New York, NY USANew York, NY USA
Roxana Mehran, MDRoxana Mehran, MDDirector of Outcomes Research, DataDirector of Outcomes Research, Data
Coordination and Analysis Coordination and Analysis Center for Interventional Vascular TherapyCenter for Interventional Vascular Therapy
New York-Presbyterian HospitalNew York-Presbyterian HospitalColumbia University Medical CenterColumbia University Medical Center
Associate Professor of MedicineAssociate Professor of MedicineDivision of CardiologyDivision of CardiologyColumbia University Columbia University
College of Physicians and Surgeons College of Physicians and Surgeons Director of the Clinical Research, Data Director of the Clinical Research, Data
Coordination and Analysis Center at the Coordination and Analysis Center at the Cardiovascular Research Foundation Cardiovascular Research Foundation
New York City, NY USANew York City, NY USA
Faculty COI Financial DisclosuresFaculty COI Financial Disclosures
Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCConsultant, Educational Grant, Research Support, and/or Employment: Consultant, Educational Grant, Research Support, and/or Employment: BMS, Guerbet LLC, sanofi-aventis, The Medicines CompanyBMS, Guerbet LLC, sanofi-aventis, The Medicines Company
Frederick Feit, MDFrederick Feit, MDConsultant:Consultant: CV Therapeutics, The Medicines CompanyCV Therapeutics, The Medicines CompanyShareholder: Shareholder: Eli Lilly, Johnson and Johnson, The Medicines CompanyEli Lilly, Johnson and Johnson, The Medicines Company
Roxana Mehran, MDRoxana Mehran, MDClinical Research Support: Clinical Research Support: sanofi-aventis, Braccosanofi-aventis, BraccoEducational Support: Educational Support: The Medicines Company, Boston Scientific, Abbott, The Medicines Company, Boston Scientific, Abbott, Medtronic, and CordisMedtronic, and CordisConsultant/Honoraria: Consultant/Honoraria: TMC, BSC, Abbott, Medtronic, sanofi-aventis, TMC, BSC, Abbott, Medtronic, sanofi-aventis, Lilly/Diachi Sankyo, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, Lilly/Diachi Sankyo, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, RegadoRegado
Contrast Induced Contrast Induced Acute Kidney InjuryAcute Kidney Injury
Roxana Mehran, MD, FACC, FAHA, FSCAI, FESCRoxana Mehran, MD, FACC, FAHA, FSCAI, FESCAssociate Professor of MedicineAssociate Professor of Medicine
Columbia University Medical CenterColumbia University Medical CenterJoint Chief Scientific OfficerJoint Chief Scientific Officer
Cardiovascular Research FoundationCardiovascular Research Foundation
How to Assess Renal Function?How to Assess Renal Function?
Abbreviated Modification of Diet in Abbreviated Modification of Diet in Renal Disease equations (MDRD) equation:Renal Disease equations (MDRD) equation:
(140- age) x Body Weight [kg]* Creatinine Clearance, ml/min =
* Multiple by 0.8 in female
Cockcroft-Gault equation: Cockcroft-Gault equation:
Serum Creatinine mg/dL] x 72
eGFR, ml/min/1.73 m2= 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-0.203) x (0.742 if female) x (1.210 if African American)
Major Causes of Acute Kidney InjuryMajor Causes of Acute Kidney Injury In Cardiac Patients In Cardiac Patients
1)1) Contrast InducedContrast Induced
Nephropathy (CIN)Nephropathy (CIN)
2)2) AKI after AKI after Cardiopulmonary Bypass Cardiopulmonary Bypass ProceduresProcedures
DefinitionDefinition
• New onset or exacerbation of renal dysfunction New onset or exacerbation of renal dysfunction after contrast administration in the absence of after contrast administration in the absence of other causes:other causes:
increase by > 25%increase by > 25%
oror
absolute absolute of > 0.5 mg/dL of > 0.5 mg/dL
Contrast-Induced AKIContrast-Induced AKI
from baselinefrom baselineserum creatinineserum creatinine
Occurs 24 to 48 hrs post–contrast exposure, with creatinine Occurs 24 to 48 hrs post–contrast exposure, with creatinine peaking 5 to 7 days later and normalizing within peaking 5 to 7 days later and normalizing within
7 to 10 days in most cases 7 to 10 days in most cases
275 consecutive patients undergoing PCI given the contrast agent ioxilan275 consecutive patients undergoing PCI given the contrast agent ioxilan
Jabara R, et al. Jabara R, et al. Am J Cardiol. Am J Cardiol. 2009;Epub ahead of print.2009;Epub ahead of print.
Impact of the Definition Utilized on the Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in PCIRate of Contrast-Induced Nephropathy in PCI
DefinitionsDefinitionsRise in SCr Rise in SCr ≥0.5 mg/dl≥0.5 mg/dl
(n = 9)(n = 9)
Decrease in Decrease in eGFR ≥25%eGFR ≥25%
(n = 21)(n = 21)
Rise in SCr Rise in SCr ≥25%≥25%(n = 28)(n = 28)
Composite of all Composite of all 3 Definitions3 Definitions
(n = 29)(n = 29)
CINCIN 3.3%3.3% 7.6%*7.6%* 10.2%10.2%## 10.5%10.5%††
Conclusion: Conclusion: The wide variation in CIN and its lack of association with adverse The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition.outcomes underscore the need for a standardized, clinically relevant definition.
**PP=0.37 vs. rise in SCr ≥0.5 mg/dl=0.37 vs. rise in SCr ≥0.5 mg/dl##PP=0.02 vs. rise in SCr ≥0.5 mg/dl=0.02 vs. rise in SCr ≥0.5 mg/dl††PP=0.001 vs. rise in SCr ≥0.5 mg/dl=0.001 vs. rise in SCr ≥0.5 mg/dl
There were no deaths or cases requiring dialysis. There were no deaths or cases requiring dialysis. Major and minor bleeding Major and minor bleeding rates were 1.5% and 1.8%. rates were 1.5% and 1.8%.
Risk Factors for the Development Risk Factors for the Development of Contrast-Induced AKI of Contrast-Induced AKI
Fixed (non-modifiable) risk factorsFixed (non-modifiable) risk factors Modifiable risk factorsModifiable risk factors
Pre-existing renal failurePre-existing renal failure Volume and type of contrast mediumVolume and type of contrast medium
Diabetes mellitusDiabetes mellitus Multiple contrast injections within 72 hoursMultiple contrast injections within 72 hours
Advanced congestive heart failureAdvanced congestive heart failure Hemodynamic instabilityHemodynamic instability
Reduced left ventricular ejection fractionReduced left ventricular ejection fraction DehydrationDehydration
Acute myocardial infarctionAcute myocardial infarction AnemiaAnemia
Cardiogenic shockCardiogenic shock Intra-aortic balloon pump Intra-aortic balloon pump
Renal transplantRenal transplant Low serum albumin level (<35 g/L)Low serum albumin level (<35 g/L)
Angiotensin converting enzyme inhibitorsAngiotensin converting enzyme inhibitors
DiureticsDiuretics
Nephrotoxic drugs (nonsteroidal anti-Nephrotoxic drugs (nonsteroidal anti-inflammatory agents, antibiotics, cyclosporine, inflammatory agents, antibiotics, cyclosporine, etc.)etc.)
RiskRiskScoreScore
RiskRiskof CINof CIN
Risk ofRisk of
DialysisDialysis
≤ ≤ 55 7.5%7.5% 0.04%0.04%
6 to 106 to 10 14.0%14.0% 0.12%0.12%
11 to 1611 to 16 26.1%26.1% 1.09%1.09%
≥ ≥ 1616 57.3%57.3% 12.6%12.6%
Mehran et al. Mehran et al. JACCJACC 2004;44:1393-1399. 2004;44:1393-1399.
Hypotension
IABP
CHF
Age >75 years
Anemia
Diabetes
Contrast media volume
Risk Factors
5
5
5
4
3
3
Integer Score
1 for each 100 cc3
Scheme to Define CIN Risk ScoreScheme to Define CIN Risk Score
Serum creatinine > 1.5mg/dl 4
eGFR <60ml/min/1.73 m2
2 for 40 – 604 for 20 – 40
6 for < 20eGFR < 60ml/min/1.73 m2 =186 x (SCr)-1.154 x (Age)-0.203
X (0.742 if female) x (1.210 if African American)
Calculate
OR
Prognostic Impact of CKD and Prognostic Impact of CKD and Contrast Induced AKIContrast Induced AKI
Contrast-induced AKI:Contrast-induced AKI: In-hospital Mortality In-hospital Mortality
% % In-hospitalIn-hospital DeathDeath
P<0.001P<0.001
McCullough et al. McCullough et al. Am J MedAm J Med 1997; 103-375 1997; 103-375
Contrast-Induced Nephropathy: Contrast-Induced Nephropathy: Resource Utilization Resource Utilization
Endpoint (%)Endpoint (%)PatientsPatients
P-valueP-valueWith CINWith CIN Without CINWithout CIN
Hospital length of stay Hospital length of stay (days)(days) 9.69.6++7.27.2 3.23.2++6.46.4 <0.001<0.001
ICU length of stay ICU length of stay (days)(days) 2.32.3++4.44.4 0.60.6++1.81.8 <0.0001<0.0001
Need for hemodialysis Need for hemodialysis (%)(%) 1212 00 <0.0001<0.0001
Iakovou I et al, Iakovou I et al, J Am Coll Cardiol.J Am Coll Cardiol. 2002;39:2A 2002;39:2A
Preventive Preventive TrialsTrials
StrategiesStrategiesPrevention of Contrast Induced NephropathyPrevention of Contrast Induced Nephropathy
Solomon R et al, N Engl J Med 1994;331(21):1416-1420
A total of 78 patients with mean baseline SCR 2.1 mg/dlwho underwent coronary angiography/PCI
N=78
0.45% saline alone 12 hours before and 12 hours
after angiography N=28
Saline plus mannitol *N=25
Primary endpoint: increase in the baseline SCr of at least 0.5 mg/dl within 48 hours after the injection of radiocontrast agents
Furosemide*N=25
* Given before angiography * Given before angiography
Randomization
Effects of Saline, Mannitol, and Effects of Saline, Mannitol, and FurosemideFurosemide
Effects of Saline, Mannitol, and Furosemide to Effects of Saline, Mannitol, and Furosemide to Prevent Acute Decreases in Renal Function Prevent Acute Decreases in Renal Function
Induced by Radiocontrast Agents Induced by Radiocontrast Agents
Solomon R et al, N Engl J Med 1994;331:1416-1420
P=0.02P=0.02 for Saline vs. Furosemide group for Saline vs. Furosemide groupP=NSP=NS for Mannitol vs. Furosemide group for Mannitol vs. Furosemide group
Optimal Hydration RegimenOptimal Hydration Regimen
Mueller et al Arch Intern Med 2002
1937 Patients Screened
317 Ineligible or No Consent
685 for Primary End Point Analysis
698 for Primary End Point Analysis
1620 Randomized
809 Received 0.9% Saline
124 Excluded From Primary End Point Analysis
Repeat Catheterization (n=78)Incomplete Data (n=46)
811 Received 0.45% Sodium Chloride
113 Excluded From Primary End Point Analysis
Repeat Catheterization (n=59)Incomplete Data (n=53)Bypass Grafting (n=1)
Optimal HydrationOptimal Hydration0.9% NS vs 0.45% NS0.9% NS vs 0.45% NS
P=.35P=.35
0
1
2
3
CNCN MortalityMortality VascularVascular
Inci
denc
e, %
Inci
denc
e, %
0.9% Saline0.45% Sodium Chloride
P=.93P=.93
P=.04P=.04
Mueller et al Mueller et al Arch Intern MedArch Intern Med 2002 2002
Periprocedural Hydration ProtocolPeriprocedural Hydration Protocol
In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with preserved In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with preserved LVEFLVEF:: IV 0.9% NS at 1cc/kg/hr 12 hours prior to procedure. The patients are IV 0.9% NS at 1cc/kg/hr 12 hours prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure.encouraged to drink fluids for 24 hours after the procedure.
In patients w/o baseline CRI and mild to moderate LV dysfunction: (LVEF In patients w/o baseline CRI and mild to moderate LV dysfunction: (LVEF 30% to 40%): 30% to 40%): IV 0.45%NS at 50 cc/hour 12 hrs prior to procedure. The IV 0.45%NS at 50 cc/hour 12 hrs prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure.patients are encouraged to drink fluids for 24 hours after the procedure.
In patients with baseline CRI and normal LVEF: In patients with baseline CRI and normal LVEF: IV 0.9% NS at 1 cc/kg/hour IV 0.9% NS at 1 cc/kg/hour for 12 hours pre- and post- procedure for 12 hours pre- and post- procedure
In patients with baseline CRI and reduced LVEF: In patients with baseline CRI and reduced LVEF: IV 0.45% NS at cc/cc IV 0.45% NS at cc/cc replacement (urine output should be match to maintain euvolemic state) for replacement (urine output should be match to maintain euvolemic state) for 12 hours pre- and post-procedure12 hours pre- and post-procedure
Consider 2 main factors:
► Baseline CRI (Yes/No)
► LVEF (Preserved/Impaired)
Prevention of CIN with Prevention of CIN with Sodium BicarbonateSodium Bicarbonate
Merten GJ et al. Merten GJ et al. JAMAJAMA, 2004;291:2328-2334, 2004;291:2328-2334
Patients With Baseline Serum Creatinine >1.8 mg/dlwho Underwent Contrast Exposure (Iopamidol in All)
N=137
Primary endpoint: increase in serum creatinine ≥25% within 2 days post-exposure
Prevention of CIN with Sodium Bicarbonate: Prevention of CIN with Sodium Bicarbonate: ResultsResults
EndpointsEndpointsSodium Sodium ChlorideChloride
N=59N=59
Sodium Sodium BicarbonateBicarbonate
N=60N=60
P P valuevalue
Incidence of CIN (%)Incidence of CIN (%) 13.6%13.6% 1.7%1.7% 0.020.02
Incidence of CIN Incidence of CIN (↑SCr 0.5 mg/dL)(↑SCr 0.5 mg/dL) 11.9%11.9% 1.7%1.7% 0.030.03
Merten GJ et al. Merten GJ et al. JAMA,JAMA, 2004;291:2328-2334 2004;291:2328-2334
REMEDIAL Trial
Saline + NAC N=118
Bicarbonate + NAC N=117
Saline+AA+NAC N=116
7 excluded
Pts with eGFR<40 N=393
Randomized N=351
Excluded N=42
NAC = NAC = NN-acetylcysteine, AA = ascorbic acid-acetylcysteine, AA = ascorbic acid
9 excluded9 excluded
107 included into analysis
108 included into analysis
111 included into analysis
Briguorio C. et al, Briguorio C. et al, CirculationCirculation 2007 2007
REMEDIAL Trial: Results REMEDIAL Trial: Results
Saline + Saline + NAC NAC N=111N=111
Bicarbonate Bicarbonate + NAC + NAC N=108N=108
Saline + Saline + Ascorbic Ascorbic
Acid + NAC Acid + NAC N=107N=107
P P ValueValue
Serum creatinine Serum creatinine increase by ≥25%increase by ≥25% 11 (9.9%)11 (9.9%) 2 (1.9%)*2 (1.9%)* 10 (10.3%)10 (10.3%) 0.0100.010
Serum creatinine Serum creatinine increase by ≥0.5 increase by ≥0.5 mg/dLmg/dL
12 (10.8%)12 (10.8%) 1 (0.9%)†1 (0.9%)† 12 (11.2%)12 (11.2%) 0.0260.026
eGFR decrease by eGFR decrease by ≥25%≥25% 10 (9.2%)10 (9.2%) 1 (0.9%)†1 (0.9%)† 10 (10.3%)10 (10.3%) 0.0180.018
**P=0.019P=0.019, †, †P<0.01P<0.01 vs. saline + NAC group vs. saline + NAC group
Briguorio C. et al, Briguorio C. et al, CirculationCirculation 2007 2007
MEENAMEENA
DesignDesign• DESIGN:DESIGN: Prospective, randomized, Prospective, randomized,
parallel-group, single-center clinical parallel-group, single-center clinical evaluation of two hydration evaluation of two hydration strategies for patients undergoing strategies for patients undergoing coronary angiographycoronary angiography
• OBJECTIVE: OBJECTIVE: To compare the To compare the incidence of CIN between incidence of CIN between periprocedural hydration with periprocedural hydration with sodium bicarbonate vs. sodium sodium bicarbonate vs. sodium chloride (0.9%, normal saline) chloride (0.9%, normal saline)
• PRIMARY ENDPOINT:PRIMARY ENDPOINT: Decrease in estimated GFR by ≥ Decrease in estimated GFR by ≥ 25% within 4 days of coronary 25% within 4 days of coronary angiographyangiography
• DESIGN:DESIGN: Prospective, randomized, Prospective, randomized, parallel-group, single-center clinical parallel-group, single-center clinical evaluation of two hydration evaluation of two hydration strategies for patients undergoing strategies for patients undergoing coronary angiographycoronary angiography
• OBJECTIVE: OBJECTIVE: To compare the To compare the incidence of CIN between incidence of CIN between periprocedural hydration with periprocedural hydration with sodium bicarbonate vs. sodium sodium bicarbonate vs. sodium chloride (0.9%, normal saline) chloride (0.9%, normal saline)
• PRIMARY ENDPOINT:PRIMARY ENDPOINT: Decrease in estimated GFR by ≥ Decrease in estimated GFR by ≥ 25% within 4 days of coronary 25% within 4 days of coronary angiographyangiography
353 patients enrolled between January 2006 and January 2007
156 evaluable patient
Brar, S et. al., i2/ACC 2007Brar, S et. al., i2/ACC 2007
147 evaluable patient
28 excluded
Hydration Protocol•3 mL/kg for 1 hr before the procedure•1.5 mL/kg during and for 4hrs post-procedure
236 patients assigned to sodium chloride
178 patients assigned to sodium bicarbonate
22 excluded
MEENAMEENA
p = 0.97p = 0.97
p = 0.82p = 0.82
Meta-AnalysisMeta-AnalysisSodium Bicarbonate for the Sodium Bicarbonate for the
Prevention of CINPrevention of CIN
Brar et al. cJASN 2009Brar et al. cJASN 2009
Meta-AnalysisMeta-AnalysisStudy FlowStudy Flow
469 Citations Identified 168 from EMBASE 261 from MEDLINE 40 from Cochrane Library
8 Citations identified from conference proceedings
424 Citations excluded based on screening of titles or abstracts
53 identified for further review
14 articles included in meta-analysis
(N=2,290)
Brar et al. cJASN 2009Brar et al. cJASN 2009
38 Citations excluded after full review 36 Design was not correct 1 Unusual protocol 1 Difference between groups in volume administered & NAC dose
Dates: 1996 to 2008Dates: 1996 to 2008Randomized TrialsRandomized TrialsNumber of Patents: 2,290Number of Patents: 2,290
Brar et al. cJASN 2009Brar et al. cJASN 2009
Change in Renal FunctionChange in Renal FunctionPublished Randomized TrialsPublished Randomized Trials
HarmHarm
BenefitBenefit
No effect
No effect
∆
∆ C
reat
inin
e S
odiu
m B
icar
bona
te (
mg/
dL)
Cre
atin
ine
Sod
ium
Bic
arbo
nate
(m
g/dL
)
∆ ∆ Creatinine Sodium Chloride (mg/dL)Creatinine Sodium Chloride (mg/dL)
BrarBrar
MaioliMaioli
AdolphAdolph MasudaMasudaOzcanOzcan
MertenMerten
BriguoriBriguori
-0.2 -0.1 0.0 0.1 0.2-0.2 -0.1 0.0 0.1 0.2
0.20.2
0.10.1
0.00.0
-0.1-0.1
\-0.2\-0.2
Improvement with Bicarb
Deteriorationwith Chloride
Meta-RegressionMeta-RegressionUnderstanding Sources of HeterogeneityUnderstanding Sources of Heterogeneity
Trial SizeSmaller trials showSmaller trials showgreater benefitgreater benefit ““Small Study Effect”Small Study Effect”
Summary: Positive effect only observed in small trials
12.6% vs. 10.7%P=0.32
13.5% vs. 6.7%P=0.03
LargeTrialsN=2290N=2290 N=2290N=2290
RRRR95% CI95% CI
0.850.850.62-1.170.62-1.17
0.500.500.27-0.930.27-0.93
Merten Merten CriteriaCriteriaN=290N=290
SmallTrials
Brar et al. cJASN 2009Brar et al. cJASN 2009
Brar et al. cJASN 2009Brar et al. cJASN 2009
Forest PlotForest PlotHigh Quality StudiesHigh Quality Studies
Brigouri, 2007Brigouri, 2007 0.19 (0.04, 0.82)0.19 (0.04, 0.82)Chen, 2007Chen, 2007 0.13 (0.02, 1.02)0.13 (0.02, 1.02)Kim, 2007Kim, 2007 0.98 (0.42, 2.28)0.98 (0.42, 2.28)Ozcan, 2007Ozcan, 2007 0.33 (0.11, 0.99)0.33 (0.11, 0.99)Shaikh, 2007Shaikh, 2007 0.75 (0.39, 1.44)0.75 (0.39, 1.44)Brar, 2008Brar, 2008 0.91 (0.56, 1.46)0.91 (0.56, 1.46)Maioli, 2008Maioli, 2008 0.87 (0.52, 1.44)0.87 (0.52, 1.44)Adolph, 2008Adolph, 2008 1.56 (0.27, 9.08)1.56 (0.27, 9.08)Overall Overall 0.71 (0.49, 1.03)0.71 (0.49, 1.03)(I-squared =33.3%, p=0.163)(I-squared =33.3%, p=0.163)
Note: weights are from Note: weights are from random effects analysisrandom effects analysis
0.1 1 100.1 1 10FavorsFavors
BicarbonateBicarbonateFavorsFavorsSalineSaline
Quality CriteriaQuality Criteria►Similar volumeSimilar volume►PatientsPatients►If NAC used, dose If NAC used, dose & route similar & route similar between groupsbetween groups►No early No early terminationtermination
Summary: No overall benefit, but trend driven by studies with extreme treatment effects
The The CONTRASTCONTRAST Trial Trial
AlgorithmAlgorithm
Primary endpointPrimary endpointWorsening renal insufficiency within 12-96 hoursWorsening renal insufficiency within 12-96 hours
Fenoldopam Fenoldopam
Matching placeboMatching placebo
Randomize
HydrateHydrate
1º prior to and 12 º after cath1º prior to and 12 º after cath
300 patientsat increased risk for contrast nephropathy undergoing PCI
CONTRASTCONTRAST STUDY: CIN STUDY: CIN
SCr at both baseline and during the 96° post drug administration period were available and analyzed at the central lab in 283 of 315 randomized
patients (90%).
P=0.84P=0.84P=0.61P=0.61
OR [95% CI] =1.11 [0.79, 1.57]
P=0.27P=0.27
Stone GW, et al. JAMA-2003Stone GW, et al. JAMA-2003
CONTRAST: CONTRAST: 30-Day Adverse Events30-Day Adverse Events
30-day incidence of death, MI or dialysis:30-day incidence of death, MI or dialysis:
• With CINWith CIN 12.2% 12.2%
• Without CINWithout CIN 4.1% 4.1%
P=NS for allP=NS for all
p=0.02p=0.02
Stone GW, et al. JAMA-2003Stone GW, et al. JAMA-2003
Targeted Renal DeliveryTargeted Renal Delivery
FEN-001 Trial DesignFEN-001 Trial Design
• Patients undergoing elective angiographyPatients undergoing elective angiography• Moderate CKD defined as CrCl Moderate CKD defined as CrCl ≤ 70≤ 70 ml/min ( ml/min (≤ 80≤ 80 ml/min if diabetic) ml/min if diabetic)• Anticipated CM volume Anticipated CM volume ≥ 80 cc≥ 80 cc
Teirstein Teirstein et alet al, Am J Cardiol 2006., Am J Cardiol 2006.
N=33
IV Placebo (no drugs/no device)
2:1 Randomization
IV FEN0.1 -> 0.2
mcg/kg/min
IR FEN0.2 mcg/kg/min
Index angiographyIndex angiography+/- interventional procedure+/- interventional procedure(+ contrast)(+ contrast)
IR = intra-renalIR = intra-renalIV = intravenousIV = intravenousFEN = fenoldopamFEN = fenoldopam
Washout x 1 hrWashout x 1 hr
Glomerular Filtration RateGlomerular Filtration Rate
Teirstein et al, Am J Cardiol Teirstein et al, Am J Cardiol 2006.2006.
5-fold GFR TRT vs IV
Sustained GFR for 2+ hrs post d/c
All data based on a Fenoldopam dose of 0.2 mcg/kg/min
GFR Response to IV-FEN and TRT-FEN vs. ControlGFR Response to IV-FEN and TRT-FEN vs. Control
4.9%
23.6%25.1%
-9.7%
9.6%
-14.0%
-20%
-10%
0%
10%
20%
30%
1 2 3
Study Period6Study Period6
Pe
rce
nt
Ch
an
ge
in G
FR
fro
m B
ase
line
[%
]P
erc
en
t C
ha
ng
e in
GF
R f
rom
Ba
selin
e [
%]
IV FEN (n=22)
TRT-FEN (n=22)
Control Group (n=11)
Pre-procedurePre-procedure(IV-FEN vs. Control)(IV-FEN vs. Control)
ProcedureProcedure(TRT-FEN vs. Control)(TRT-FEN vs. Control)
Post-ProcedurePost-Procedure(Active vs. Control)(Active vs. Control)
p=0.0007p<0.05
p=NS
Be-RITe! Registry: Higher Dose More Effective Be-RITe! Registry: Higher Dose More Effective (TRT-Fenoldopam patients only)(TRT-Fenoldopam patients only)
Predicted values per Mehran et al, JACC 2004.
CIN Incidence Stratified by TRT DoseCIN Incidence Stratified by TRT Dose
30.3%30.3%
3.7%3.7%
28.3%28.3% 27.7%27.7%
0%
10%
20%
30%
40%
50%
0.2 mcg/kg/min0.2 mcg/kg/min 0.4 mcg/kg/min0.4 mcg/kg/min
CIN
Inci
denc
e or
Pre
dict
ed In
cide
nce
[%]
CIN
Inci
denc
e or
Pre
dict
ed In
cide
nce
[%]
CIN Incidence Predicted
n=33 n=242
p=0.79p=0.79
p<0.0001p<0.0001
Renal Protective Effects and the Prevention of Contrast-Renal Protective Effects and the Prevention of Contrast-InducedcNephropathy by Atrial Natriuretic PeptideInducedcNephropathy by Atrial Natriuretic Peptide
Both ANP(0.042 µg/kg/min) and Hydration (1.3 ml/kg/h Both ANP(0.042 µg/kg/min) and Hydration (1.3 ml/kg/h of Ringer) infusions were initiated 4 to 6 h before the of Ringer) infusions were initiated 4 to 6 h before the
angiographic and continued forangiographic and continued for48 h after48 h after
14 pts excluded14 pts excluded
261 pts Randomized
126 pts ANP plus hydration
128 pts hydration
Morikawa et al. J Am Coll Cardiol 2009;53:1040–6Morikawa et al. J Am Coll Cardiol 2009;53:1040–6
Incidence on CIN in the ANP Group Incidence on CIN in the ANP Group Compared with the Control GroupCompared with the Control Group
P=0.015P=0.015
P= 0.042P= 0.042P=0.023P=0.023
Inci
denc
e of
CIN
(%
)In
cide
nce
of C
IN (
%)
CreatinineCreatinine>>0.5 mg/dl0.5 mg/dl
CreatinineCreatinine>>25% of baseline25% of baseline
CreatinineCreatinine>>0.5 mg/dl or 0.5 mg/dl or
>>25% of baseline25% of baseline
Morikawa et al. J Am Coll Cardiol 2009;53:1040–6Morikawa et al. J Am Coll Cardiol 2009;53:1040–6
N-Acetylcysteine (NAC)N-Acetylcysteine (NAC)
CIN: Effect of n-AcetylcysteineCIN: Effect of n-Acetylcysteine
► Prospective, randomizedProspective, randomized
► 83 high risk patients83 high risk patients CrCl < 50 ml/minCrCl < 50 ml/min Diabetes 33%Diabetes 33%
► IV CONTRAST for CT (75 ml IV CONTRAST for CT (75 ml of Low Osmolar CM)of Low Osmolar CM)
► n-AC 600 bid x 2 days pre-n-AC 600 bid x 2 days pre-
► CIN definition: creatinine CIN definition: creatinine increase of 0.5 mg/dl increase of 0.5 mg/dl
► Hydration with 0.45% @ 1 Hydration with 0.45% @ 1 ml/kg/h x 24 hml/kg/h x 24 h
Tepel Tepel NEJMNEJM 2000 2000
p= 0.01p= 0.01
Zagler et al. Zagler et al. Am Heart JAm Heart J 2006;151:140-145. 2006;151:140-145.
Relative Risk for Developing CIN after NACRelative Risk for Developing CIN after NAC
Risk Ratio (Random) Risk Ratio (Random) 95% Cl95% Cl
0.10.1 11 1010Favors treatmentFavors treatment Favors controlFavors control
0.20.2 0.50.5 22 55
RR (Random) RR (Random) 95% Cl95% Cl
ControlControln/Nn/N
NACNACn/Nn/N
Study or Study or substudysubstudy
Review: Review: Acetylcysteine and CINAcetylcysteine and CINComparison: Comparison: 01 NAC on CIN01 NAC on CINOutcome: Outcome: 01 CIN01 CIN
Total events: Total events: 124 (NAC), 162 (Control)124 (NAC), 162 (Control)Test for heterogenety: Test for heterogenety: Ch=27.54 (P0.005), 1Ch=27.54 (P0.005), 122=56.4%=56.4%Test for overall effect: Test for overall effect: Z=1.88 (Z=1.88 (P=0.05P=0.05))
Allaqaband et al 8/45 6/40 1.19 (0.45, 3.12)Briguori et al 6/92 10/91 0.59 (0.23, 1.57)Diaz-Sandoval et al 2/25 13/29 0.18 (0.04, 0.72)Durham et al 10/38 9/41 1.20 (0.55, 2.63)Goldenberg et al 4/41 3/39 1.27 (0.30, 5.31)Gomes et al 8/78 8/78 1.00 (0.40, 2.53)Kay et al 4/102 12/98 0.32 (0.11, 0.96)Nguyen-Ho et al 9/95 19/85 0.42 (0.20, 0.89)Oldemeyer 4/49 3/47 1.28 (0.30, 5.41)Pate et al 57/238 50/239 1.14 (0.82, 1.60) RAPIDO 2/41 8/39 0.24 (0.05, 1.05)Shyu 2/60 15/61 0.14 (0.03, 0.57)Fung et al 8/46 6/45 1.30 (0.49, 3.46)
Total: (95% Cl)Total: (95% Cl) 950950 932932 0.68 (0.46, 1.02)0.68 (0.46, 1.02)
NEPHRICNEPHRIC Study: ProtocolStudy: Protocol
• Randomized, double blind, prospective, multicenterRandomized, double blind, prospective, multicenter
• Primary endpoint: peak increase in serum creatinine Primary endpoint: peak increase in serum creatinine concentration @ 3 days after angiographyconcentration @ 3 days after angiography
Patients with diabetes and serum creatinine 1.5-3.5 mg/dl who underwent coronary or aortofemoral angiography
Iso-osmolar, non-ionicIodixanol [Visipaque]
N=64Mean Contrast Volume = 163 ml
PTCA – 17%
Low-osmolar, non-ionicIohexol [Omnipaque]
N=65Mean Contrast Volume = 162 ml
PTCA – 25%
Aspelin P et al,Aspelin P et al, NEJM NEJM, 2003; 348: 491-499, 2003; 348: 491-499
Primary Endpoint –Primary Endpoint –Peak Increase in Scr from Baseline to Day 3Peak Increase in Scr from Baseline to Day 3
(µmol/l) (µmol/l) p=0.002p=0.002
Iodixanol Iodixanol (Visipaque)(Visipaque)
n=62n=62
Iohexol Iohexol (Omnipaque)(Omnipaque)
n=64n=64
MeanMean 11.2 ±19.711.2 ±19.7 41.5 ± 68.641.5 ± 68.6
MinimumMinimum - 19.0- 19.0 - 21.0- 21.0
MaxMax 74.074.0 331.0331.0
Effect of Nonionic Radiocontrast Agents on Effect of Nonionic Radiocontrast Agents on Occurrence of CIN in Patients with Mild-moderate Occurrence of CIN in Patients with Mild-moderate
CRI: Pooled Analysis of the Randomized TrialsCRI: Pooled Analysis of the Randomized Trials
• Significantly highest incidence of CIN with iohexol then two other agentsSignificantly highest incidence of CIN with iohexol then two other agents
Difference between iopamidol and iodixanol was not statistically significant Difference between iopamidol and iodixanol was not statistically significant
((P=0.227P=0.227))
Incidence of CINIncidence of CIN P P valuevalue
Iopamidol (Isovue)Iopamidol (Isovue)Low osmolarLow osmolar
Iohexol (Omnipaque)Iohexol (Omnipaque)Low osmolarLow osmolar
Iodixanol (Visipaque)Iodixanol (Visipaque)Iso-osmolarIso-osmolar
13.5%13.5%
25.0%25.0%
11.0%11.0%
0.0240.024
0.0010.001
Sharma et al. Sharma et al. Catheter Cardiovasc IntervCatheter Cardiovasc Interv 2005;65:386-393. 2005;65:386-393.
The ICON Trial: ProtocolThe ICON Trial: Protocol
Patients With Chronic Renal Insufficiencyto Undergo Angiography/PCI
n=130
Ioxaglate (Hexabrix)
Low-osmolar, ionic
Iodixanol (Visipaque)
Isoosmolar, non-ionic
Primary Endpoint: Primary Endpoint: Peak increase in the serum creatinine Peak increase in the serum creatinine concentration between day 0 (when contrast medium was concentration between day 0 (when contrast medium was
administered) and day 3administered) and day 3
Mehran et al. TCT 2006Mehran et al. TCT 2006
ICON Trial: Increase of Serum Creatinine from ICON Trial: Increase of Serum Creatinine from Baseline (Secondary Study End Point)Baseline (Secondary Study End Point)
IoxaglateIoxaglate
N=74N=74IodixanolIodixanol
N=71N=71 pp
≥ ≥ 0.5 mg/dL0.5 mg/dL 18.2 %18.2 % 16.2 %16.2 % 0.820.82
≥ ≥ 1 mg/dL1 mg/dL 4.5 %4.5 % 1.5 %1.5 % 0.360.36
≥ ≥ 25%25% 24.2 %24.2 % 16.2 %16.2 % 0.290.29
≥ ≥ 25% or ≥ 0.5 mg/dL25% or ≥ 0.5 mg/dL 24.2 %24.2 % 16.2 %16.2 % 0.290.29
JACC Intv 2009JACC Intv 2009
CARECARE
DesignDesign
• DESIGN: Prospective, randomized, double-blind, parallel-group, multi-center clinical evaluation ipamidol-370 and iodixanol-320
• OBJECTIVE: To compare the incidence of CIN between iopamidol-370 and iodixanol-320
• PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration
• DESIGN: Prospective, randomized, double-blind, parallel-group, multi-center clinical evaluation ipamidol-370 and iodixanol-320
• OBJECTIVE: To compare the incidence of CIN between iopamidol-370 and iodixanol-320
• PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration
482 patients enrolled between July 2005 and June 2006 in 25 clinical site in North America
14 patients withdrew consent
468 assigned to a treatment arm
236 patients assigned to Iodixanol-320
230 patients assigned to Iopamidol-370
204 evaluable patient
Solomon, RJ et. al., Circulation 115, 3189 (2007)Solomon, RJ et. al., Circulation 115, 3189 (2007)
210 evaluable patient
26 excluded 26 excluded
CARECARE
p = 0.39p = 0.39 p = 0.44p = 0.44 p = 0.15p = 0.15
CARECARE
p = 0.11p = 0.11 p = 0.37p = 0.37 p = 0.20p = 0.20
Diabetic SubgroupDiabetic Subgroup
Conclusions (1)Conclusions (1)
► CRI is one of the most important independent CRI is one of the most important independent predictors of poor outcome post PCIpredictors of poor outcome post PCI
► CIN remains a frequent source of acute renal failure CIN remains a frequent source of acute renal failure and is associated with increased morbidity and and is associated with increased morbidity and mortality, and higher resource utilizationmortality, and higher resource utilization
► Several factors predispose patients to CINSeveral factors predispose patients to CIN
► Preventive measures pre procedure, as well as Preventive measures pre procedure, as well as careful post procedure management should be careful post procedure management should be routine in all patientsroutine in all patients
Conclusions (2)Conclusions (2)
► Hydration pre-PCI (12 hours recommended)Hydration pre-PCI (12 hours recommended)
► D/C nephrotoxic drugs (NSAIDS, antibiotics, etc)D/C nephrotoxic drugs (NSAIDS, antibiotics, etc)
► Role of n-acetylcysteine is disputableRole of n-acetylcysteine is disputable
► No Role for IV FenoldopamNo Role for IV Fenoldopam
► Sodium bicarbonate may be useful, but need more definitive Sodium bicarbonate may be useful, but need more definitive data data
► Limit contrast agent volumeLimit contrast agent volume
► Low-osmolar agents are better than high-osmolarLow-osmolar agents are better than high-osmolar
Within non-ionic contrast, the data are contradictory Within non-ionic contrast, the data are contradictory
► Role of local drug delivery for prevention of CIN requires Role of local drug delivery for prevention of CIN requires further investigationfurther investigation
Mechanism of Thrombosis Induction Mechanism of Thrombosis Induction and Mitigation with Contrast Mediaand Mitigation with Contrast Media
Comparative Effects, Cautionary Notes Comparative Effects, Cautionary Notes and Implications for PCIand Implications for PCI
Frederick Feit, MD, FACCFrederick Feit, MD, FACCAssociate Professor of MedicineAssociate Professor of Medicine
New York University School of MedicineNew York University School of MedicineDirector, Interventional CardiologyDirector, Interventional Cardiology
New York University School of MedicineNew York University School of MedicineNew York, NYNew York, NY
Thrombosis Induction and Mitigation with Thrombosis Induction and Mitigation with Contrast Media: OutlineContrast Media: Outline
► Thrombin generation, platelet activation and their Thrombin generation, platelet activation and their interrelationshipinterrelationship
► Contrast media: The basicsContrast media: The basics
► Experimental data exploring the interaction of Experimental data exploring the interaction of differing contrast media and thrombosis in differing contrast media and thrombosis in animals and humansanimals and humans
► Potential relevance in clinical practice Potential relevance in clinical practice
XIIa, XIaXIIa, XIa IXIX
IXaIXaVIII, CaVIII, Ca
Intrinsic SystemIntrinsic SystemExtrinsic SystemExtrinsic SystemInjuryInjury
Tissue thromboplastinTissue thromboplastinXX
XaXaCa ,VCa ,V
ProthrombinProthrombin ThrombinThrombin
PlateletPlateletActivationActivation
FibrinogenFibrinogen
FibrinFibrin
XIIIXIII
XIIIaXIIIa
Mature ThrombusMature Thrombus
Extrinsic SystemExtrinsic System Intrinsic SystemIntrinsic System
Sites of Anti-thrombotic Drug ActionSites of Anti-thrombotic Drug Action
Tissue factorTissue factor
Plasma clottingPlasma clottingcascadecascade
ProthrombinProthrombin
ThrombinThrombin
FibrinogenFibrinogen FibrinFibrin
ThrombusThrombus
Platelet aggregationPlatelet aggregation
Conformational Conformational activation of GPIIb/IIIaactivation of GPIIb/IIIa
CollagenCollagen
Thromboxane AThromboxane A22
ADPADP
ATAT
ATAT
Aspirin
TiclopidineClopidogrelPrasugrel
GPIIb/IIIainhibitors
BivalirudinHirudin
Argatroban
FactorFactorXaXa
Thrombo-lytics
Aspirin
Thrombolytics
GPIIb/IIIa inhibitors
LMWHFondaparinux
Heparin
TiclopidineClopidogrelPrasugrel
BivalirudinHirudin
Argatroban
Anion Anion binding binding exositeexosite
ActiveActivecatalytic sitecatalytic site
FibrinogenFibrinogen
Thrombin
Anion binding exosite
Activecatalytic site
Active Fibrin
Thrombin
The PlateletThe Platelet
CollagenCollagen
ActivationActivation
PlateletPlatelet
GP
IIb/II
IaG
PIIb
/IIIa
GPIIb/IIIaGPIIb/IIIa
ADPADPEPIEPI ThrombinThrombin
ThromboxaneThromboxane
FibrinogenFibrinogen
COXCOX
Coagulation – “The Real Story”Coagulation – “The Real Story”
Complex interplay on the surface of plateletsComplex interplay on the surface of platelets
CollagenCollagen
TissueTissueFactorFactor
ThrombinThrombin
PlateletPlateletactivationactivation
Prothrombin
ADP
TXA2
PlasmaPlasmaClottingClottingcascadecascade
THROMBUSTHROMBUS
FibrinogenFibrinogen Fibrin
GP2b3a expression& platelet aggregation
Xa
Ca Va
Contrast Media: Preconceived Notions Contrast Media: Preconceived Notions
► Ionic Contrast: Ionic Contrast: What they used to useWhat they used to use
► Nonionic Contrast: Nonionic Contrast: What we use now, because it What we use now, because it has lower osmolality (the good stuff)has lower osmolality (the good stuff)
► Visipaque: Visipaque: The really good stuff, both theoretically The really good stuff, both theoretically and confirmed by the COURT trialand confirmed by the COURT trial
► Hexabrix: Hexabrix: I heard of that; I think it’s pretty good, I heard of that; I think it’s pretty good, tootoo
Contrast Media: More Evolved NotionsContrast Media: More Evolved Notions
►Ratio of iodine:osmotically active particles Ratio of iodine:osmotically active particles determines osmolalitydetermines osmolality
► Ioxaglate (Hexabrix), an ionic dimer has lower Ioxaglate (Hexabrix), an ionic dimer has lower osmolality than nonionic monomersosmolality than nonionic monomers
► Iodixanol (Visipaque) a nonionic dimer is Iodixanol (Visipaque) a nonionic dimer is isoosmolar to plasmaisoosmolar to plasma
Basic Structures of Contrast MediaBasic Structures of Contrast Media
Voeltz MD, et alVoeltz MD, et al. J Invasive Cardiol. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review. 2007 Mar;19(3):1A-9A. Review
Contrast Media: Very Evolved NotionsContrast Media: Very Evolved Notions
► Ionic contrast: conjugation of the benzene ring Ionic contrast: conjugation of the benzene ring structure (anion) with a non-radioopaque cation structure (anion) with a non-radioopaque cation resulting in a water soluble compound.resulting in a water soluble compound.
► Ionic monomers dissociate in vivo resulting in Ionic monomers dissociate in vivo resulting in an iodine:particle ratio of 3:2; for ionic dimers, an iodine:particle ratio of 3:2; for ionic dimers, 6:26:2
►Nonionic monomers do not dissociate so I:p Nonionic monomers do not dissociate so I:p ratio is 3:1; for nonionic dimers, 6:1ratio is 3:1; for nonionic dimers, 6:1
72
6 cPs6 cPs 8 cPs8 cPs 5-10 cPs5-10 cPs 11 cPs11 cPsViscosityat 370C
Viscosityat 370C
DiatrizoateDiatrizoate ioxaglateioxaglateIoxilanIohexol
IopamidolIopromideIoversol
IoxilanIohexol
IopamidolIopromideIoversol
IodixanolIodixanolNameName
MonomerMonomer DimerDimer MonomerMonomer DimerDimer# Benz.Rings# Benz.Rings
IonicityIonicity IonicIonic IonicIonic NonionicNonionic
OsmolalityOsmolality(mOsm/kg)(mOsm/kg)OsmolalityOsmolality(mOsm/kg)(mOsm/kg) HOCMHOCM
(>1,500)(>1,500)HOCMHOCM
(>1,500)(>1,500)LOCMLOCM
(280 – 1,000)(280 – 1,000)LOCMLOCM
(280 – 1,000)(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: Comparative Characteristics of Contrast Media: Molecular StructuresMolecular Structures
Classification and OsmolalityClassification and Osmolality
ClassClass Chemical Chemical NameName
Trade Name Trade Name and and
ManufacturerManufacturer
Osmolality Osmolality (mOsm/kg (mOsm/kg
HH220)0)
High-OsmolarHigh-Osmolar(HOCM)(HOCM) Ionic Ionic
MonomersMonomers
DiatrizoateDiatrizoate
HypaqueHypaque®® (GEH) (GEH) 20162016
RenoCal-76RenoCal-76® ® (B)(B) 18701870
MD-76MD-76®®R (M)R (M) 15511551
IothalamateIothalamate Conray Conray ® ® (M)(M) 14001400
Low-Osmolar Low-Osmolar (LOCM)(LOCM)
High-Viscosity High-Viscosity (HVCM)(HVCM)
Low-Viscosity Low-Viscosity (LVCM)(LVCM)
Nonionic Nonionic DimerDimer IodoxinalIodoxinal VisipaqueVisipaqueTM TM 320 320
(GEH)(GEH) 290290
Nonionic Nonionic MonomersMonomers
IopromideIopromide UltravistUltravist®® 370 (BR) 370 (BR) 774774
IopamidolIopamidol IsovueIsovue®® 370 (B) 370 (B) 796796
IohexolIohexol OmnipaqueOmnipaqueTM TM 350 350 (GEH)(GEH) 844844
IoversolIoversol OptirayOptiray®® 350 (M) 350 (M) 792792
IoxilanIoxilan OxilanOxilan®® 350 (G) 350 (G) 695695
Ionic DimerIonic Dimer IoxaglateIoxaglate HexabrixHexabrix®® 320 320 (G-M)(G-M) 600600
Voeltz MD, et alVoeltz MD, et al. J Invasive Cardiol. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review. 2007 Mar;19(3):1A-9A. Review
Engelhart et al. Engelhart et al. Invest Radiol Invest Radiol 1988;23:922-71988;23:922-7
Methods: Patients Undergoing angiographyMethods: Patients Undergoing angiography
1.1.Blood drawn from 5F pigtail in aorta utilizing 50cc syringe Blood drawn from 5F pigtail in aorta utilizing 50cc syringe
2.2.5ml blood injected in multiple 10cc syringes5ml blood injected in multiple 10cc syringes
3.3.2ml contrast drawn into syringe (no mixing) 2ml contrast drawn into syringe (no mixing)
4.4.Inject onto filter paper at 10, 30, 60, 90 min. to assess thrombusInject onto filter paper at 10, 30, 60, 90 min. to assess thrombus
Incubation of Blood with ContrastIncubation of Blood with Contrast
Engelhart et al. Invest Radiol 1988;23:922-7Engelhart et al. Invest Radiol 1988;23:922-7
Differential Effects of Contrast Media Differential Effects of Contrast Media on Platelet Aggregationon Platelet Aggregation
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
IopamidolIopamidol: directly induced platelet: directly induced plateletaggregation and potentiated thataggregation and potentiated thatinduced by ADPinduced by ADP
IodixanolIodixanol: potentiated aggregation: potentiated aggregationinduced by ADPinduced by ADP
IoxaglateIoxaglate: inhibited aggregation: inhibited aggregationinduced by ADPinduced by ADP
ADP antagonists, but not ASA ADP antagonists, but not ASA inhibited Iopamidol induced plateletinhibited Iopamidol induced plateletaggregation indicating that thisaggregation indicating that thisphenomenon is not mediated byphenomenon is not mediated byTXA2 and is at least in part by TXA2 and is at least in part by ADP
% A
ggre
gatio
n%
Agg
rega
tion
Platelet aggregation and P-selectin expression in Platelet aggregation and P-selectin expression in hirudinized whole blood containing iopamidol, hirudinized whole blood containing iopamidol, iodixanol, or ioxaglate in the absence (open iodixanol, or ioxaglate in the absence (open histograms) or presence (thatched histograms) of AR-histograms) or presence (thatched histograms) of AR-C66096 (10 C66096 (10 uumol/l).mol/l).
*
In Vitro Comparison of the Effects of Contrast In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet ActivationMedia on Coagulation and Platelet Activation
Corot et al. Corot et al. Blood Coagulation and Fibrinolysis Blood Coagulation and Fibrinolysis 1996;7:602-81996;7:602-8
Methods:1.1.Pooled human plasma mixed with saline control or Pooled human plasma mixed with saline control or contrast Iohexol (Omnipaque), or Iodixanol contrast Iohexol (Omnipaque), or Iodixanol (Visipaque), or Ioxaglate (Hexabrix) to a final (Visipaque), or Ioxaglate (Hexabrix) to a final concentration of 60mg I/ml for aPTT and TT studiesconcentration of 60mg I/ml for aPTT and TT studies
2.2.Platelet studies performed using ELISA testsPlatelet studies performed using ELISA tests
In Vitro Comparison of the Effects of Contrast In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet ActivationMedia on Coagulation and Platelet Activation
Corot et al. Corot et al. Blood Coagulation and Fibrinolysis Blood Coagulation and Fibrinolysis 1996;7:602-81996;7:602-8
NaCL 9 g/l Iodixanol Iohexol Ioxaglate
TT (s)TT (s) 19 19 ± 2± 2 84 84 ± 10± 10 110 110 ± 18± 18 >500>500
APTT (s)APTT (s) 44 44 ± 2± 2 74 74 ± 1± 1 81 81 ± 2± 2 303 303 ± 13± 13
P <0.01P <0.01 P <0.01P <0.01 P < 0.01P < 0.01
In Vitro Comparison of the Effects of Contrast In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet ActivationMedia on Coagulation and Platelet Activation
Corot et al. Corot et al. Blood Coagulation and Fibrinolysis Blood Coagulation and Fibrinolysis 1996;7:602-81996;7:602-8
30 min 30 min intubationintubation
PF4PF4IU/mlIU/ml
5-HT5-HTNg/mlNg/ml
PDGF-ABPDGF-ABPg/mlPg/ml
TXBTXB22
Ng/mlNg/mlFpAFpA
Ng/mlNg/ml
Control 786 185 6951 33 >1500
Ioxaglate 43 18 <186 47 9
Iodixanol 209 506 2173 48 35
Iohexol 1446 801 18606 25 5
Thrombin 4061 1378 26421 10614 >1500
In Vitro Comparison of the Effects of Contrast In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet ActivationMedia on Coagulation and Platelet Activation
Corot et alCorot et al. Blood Coagulation and Fibrinolysis . Blood Coagulation and Fibrinolysis 1996;7:602-81996;7:602-8
PF4PF4
P<0.001P<0.001
IU/m
lIU
/ml
PF4 determinations (platelet factor 4) which represent platelet degranulation PF4 determinations (platelet factor 4) which represent platelet degranulation induced by contrast media mixed 1:1 with blood for 1 min (mean induced by contrast media mixed 1:1 with blood for 1 min (mean ± SD, n=4).± SD, n=4).
Corot et al: ConclusionsCorot et al: Conclusions
► Ioxaglate demonstrated the most powerful Ioxaglate demonstrated the most powerful anticoagulant properties, followed by iohexol and anticoagulant properties, followed by iohexol and IodixanolIodixanol
► Iohexol resulted in major platelet activation; Iohexol resulted in major platelet activation; iodixanol in less platelet activation, only with 30 iodixanol in less platelet activation, only with 30 minutes of incubation; ioxaglate did not activate minutes of incubation; ioxaglate did not activate plateletsplatelets
Differential Effects on Thrombus FormationDifferential Effects on Thrombus Formation
Jones C et al. Jones C et al. Thrombosis Research Thrombosis Research 2003;112:65-712003;112:65-71
Methods: Methods:
1.1.Contrast agent added to blood collected from normal volunteers Contrast agent added to blood collected from normal volunteers in ratio of either 20% or 50% in ratio of either 20% or 50%
2.2.Mixed for 1 min. Mixed for 1 min.
3.3.Thrombi formed in vitro by adding 1ml recalcified blood/contrast Thrombi formed in vitro by adding 1ml recalcified blood/contrast to the chandler loop (45 cm long, 3 mm inner circumference) PVC to the chandler loop (45 cm long, 3 mm inner circumference) PVC tubing tubing
4.4.Rotated at 37 rpm for 90 minsRotated at 37 rpm for 90 mins
5.5.Thrombus analyzed by immunofluorescence and weighedThrombus analyzed by immunofluorescence and weighed
6.6.Thrombolysis over 24 hours, both spontaneous and by tPA Thrombolysis over 24 hours, both spontaneous and by tPA assessed, by weight of thrombus and measuring free FITC in assessed, by weight of thrombus and measuring free FITC in supernatant (a product of lysis of FITC-labeled fibrinogensupernatant (a product of lysis of FITC-labeled fibrinogen
Differential Effects on Thrombus FormationDifferential Effects on Thrombus Formation
Jones C et al. Jones C et al. Thrombosis Research Thrombosis Research 2003;112:65-712003;112:65-71
Wei
ght
(mg)
Wei
ght
(mg)
SalineSaline 20%20% -- -- -- -- -- --IoxaglateIoxaglate -- 50%50% 20%20% -- -- --IobexolIobexol -- -- -- 50%50% 20%20% -- --IodixanolIodixanol -- -- -- -- -- 50%50% 20%20%
P<0.0005
Differential Effects on Platelet DegranulationDifferential Effects on Platelet Degranulation
Jones C et al. Jones C et al. Thrombosis Research Thrombosis Research 2003;112:65-712003;112:65-71
Per
cent
Pos
itive
Per
cent
Pos
itive
SalineSaline 50%50% -- -- -- -- -- --IoxaglateIoxaglate -- 50%50% 20%20% -- -- --IobexolIobexol -- -- -- 50%50% 20%20% -- --IodixanolIodixanol -- -- -- -- -- 50%50% 20%20%
Percentage of platelets positive for P-selectin expression in the presence of CMPercentage of platelets positive for P-selectin expression in the presence of CM
P<0.02
P<0.03
Fibrinolysis: Spontaneous or with tPAFibrinolysis: Spontaneous or with tPA
Jones C et al. Jones C et al. Thrombosis Research Thrombosis Research 2003;112:65-712003;112:65-71
Wei
ght (
mg)
Wei
ght (
mg)
Flo
rese
nce
(arb
itrar
y U
)F
lore
senc
e (a
rbitr
ary
U)
SalineSaline 20%20% 20%20% -- -- -- --IohexolIohexol -- -- 20%20% 20%20% -- --IodixanolIodixanol -- -- -- -- 20%20% 20%20%tPAtPA -- ++ -- ++ -- ++
SalineSaline 20%20% 20%20% -- -- -- --IohexolIohexol -- -- 20%20% 20%20% -- --IodixanolIodixanol -- -- -- -- 20%20% 20%20%tPAtPA -- ++ -- ++ -- ++
P<0.02 P<0.02
Thrombus HistopathologyThrombus Histopathology
Jones C et al. Jones C et al. Thrombosis Research Thrombosis Research 2003;112:65-712003;112:65-71
Head and tail regions of thrombi forHead and tail regions of thrombi forSaline control (top), Iohexol (mid), Saline control (top), Iohexol (mid), Iodixanol (bot). Thrombi formed in Iodixanol (bot). Thrombi formed in the presence of either contrast hadthe presence of either contrast hadlarger, more platelet-rich heads larger, more platelet-rich heads and much larger tails, composed ofand much larger tails, composed ofan open irregular meshwork ofan open irregular meshwork offibrinogen/fibrin enclosing largefibrinogen/fibrin enclosing largedense RBC areas and scattered dense RBC areas and scattered WBC.WBC.
Iohexol thrombi had larger “heads”Iohexol thrombi had larger “heads”than iodixanol thrombi, which had than iodixanol thrombi, which had a much more irregular structure a much more irregular structure with areas of very strong fibrinogenwith areas of very strong fibrinogenantibody binding interspersed withantibody binding interspersed withWBC aggregates.WBC aggregates.
Differential Effects on Thrombus Formation Differential Effects on Thrombus Formation ConclusionsConclusions
►No thrombi formed from blood incubated with No thrombi formed from blood incubated with Ioxaglate Ioxaglate
►Thrombi formed with Iohexol or Iodixanol weighed Thrombi formed with Iohexol or Iodixanol weighed >10x more than those formed with saline controls, >10x more than those formed with saline controls, had different structure and were more resistant to had different structure and were more resistant to thrombolysisthrombolysis
► Iohexol, but neither Iodixanol nor Ioxaglate Iohexol, but neither Iodixanol nor Ioxaglate increased platelet degranulationincreased platelet degranulation
Contrast Media: Mechanistic Assessment of Contrast Media: Mechanistic Assessment of Thrombin GenerationThrombin Generation
Methods: Methods: 1.1.Pooled plasma from healthy donors to prepare PRP Pooled plasma from healthy donors to prepare PRP and PPPand PPP
2.2.Thrombograms obtained by mixing PPP or PRP Thrombograms obtained by mixing PPP or PRP with activator (TF for extrinsic system and kaolin for with activator (TF for extrinsic system and kaolin for intrinsic system) plus ioxaglate, iodixanol, abciximab intrinsic system) plus ioxaglate, iodixanol, abciximab (as shown)(as shown)
3.3.Thrombograms assessed by lag time (clotting Thrombograms assessed by lag time (clotting time), peak height (maximal velocity of net thrombin time), peak height (maximal velocity of net thrombin production, area under the curve (endogenous production, area under the curve (endogenous thrombin potential) thrombin potential)
Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274
Thrombogram: Iodixanol vs. IoxaglateThrombogram: Iodixanol vs. Ioxaglate
Al Dieri R et al. Al Dieri R et al. J of Thombosis and HemostasisJ of Thombosis and Hemostasis, 2003, 1:269-274, 2003, 1:269-274
Influence of the contrast media addition on Influence of the contrast media addition on the thrombogram in PPP and PRP. (a) In the thrombogram in PPP and PRP. (a) In defibrinated PPP initiated with rTF. (b) In defibrinated PPP initiated with rTF. (b) In defibrinated PPP initiated with contact defibrinated PPP initiated with contact activator. (c) In PRP initiated only with CA activator. (c) In PRP initiated only with CA 2+2+
●●control; control; ○○iodixanol (5% v/v); iodixanol (5% v/v); ioxaglate ioxaglate (5%, v/v). Data represent median of four (5%, v/v). Data represent median of four independent experimentsindependent experiments
Abciximab + Iodixanol or IoxaglateAbciximab + Iodixanol or Ioxaglate
Al Dieri R et al. Al Dieri R et al. J of Thombosis and HemostasisJ of Thombosis and Hemostasis, 2003, 1:269-274, 2003, 1:269-274
Effect of abciximab on the thrombogram in PRP in the absence and Effect of abciximab on the thrombogram in PRP in the absence and presence of CM (5% v/v ). presence of CM (5% v/v ). ●●control; control; ○○abciximab alone (40 ug mLabciximab alone (40 ug mL-1-1); ); abciximab + iodixanol; abciximab + iodixanol; abciximab + ioxaglate. Data represent median of abciximab + ioxaglate. Data represent median of three independent experimentsthree independent experiments
Al Dieri et al: Conclusions
► Ioxaglate is a potent inhibitor of thrombus Ioxaglate is a potent inhibitor of thrombus formation in prp and ppp. Effects of iodixanol formation in prp and ppp. Effects of iodixanol are to slightly enhance thrombin generationare to slightly enhance thrombin generation
► Ioxaglate amplifies the effect of abciximabIoxaglate amplifies the effect of abciximab
► Ioxaglate inhibits activation of factors V and VIII Ioxaglate inhibits activation of factors V and VIII (thrombograms not shown) and of platelets by (thrombograms not shown) and of platelets by thrombinthrombin
► These data suggest that ioxaglate interferes with These data suggest that ioxaglate interferes with binding of substrates to exosite I of thrombin binding of substrates to exosite I of thrombin and inhibits thrombin generation via inhibition of and inhibits thrombin generation via inhibition of thrombin-mediated feedback activationthrombin-mediated feedback activation
Antithrombotic Effects of Ionic and Non-Ionic Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman PrimatesContrast Media in Nonhuman Primates
Methods: Methods: 1)1)Healthy baboons with chronic AV (femoral) Healthy baboons with chronic AV (femoral) shuntsshunts
2)2)PS 153 stent deployed at 10 atm in AV shuntPS 153 stent deployed at 10 atm in AV shunt
3)3)Labeled platelets usedLabeled platelets used
4)4)Saline control or contrast (Iodixanol, Isovue, Saline control or contrast (Iodixanol, Isovue, Ioxaglate) locally infusedIoxaglate) locally infused
5)5)The fluid mechanics and mass transfer The fluid mechanics and mass transfer characteristics of the infused contrast were characteristics of the infused contrast were modeled using computational fluid dynamicsmodeled using computational fluid dynamics
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Antithrombotic Effects of Ionic and Non-Ionic Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman PrimatesContrast Media in Nonhuman Primates
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Schematic of the local infusion system, stented segment, and expanded diameter Schematic of the local infusion system, stented segment, and expanded diameter chamber region of the thrombogenic device showing their relative placement in the A-chamber region of the thrombogenic device showing their relative placement in the A-V baboon shunt. The top panel shows an in-platelet image of platelet deposition on a V baboon shunt. The top panel shows an in-platelet image of platelet deposition on a control stent and within chamber region of flow recirculation.control stent and within chamber region of flow recirculation.
Platelet Deposition in the Expanded RegionPlatelet Deposition in the Expanded Region
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Time course of platelet deposition within the chamber regions of expanded Time course of platelet deposition within the chamber regions of expanded diameter (9.0 mm i.d.) exhibiting low shear blow flow recirculation and stasis. diameter (9.0 mm i.d.) exhibiting low shear blow flow recirculation and stasis. The blood flow rate was 100 ml/min. Platelet deposition was monitored by The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of measuring the accumulation of 111111Indium-radiolabeled platelets. A) CM infusion Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ±± 1 SEM 1 SEM
Time (min) Time (min)
Pla
tele
ts D
epos
ited
x 10
-6
Pla
tele
ts D
epos
ited
x 10
-6
A B
Platelet Deposition in the Stented RegionPlatelet Deposition in the Stented Region
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Time course of platelet deposition onto 4.0 mm i.d. metallic stents (Palmaz-Time course of platelet deposition onto 4.0 mm i.d. metallic stents (Palmaz-Schatz) deployed into A-V shunts in baboons. The blood flow rate was 100 Schatz) deployed into A-V shunts in baboons. The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of ml/min. Platelet deposition was monitored by measuring the accumulation of 111111Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean infusion rate = 0.3 ml/min. Values are mean ±± 1 SEM 1 SEM
Time (min) Time (min)
Pla
tele
ts D
epos
ited
x 10
-6
Pla
tele
ts D
epos
ited
x 10
-6
A B
Fibrin Deposition on Stented Segment
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Fib
rin (
mg)
Fib
rin (
mg)
44
44
2
4
Deposition of fibrin on the stented segmentDeposition of fibrin on the stented segment
Fib
rin (
mg)
Fib
rin (
mg)
7
The blood flow rate was 100 ml/mi. Fibrin deposition was determined by measuring the The blood flow rate was 100 ml/mi. Fibrin deposition was determined by measuring the accumulation of accumulation of 125125iodine-labeled fibrinogen. A) CME infusion rate = 0.1 ml/min. B. CME infusion iodine-labeled fibrinogen. A) CME infusion rate = 0.1 ml/min. B. CME infusion rate = 0.3 ml/min. Values are mean rate = 0.3 ml/min. Values are mean ±± 1 SEM 1 SEM
Photographs of Thrombus Formed in StentsPhotographs of Thrombus Formed in Stents
97
.
Markou et al. Markou et al. Thromb Haemost Thromb Haemost 2001;85:488-932001;85:488-93
Antithrombotic Effects of Ionic and Non-Ionic Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman PrimatesContrast Media in Nonhuman Primates
► Ioxaglate reduced both platelet and fibrin deposition on stents by 75-80% (p<0.005), while the non-ionic agents reduced platelet deposition by 52% (p<0.05)
► In the regions of low shear flow, only ioxaglate (0.3ml/min) reduced platelet deposition sgnificantly (by 52%; p<0.05)
► In this model, while all three agents were inherently antithrombotic, the most striking effects were seen with ioxaglate
Primary endpoint: In-Lab ThrombusPrimary endpoint: In-Lab Thrombus
All ComersPTCA
Iohexol Ioxaglate
Randomized Blinded
Randomized Blinded
UFH: 10,000 u IVAspirin
UFH: 10,000 u IVAspirin
Plessens et al. Plessens et al. Cathet Cardiovasc Diagn Cathet Cardiovasc Diagn 1993;28:99-1051993;28:99-105
All Comers PTCA
Iohexol Ioxaglate
Primary Endpoint: In-Lab Thrombus
Iohexol (Omnipaque) vs Ioxaglate (Hexabrix)Iohexol (Omnipaque) vs Ioxaglate (Hexabrix)For PTCAFor PTCA
Coronary Angioplasty: In-Lab ThrombusCoronary Angioplasty: In-Lab Thrombus
P = 0.04
Plessens et al. Plessens et al. Cathet Cardiovasc Diagn Cathet Cardiovasc Diagn 1993;28:99-1051993;28:99-105
Primary endpoint: Thrombus During AngiographyPrimary endpoint: Thrombus During Angiography
All ComersPTCA
Iohexol Ioxaglate
Randomized Randomized
UFH: 10,000 u IVAspirin
UFH: 10,000 u IVAspirin
Esplugas et al. Esplugas et al. Am J Cardiol Am J Cardiol 1991;68:1020-41991;68:1020-4Esplugas et al. Esplugas et al. Am J Cardiol Am J Cardiol 1991;68:1020-41991;68:1020-4
All Comers PTCA
Iohexol Ioxaglate
Primary Endpoint: Thrombus During Angiography
Iohexol (Omnigraf) vs Ioxaglate (Hexabrix)Iohexol (Omnigraf) vs Ioxaglate (Hexabrix)For PTCAFor PTCA
In-Lab Angiographic Thrombus In-Lab Angiographic Thrombus
P < 0.005
Esplugas et al. Esplugas et al. Am J Cardiol Am J Cardiol 1991;68:1020-41991;68:1020-4Esplugas et al. Esplugas et al. Am J Cardiol Am J Cardiol 1991;68:1020-41991;68:1020-4
All ComersPCI Patients
Iodixanol Ioxaglate
Sequential Design
Sequential Design
Enoxaparin 1 mg/kg SC Q12 h, or 0.5 mg/kg 5 min prior to PCI
Enoxaparin 1 mg/kg SC Q12 h, or 0.5 mg/kg 5 min prior to PCI
Le Feuvre et al. Le Feuvre et al. Cath and Cardiovasc IntCath and Cardiovasc Int. 2006;67:852-8. 2006;67:852-8Le Feuvre et al. Le Feuvre et al. Cath and Cardiovasc IntCath and Cardiovasc Int. 2006;67:852-8. 2006;67:852-8
All Comers PCI Patients
Iodixanol Ioxaglate
Primary Endpoint: In-Hospitral MACE (cardiac death, MI, TVR, CVA, systemic embolic event) Secondary endpoint: Angiographic outcomes (large thrombus > 2 vessel diameters)
ASA, 250 mg PO OD, clopidogrel 300 mg PO >6h ASA, 250 mg PO OD, clopidogrel 300 mg PO >6h GP IIb/IIIa in 43% (operator discretion)GP IIb/IIIa in 43% (operator discretion)
(Peak anti Xa > 0.5 IU/ml in 97% of patients)(Peak anti Xa > 0.5 IU/ml in 97% of patients)
Le Feuvre et al: Intraprocedural Large ThrombusLe Feuvre et al: Intraprocedural Large Thrombus
P < 0.0001
Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8
Iodixanol vs. Ioxaglate for PCI Iodixanol vs. Ioxaglate for PCI Stent in 91%Stent in 91%
Thrombosis Induction and Thrombosis Induction and Mitigation with Contrast Media: ConclusionsMitigation with Contrast Media: Conclusions
► Data from in vitro studies and from animal models Data from in vitro studies and from animal models indicate significant differences in the effects of indicate significant differences in the effects of different contrast media on thrombin generation, different contrast media on thrombin generation, thrombolysis and platelet activation.thrombolysis and platelet activation.
► Among commonly used agents, the ionic dimer, Among commonly used agents, the ionic dimer, Ioxaglate (Hexabrix) inhibits both thrombin Ioxaglate (Hexabrix) inhibits both thrombin generation and platelet activationgeneration and platelet activation
► Non-ionic monomers activate platelets, enhance Non-ionic monomers activate platelets, enhance thrombin generation and inhibit thrombolysisthrombin generation and inhibit thrombolysis
► The non-ionic dimer, Iodixanol (Visipaque) has The non-ionic dimer, Iodixanol (Visipaque) has intermediate resultsintermediate results
Thrombosis Induction and Mitigation with Contrast Media: Conclusions
► There are some provocative clinical data, but are they relevant in the current era?
► Stay Tuned!
The Role of Contrast Media (CM) on The Role of Contrast Media (CM) on Clinical Outcomes in Patients with Clinical Outcomes in Patients with
STEMI and High-Risk ACS: STEMI and High-Risk ACS: The Evidence-Based Case for The Evidence-Based Case for
Risk-Directed Selection of CM in PCIRisk-Directed Selection of CM in PCI
The Journey from Clinical Trials to Choices for CM in the The Journey from Clinical Trials to Choices for CM in the Cardiac Catheterization Laboratory: How Should Recent Cardiac Catheterization Laboratory: How Should Recent
Evidence and Trials Affect Our Choices?Evidence and Trials Affect Our Choices?
Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCProgram ChairmanProgram Chairman
Director, Cardiovascular Research | Sarah Cannon Research Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Institute | Centennial Heart Cardiovascular Consultants |
Medical Director, Cardiovascular Services | Clinical ServicesMedical Director, Cardiovascular Services | Clinical ServicesGroup | Hospital Corporation of America (HCA) | Nashville, TNGroup | Hospital Corporation of America (HCA) | Nashville, TN
Clots, Contrast Media, and Catheterization Clots, Contrast Media, and Catheterization OutlineOutline
► PCI ischemic complicationsPCI ischemic complications
► Anticoagulation in PCIAnticoagulation in PCI
► Bleeding complications of PCI anticoagulationBleeding complications of PCI anticoagulation
► Impact of PCI periprocedural MIImpact of PCI periprocedural MI
► Clinical trials of contrast media in PCIClinical trials of contrast media in PCI
► ConclusionsConclusions
Ischemic Complications of PCIIschemic Complications of PCI
Lincoff AM et al. JAMA 2003;289:853-863.Lincoff AM et al. JAMA 2003;289:853-863.Stone GW et al. Lancet 2007;369:907-19.Stone GW et al. Lancet 2007;369:907-19.Stone GW et al. NEJM 2008;358:2218-30.Stone GW et al. NEJM 2008;358:2218-30.
30-Day Event Rates Adapted from REPLACE-2, ACUITY-PCI, HORIZONS PCI Subset30-Day Event Rates Adapted from REPLACE-2, ACUITY-PCI, HORIZONS PCI Subset
EPILOG: 30-Day Primary Efficacy EndpointEPILOG: 30-Day Primary Efficacy Endpoint
EPILOG Investigators. EPILOG Investigators. NEJMNEJM 1997;336:1689-96. 1997;336:1689-96.
0.120.12
0.100.10
0.080.08
0.060.06
0.040.04
0.020.02
0.010.0100 5 5 10 10 15 15 20 20 25 25 30 30
Pro
babi
lity
of D
eath
, P
roba
bilit
y of
Dea
th,
Myo
card
ial I
nfar
ctio
n, o
rM
yoca
rdia
l Inf
arct
ion,
or
Urg
ent
Rev
ascu
lariz
atio
n U
rgen
t R
evas
cula
rizat
ion
Days After RandomizationDays After Randomization
P<0.001P<0.001
PlaceboPlacebo
Abciximab + standard-dose heparinAbciximab + standard-dose heparin
Abciximab + low-dose heparinAbciximab + low-dose heparin
EPILOG: 30-Day Individual EndpointsEPILOG: 30-Day Individual Endpoints
EPILOG Investigators. EPILOG Investigators. NEJMNEJM 1997;336:1689-96. 1997;336:1689-96.
Efficacy End PointEfficacy End Point
Placebo + Placebo + Standard-Standard-
Dose Dose Heparin Heparin (n=939)(n=939)
Abciximab + Abciximab + Low-Dose Low-Dose Heparin Heparin (n=935)(n=935)
P ValueP Value
Abciximab + Abciximab + Standard-Standard-
Dose Dose Heparin Heparin (n=918)(n=918)
P ValueP Value
No. of patients (%)No. of patients (%) No. patients (%)No. patients (%)
CompositeComposite 109 (11.7)109 (11.7) 48 (5.2)48 (5.2) <0.001<0.001 49 (5.4)49 (5.4) <0.001<0.001
DeathDeath 7 (0.8)7 (0.8) 3 (0.3)3 (0.3) 0.210.21 4 (0.4)4 (0.4) 0.390.39
Myocardial infarctionMyocardial infarction 81 (8.7)81 (8.7) 34 (3.7)34 (3.7) <0.001<0.001 35 (3.8)35 (3.8) <0.001<0.001
Q-waveQ-wave 7 (0.8)7 (0.8) 4 (0.4)4 (0.4) 0.360.36 4 (0.5)4 (0.5) 0.380.38
Non-Q-waveNon-Q-wave 74 (7.9)74 (7.9) 30 (3.2)30 (3.2) <0.001<0.001 31 (3.4)31 (3.4) <0.001<0.001
Large non-Q-wave (CK MB Large non-Q-wave (CK MB >> 5 x 5 x control)control) 53 (5.6)53 (5.6) 19 (2.0)19 (2.0) <0.001<0.001 23 (2.5)23 (2.5) <0.001<0.001
Small non-Q-wave (CK MB 3-5x Small non-Q-wave (CK MB 3-5x control)control) 18 (1.9)18 (1.9) 11 (1.2)11 (1.2) 0.260.26 8 (0.9)8 (0.9) 0.070.07
Non-Q-wave after hospitalizationNon-Q-wave after hospitalization 3(0.03)3(0.03) 00 0.250.25 00 0.250.25
Urgent revascularizationUrgent revascularization 48 (5.2)48 (5.2) 15 (1.6)15 (1.6) <0.001<0.001 21 (2.3)21 (2.3) 0.0010.001
Repeated percutaneous Repeated percutaneous interventionintervention 35 (3.8)35 (3.8) 11 (1.2)11 (1.2) <0.001<0.001 14 (1.5)14 (1.5) 0.0030.003
Coronary-artery bypass graftingCoronary-artery bypass grafting 16 (1.7)16 (1.7) 4 (0.4)4 (0.4) 0.0070.007 8 (0.9)8 (0.9) 0.110.11
Death or myocardial infarctionDeath or myocardial infarction 85 (9.1)85 (9.1) 35 (3.8)35 (3.8) <0.001<0.001 38 (4.2)38 (4.2) <0.001<0.001
ACUITY: Early Composite IschemiaACUITY: Early Composite Ischemia
Stone GW et al. Stone GW et al. NEJMNEJM 2006;355:2203-16. 2006;355:2203-16.
Days After RandomizationDays After Randomization
00 5 5 10 10 15 15 20 20 25 25 30 35 30 35
1515
1010
55
00
Bivalirudin alone, 8.0%, P=0.30Bivalirudin alone, 8.0%, P=0.30
Bivalirudin + GP IIb/IIIa inhibitor, 7.9%, P=0.37Bivalirudin + GP IIb/IIIa inhibitor, 7.9%, P=0.37
Heparin + GP IIb/IIIa inhibitor, 7.4%Heparin + GP IIb/IIIa inhibitor, 7.4%
ACUITY: Major BleedingACUITY: Major Bleeding
Stone GW et al. Stone GW et al. NEJMNEJM 2006;355:2203-16. 2006;355:2203-16.
Days After RandomizationDays After Randomization
00 5 5 10 10 15 15 20 20 25 25 30 35 30 35
1515
1010
55
00
Heparin + GP IIb/IIIa inhibitor, 5.7%Heparin + GP IIb/IIIa inhibitor, 5.7%
Bivalirudin + GP IIb/IIIa inhibitor, 5.3%, P=0.41Bivalirudin + GP IIb/IIIa inhibitor, 5.3%, P=0.41
Bivalirudin alone, 3.1%, P<0.001Bivalirudin alone, 3.1%, P<0.001
ACUITY: Major Bleeding and MortalityACUITY: Major Bleeding and Mortality
Manoukian SV et al. Manoukian SV et al. JACCJACC 2007;49:1362-8. 2007;49:1362-8.
Long rank p Value:Long rank p Value:<0.0001<0.0001
7.3%7.3%
Patients with major bleedingPatients with major bleedingPatients without major bleedingPatients without major bleeding
Per
cent
Mor
talit
yP
erce
nt M
orta
lity
Days After RandomizationDays After Randomization
00 5 5 10 10 15 15 20 20 25 30 35 25 30 35
88
77
66
55
44
33
22
11
00
1.2%1.2%
ACUITY: Predictors of Major BleedingACUITY: Predictors of Major Bleeding
Manoukian SV et al. Manoukian SV et al. JACCJACC 2007;49:1362-8. 2007;49:1362-8.
Age > 75 yearsAge > 75 years 1.64 (1.32-2.02)1.64 (1.32-2.02) <0.0001<0.0001
Female genderFemale gender 1.92 (1.61-2.29)1.92 (1.61-2.29) <0.0001<0.0001
DiabetesDiabetes 1.20 (1.00-1.44)1.20 (1.00-1.44) 0.0570.057
HypertensionHypertension 1.24 (1.01-1.52)1.24 (1.01-1.52) 0.0400.040
No prior PCINo prior PCI 1.32 (1.08-1.62)1.32 (1.08-1.62) 0.0060.006
AnemiaAnemia 1.87 (1.54-2.28)1.87 (1.54-2.28) <0.0001<0.0001
Renal insufficiencyRenal insufficiency 1.53 (1.24-1.90)1.53 (1.24-1.90) <0.0001<0.0001
Baseline ST-segment deviation Baseline ST-segment deviation >> 1 mm 1 mm 1.35 (1.13-1.61)1.35 (1.13-1.61) 0.00080.0008
Baseline cardiac biomarker elevationBaseline cardiac biomarker elevation 1.43 (1.19-1.74)1.43 (1.19-1.74) 0.00020.0002
Heparin plus GPI vs bivalirudin monotherapyHeparin plus GPI vs bivalirudin monotherapy 1.95 (1.56-2.44)1.95 (1.56-2.44) <0.0001<0.0001
Odds Ratio Odds Ratio ± 95% CI OR (95% CI) p value± 95% CI OR (95% CI) p value
0 1 2 30 1 2 3
Clinical Classification of MIClinical Classification of MI
Thygesen K et alThygesen K et al. J Am Coll Cardiol. J Am Coll Cardiol 2007;50:2173-95. 2007;50:2173-95.
Type 1Type 1Spontaneous myocardial infarction related to ischaemia due to primary coronary event Spontaneous myocardial infarction related to ischaemia due to primary coronary event such as plaque erosion and/or rupture, fissuring, or dissectionsuch as plaque erosion and/or rupture, fissuring, or dissection
Type 2Type 2Myocardial infarction secondary to ischaemia due to either increased oxygen demand or Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotensionhypertension, or hypotension
Type3Type3Sudden unexpected cardiac death, including cardiac arrest, often with symptoms Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischaemia, accompanied by presumably new ST-elevation, or suggestive of myocardial ischaemia, accompanied by presumably new ST-elevation, or new LBB,B, or evidence of fresh thrombus in a coronary artery by angiography and/or at new LBB,B, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the bloodthe appearance of cardiac biomarkers in the blood
Type 4aType 4aMyocardial infarction associated with PCIMyocardial infarction associated with PCI
Type 4bType 4bMyocardial infarction associated with stent thrombosis as documented by angiography or Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsyat autopsy
Type 5Type 5Myocardial infarction associated with CABGMyocardial infarction associated with CABG
ACUITY: Periprocedural MI and MortalityACUITY: Periprocedural MI and Mortality30-Day Event Rates, PCI Population30-Day Event Rates, PCI Population
Prasad A et al. Prasad A et al. J Am Coll Cardiol J Am Coll Cardiol 2009;54:477-86.2009;54:477-86.
30-d
ay e
vent
s (%
)30
-day
eve
nts
(%)
P<0.0001
P=0.27 P<0.0001
P<0.0001
P=0.8
P<0.0001
P<0.0001
P=0.41
P=0.0004
Age (Age (>> 75 years) 75 years) 2.53 (2.01-3.18)2.53 (2.01-3.18) <0.0001<0.0001
AnemiaAnemia 1.51 (1.22-1.86)1.51 (1.22-1.86) 0.00020.0002
Prior strokePrior stroke 1.29 (1.04-1.60)1.29 (1.04-1.60) 0.020.02
MaleMale 1.53 (1.23-1.90)1.53 (1.23-1.90) 0.00010.0001
DiabetesDiabetes 1.51 (1.25-1.82)1.51 (1.25-1.82) <0.0001<0.0001
Baseline CrCl <60 mL/minBaseline CrCl <60 mL/min 1.43 (1.13-1.80)1.43 (1.13-1.80) 0.0030.003
Pre-randomization UFHPre-randomization UFH 1.25 (1.02-1.54)1.25 (1.02-1.54) 0.030.03
Prior MIPrior MI 1.33 (1.09-1.61)1.33 (1.09-1.61) 0.0050.005
CKMB/troponin+ at baselineCKMB/troponin+ at baseline 1.70 (1.37-2.12)1.70 (1.37-2.12) <0.0001<0.0001
ECG changes at baselineECG changes at baseline 1.76 (1.45-2.13)1.76 (1.45-2.13) <0.0001<0.0001
30-day major bleed30-day major bleed 3.03 (2.33-3.94)3.03 (2.33-3.94) <0.0001<0.0001
30-day revascularization30-day revascularization 1.76 (1.16-2.67)1.76 (1.16-2.67) 0.0080.008
Periprocedural MIPeriprocedural MI 1.30 (0.85-1.98)1.30 (0.85-1.98) 0.220.22
Spontaneously occurring MISpontaneously occurring MI 7.49 (4.95-11.33)7.49 (4.95-11.33) <0.0001<0.0001
ACUITY: Periprocedural MI and 1-Year MortalityACUITY: Periprocedural MI and 1-Year Mortality
Prasad A et al. Prasad A et al. J Am Coll Cardiol J Am Coll Cardiol 2009;54:477-86.2009;54:477-86.
PCI PopulationPCI Population
0.10.1 1 1 1010
HR HR ± 95% CI± 95% CI HR (95% CI) P-value HR (95% CI) P-value
Periprocedural Troponin and MortalityPeriprocedural Troponin and Mortality
Nienhuis NB et al. Catheter Cardiovasc Interv 2008;71:325-6. Nienhuis NB et al. Catheter Cardiovasc Interv 2008;71:325-6.
Meta-Analysis, n=15,581Meta-Analysis, n=15,581
FuchsFuchsCantorCantor
GrubergGrubergNallamothuNallamothu
RicciardiRicciardiKiniKini
NatarajanNatarajanCavalliniCavallini
OkmenOkmenShyuShyu
HermannHermannKizerKizerMillerMiller
PrasadPrasad
All trialsAll trials 1.35 (1.13-1.60) 1.35 (1.13-1.60)
0 2 4 6 8 10 120 2 4 6 8 10 12
What do the Vascular Biology What do the Vascular Biology and Clinical Trials Teach Us?and Clinical Trials Teach Us?
The Impact of Cardiac Contrast Media onThe Impact of Cardiac Contrast Media onMACE End Points In ACSMACE End Points In ACS
Ioxaglate Characteristics:Ioxaglate Characteristics:Thrombotic Risk and MACEThrombotic Risk and MACE
Ioxaglate has been shown to reduce platelet Ioxaglate has been shown to reduce platelet accumulation in stents (in animals)*accumulation in stents (in animals)*
* The clinical significance of this data is not known.
Markou CP et al, Thromb and Haemost, 2001, 85:488-493.
Fibrin forms mesh which encapsulates the clot
FibrinogenThrombin helps convert
another protein, fibrinogen, into fibrin
Activated PlateletsAggregate and adhere
to the exposed collagen on the vessel wall,
forming the initial clot
CollagenActivates Resting
Platelets
ThrombinActivates Resting
Platelets
Antithrombotic and Anticoagulant Antithrombotic and Anticoagulant Properties of IoxaglateProperties of Ioxaglate
So what happens? So what happens? Vessel Injured
Exposes endothelial proteins, including
collagen
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Jones C et al. Thrombosis Research 2003;112:65-71Jones C et al. Thrombosis Research 2003;112:65-71
Antithrombotic and Anticoagulant Properties of Ioxaglate
CollagenCollagen VWFVWFINJURYINJURY
Platelet Adhesion& Secretion
Tissue FactorTissue Factor
Coagulation Cascade
Thrombin
Haemostatic plugHaemostatic plug
Vaso-constriction
Blood VesselBlood VesselEndotheliumEndothelium
SubendotheliumSubendothelium
Dr Isobel FordDr Isobel Ford
Coagulation Cascade
Thrombin
FibrinPlatelet aggregation
Platelet adhesion and secretion
Vaso-constriction
Antithrombotic and Anticoagulant Antithrombotic and Anticoagulant Properties of IoxaglateProperties of Ioxaglate
► What are issues and concerns for interventional What are issues and concerns for interventional cardiologists? cardiologists?
This process can lead to occlusion of the vessels, This process can lead to occlusion of the vessels, such as coronary arteries during PCI such as coronary arteries during PCI
End point includes mortality End point includes mortality
End point includes NSTEMI and STEMIEnd point includes NSTEMI and STEMI
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Jones C et al. Thrombosis Research 2003;112:65-71Jones C et al. Thrombosis Research 2003;112:65-71
Antithrombotic and Anticoagulant Antithrombotic and Anticoagulant Properties of IoxaglateProperties of Ioxaglate
So what role does ioxaglate play? So what role does ioxaglate play?
Vessel Injured
Exposes endothelial proteins, including Collagen.
CollagenActivates Resting
Platelets
Vessel InjuredExposes endothelial proteins, including
collagen
FibrinogenThrombin helps convert
another protein, fibrinogen, into fibrin
Activated PlateletsAggregate and adhere
to the exposed collagen on the vessel wall,
forming the initial clot
Fibrin forms mesh which encapsulates the clot
ThrombinActivates Resting
Platelets
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Jones C et al. Thrombosis Research 2003;112:65-71Jones C et al. Thrombosis Research 2003;112:65-71
Antithrombotic and Anticoagulant Antithrombotic and Anticoagulant Properties of IoxaglateProperties of Ioxaglate
Interface of ioxaglate with thrombosis generation Interface of ioxaglate with thrombosis generation
• Ioxaglate, does not activate resting platelets, unlike nonionic Ioxaglate, does not activate resting platelets, unlike nonionic monomers.monomers.
• Doesn’t direct platelets to change shape, release pro-coagulant Doesn’t direct platelets to change shape, release pro-coagulant mediators or to adhere to anything. mediators or to adhere to anything.
• This prevents/delays formation of the platelet clot.This prevents/delays formation of the platelet clot.
• Ioxaglate inhibits the generation of thrombin, reducing the Ioxaglate inhibits the generation of thrombin, reducing the amount of thrombin: inhibits the formation of fibrin.amount of thrombin: inhibits the formation of fibrin.
• Mechanisms that may be responsible for preventing/delaying Mechanisms that may be responsible for preventing/delaying formation of the fibrin mesh.formation of the fibrin mesh.
• Ioxaglate binds w/thrombin, preventing it from activating Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelets; therefore preventing/delaying the formation of the platelet plug.platelet plug.
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Heptinstall et al. British Journal of Haemotology 1998;103:1023-30Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8Jones C et al. Thrombosis Research 2003;112:65-71Jones C et al. Thrombosis Research 2003;112:65-71
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCAContrast in Patients with MI/UA Undergoing PTCA
Grines CL et al. J Am Coll Cardiol 1996;27:1381-6.Grines CL et al. J Am Coll Cardiol 1996;27:1381-6.
Baseline Demographic CharacteristicsBaseline Demographic Characteristics Low Osmolar Ionic Low Osmolar Ionic Contrast Media (n=106)Contrast Media (n=106)
Nonionic Contrast Nonionic Contrast Media (n=105)Media (n=105)
Age (yr) (mean Age (yr) (mean ± SD)± SD) 63.7 63.7 ± 12.7± 12.7 61.9 61.9 ± 12± 12
Male patients (%)Male patients (%) 6464 6262
Clinical history (%)Clinical history (%)
HypertensionHypertension 51.951.9 50.550.5
DiabetesDiabetes 24.524.5 21.021.0
SmokingSmoking 56.656.6 67.667.6
Prior MIPrior MI 40.640.6 39.139.1
Prior PTCAPrior PTCA 15.115.1 17.117.1
Treatment history (%)Treatment history (%)
AspirinAspirin 68.968.9 61.061.0
HeparinHeparin 53.853.8 59.159.1
NitratesNitrates 67.067.0 66.766.7
Tissue plasminogen activatorTissue plasminogen activator 3.83.8 8.68.6
Indication for PTCA, %Indication for PTCA, %
Acute MIAcute MI 44.444.4 40.940.9
Post-MI ischemiaPost-MI ischemia 33.933.9 33.433.4
Unstable anginaUnstable angina 21.721.7 25.725.7
IoxaglateIoxaglate►Significant reductions in:Significant reductions in:
Ischemic complications acutely and at one monthIschemic complications acutely and at one month Decreased blood flow during PTCADecreased blood flow during PTCA Recurrent ischemia with repeat catheterizationRecurrent ischemia with repeat catheterization Repeat PTCARepeat PTCA AnginaAngina Risk of CABGRisk of CABG
►Authors: “Strongly consider for unstable Authors: “Strongly consider for unstable angina/MI PTCA.”angina/MI PTCA.”
Grines CL et alGrines CL et al. J Am Coll Car. J Am Coll Cardiol 1996;27:1381-6.diol 1996;27:1381-6.
ConclusionsConclusions
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCA
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA
Bertrand ME et al. Circulation 2000;101:131-136.Bertrand ME et al. Circulation 2000;101:131-136.
Baseline Clinical CharacteristicsBaseline Clinical Characteristics Iodixanol Iodixanol (Nonionic; n=697)(Nonionic; n=697)
IoxaglateIoxaglate(Ionic; n=714)(Ionic; n=714)
Age, yAge, y 61.6 61.6 ± 10.6± 10.6 62.3 62.3 ± 10.2± 10.2
Male, %Male, % 78.278.2 76.276.2
Weight, kgWeight, kg 75.9 75.9 ± 12.2± 12.2 76.2 76.2 ± 12.4± 12.4
Height, cmHeight, cm 168.2 168.2 ± 8.6± 8.6 168.0 168.0 ± 8.6± 8.6
Diabetes, %Diabetes, % 20.220.2 15.815.8
Current smokers, %Current smokers, % 23.223.2 22.122.1
Former smokers, %Former smokers, % 35.035.0 36.336.3
Obesity, %Obesity, % 20.120.1 20.220.2
Family history of CAD, %Family history of CAD, % 30.730.7 26.326.3
Prior MI, %Prior MI, % 19.119.1 18.518.5
Prior PTCA, %Prior PTCA, % 16.116.1 14.714.7
Prior CAG, %Prior CAG, % 7.17.1 6.76.7
History of allergy/hypersensitivity, % History of allergy/hypersensitivity, % 4.74.7 5.75.7
Indication for PTCA, %Indication for PTCA, %
Unstable anginaUnstable angina 51.951.9 49.349.3
Stable anginaStable angina 38.338.3 40.140.1
Silent ischemiaSilent ischemia 9.59.5 10.110.1
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Bertrand ME et al. Circulation 2000;101:131-136.
MACE at 2-Day Follow-UpMACE at 2-Day Follow-Up
Iodixanol Iodixanol (Nonionic; n=697)(Nonionic; n=697)
IoxaglateIoxaglate(Ionic; n=714)(Ionic; n=714)
pp
During hospital stay (2 days)During hospital stay (2 days) 33 (4.7%)33 (4.7%) 28 (3.9%)28 (3.9%) 0.450.45
DeathDeath 00 22 NN
StrokeStroke 22 11 NSNS
Q-wave MIQ-wave MI 33 33 NSNS
NQWMINQWMI 2424 1717 0.240.24
CABGCABG 11 11 NSNS
Re-PTCARe-PTCA 33 44 NSNS
► No significant difference in in-hospital MACE No significant difference in in-hospital MACE between ioxaglate and iodixanol.between ioxaglate and iodixanol.
ConclusionsConclusions
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Bertrand ME et al. Bertrand ME et al. CirculationCirculation 2000;101:131-136. 2000;101:131-136.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA
Davidson CJ et al. Davidson CJ et al. CirculationCirculation 2000;101:2172-2177. 2000;101:2172-2177.
DemographicsIodixanol (n=405)Iodixanol (n=405) Ioxaglate (n=410)Ioxaglate (n=410)
NN %% N%N% %%
Average age, yAverage age, y 6161±12±12 6262±12±12
MaleMale 280280 6969 270270 6666
HypertensionHypertension 240240 5959 249249 6161
Diabetes mellitusDiabetes mellitus 110110 2727 110110 2727
Current smokerCurrent smoker 129129 3232 137137 3333
Past smokerPast smoker 238238 5959 251251 6161
Previous MIPrevious MI 142142 3535 168168 4141
HyperlipidemiaHyperlipidemia 249249 6161 157157 6363
AnginaAngina 353353 8787 383383 9393
Angina CHS class IVAngina CHS class IV 290290 7272 311311 7676
Family CAD historyFamily CAD history 242242 6060 240240 5959
Prior interventionPrior intervention 128128 3232 133133 3232
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Davidson CJ et al. Circulation 2000;101:2172-2177.
Hospital Stay Primary Clinical OutcomesHospital Stay Primary Clinical Outcomes
Iodixanol Iodixanol (n=405)(n=405) Ioxaglate Ioxaglate (n=410)(n=410)PP
NN %% N%N% %%
Emergent Emergent recatheterizationrecatheterization 55 1.21.2 99 2.22.2 0.290.29
Repeat Repeat revascularizationrevascularization 44 1.01.0 88 2.902.90 0.250.25
In-hospital abrupt In-hospital abrupt closureclosure 33 0.70.7 1010 2.42.4 0.050.05
Stroke/TIAStroke/TIA 11 0.20.2 11 0.20.2 0.990.99
Thromboembolic Thromboembolic eventevent 22 0.50.5 44 1010 0.420.42
Cardiac deathCardiac death 55 1.21.2 11 0.20.2 0.100.10
Nonfatal MINonfatal MI 88 2.02.0 1818 4.44.4 0.050.05
Emergent CABGEmergent CABG 22 0.50.5 33 .07.07 0.660.66
Composite outcomeComposite outcome 2222 5.45.4 3939 9.59.5 0.0270.027
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Davidson CJ et al. Circulation 2000;101:2172-2177.
Events from Hospital Discharge to 30 Days
Iodixanol Iodixanol (n=390)(n=390) Ioxaglate Ioxaglate (n=400)(n=400)PP
NN %% N%N% %%
Emergent Emergent recatheterization or recatheterization or revascularizationrevascularization
1313 3.33.3 1212 3.03.0 0.790.79
Abrupt closureAbrupt closure 00 00 22 0.50.5 0.160.16
Stroke/TIAStroke/TIA 11 0.30.3 11 0.30.3 0.990.99
Thromboembolic Thromboembolic eventevent 00 00 22 0.50.5 0.160.16
Cardiac deathCardiac death 00 00 11 0.30.3 0.320.32
Nonfatal MINonfatal MI 11 0.30.3 11 0.30.3 0.990.99
Emergent CABGEmergent CABG 11 0.30.3 11 0.30.3 0.990.99
Composite outcomeComposite outcome 1515 3.83.8 1515 3.83.8 0.940.94
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Davidson CJ et al. Circulation 2000;101:2172-2177.Davidson CJ et al. Circulation 2000;101:2172-2177.
Angiographic and Procedural Outcome
Iodixanol Iodixanol (n=400)(n=400) Ioxaglate Ioxaglate (n=396)(n=396)PP
NN %% N%N% %%Abrupt closureAbrupt closure 22 0.50.5 77 1.81.8 0.090.09
Prolonged no-reflowProlonged no-reflow 33 0.80.8 33 0.80.8 0.990.99
Distal embolizationDistal embolization 22 0.50.5 11 0.30.3 0.570.57
Side-branch occlusionSide-branch occlusion 66 1.51.5 66 1.51.5 0.990.99
Development of moderate to Development of moderate to large thrombuslarge thrombus 00 00 00 00 ----
DissectionDissection 1818 4.54.5 2525 6.36.3 0.250.25
Unplanned IABPUnplanned IABP 44 1.01.0 77 1.81.8 0.370.37
Unplanned abciximabUnplanned abciximab 2929 7.37.3 3232 8.18.1 0.660.66
Procedural successProcedural success 369369 92.292.2 340340 85.985.9 0.0040.004
>20% absolute decrease>20% absolute decrease 375375 93.993.9 355355 90.090.0 ------
<50% residual stenosis<50% residual stenosis 389389 97.397.3 379379 94.994.9 ------
TIME-3 flowTIME-3 flow 397397 99.399.3 391391 98.898.8 ------
Composite outcomeComposite outcome 6969 17.317.3 8787 22.022.0 0.0930.093
Conclusions Regarding Ionic Contrast
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCANonionic (Iodixanol) Contrast in PTCA
Davidson CJ et al. Davidson CJ et al. CirculationCirculation 2000;101:2172-2177. 2000;101:2172-2177.
►Iodixanol, significantIodixanol, significant Reduction in in-hospital adverse compositeReduction in in-hospital adverse composite
Increase in angiographic successIncrease in angiographic success
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Scheller B et al. Eur Heart J 2001;22:385-91.
n=3,990
Ioxaglate (HexabrixIoxaglate (Hexabrix®® 320) 320) Dimer, ionicDimer, ionic
Iobitridol (XenetixIobitridol (Xenetix®® 350) 350) Monomer, non-ionicMonomer, non-ionic
Iomeprol (ImeronIomeprol (Imeron®® 400) 400) Monomer, non-ionicMonomer, non-ionic
Iopamidol (SolutrastIopamidol (Solutrast®® 370) 370) Monomer, non-ionic Monomer, non-ionic
Iopromid (UltravistIopromid (Ultravist®® 370) 370) Monomer, non-ionic Monomer, non-ionic
Ioversol (OptirayIoversol (Optiray®® 350) 350) Monomer, non-ionic Monomer, non-ionic
Iodixanol (VisipaqueIodixanol (Visipaque®® 320) 320) Dimer, non-ionicDimer, non-ionic
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Demographic Data, n=3,990Demographic Data, n=3,990
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Non-ionic CMNon-ionic CM IoxaglateIoxaglate pp
NN 18081808 21822182
Gender (male)Gender (male) 76%76% 74%74% NSNS
AgeAge 63.9 63.9 ± 10.3 years± 10.3 years 63.9 63.9 ± 10.3 years± 10.3 years NSNS
DiabetesDiabetes 18.9%18.9% 17.2%17.2% NSNS
Angina pectorisAngina pectoris
CCS 0-I 22.8%CCS 0-I 22.8% CCS 0-I 26.4%CCS 0-I 26.4% NSNS
CCS II 36.6%CCS II 36.6% CCS II 37.5%CCS II 37.5%
CCS III 28.2%CCS III 28.2% CCS III 25.3%CCS III 25.3%
CCS IV 12.5%CCS IV 12.5% CCS IV 10.9%CCS IV 10.9%
Acute coronary syndromeAcute coronary syndrome 34.2%34.2% 32.3%32.3% NSNS
Unstable anginaUnstable angina 24.9%24.9% 21.3%21.3%
AMIAMI 9.3%9.3% 11.0%11.0%
Known CM intoleranceKnown CM intolerance 4.1%4.1% 4.3%4.3%
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Angiographic Data, n=3,990Angiographic Data, n=3,990
Non-ionic CMNon-ionic CM IoxaglateIoxaglate pp
NN 18081808 21822182
LVEFLVEF 55 55 ± 15.9%± 15.9% 54.8 54.8 ± 17.8%± 17.8% NSNS
Vessels diseasedVessels diseased
Single vessel 26%Single vessel 26% Single vessel Single vessel 28%28% NSNS
Two vessel 35%Two vessel 35% Two vessel 35%Two vessel 35%
Three vessel 39%Three vessel 39% Three vessel Three vessel 37%37%
Stented vesselStented vessel
LCA 1.4%LCA 1.4% LCA 1.2%LCA 1.2% NSNS
LAD 35.5%LAD 35.5% LAD 34.4%LAD 34.4% NSNS
CX 19.8%CX 19.8% CX 26.4%CX 26.4% <0.05<0.05
RCA 36.5%RCA 36.5% RCA 32.8%RCA 32.8% <0.05<0.05
ACB 6.7%ACB 6.7% ACB 5.2%ACB 5.2% NSNS
Stented vessel localizationStented vessel localization Proximal 31.5%Proximal 31.5% Proximal 28.8%Proximal 28.8% NSNS
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Angiographic Data, n=3,990Angiographic Data, n=3,990
Non-ionic CMNon-ionic CM IoxaglateIoxaglate pp
Stented vessel localizationStented vessel localization
Proximal 31.5%Proximal 31.5% Proximal 28.8%Proximal 28.8% NSNS
Middle 60.5%Middle 60.5% Middle 62.2%Middle 62.2%
Distal 8.0%Distal 8.0% Distal 9.0%Distal 9.0%
Restenotic lesionRestenotic lesion 18.6%18.6% 17.4%17.4% NSNS
RFDRFD 3.37 3.37 ± 0.43 mm± 0.43 mm 3.37 3.37 ± 0.81 mm± 0.81 mm NSNS
MLDMLD 0.68 0.68 ± 0.63 mm± 0.63 mm 0.67 0.67 ± 0.58 mm± 0.58 mm NSNS
Diameter stenosisDiameter stenosis 79.7 79.7 ± 17.8%± 17.8% 80.1 80.1 ± 5.5%± 5.5% NSNS
Volume of CMEVolume of CME 280.9 280.9 ± 120.5 ml± 120.5 ml 257.8 257.8 ± 101.6 ml± 101.6 ml 0.0010.001
Heparin doseHeparin dose 12901 12901 ± 4640 IU± 4640 IU 11938 11938 ± 3914 IU± 3914 IU 0.0010.001
ReoPro®ReoPro® 4.9%4.9% 5.3%5.3% NSNS
Primary Endpoint: 12-Month Acute and Subacute Stent OcclusionPrimary Endpoint: 12-Month Acute and Subacute Stent Occlusionn=3,990n=3,990
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
PatientsPatients EventEvent Non-Ionic CMNon-Ionic CM IoxaglateIoxaglate PP
AOS and SATAOS and SAT All patients n=3990All patients n=3990
AOSAOS 24/1808 (1.3%)24/1808 (1.3%) 7/2182 (0.3%)7/2182 (0.3%) 0.0010.001
SATSAT 44/1808 (2.45)%44/1808 (2.45)% 16/2182 (0.7%)16/2182 (0.7%) 0.0010.001
RestonosisRestonosis All patients n=3990All patients n=3990
ReangiographyReangiography 968/1808 (53.5%)968/1808 (53.5%) 1062/2182 (48.7%)1062/2182 (48.7%) 0.0020.002
RestenosisRestenosis 329/968 (34.0%)329/968 (34.0%) 296/1062 (27.8%)296/1062 (27.8%) 0.0030.003
Combined clinical Combined clinical end point (TLR, end point (TLR, CABG, death)CABG, death) All patients n=3990All patients n=3990
CombinedCombined 414/1808 (22.9%)414/1808 (22.9%) 356/2182 (16.3%)356/2182 (16.3%) 0.0010.001
TLRTLR 301/1808 (16.6%)301/1808 (16.6%) 229/2182 (10.5%)229/2182 (10.5%) 0.0010.001
CABGCABG 22/1808 (1.2%)22/1808 (1.2%) 31/2182 (1.4%)31/2182 (1.4%) NSNS
DeathDeath 110/1808 (6.1%)110/1808 (6.1%) 109/2182 (5.0%)109/2182 (5.0%) 0.0070.007
Multivariate Analysis of Acute and Subacute Stent ThrombosisMultivariate Analysis of Acute and Subacute Stent Thrombosis
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Variable, n=3990Variable, n=3990 WaldWald PP
CMECME 5.86815.8681 0.01540.0154
AgeAge 0.00130.0013 0.97070.9707
LVEFLVEF 1.60271.6027 0.20550.2055
CADCAD 1.53911.5391 0.21470.2147
CM side effectCM side effect 0.13680.1368 0.71150.7115
ReoPro®ReoPro® 0.14820.1482 0.70030.7003
Unstable APUnstable AP 0.17420.1742 0.67640.6764
AMIAMI 2.10492.1049 0.14680.1468
CCSCCS 3.25123.2512 0.07140.0714
MLDMLD 2.72562.7256 0.09880.0988
HeparinHeparin 1.98421.9842 0.15890.1589
LocalizationLocalization 0.01080.0108 0.91730.9173
Vessel diameterVessel diameter 0.61860.6186 0.43160.4316
n=3,990
►Ioxaglate, significant reductions in:Ioxaglate, significant reductions in: Acute stent thrombosisAcute stent thrombosis
Subacute stent thrombosis Subacute stent thrombosis
ReangiographyReangiography
RestenosisRestenosis
Target lesion revascularizationTarget lesion revascularization
DeathDeath
Scheller B et al. Eur Heart J 2001;22:385-91.Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs. Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary StentingNonionic Contrast in Coronary Stenting
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Le Feuvre C et al. Catheter Cardiovasc Interv Catheter Cardiovasc Interv 2006;67:852-8.2006;67:852-8.
Baseline Clinical CharacteristicsBaseline Clinical Characteristics Iodixanol Iodixanol IoxaglateIoxaglate PP
NN 231231 267267
Age (y)Age (y) 6464 ± 12 ± 12 63 63 ± 11± 11 NSNS
Male gender, nMale gender, n 189 (82)189 (82) 211 (79)211 (79) NSNS
Diabetes mellitus, nDiabetes mellitus, n 64 (28)64 (28) 92 (34)92 (34) NSNS
Hypertension, nHypertension, n 121 (53)121 (53) 133 (50)133 (50) NSNS
Smoking history, nSmoking history, n 94 (41)94 (41) 97 (36)97 (36) NSNS
LDL cholesterol > 3.3 mmol/lLDL cholesterol > 3.3 mmol/l 162 (70)162 (70) 184 (69)184 (69) NSNS
Family history of CAD, nFamily history of CAD, n 46 (20)46 (20) 51 (19)51 (19) NSNS
Prior CABG, nPrior CABG, n 16 (7)16 (7) 23 (9)23 (9) NSNS
Prior MI, nPrior MI, n 46 (20)46 (20) 63 (24)63 (24) NSNS
Chronic renal failureChronic renal failure 35 (15)35 (15) 44 (16)44 (16) NSNS
Statin treatment before PCIStatin treatment before PCI 120 (52)120 (52) 136 (51)136 (51) NSNS
Prior left ventricular failure, nPrior left ventricular failure, n 29 (13)29 (13) 27 (10)27 (10) NSNS
PCI for acute MI, nPCI for acute MI, n 57 (25)57 (25) 74 (28)74 (28) NSNS
PCI for unstable angina, nPCI for unstable angina, n 37 (16)37 (16) 58 (22)58 (22) NSNS
PCI for silent myocardial ischemia, nPCI for silent myocardial ischemia, n 29 (13)29 (13) 27 (10) 27 (10) NSNS
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Angiographic Baseline Characteristics and Procedural DataAngiographic Baseline Characteristics and Procedural Data
Iodixanol Iodixanol IoxaglateIoxaglate pp
Volume of contrast media (ml)Volume of contrast media (ml) 267 267 ± 125± 125 276 276 ± 120± 120 NSNS
Peak anti-Xa >0.5 IU/ml, nPeak anti-Xa >0.5 IU/ml, n 224 (97)224 (97) 259 (97)259 (97) NSNS
Peak anti-Xa > 1 IU/ml, nPeak anti-Xa > 1 IU/ml, n 67 (29)67 (29) 72 (27)72 (27) NSNS
Intravenous antiplatelet therapy, nIntravenous antiplatelet therapy, n 99 (43)99 (43) 112 (42)112 (42) NSNS
Planned, nPlanned, n 88 (38)88 (38) 93 (35)93 (35) NSNS
Rescue, nRescue, n 11 (5)11 (5) 19 (7)19 (7) NSNS
Bifurcation/ostial lesion, nBifurcation/ostial lesion, n 23 (10)23 (10) 29 (11)29 (11) NSNS
Number of vessel PCI per patientNumber of vessel PCI per patient
One vessel, PCI, nOne vessel, PCI, n 192 (83)192 (83) 219 (82)219 (82) NSNS
Two vessel PCI, nTwo vessel PCI, n 37 (16)37 (16) 43 (16)43 (16)
Three vessel PCI, nThree vessel PCI, n 2 (1) 2 (1) 5 (2)5 (2)
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Angiographic Baseline Characteristics and Procedural Data (continued)Angiographic Baseline Characteristics and Procedural Data (continued)
Iodixanol Iodixanol IoxaglateIoxaglate pp
Treatment deviceTreatment device
Failure to cross the lesion, nFailure to cross the lesion, n 6 (3)6 (3) 10 (4)10 (4) NSNS
Balloon, nBalloon, n 10 (4)10 (4) 17 (6)17 (6) NSNS
Stent, nStent, n 215 (93)215 (93) 240 (90)240 (90) NSNS
Number of stent used per patientNumber of stent used per patient
One stent, nOne stent, n 143 (62)143 (62) 162 (61)162 (61) NSNS
Two stents, nTwo stents, n 47 (20)47 (20) 54 (20)54 (20)
Three stentsThree stents 16 (7)16 (7) 15 (6)15 (6)
Four stents or more, nFour stents or more, n 9 (4)9 (4) 9 (3)9 (3)
Direct stenting, nDirect stenting, n 159 (69)159 (69) 187 (70)187 (70) NSNS
Drug eluting stent, nDrug eluting stent, n 69 (30)69 (30) 72 (27)72 (27) NSNS
Use of intra-aortic balloon pump, nUse of intra-aortic balloon pump, n 16 (7)16 (7) 11 (4)11 (4) NSNS
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Clinical EventsClinical Events
Iodixanol Iodixanol IoxaglateIoxaglate pp
Procedural eventsProcedural events
Cardiac death, nCardiac death, n 2 (0.8)2 (0.8) 00 NSNS
Non fatal MI or reinfarction, nNon fatal MI or reinfarction, n 7 (3)7 (3) 1 (0.3)1 (0.3) 0.050.05
Emergency CABG, nEmergency CABG, n 1 (0.4)1 (0.4) 00 NSNS
Stroke or systemic thromboembolic event, nStroke or systemic thromboembolic event, n 00 00 NSNS
In-hospital eventsIn-hospital events
Cardiac death, nCardiac death, n 2 (0.8)2 (0.8) 00 NSNS
Non fatal MI or reinfarction, nNon fatal MI or reinfarction, n 7(3)7(3) 1 (0.3)1 (0.3) 0.050.05
Emergency repeat PCI, nEmergency repeat PCI, n 3 (1.3)3 (1.3) 00 NSNS
Emergency CABG, nEmergency CABG, n 1 (0.4)1 (0.4) 00 NSNS
Stroke or systemic thromboembolic event, nStroke or systemic thromboembolic event, n 00 00 NSNS
Composite outcome, nComposite outcome, n 11 (4.8)11 (4.8) 1 (0.3)1 (0.3) 0.0050.005
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Clinical Events (continued)Clinical Events (continued)
Iodixanol Iodixanol IoxaglateIoxaglate pp
30-day events30-day events
Cardiac death, nCardiac death, n 3 (1.3)3 (1.3) 00 NSNS
Non fatal MI or reinfarction, nNon fatal MI or reinfarction, n 7 (3)7 (3) 1 (0.3)1 (0.3) 0.050.05
Emergency repeat PCI, nEmergency repeat PCI, n 5 (2.2)5 (2.2) 1 (0.3)1 (0.3) NSNS
Emergency CABG, nEmergency CABG, n 1 (0.4)1 (0.4) 00 NSNS
Stroke or systemic thromboembolic event, nStroke or systemic thromboembolic event, n 00 00 NSNS
Composite outcome, nComposite outcome, n 14 (6)14 (6) 2 (0.7)2 (0.7) 0.0020.002
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Angiographic and Procedural Complications During or Immediately After PCIAngiographic and Procedural Complications During or Immediately After PCI
Iodixanol Iodixanol IoxaglateIoxaglate pp
Appearance of a large thrombus, Appearance of a large thrombus, nn 14 (6)14 (6) 1 (0.3)1 (0.3) 0.00010.0001
Target vessel occlusion, Target vessel occlusion, nn 12 (5.2)12 (5.2) 1 (0.3)1 (0.3) 0.0030.003
Side branch (Side branch (>> 2 mm) occlusion, 2 mm) occlusion, nn 2 (0.9)2 (0.9) 1 (0.3)1 (0.3) NSNS
Composite endpoint, Composite endpoint, nn 14 (6)14 (6) 1 (0.3)1 (0.3) 0.00010.0001
Sustained ventricular arrhythmiaSustained ventricular arrhythmia 2 (0.9)2 (0.9) 1 (0.3)1 (0.3) NSNS
Hypotension with interventionHypotension with intervention 4 (1.7)4 (1.7) 4 (1.5)4 (1.5) NSNS
Renal failure requiring treatmentRenal failure requiring treatment 00 3 (1)3 (1) NSNS
Contrast induced nephropathyContrast induced nephropathy 2 (1)2 (1) 7 (2.6)7 (2.6) NSNS
Large thrombus, largest dimension greater than two vessel diameters; Contrast induced Large thrombus, largest dimension greater than two vessel diameters; Contrast induced nephropathy, > 0.5 mg/dl and/or 25% increase in creatinine levels from day 0 to day 3nephropathy, > 0.5 mg/dl and/or 25% increase in creatinine levels from day 0 to day 3
►Ioxaglate:Ioxaglate: Thrombus-related events significantly less likely.Thrombus-related events significantly less likely.
• In-hospital MACEIn-hospital MACE
• Large thrombusLarge thrombus
►Iodixanol:Iodixanol: Independent predictor of in-hospital MACE.Independent predictor of in-hospital MACE.
Conclusions Regarding Ionic ContrastConclusions Regarding Ionic Contrast
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCINonionic (Iodixanol) Contrast in PCI
Le Feuvre C et al. Le Feuvre C et al. Catheter Cardiovasc Interv Catheter Cardiovasc Interv 2006;67:852-8.2006;67:852-8.
Non-Ionic Contrast Prescribing Information
Prescribing Information.Prescribing Information.
VisipaqueVisipaque
OmnipaqueOmnipaque
OxilanOxilan
IsovueIsovue
OptirayOptiray
UltravistUltravist
Clots, Contrast Media, and CatheterizationClots, Contrast Media, and Catheterization ConclusionsConclusions
► In PCI, ischemic complications are associated with In PCI, ischemic complications are associated with adverse outcomesadverse outcomes
►Aggressive PCI anticoagulation regimens are Aggressive PCI anticoagulation regimens are effective in reducing ischemic events but increase effective in reducing ischemic events but increase bleeding complicationsbleeding complications
►Active decision-making with regard to the type of Active decision-making with regard to the type of contrast media may:contrast media may: Favorably impact rates of ischemic complicationsFavorably impact rates of ischemic complications Not adversely affect rates of bleeding complicationsNot adversely affect rates of bleeding complications Obviate the need for aggressive anticoagulation regimensObviate the need for aggressive anticoagulation regimens Improve overall PCI outcomesImprove overall PCI outcomes