Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary...

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



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


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)


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


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



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


Solomon, RJ et. al., Circulation 115, 3189 (2007)Solomon, RJ et. al., Circulation 115, 3189 (2007)


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


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


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



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



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


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


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


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


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


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



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


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


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


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

.



► 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


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



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

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of D

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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.


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.


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


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


► 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



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



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.


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


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


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


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

Events from Hospital Discharge to 30 Days


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



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

Angiographic and Procedural Outcome


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 ------


Conclusions Regarding Ionic Contrast


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


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%



Angiographic Data, n=3,990Angiographic Data, n=3,990


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



Angiographic Data, n=3,990Angiographic Data, n=3,990


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



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



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



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


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)



Angiographic Baseline Characteristics and Procedural Data (continued)Angiographic Baseline Characteristics and Procedural Data (continued)


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



Clinical EventsClinical Events


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


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



Composite outcome, nComposite outcome, n 11 (4.8)11 (4.8) 1 (0.3)1 (0.3) 0.0050.005



Clinical Events (continued)Clinical Events (continued)


30-day events30-day events


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



Composite outcome, nComposite outcome, n 14 (6)14 (6) 2 (0.7)2 (0.7) 0.0020.002



Angiographic and Procedural Complications During or Immediately After PCIAngiographic and Procedural Complications During or Immediately After PCI


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


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

Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary...

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