Evolving Science ● New Mechanisms ● Optimal Management
Clots, Contrast Media,
and Catheterization
Maximizing Patient Safety and Outcomes
in Coronary Angioplasty
Focus on Comparative Effects of Contrast Media on
Thrombosis Mitigation, Mortality, and Renal Function
Steven V. Manoukian, MD, FACC
Program Chairman
Director, Cardiovascular Research | Sarah Cannon Research
Institute | Centennial Heart Cardiovascular Consultants |
Medical Director, Cardiovascular Services | Clinical Services
Group | Hospital Corporation of America (HCA) | Nashville, TN
Welcome and Program Overview
CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the
beginning of the program
Welcome and Program Overview
Commercial Support: This program is sponsored by
an independent educational grant from Guerbet, LLC
Program Educational Objectives
As a result of this session, participants will be able to:
► Discuss the role that cardiovascular contrast media (CM) can play in
thrombosis mitigation and renal preservation in the setting of PCI
► Detail the physical, chemical, and biological properties—ionicity,
molecular structure, and viscosity—of contrast agents used in PCI and
their potential impact on renal function, thrombosis, and patient safety
► Apply landmark trials, registry data, and observational studies to optimize
selection of CM in patients undergoing PCI
► Identify high-risk patients that may be appropriate candidates for specific
CM shown to decrease risk of thrombotic events and/or renal dysfunction
► Explain how ionic properties, viscosity, and other chemical features may
affect renal function and coagulation in the setting of PCI
Program Faculty
Steven V. Manoukian, MD, FACC
Program Chairman
Director, Cardiovascular Research
Sarah Cannon Research Institute
Centennial Heart Cardiovascular
Consultants
Medical Director
Cardiovascular Services
Clinical Services Group
Hospital Corporation of America (HCA)
Nashville, TN
Frederick Feit, MD
Associate Professor
Department of Medicine
Division of Cardiology
New York University School of Medicine
Member, NYU Cardiac Catheterization
Associates
New York, NY USA
Roxana Mehran, MD
Director of Outcomes Research, Data
Coordination and Analysis
Center for Interventional Vascular Therapy
New York-Presbyterian Hospital
Columbia University Medical Center
Associate Professor of Medicine
Division of Cardiology
Columbia University
College of Physicians and Surgeons
Director of the Clinical Research, Data
Coordination and Analysis Center at the
Cardiovascular Research Foundation
New York City, NY USA
Faculty COI Financial Disclosures
Steven V. Manoukian, MD, FACC
Consultant, Educational Grant, Research Support, and/or Employment:
BMS, Guerbet LLC, sanofi-aventis, The Medicines Company
Frederick Feit, MD
Consultant: CV Therapeutics, The Medicines Company
Shareholder: Eli Lilly, Johnson and Johnson, The Medicines Company
Roxana Mehran, MD
Clinical Research Support: sanofi-aventis, Bracco
Educational Support: The Medicines Company, Boston Scientific, Abbott,
Medtronic, and Cordis
Consultant/Honoraria: TMC, BSC, Abbott, Medtronic, sanofi-aventis,
Lilly/Diachi Sankyo, Astra Zeneca, Cordis, Therox, Bracco, Guerbert,
Regado
Contrast Induced
Acute Kidney Injury
Roxana Mehran, MD, FACC, FAHA, FSCAI, FESC
Associate Professor of Medicine
Columbia University Medical Center
Joint Chief Scientific Officer
Cardiovascular Research Foundation
How to Assess Renal Function?
Abbreviated Modification of Diet in
Renal Disease equations (MDRD) equation:
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)
Cockcroft-Gault equation:
(140- age) x Body Weight [kg]*
Creatinine Clearance, ml/min =
* Multiple by 0.8 in female
Serum Creatinine mg/dL] x 72
Major Causes of Acute Kidney Injury
In Cardiac Patients
1) Contrast Induced
Nephropathy (CIN)
2) AKI after
Cardiopulmonary Bypass
Procedures
Contrast-Induced AKI
Definition
• New onset or exacerbation of renal dysfunction
after contrast administration in the absence of other
causes:
increase by > 25%
or
from baseline
serum creatinine
absolute  of > 0.5 mg/dL
Occurs 24 to 48 hrs post–contrast exposure, with creatinine
peaking 5 to 7 days later and normalizing within
7 to 10 days in most cases
Impact of the Definition Utilized on the
Rate of Contrast-Induced Nephropathy in PCI
275 consecutive patients undergoing PCI given the contrast agent ioxilan
Definitions
CIN
Rise in SCr
≥0.5 mg/dl
Decrease in
eGFR ≥25%
Rise in SCr
≥25%
Composite of all
3 Definitions
(n = 9)
(n = 21)
(n = 28)
(n = 29)
3.3%
7.6%*
10.2%#
10.5%†
*P=0.37 vs. rise in SCr ≥0.5 mg/dl
#P=0.02 vs. rise in SCr ≥0.5 mg/dl
†P=0.001 vs. rise in SCr ≥0.5 mg/dl
There were no deaths or cases requiring dialysis. Major and minor bleeding
rates were 1.5% and 1.8%.
Conclusion: The wide variation in CIN and its lack of association with adverse
outcomes underscore the need for a standardized, clinically relevant definition.
Jabara R, et al. Am J Cardiol. 2009;Epub ahead of print.
Risk Factors for the Development
of Contrast-Induced AKI
Fixed (non-modifiable) risk factors
Modifiable risk factors
Pre-existing renal failure
Volume and type of contrast medium
Diabetes mellitus
Multiple contrast injections within 72 hours
Advanced congestive heart failure
Hemodynamic instability
Reduced left ventricular ejection fraction
Dehydration
Acute myocardial infarction
Anemia
Cardiogenic shock
Intra-aortic balloon pump
Renal transplant
Low serum albumin level (<35 g/L)
Angiotensin converting enzyme inhibitors
Diuretics
Nephrotoxic drugs (nonsteroidal antiinflammatory agents, antibiotics, cyclosporine,
etc.)
Scheme to Define CIN Risk Score
Risk Factors
Integer Score
Hypotension
5
IABP
5
CHF
5
Age >75 years
4
Anemia
3
Diabetes
3
Contrast media volume
Risk
of CIN
Dialysis
≤5
7.5%
0.04%
6 to 10
14.0%
0.12%
4
11 to 16
26.1%
1.09%
2 for 40 – 60
4 for 20 – 40
6 for < 20
≥ 16
57.3%
12.6%
1 for each 100 cc3
Serum creatinine > 1.5mg/dl
OR
eGFR <60ml/min/1.73
Risk
Score
m2
eGFR < 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)
Mehran et al. JACC 2004;44:1393-1399.
Calculate
Risk of
Prognostic Impact of CKD and
Contrast Induced AKI
Contrast-induced AKI:
In-hospital Mortality
% In-hospital Death
P<0.001
McCullough et al. Am J Med 1997; 103-375
Contrast-Induced Nephropathy:
Resource Utilization
Patients
Endpoint (%)
P-value
With CIN
Without CIN
Hospital length of stay
(days)
9.6+7.2
3.2+6.4
<0.001
ICU length of stay
(days)
2.3+4.4
0.6+1.8
<0.0001
12
0
<0.0001
Need for hemodialysis
(%)
Iakovou I et al, J Am Coll Cardiol. 2002;39:2A
Preventive
Trials
Strategies
Prevention of Contrast Induced Nephropathy
Effects of Saline, Mannitol, and
Furosemide
A total of 78 patients with mean baseline SCR 2.1 mg/dl
who underwent coronary angiography/PCI
N=78
Randomization
0.45% saline alone 12
hours before and 12 hours
after angiography
N=28
Saline plus mannitol *
N=25
Furosemide*
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
* Given before angiography
Solomon R et al, N Engl J Med 1994;331(21):1416-1420
Effects of Saline, Mannitol, and Furosemide to
Prevent Acute Decreases in Renal Function
Induced by Radiocontrast Agents
P=0.02 for Saline vs. Furosemide group
P=NS for Mannitol vs. Furosemide group
Solomon R et al, N Engl J Med 1994;331:1416-1420
Optimal Hydration Regimen
1937 Patients Screened
317 Ineligible or
No Consent
1620 Randomized
809 Received 0.9% Saline
811 Received 0.45%
Sodium Chloride
124 Excluded From Primary
End Point Analysis
Repeat Catheterization (n=78)
Incomplete Data (n=46)
113 Excluded From Primary End
Point Analysis
Repeat Catheterization (n=59)
Incomplete Data (n=53)
Bypass Grafting (n=1)
685 for Primary End Point
Analysis
698 for Primary End Point
Analysis
Mueller et al Arch Intern Med 2002
Optimal Hydration
0.9% NS vs 0.45% NS
3
0.9% Saline
0.45% Sodium Chloride
Incidence, %
P=.04
2
P=.93
P=.35
1
0
CN
Mueller et al Arch Intern Med 2002
Mortality
Vascular
Periprocedural Hydration Protocol
Consider 2 main factors:
► Baseline CRI (Yes/No)
► LVEF (Preserved/Impaired)
 In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with
preserved LVEF: 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.
 In patients w/o baseline CRI and mild to moderate LV dysfunction:
(LVEF 30% to 40%): 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.
 In patients with baseline CRI and normal LVEF: IV 0.9% NS at 1
cc/kg/hour for 12 hours pre- and post- procedure
 In patients with baseline CRI and reduced LVEF: IV 0.45% NS at
cc/cc replacement (urine output should be match to maintain
euvolemic state) for 12 hours pre- and post-procedure
Prevention of CIN with
Sodium Bicarbonate
Patients With Baseline Serum Creatinine >1.8 mg/dl
who Underwent Contrast Exposure (Iopamidol in All)
N=137
Sodium Chloride Hydration
(154 mEq/L of Sodium
Chloride)
N=68
Sodium Bicarbonate Hydration
(154 mEq/L of Sodium Bicarbonate)
N=69
Primary endpoint: increase in serum creatinine ≥25% within 2 days
post-exposure
Merten GJ et al. JAMA, 2004;291:2328-2334
Prevention of CIN with Sodium Bicarbonate:
Results
Sodium
Chloride
Sodium
Bicarbonate
N=59
N=60
Incidence of CIN (%)
13.6%
1.7%
0.02
Incidence of CIN
(↑SCr 0.5 mg/dL)
11.9%
1.7%
0.03
Endpoints
Merten GJ et al. JAMA, 2004;291:2328-2334
P
value
REMEDIAL Trial
Pts with eGFR<40
N=393
Excluded N=42
Randomized N=351
Saline + NAC
Bicarbonate + NAC
Saline+AA+NAC
N=118
N=117
7 excluded
9 excluded
9 excluded
111 included into
analysis
108 included
into analysis
107 included into
analysis
NAC = N-acetylcysteine, AA = ascorbic acid
Briguorio C. et al, Circulation 2007
N=116
REMEDIAL Trial: Results
Saline +
NAC
Bicarbonate
+ NAC
N=111
N=108
Saline +
Ascorbic
Acid + NAC
Serum creatinine
increase by ≥25%
11 (9.9%)
2 (1.9%)*
10 (10.3%)
0.010
Serum creatinine
increase by ≥0.5
mg/dL
12 (10.8%)
1 (0.9%)†
12 (11.2%)
0.026
eGFR decrease by
≥25%
10 (9.2%)
1 (0.9%)†
10 (10.3%)
0.018
*P=0.019, †P<0.01 vs. saline + NAC group
Briguorio C. et al, Circulation 2007
P
Value
N=107
MEENA
Design
• DESIGN: Prospective, randomized,
parallel-group, single-center clinical
evaluation of two hydration
strategies for patients undergoing
coronary angiography
• OBJECTIVE: To compare the
incidence of CIN between
periprocedural hydration with
sodium bicarbonate vs. sodium
chloride (0.9%, normal saline)
• PRIMARY ENDPOINT:
Decrease in estimated GFR by ≥
25% within 4 days of coronary
angiography
Brar, S et. al., i2/ACC 2007
353 patients enrolled between
January 2006 and January 2007
178 patients assigned
to sodium bicarbonate
22 excluded
156 evaluable
patient
236 patients assigned
to sodium chloride
28 excluded
147 evaluable
patient
Hydration Protocol
• 3 mL/kg for 1 hr before the procedure
• 1.5 mL/kg during and for 4hrs postprocedure
MEENA
p = 0.82
p = 0.97
Meta-Analysis
Sodium Bicarbonate for the
Prevention of CIN
Brar et al. cJASN 2009
Meta-Analysis
Study Flow
469 Citations Identified
168 from EMBASE
261 from MEDLINE
40 from Cochrane Library
Dates: 1996 to 2008
Randomized Trials
Number of Patents: 2,290
8 Citations identified from
conference proceedings
424 Citations excluded based on
screening of titles or abstracts
53 identified for
further review
38 Citations excluded after full review
36 Design was not correct
1 Unusual protocol
1 Difference between groups in
volume administered & NAC dose
14 articles included in
meta-analysis
(N=2,290)
Brar et al. cJASN 2009
Change in Renal Function
∆ Creatinine Sodium Bicarbonate (mg/dL)
Published Randomized Trials
0.2
Harm
Brar
0.1
Maioli
Adolph
Masuda
Ozcan
0.0
Merten
-0.1
Improvement
with Bicarb
Briguori
Deterioration
with Chloride
\-0.2
-0.2
-0.1
0.0
Benefit
0.1
0.2
∆ Creatinine Sodium Chloride (mg/dL)
Brar et al. cJASN 2009
Meta-Regression
Understanding Sources of Heterogeneity
Smaller trials show
greater benefit
N=2290
“Small Study Effect”
Trial Size
Large
Trials
Merten
Criteria
N=290
12.6% vs. 10.7%
Small
Trials
13.5% vs. 6.7%
P=0.32
RR
95% CI
0.85
0.62-1.17
N=2290
P=0.03
0.50
0.27-0.93
Summary: Positive effect only observed in small trials
Brar et al. cJASN 2009
Forest Plot
High Quality Studies
Brigouri, 2007
Chen, 2007
Kim, 2007
Ozcan, 2007
Shaikh, 2007
Brar, 2008
Maioli, 2008
Adolph, 2008
Overall
0.19 (0.04, 0.82)
0.13 (0.02, 1.02)
0.98 (0.42, 2.28)
0.33 (0.11, 0.99)
0.75 (0.39, 1.44)
0.91 (0.56, 1.46)
0.87 (0.52, 1.44)
1.56 (0.27, 9.08)
0.71 (0.49, 1.03)
(I-squared =33.3%, p=0.163)
0.1
Favors
Bicarbonate
1
10
Favors
Saline
Quality Criteria
► Similar volume
► Patients
► If NAC used,
dose & route
similar between
groups
► No early
termination
Note: weights are from
random effects analysis
Summary: No overall benefit, but trend driven by studies with
extreme treatment effects
Brar et al. cJASN 2009
The CONTRAST Trial
Algorithm
300 patients
at increased risk for contrast nephropathy undergoing PCI
Hydrate
Randomize
Fenoldopam
Matching placebo
1º prior to and 12 º after cath
Primary endpoint
Worsening renal insufficiency within 12-96 hours
CONTRAST 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=0.61
OR [95% CI] =
1.11 [0.79, 1.57]
Stone GW, et al. JAMA-2003
P=0.84
P=0.27
CONTRAST: 30-Day Adverse Events
30-day incidence of death, MI or dialysis:
• With CIN
• Without CIN
12.2%
4.1%
p=0.02
P=NS for all
Stone GW, et al. JAMA-2003
Targeted Renal Delivery
FEN-001 Trial Design
IV Placebo (no drugs/no device)
N=33
Index angiography
+/- interventional procedure
(+ contrast)
2:1 Randomization
IV FEN
0.1 -> 0.2
mcg/kg/min
IR FEN
0.2 mcg/kg/min
IR = intra-renal
IV = intravenous
FEN = fenoldopam
Washout x 1 hr
• Patients undergoing elective angiography
• Moderate CKD defined as CrCl ≤ 70 ml/min (≤ 80 ml/min if diabetic)
• Anticipated CM volume ≥ 80 cc
Teirstein et al, Am J Cardiol 2006.
Glomerular Filtration Rate
GFR Response to IV-FEN and TRT-FEN vs. Control
p<0.05
p=0.0007
Percent Change in GFR from Baseline [%]
30%
23.6%
Sustained  GFR
for 2+ hrs post d/c
25.1%
20%
5-fold  GFR
TRT vs IV
All data based on a
Fenoldopam dose of
0.2 mcg/kg/min
9.6%
10%
IV FEN (n=22)
TRT-FEN (n=22)
Control Group (n=11)
4.9%
0%
-10%
1
2
-9.7%
3
p=NS
-14.0%
Pre-procedure
Procedure
-20% (IV-FEN vs. Control) (TRT-FEN vs. Control)
Study Period6
Teirstein et al, Am J Cardiol 2006.
Post-Procedure
(Active vs. Control)
Be-RITe! Registry: Higher Dose More Effective
(TRT-Fenoldopam patients only)
CIN Incidence or Predicted Incidence [%]
CIN Incidence Stratified by TRT Dose
50%
p=0.79
40%
p<0.0001
30.3%
30%
28.3%
27.7%
20%
10%
3.7%
n=33
n=242
0%
0.2 mcg/kg/min
0.4 mcg/kg/min
CIN Incidence
Predicted values per Mehran et al, JACC 2004.
Predicted
Renal Protective Effects and the Prevention of ContrastInducedcNephropathy by Atrial Natriuretic Peptide
261 pts Randomized
14 pts excluded
126 pts
ANP plus hydration
128 pts
hydration
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
angiographic and continued for
48 h after
Morikawa et al. J Am Coll Cardiol 2009;53:1040–6
Incidence on CIN in the ANP Group
Compared with the Control Group
Incidence of CIN (%)
P=0.015
P=0.023
P= 0.042
 Creatinine
>0.5 mg/dl
 Creatinine
>25% of baseline
Morikawa et al. J Am Coll Cardiol 2009;53:1040–6
 Creatinine
>0.5 mg/dl or
>25% of baseline
N-Acetylcysteine (NAC)
CIN: Effect of n-Acetylcysteine
► Prospective, randomized
► 83 high risk patients

CrCl < 50 ml/min

Diabetes 33%
► IV CONTRAST for CT (75 ml
of Low Osmolar CM)
► n-AC 600 bid x 2 days pre► CIN definition: creatinine
increase of 0.5 mg/dl
► Hydration with 0.45% @ 1
ml/kg/h x 24 h
Tepel NEJM 2000
p= 0.01
Relative Risk for Developing CIN after NAC
Review: Acetylcysteine and CIN
Comparison: 01 NAC on CIN
Outcome: 01 CIN
Study or
substudy
Allaqaband et al
Briguori et al
Diaz-Sandoval et al
Durham et al
Goldenberg et al
Gomes et al
Kay et al
Nguyen-Ho et al
Oldemeyer
Pate et al
RAPIDO
Shyu
Fung et al
Total: (95% Cl)
NAC
n/N
Control
n/N
RR (Random)
95% Cl
Risk Ratio (Random)
95% Cl
8/45
6/92
2/25
10/38
4/41
8/78
4/102
9/95
4/49
57/238
2/41
2/60
8/46
6/40
10/91
13/29
9/41
3/39
8/78
12/98
19/85
3/47
50/239
8/39
15/61
6/45
1.19 (0.45, 3.12)
0.59 (0.23, 1.57)
0.18 (0.04, 0.72)
1.20 (0.55, 2.63)
1.27 (0.30, 5.31)
1.00 (0.40, 2.53)
0.32 (0.11, 0.96)
0.42 (0.20, 0.89)
1.28 (0.30, 5.41)
1.14 (0.82, 1.60)
0.24 (0.05, 1.05)
0.14 (0.03, 0.57)
1.30 (0.49, 3.46)
950
932
0.68 (0.46, 1.02)
Total events: 124 (NAC), 162 (Control)
Test for heterogenety: Ch=27.54 (P0.005), 12=56.4%
Test for overall effect: Z=1.88 (P=0.05)
0.1 0.2
Favors treatment
Zagler et al. Am Heart J 2006;151:140-145.
0.5 1
2
5 10
Favors control
NEPHRIC Study: Protocol
Patients with diabetes and serum creatinine 1.5-3.5 mg/dl who
underwent coronary or aortofemoral angiography
Iso-osmolar, non-ionic
Iodixanol [Visipaque]
N=64
Mean Contrast Volume = 163 ml
PTCA – 17%
Low-osmolar, non-ionic
Iohexol [Omnipaque]
N=65
Mean Contrast Volume = 162 ml
PTCA – 25%
• Randomized, double blind, prospective, multicenter
• Primary endpoint: peak increase in serum creatinine
concentration @ 3 days after angiography
Aspelin P et al, NEJM, 2003; 348: 491-499
Primary Endpoint –
Peak Increase in Scr from Baseline to Day 3
(µmol/l) p=0.002
Mean
Minimum
Max
Iodixanol
(Visipaque)
Iohexol
(Omnipaque)
n=62
n=64
11.2 ±19.7
41.5 ± 68.6
- 19.0
- 21.0
74.0
331.0
Effect of Nonionic Radiocontrast Agents on
Occurrence of CIN in Patients with Mild-moderate
CRI: Pooled Analysis of the Randomized Trials
•
Significantly highest incidence of CIN with iohexol then two other agents
Incidence of CIN
Iopamidol (Isovue)
Low osmolar
13.5%
Iohexol (Omnipaque)
Low osmolar
25.0%
Iodixanol (Visipaque)
Iso-osmolar
11.0%
P value
0.024
0.001
Difference between iopamidol and iodixanol was not statistically significant
(P=0.227)
Sharma et al. Catheter Cardiovasc Interv 2005;65:386-393.
The ICON Trial: Protocol
Patients With Chronic Renal Insufficiency
to Undergo Angiography/PCI
n=130
Ioxaglate (Hexabrix)
Iodixanol (Visipaque)
Low-osmolar, ionic
Isoosmolar, non-ionic
Primary Endpoint: Peak increase in the serum creatinine
concentration between day 0 (when contrast medium was
administered) and day 3
Mehran et al. TCT 2006
ICON Trial: Increase of Serum Creatinine from
Baseline (Secondary Study End Point)
Ioxaglate
N=74
Iodixanol
N=71
p
≥ 0.5 mg/dL
18.2 %
16.2 %
0.82
≥ 1 mg/dL
4.5 %
1.5 %
0.36
≥ 25%
24.2 %
16.2 %
0.29
≥ 25% or ≥ 0.5 mg/dL
24.2 %
16.2 %
0.29
JACC Intv 2009
CARE
Design
•
•
•
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
Solomon, RJ et. al., Circulation 115, 3189 (2007)
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
230 patients assigned
to Iopamidol-370
26 excluded
204 evaluable
patient
236 patients assigned
to Iodixanol-320
26 excluded
210 evaluable
patient
CARE
p = 0.39
p = 0.44
p = 0.15
CARE
Diabetic Subgroup
p = 0.11
p = 0.37
p = 0.20
Conclusions (1)
► CRI is one of the most important independent
predictors of poor outcome post PCI
► CIN remains a frequent source of acute renal failure
and is associated with increased morbidity and
mortality, and higher resource utilization
► Several factors predispose patients to CIN
► Preventive measures pre procedure, as well as
careful post procedure management should be
routine in all patients
Conclusions (2)
► Hydration pre-PCI (12 hours recommended)
► D/C nephrotoxic drugs (NSAIDS, antibiotics, etc)
► Role of n-acetylcysteine is disputable
► No Role for IV Fenoldopam
► Sodium bicarbonate may be useful, but need more
definitive data
► Limit contrast agent volume
► Low-osmolar agents are better than high-osmolar
 Within non-ionic contrast, the data are contradictory
► Role of local drug delivery for prevention of CIN
requires further investigation
Mechanism of Thrombosis Induction
and Mitigation with Contrast Media
Comparative Effects, Cautionary Notes
and Implications for PCI
Frederick Feit, MD, FACC
Associate Professor of Medicine
New York University School of Medicine
Director, Interventional Cardiology
New York University School of Medicine
New York, NY
Thrombosis Induction and Mitigation with
Contrast Media: Outline
► Thrombin generation, platelet activation and their
interrelationship
► Contrast media: The basics
► Experimental data exploring the interaction of
differing contrast media and thrombosis in
animals and humans
► Potential relevance in clinical practice
ExtrinsicSystem
System
Extrinsic
Intrinsic System
System
Intrinsic
Injury
XIIa, XIa
Tissue thromboplastin
IX
IXa
VIII, Ca
X
Fibrinogen
Xa
Ca ,V
Prothrombin
Thrombin
Fibrin
XIII
XIIIa
Mature Thrombus
Platelet
Activation
Sites of Anti-thrombotic Drug Action
Tissue factor
Collagen
Aspirin
Aspirin
Plasma clotting
cascade
ADP
Thromboxane A2
LMWH
Fondaparinux
Heparin
Prothrombin
AT
AT
Factor
Xa
Bivalirudin
Bivalirudin
Hirudin
Hirudin
Argatroban
Argatroban
Ticlopidine
Ticlopidine
Clopidogrel
Clopidogrel
Prasugrel
Prasugrel
Conformational
activation of GPIIb/IIIa
Thrombin
Fibrinogen
ThromboThrombolytics
lytics
Platelet aggregation
Fibrin
Thrombus
GPIIb/IIIa
GPIIb/IIIa
inhibitors
inhibitors
Active
catalytic site
Thrombin
Anion
binding
exosite
Fibrinogen
Active
catalytic site
Thrombin
Anion
binding
exosite
Active Fibrin
The Platelet
ADP
EPI
Collagen
Thrombin
Thromboxane
GPIIb/IIIa
Fibrinogen
GPIIb/IIIa
COX
Platelet
Coagulation – “The Real Story”
Complex interplay on the surface of platelets
ADP
Platelet
activation
GP2b3a expression
& platelet aggregation
Collagen
TXA2
Thrombin
Fibrinogen
Fibrin
Xa
Tissue
Factor
Plasma
Clotting
cascade
Prothrombin
Ca
Va
THROMBUS
Contrast Media: Preconceived Notions
► Ionic Contrast: What they used to use
► Nonionic Contrast: What we use now, because it
has lower osmolality (the good stuff)
► Visipaque: The really good stuff, both theoretically
and confirmed by the COURT trial
► Hexabrix: I heard of that; I think it’s pretty good,
too
Contrast Media: More Evolved Notions
► Ratio of iodine:osmotically active particles
determines osmolality
► Ioxaglate (Hexabrix), an ionic dimer has lower
osmolality than nonionic monomers
► Iodixanol (Visipaque) a nonionic dimer is
isoosmolar to plasma
Basic Structures of Contrast Media
Voeltz MD, et al. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review
Contrast Media: Very Evolved Notions
► Ionic contrast: conjugation of the benzene ring
structure (anion) with a non-radioopaque cation
resulting in a water soluble compound.
► Ionic monomers dissociate in vivo resulting in
an iodine:particle ratio of 3:2; for ionic dimers,
6:2
► Nonionic monomers do not dissociate so I:p
ratio is 3:1; for nonionic dimers, 6:1
Comparative Characteristics of Contrast Media:
Molecular Structures
Osmolality
(mOsm/kg)
HOCM
(>1,500)
Ionicity
Ionic
Ionic
# Benz.Rings
Monomer
Dimer
LOCM
(280 – 1,000)
Nonionic
Monomer
Dimer
Ioxilan
Name
Diatrizoate
ioxaglate
Iohexol
Iopamidol
Iopromide
Ioversol
Iodixanol
Viscosity
at 370C
6 cPs
8 cPs
5-10 cPs
11 cPs
Viscosity
at 20°C
14 cPs
16 cPs
10-22 cPs
26 cPs
7
1
Classification and Osmolality
Class
High-Osmolar
(HOCM)
High-Viscosity
(HVCM)
Low-Osmolar
(LOCM)
Ionic
Monomers
Nonionic
Dimer
Nonionic
Monomers
Low-Viscosity
(LVCM)
Trade Name
and
Manufacturer
Osmolality
(mOsm/kg
H20)
Hypaque® (GEH)
2016
RenoCal-76® (B)
1870
MD-76®R (M)
1551
Iothalamate
Conray ® (M)
1400
Iodoxinal
VisipaqueTM 320
(GEH)
290
Iopromide
Ultravist® 370 (BR)
774
Iopamidol
Isovue® 370 (B)
796
Iohexol
OmnipaqueTM 350
(GEH)
844
Ioversol
Optiray® 350 (M)
792
Ioxilan
Oxilan® 350 (G)
695
Ioxaglate
Hexabrix® 320
(G-M)
600
Chemical
Name
Ionic Dimer
Diatrizoate
Voeltz MD, et al. J Invasive Cardiol. 2007 Mar;19(3):1A-9A. Review
Methods: Patients Undergoing angiography
1.
2.
3.
4.
Blood drawn from 5F pigtail in aorta utilizing 50cc syringe
5ml blood injected in multiple 10cc syringes
2ml contrast drawn into syringe (no mixing)
Inject onto filter paper at 10, 30, 60, 90 min. to assess thrombus
Engelhart et al. Invest Radiol 1988;23:922-7
Incubation of Blood with Contrast
Engelhart et al. Invest Radiol 1988;23:922-7
% Aggregation
Differential Effects of Contrast Media
on Platelet Aggregation
Iopamidol: directly induced platelet
aggregation and potentiated that
induced by ADP
*
Platelet aggregation and P-selectin expression in
hirudinized whole blood containing iopamidol,
iodixanol, or ioxaglate in the absence (open
histograms) or presence (thatched histograms) of ARC66096 (10 umol/l).
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
Iodixanol: potentiated aggregation
induced by ADP
Ioxaglate: inhibited aggregation
induced by ADP
ADP antagonists, but not ASA
inhibited Iopamidol induced platelet
aggregation indicating that this
phenomenon is not mediated by
TXA2 and is at least in part by ADP
In Vitro Comparison of the Effects of Contrast
Media on Coagulation and Platelet Activation
Methods:
1. Pooled human plasma mixed with saline control
or contrast Iohexol (Omnipaque), or Iodixanol
(Visipaque), or Ioxaglate (Hexabrix) to a final
concentration of 60mg I/ml for aPTT and TT
studies
2. Platelet studies performed using ELISA tests
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
In Vitro Comparison of the Effects of Contrast
Media on Coagulation and Platelet Activation
NaCL 9 g/l
Iodixanol
Iohexol
Ioxaglate
TT (s)
19 ± 2
84 ± 10
110 ± 18
>500
APTT (s)
44 ± 2
74 ± 1
81 ± 2
303 ± 13
P <0.01
P <0.01
P < 0.01
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
In Vitro Comparison of the Effects of Contrast
Media on Coagulation and Platelet Activation
30 min
intubation
PF4
IU/ml
5-HT
Ng/ml
PDGF-AB
Pg/ml
TXB2
Ng/ml
FpA
Ng/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 al. Blood Coagulation and Fibrinolysis 1996;7:602-8
In Vitro Comparison of the Effects of Contrast
Media on Coagulation and Platelet Activation
P<0.001
IU/ml
PF4
PF4 determinations (platelet factor 4) which represent platelet degranulation
induced by contrast media mixed 1:1 with blood for 1 min (mean ± SD, n=4).
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
Corot et al: Conclusions
► Ioxaglate demonstrated the most powerful
anticoagulant properties, followed by iohexol and
Iodixanol
► Iohexol resulted in major platelet activation;
iodixanol in less platelet activation, only with 30
minutes of incubation; ioxaglate did not activate
platelets
Differential Effects on Thrombus Formation
Methods:
1. Contrast agent added to blood collected from normal volunteers
in ratio of either 20% or 50%
2. Mixed for 1 min.
3. Thrombi formed in vitro by adding 1ml recalcified blood/contrast
to the chandler loop (45 cm long, 3 mm inner circumference)
PVC tubing
4. Rotated at 37 rpm for 90 mins
5. Thrombus analyzed by immunofluorescence and weighed
6. Thrombolysis over 24 hours, both spontaneous and by tPA
assessed, by weight of thrombus and measuring free FITC in
supernatant (a product of lysis of FITC-labeled fibrinogen
Jones C et al. Thrombosis Research 2003;112:65-71
Differential Effects on Thrombus Formation
Weight (mg)
P<0.0005
Saline
Ioxaglate
Iobexol
Iodixanol
20%
-
-
-
-
50%
-
20%
-
-
-
-
50%
20%
-
-
-
-
-
50%
20%
Jones C et al. Thrombosis Research 2003;112:65-71
Differential Effects on Platelet Degranulation
Percentage of platelets positive for P-selectin expression in the presence of CM
P<0.02
Percent Positive
P<0.03
Saline
Ioxaglate
Iobexol
Iodixanol
50%
-
-
-
-
50%
-
20%
-
-
-
-
50%
20%
-
-
-
-
-
50%
20%
Jones C et al. Thrombosis Research 2003;112:65-71
Fibrinolysis: Spontaneous or with tPA
P<0.02
Weight (mg)
Floresence (arbitrary U)
P<0.02
Saline
20%
Iohexol
Iodixanol
tPA
-
20%
+
20%
-
20%
+
20%
-
20%
+
Jones C et al. Thrombosis Research 2003;112:65-71
Saline
20%
Iohexol
Iodixanol
tPA
-
20%
+
20%
-
20%
+
20%
-
20%
+
Thrombus Histopathology
Head and tail regions of thrombi for
Saline control (top), Iohexol (mid),
Iodixanol (bot). Thrombi formed in
the presence of either contrast had
larger, more platelet-rich heads
and much larger tails, composed of
an open irregular meshwork of
fibrinogen/fibrin enclosing large
dense RBC areas and scattered
WBC.
Iohexol thrombi had larger “heads”
than iodixanol thrombi, which had
a much more irregular structure
with areas of very strong fibrinogen
antibody binding interspersed with
WBC aggregates.
Jones C et al. Thrombosis Research 2003;112:65-71
Differential Effects on Thrombus Formation
Conclusions
► No thrombi formed from blood incubated with
Ioxaglate
► Thrombi formed with Iohexol or Iodixanol weighed
>10x more than those formed with saline controls,
had different structure and were more resistant to
thrombolysis
► Iohexol, but neither Iodixanol nor Ioxaglate
increased platelet degranulation
Contrast Media: Mechanistic Assessment of
Thrombin Generation
Methods:
1. Pooled plasma from healthy donors to prepare
PRP and PPP
2. Thrombograms obtained by mixing PPP or PRP
with activator (TF for extrinsic system and kaolin
for intrinsic system) plus ioxaglate, iodixanol,
abciximab (as shown)
3. Thrombograms assessed by lag time (clotting
time), peak height (maximal velocity of net
thrombin production, area under the curve
(endogenous thrombin potential)
Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274
Thrombogram: Iodixanol vs. Ioxaglate
Influence of the contrast media addition on
the thrombogram in PPP and PRP. (a) In
defibrinated PPP initiated with rTF. (b) In
defibrinated PPP initiated with contact
activator. (c) In PRP initiated only with CA 2+
●control; ○iodixanol (5% v/v); ioxaglate
(5%, v/v). Data represent median of four
independent experiments
Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274
Abciximab + Iodixanol or Ioxaglate
Effect of abciximab on the thrombogram in PRP in the absence and
presence of CM (5% v/v ). ●control; ○abciximab alone (40 ug mL-1); 
abciximab + iodixanol;  abciximab + ioxaglate. Data represent median of
three independent experiments
Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:269-274
Al Dieri et al: Conclusions
► Ioxaglate is a potent inhibitor of thrombus
formation in prp and ppp. Effects of iodixanol
are to slightly enhance thrombin generation
► Ioxaglate amplifies the effect of abciximab
► Ioxaglate inhibits activation of factors V and VIII
(thrombograms not shown) and of platelets by
thrombin
► These data suggest that ioxaglate interferes with
binding of substrates to exosite I of thrombin
and inhibits thrombin generation via inhibition of
thrombin-mediated feedback activation
Antithrombotic Effects of Ionic and Non-Ionic
Contrast Media in Nonhuman Primates
Methods:
1) Healthy baboons with chronic AV (femoral)
shunts
2) PS 153 stent deployed at 10 atm in AV shunt
3) Labeled platelets used
4) Saline control or contrast (Iodixanol, Isovue,
Ioxaglate) locally infused
5) The fluid mechanics and mass transfer
characteristics of the infused contrast were
modeled using computational fluid dynamics
Markou et al. Thromb Haemost 2001;85:488-93
Antithrombotic Effects of Ionic and Non-Ionic
Contrast Media in Nonhuman Primates
Schematic of the local infusion system, stented segment, and expanded diameter
chamber region of the thrombogenic device showing their relative placement in the AV baboon shunt. The top panel shows an in-platelet image of platelet deposition on a
control stent and within chamber region of flow recirculation.
Markou et al. Thromb Haemost 2001;85:488-93
A
Platelets Deposited x 10-6
Platelets Deposited x 10-6
Platelet Deposition in the Expanded Region
Time (min)
B
Time (min)
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.
The blood flow rate was 100 ml/min. Platelet deposition was monitored by
measuring the accumulation of 111Indium-radiolabeled platelets. A) CM infusion
rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ± 1 SEM
Markou et al. Thromb Haemost 2001;85:488-93
Platelets Deposited x 10-6
Platelets Deposited x 10-6
Platelet Deposition in the Stented Region
A
Time (min)
B
Time (min)
Time course of platelet deposition onto 4.0 mm i.d. metallic stents (PalmazSchatz) deployed into A-V shunts in baboons. The blood flow rate was 100
ml/min. Platelet deposition was monitored by measuring the accumulation of
111Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM
infusion rate = 0.3 ml/min. Values are mean ± 1 SEM
Markou et al. Thromb Haemost 2001;85:488-93
Fibrin Deposition on Stented Segment
Fibrin (mg)
Deposition of fibrin on the stented segment
Fibrin (mg)
4
2
7
4
4
The blood flow rate was 100 ml/mi. Fibrin deposition was determined by measuring the
accumulation of 125iodine-labeled fibrinogen. A) CME infusion rate = 0.1 ml/min. B. CME infusion
rate = 0.3 ml/min. Values are mean ± 1 SEM
Markou et al. Thromb Haemost 2001;85:488-93
Photographs of Thrombus Formed in Stents
.
9
6
Markou et al. Thromb Haemost 2001;85:488-93
Antithrombotic Effects of Ionic and Non-Ionic
Contrast Media in Nonhuman Primates
► Ioxaglate reduced both platelet and fibrin
deposition on stents by 75-80% (p<0.005), while
the non-ionic agents reduced platelet deposition by
52% (p<0.05)
► In the regions of low shear flow, only ioxaglate
(0.3ml/min) reduced platelet deposition sgnificantly
(by 52%; p<0.05)
► In this model, while all three agents were inherently
antithrombotic, the most striking effects were seen
with ioxaglate
All Comers
All Comers
PTCA
PTCA
Randomized
Blinded
Iohexol
Iohexol
Ioxaglate
Ioxaglate
UFH: 10,000 u IV
Aspirin
Primary
endpoint: In-Lab
In-Lab Thrombus
Primary
Endpoint:
Thrombus
Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105
Coronary Angioplasty: In-Lab Thrombus
Iohexol (Omnipaque) vs Ioxaglate (Hexabrix)
For PTCA
P = 0.04
Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105
All Comers
All Comers
PTCA
PTCA
Randomized
Iohexol
Iohexol
Ioxaglate
Ioxaglate
UFH: 10,000 u IV
Aspirin
Primary
endpoint:
Thrombus During
Angiography
Primary
Endpoint:
Thrombus
During
Angiography
Esplugas et al. Am J Cardiol 1991;68:1020-4
In-Lab Angiographic Thrombus
Iohexol (Omnigraf) vs Ioxaglate (Hexabrix)
For PTCA
P < 0.005
Esplugas et al. Am J Cardiol 1991;68:1020-4
All Comers
All Comers
PCI
Patients
PCI Patients
Sequential
Design
Iodixanol
Iodixanol
Ioxaglate
Ioxaglate
Enoxaparin 1 mg/kg SC Q12 h, or
0.5 mg/kg 5 min prior to PCI
ASA, 250 mg PO OD, clopidogrel 300 mg PO >6h
GP IIb/IIIa in 43% (operator discretion)
(Peak anti Xa > 0.5 IU/ml in 97% of patients)
Primary Endpoint: In-Hospitral MACE (cardiac death, MI, TVR, CVA, systemic embolic event)
Secondary endpoint: Angiographic outcomes (large thrombus > 2 vessel diameters)
Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8
Le Feuvre et al: Intraprocedural Large Thrombus
Iodixanol vs. Ioxaglate for PCI
Stent in 91%
P < 0.0001
Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8
Thrombosis Induction and
Mitigation with Contrast Media: Conclusions
► Data from in vitro studies and from animal models
indicate significant differences in the effects of
different contrast media on thrombin generation,
thrombolysis and platelet activation.
► Among commonly used agents, the ionic dimer,
Ioxaglate (Hexabrix) inhibits both thrombin
generation and platelet activation
► Non-ionic monomers activate platelets, enhance
thrombin generation and inhibit thrombolysis
► The non-ionic dimer, Iodixanol (Visipaque) has
intermediate 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
Clinical Outcomes in Patients with
STEMI and High-Risk ACS:
The Evidence-Based Case for
Risk-Directed Selection of CM in PCI
The Journey from Clinical Trials to Choices for CM in the
Cardiac Catheterization Laboratory: How Should Recent
Evidence and Trials Affect Our Choices?
Steven V. Manoukian, MD, FACC
Program Chairman
Director, Cardiovascular Research | Sarah Cannon Research
Institute | Centennial Heart Cardiovascular Consultants |
Medical Director, Cardiovascular Services | Clinical Services
Group | Hospital Corporation of America (HCA) | Nashville, TN
Clots, Contrast Media, and Catheterization
Outline
► PCI ischemic complications
► Anticoagulation in PCI
► Bleeding complications of PCI anticoagulation
► Impact of PCI periprocedural MI
► Clinical trials of contrast media in PCI
► Conclusions
Ischemic Complications of PCI
30-Day Event Rates Adapted from REPLACE-2, ACUITY-PCI, HORIZONS PCI Subset
Lincoff AM et al. JAMA 2003;289:853-863.
Stone GW et al. Lancet 2007;369:907-19.
Stone GW et al. NEJM 2008;358:2218-30.
EPILOG: 30-Day Primary Efficacy Endpoint
Abciximab + standard-dose heparin
Placebo
Abciximab + low-dose heparin
Probability of Death,
Myocardial Infarction, or
Urgent Revascularization
0.12
0.10
0.08
0.06
0.04
0.02
0.01
P<0.001
0
5
10
15
20
Days After Randomization
EPILOG Investigators. NEJM 1997;336:1689-96.
25
30
EPILOG: 30-Day Individual Endpoints
Efficacy End Point
Placebo +
StandardDose
Heparin
(n=939)
Abciximab +
Low-Dose
Heparin
P Value
(n=935)
No. of patients (%)
Composite
Abciximab +
StandardDose
Heparin
(n=918)
P Value
No. patients (%)
109 (11.7)
48 (5.2)
<0.001
49 (5.4)
<0.001
Death
7 (0.8)
3 (0.3)
0.21
4 (0.4)
0.39
Myocardial infarction
81 (8.7)
34 (3.7)
<0.001
35 (3.8)
<0.001
Q-wave
7 (0.8)
4 (0.4)
0.36
4 (0.5)
0.38
Non-Q-wave
74 (7.9)
30 (3.2)
<0.001
31 (3.4)
<0.001
Large non-Q-wave (CK MB > 5 x
control)
53 (5.6)
19 (2.0)
<0.001
23 (2.5)
<0.001
Small non-Q-wave (CK MB 3-5x
control)
18 (1.9)
11 (1.2)
0.26
8 (0.9)
0.07
Non-Q-wave after hospitalization
3(0.03)
0
0.25
0
0.25
Urgent revascularization
48 (5.2)
15 (1.6)
<0.001
21 (2.3)
0.001
Repeated percutaneous
intervention
35 (3.8)
11 (1.2)
<0.001
14 (1.5)
0.003
Coronary-artery bypass grafting
16 (1.7)
4 (0.4)
0.007
8 (0.9)
0.11
Death or myocardial infarction
85 (9.1)
35 (3.8)
<0.001
38 (4.2)
<0.001
EPILOG Investigators. NEJM 1997;336:1689-96.
ACUITY: Early Composite Ischemia
15
Bivalirudin + GP IIb/IIIa inhibitor, 7.9%, P=0.37
Bivalirudin alone, 8.0%, P=0.30
Heparin + GP IIb/IIIa inhibitor, 7.4%
10
5
0
0
5
10
15
20
Days After Randomization
Stone GW et al. NEJM 2006;355:2203-16.
25
30
35
ACUITY: Major Bleeding
15
Bivalirudin + GP IIb/IIIa inhibitor, 5.3%, P=0.41
Bivalirudin alone, 3.1%, P<0.001
Heparin + GP IIb/IIIa inhibitor, 5.7%
10
5
0
0
5
10
15
20
Days After Randomization
Stone GW et al. NEJM 2006;355:2203-16.
25
30
35
ACUITY: Major Bleeding and Mortality
8
Patients with major bleeding
Patients without major bleeding
7
6
Percent Mortality
7.3%
Long rank p Value:
<0.0001
5
4
3
2
1
1.2%
0
0
5
10
15
20
Days After Randomization
Manoukian SV et al. JACC 2007;49:1362-8.
25
30
35
ACUITY: Predictors of Major Bleeding
Odds Ratio ± 95% CI
OR (95% CI)
p value
Age > 75 years
1.64 (1.32-2.02)
<0.0001
Female gender
1.92 (1.61-2.29)
<0.0001
Diabetes
1.20 (1.00-1.44)
0.057
Hypertension
1.24 (1.01-1.52)
0.040
No prior PCI
1.32 (1.08-1.62)
0.006
Anemia
1.87 (1.54-2.28)
<0.0001
Renal insufficiency
1.53 (1.24-1.90)
<0.0001
Baseline ST-segment deviation > 1 mm
1.35 (1.13-1.61)
0.0008
Baseline cardiac biomarker elevation
1.43 (1.19-1.74)
0.0002
Heparin plus GPI vs bivalirudin monotherapy
1.95 (1.56-2.44)
<0.0001
0
Manoukian SV et al. JACC 2007;49:1362-8.
1
2
3
Clinical Classification of MI
Type 1
Spontaneous myocardial infarction related to ischaemia due to primary coronary event
such as plaque erosion and/or rupture, fissuring, or dissection
Type 2
Myocardial infarction secondary to ischaemia due to either increased oxygen demand or
decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias,
hypertension, or hypotension
Type3
Sudden unexpected cardiac death, including cardiac arrest, often with symptoms
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
autopsy, but death occurring before blood samples could be obtained, or at a time before
the appearance of cardiac biomarkers in the blood
Type 4a
Myocardial infarction associated with PCI
Type 4b
Myocardial infarction associated with stent thrombosis as documented by angiography or
at autopsy
Type 5
Myocardial infarction associated with CABG
Thygesen K et al. J Am Coll Cardiol 2007;50:2173-95.
ACUITY: Periprocedural MI and Mortality
30-Day Event Rates, PCI Population
30-day events (%)
P<0.0001
P<0.0001
P=0.8
P=0.41
P<0.0001
P<0.0001
P=0.0004
P=0.27
P<0.0001
Prasad A et al. J Am Coll Cardiol 2009;54:477-86.
ACUITY: Periprocedural MI and 1-Year Mortality
PCI Population
HR ± 95% CI
HR (95% CI)
P-value
Age (> 75 years)
2.53 (2.01-3.18)
<0.0001
Anemia
1.51 (1.22-1.86)
0.0002
Prior stroke
1.29 (1.04-1.60)
0.02
Male
1.53 (1.23-1.90)
0.0001
Diabetes
1.51 (1.25-1.82)
<0.0001
Baseline CrCl <60 mL/min
1.43 (1.13-1.80)
0.003
Pre-randomization UFH
1.25 (1.02-1.54)
0.03
Prior MI
1.33 (1.09-1.61)
0.005
CKMB/troponin+ at baseline
1.70 (1.37-2.12)
<0.0001
ECG changes at baseline
1.76 (1.45-2.13)
<0.0001
30-day major bleed
3.03 (2.33-3.94)
<0.0001
30-day revascularization
1.76 (1.16-2.67)
0.008
Periprocedural MI
1.30 (0.85-1.98)
0.22
7.49 (4.95-11.33)
<0.0001
Spontaneously occurring MI
0.1
1
Prasad A et al. J Am Coll Cardiol 2009;54:477-86.
10
Periprocedural Troponin and Mortality
Meta-Analysis, n=15,581
Fuchs
Cantor
Gruberg
Nallamothu
Ricciardi
Kini
Natarajan
Cavallini
Okmen
Shyu
Hermann
Kizer
Miller
Prasad
All trials
1.35 (1.13-1.60)
0
2
4
Nienhuis NB et al. Catheter Cardiovasc Interv 2008;71:325-6.
6
8
10
12
The Impact of Cardiac Contrast Media on
MACE End Points In ACS
What do the Vascular Biology
and Clinical Trials Teach Us?
Ioxaglate Characteristics:
Thrombotic Risk and MACE
Ioxaglate has been shown to reduce platelet
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.
Antithrombotic and Anticoagulant
Properties of Ioxaglate
So what happens?
Vessel Injured
Exposes endothelial
proteins, including
collagen
Collagen
Activates Resting
Platelets
Thrombin
Activates Resting
Platelets
Activated Platelets
Aggregate and adhere
to the exposed collagen
on the vessel wall,
forming the initial clot
Fibrin forms mesh which
encapsulates the clot
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
Jones C et al. Thrombosis Research 2003;112:65-71
Fibrinogen
Thrombin helps convert
another protein,
fibrinogen, into fibrin
Antithrombotic and Anticoagulant
Properties of Ioxaglate
Blood Vessel
Endothelium
Subendothelium
Collagen
INJURY
VWF
Tissue Factor
VasoVasoconstriction
constriction
Platelet
PlateletAdhesion
adhesion
Secretion
and&secretion
Coagulation
Cascade
Coagulation Cascade
Thrombin
Thrombin
Fibrin
Platelet aggregation
Dr Isobel Ford
Haemostatic plug
Antithrombotic and Anticoagulant
Properties of Ioxaglate
► What are issues and concerns for interventional
cardiologists?
 This process can lead to occlusion of the vessels,
such as coronary arteries during PCI
 End point includes mortality
 End point includes NSTEMI and STEMI
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
Jones C et al. Thrombosis Research 2003;112:65-71
Antithrombotic and Anticoagulant
Properties of Ioxaglate
So what role does ioxaglate play?
Vessel
Vessel Injured
Injured
Exposes endothelial
Exposes
endothelial
proteins,
proteins,
including
including
Collagen.
collagen
Thrombin
Activates Resting
Platelets
Collagen
Activates Resting
Platelets
Activated Platelets
Aggregate and adhere
to the exposed collagen
on the vessel wall,
forming the initial clot
Fibrin forms mesh which
encapsulates the clot
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
Jones C et al. Thrombosis Research 2003;112:65-71
Fibrinogen
Thrombin helps convert
another protein,
fibrinogen, into fibrin
Antithrombotic and Anticoagulant
Properties of Ioxaglate
Interface of ioxaglate with thrombosis generation
• Ioxaglate, does not activate resting platelets, unlike nonionic
monomers.
• Doesn’t direct platelets to change shape, release pro-coagulant
mediators or to adhere to anything.
• This prevents/delays formation of the platelet clot.
• Ioxaglate binds w/thrombin, preventing it from activating platelets;
therefore preventing/delaying the formation of the platelet plug.
• Ioxaglate inhibits the generation of thrombin, reducing the amount
of thrombin: inhibits the formation of fibrin.
• Mechanisms that may be responsible for preventing/delaying
formation of the fibrin mesh.
R. Al Dieri Journal of Thrombosis and Haemostasis, 1: 269-274
Heptinstall et al. British Journal of Haemotology 1998;103:1023-30
Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8
Jones C et al. Thrombosis Research 2003;112:65-71
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol)
Contrast in Patients with MI/UA Undergoing PTCA
Low Osmolar Ionic
Contrast Media (n=106)
Nonionic Contrast
Media (n=105)
63.7 ± 12.7
61.9 ± 12
64
62
Hypertension
51.9
50.5
Diabetes
24.5
21.0
Smoking
56.6
67.6
Prior MI
40.6
39.1
Prior PTCA
15.1
17.1
Aspirin
68.9
61.0
Heparin
53.8
59.1
Nitrates
67.0
66.7
Tissue plasminogen activator
3.8
8.6
Acute MI
44.4
40.9
Post-MI ischemia
33.9
33.4
Unstable angina
21.7
25.7
Baseline Demographic Characteristics
Age (yr) (mean ± SD)
Male patients (%)
Clinical history (%)
Treatment history (%)
Indication for PTCA, %
Grines CL et al. J Am Coll Cardiol 1996;27:1381-6.
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol)
Contrast in Patients with MI/UA Undergoing PTCA
Conclusions
Ioxaglate
►Significant reductions in:
 Ischemic complications acutely and at one month
 Decreased blood flow during PTCA
 Recurrent ischemia with repeat catheterization
 Repeat PTCA
 Angina
 Risk of CABG
►Authors: “Strongly consider for unstable
angina/MI PTCA.”
Grines CL et al. J Am Coll Cardiol 1996;27:1381-6.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Iodixanol
Ioxaglate
(Nonionic; n=697)
(Ionic; n=714)
61.6 ± 10.6
62.3 ± 10.2
78.2
76.2
Weight, kg
75.9 ± 12.2
76.2 ± 12.4
Height, cm
168.2 ± 8.6
168.0 ± 8.6
Diabetes, %
20.2
15.8
Current smokers, %
23.2
22.1
Former smokers, %
35.0
36.3
Obesity, %
20.1
20.2
Family history of CAD, %
30.7
26.3
Prior MI, %
19.1
18.5
Prior PTCA, %
16.1
14.7
Prior CAG, %
7.1
6.7
History of allergy/hypersensitivity, %
4.7
5.7
Unstable angina
51.9
49.3
Stable angina
38.3
40.1
Silent ischemia
9.5
10.1
Baseline Clinical Characteristics
Age, y
Male, %
Indication for PTCA, %
Bertrand ME et al. Circulation 2000;101:131-136.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
MACE at 2-Day Follow-Up
Iodixanol
Ioxaglate
(Nonionic; n=697)
(Ionic; n=714)
33 (4.7%)
28 (3.9%)
0.45
Death
0
2
N
Stroke
2
1
NS
Q-wave MI
3
3
NS
NQWMI
24
17
0.24
CABG
1
1
NS
Re-PTCA
3
4
NS
During hospital stay (2 days)
Bertrand ME et al. Circulation 2000;101:131-136.
p
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Conclusions
► No significant difference in in-hospital MACE
between ioxaglate and iodixanol.
Bertrand ME et al. Circulation 2000;101:131-136.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Iodixanol
(n=405)
Demographics
N
Average age, y
%
Ioxaglate (n=410)
N%
61±12
%
62±12
Male
280
69
270
66
Hypertension
240
59
249
61
Diabetes mellitus
110
27
110
27
Current smoker
129
32
137
33
Past smoker
238
59
251
61
Previous MI
142
35
168
41
Hyperlipidemia
249
61
157
63
Angina
353
87
383
93
Angina CHS class IV
290
72
311
76
Family CAD history
242
60
240
59
Prior intervention
128
32
133
32
Davidson CJ et al. Circulation 2000;101:2172-2177.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Hospital Stay Primary Clinical Outcomes
Iodixanol
(n=405)
Ioxaglate (n=410)
P
N
%
N%
%
Emergent
recatheterization
5
1.2
9
2.2
0.29
Repeat
revascularization
4
1.0
8
2.90
0.25
In-hospital abrupt
closure
3
0.7
10
2.4
0.05
Stroke/TIA
1
0.2
1
0.2
0.99
Thromboembolic
event
2
0.5
4
10
0.42
Cardiac death
5
1.2
1
0.2
0.10
Nonfatal MI
8
2.0
18
4.4
0.05
Emergent CABG
2
0.5
3
.07
0.66
Composite outcome
22
5.4
39
9.5
0.027
Davidson CJ et al. Circulation 2000;101:2172-2177.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Events from Hospital Discharge to 30 Days
Iodixanol
(n=390)
Ioxaglate (n=400)
P
N
%
N%
%
Emergent
recatheterization or
revascularization
13
3.3
12
3.0
0.79
Abrupt closure
0
0
2
0.5
0.16
Stroke/TIA
1
0.3
1
0.3
0.99
Thromboembolic
event
0
0
2
0.5
0.16
Cardiac death
0
0
1
0.3
0.32
Nonfatal MI
1
0.3
1
0.3
0.99
Emergent CABG
1
0.3
1
0.3
0.99
Composite outcome
15
3.8
15
3.8
0.94
Davidson CJ et al. Circulation 2000;101:2172-2177.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Angiographic and Procedural Outcome
Iodixanol
N
Abrupt closure
Prolonged no-reflow
Distal embolization
Side-branch occlusion
Development of moderate to
large thrombus
Dissection
Unplanned IABP
Unplanned abciximab
Procedural success
>20% absolute decrease
<50% residual stenosis
TIME-3 flow
Composite outcome
(n=400)
%
Ioxaglate (n=396)
N%
%
P
2
3
2
6
0.5
0.8
0.5
1.5
7
3
1
6
1.8
0.8
0.3
1.5
0.09
0.99
0.57
0.99
0
0
0
0
--
18
4
29
369
375
389
397
69
4.5
1.0
7.3
92.2
93.9
97.3
99.3
17.3
25
7
32
340
355
379
391
87
6.3
1.8
8.1
85.9
90.0
94.9
98.8
22.0
0.25
0.37
0.66
0.004
------0.093
Davidson CJ et al. Circulation 2000;101:2172-2177.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PTCA
Conclusions Regarding Ionic Contrast
►Iodixanol, significant
 Reduction in in-hospital adverse composite
 Increase in angiographic success
Davidson CJ et al. Circulation 2000;101:2172-2177.
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
n=3,990
Ioxaglate (Hexabrix® 320)
Dimer, ionic
Iobitridol (Xenetix® 350)
Monomer, non-ionic
Iomeprol (Imeron® 400)
Monomer, non-ionic
Iopamidol (Solutrast® 370)
Monomer, non-ionic
Iopromid (Ultravist® 370)
Monomer, non-ionic
Ioversol (Optiray® 350)
Monomer, non-ionic
Iodixanol (Visipaque® 320)
Dimer, non-ionic
Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
Demographic Data, n=3,990
Non-ionic CM
Ioxaglate
N
1808
2182
Gender (male)
76%
74%
NS
63.9 ± 10.3 years
63.9 ± 10.3 years
NS
18.9%
17.2%
NS
CCS 0-I 22.8%
CCS 0-I 26.4%
NS
CCS II 36.6%
CCS II 37.5%
CCS III 28.2%
CCS III 25.3%
CCS IV 12.5%
CCS IV 10.9%
34.2%
32.3%
Unstable angina
24.9%
21.3%
AMI
9.3%
11.0%
4.1%
4.3%
Age
Diabetes
Angina pectoris
Acute coronary syndrome
Known CM intolerance
Scheller B et al. Eur Heart J 2001;22:385-91.
p
NS
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
Angiographic Data, n=3,990
N
LVEF
Vessels diseased
Stented vessel
Stented vessel localization
Scheller B et al. Eur Heart J 2001;22:385-91.
Non-ionic CM
Ioxaglate
p
1808
2182
55 ± 15.9%
54.8 ± 17.8%
NS
Single vessel 26%
Single vessel
28%
NS
Two vessel 35%
Two vessel 35%
Three vessel 39%
Three vessel
37%
LCA 1.4%
LCA 1.2%
NS
LAD 35.5%
LAD 34.4%
NS
CX 19.8%
CX 26.4%
<0.05
RCA 36.5%
RCA 32.8%
<0.05
ACB 6.7%
ACB 5.2%
NS
Proximal 31.5%
Proximal 28.8%
NS
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
Angiographic Data, n=3,990
Non-ionic CM
Ioxaglate
p
Proximal 31.5%
Proximal 28.8%
NS
Middle 60.5%
Middle 62.2%
Distal 8.0%
Distal 9.0%
18.6%
17.4%
NS
RFD
3.37 ± 0.43 mm
3.37 ± 0.81 mm
NS
MLD
0.68 ± 0.63 mm
0.67 ± 0.58 mm
NS
79.7 ± 17.8%
80.1 ± 5.5%
NS
Volume of CME
280.9 ± 120.5 ml
257.8 ± 101.6 ml
0.001
Heparin dose
12901 ± 4640 IU
11938 ± 3914 IU
0.001
4.9%
5.3%
NS
Stented vessel localization
Restenotic lesion
Diameter stenosis
ReoPro®
Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
Primary Endpoint: 12-Month Acute and Subacute Stent Occlusion
n=3,990
Patients
AOS and SAT
All patients n=3990
Restonosis
All patients n=3990
Combined clinical
end point (TLR,
CABG, death)
All patients n=3990
Event
Non-Ionic CM
Ioxaglate
P
AOS
24/1808 (1.3%)
7/2182 (0.3%)
0.001
SAT
44/1808 (2.45)%
16/2182 (0.7%)
0.001
Reangiography
968/1808 (53.5%)
1062/2182 (48.7%)
0.002
Restenosis
329/968 (34.0%)
296/1062 (27.8%)
0.003
Combined
414/1808 (22.9%)
356/2182 (16.3%)
0.001
TLR
301/1808 (16.6%)
229/2182 (10.5%)
0.001
CABG
22/1808 (1.2%)
31/2182 (1.4%)
NS
Death
110/1808 (6.1%)
109/2182 (5.0%)
0.007
Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
Multivariate Analysis of Acute and Subacute Stent Thrombosis
Variable, n=3990
Wald
P
CME
5.8681
0.0154
Age
0.0013
0.9707
LVEF
1.6027
0.2055
CAD
1.5391
0.2147
CM side effect
0.1368
0.7115
ReoPro®
0.1482
0.7003
Unstable AP
0.1742
0.6764
AMI
2.1049
0.1468
CCS
3.2512
0.0714
MLD
2.7256
0.0988
Heparin
1.9842
0.1589
Localization
0.0108
0.9173
Vessel diameter
0.6186
0.4316
Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs.
Nonionic Contrast in Coronary Stenting
n=3,990
►Ioxaglate, significant reductions in:
 Acute stent thrombosis
 Subacute stent thrombosis
 Reangiography
 Restenosis
 Target lesion revascularization
 Death
Scheller B et al. Eur Heart J 2001;22:385-91.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Baseline Clinical Characteristics
Iodixanol
Ioxaglate
231
267
Age (y)
64 ± 12
63 ± 11
NS
Male gender, n
189 (82)
211 (79)
NS
Diabetes mellitus, n
64 (28)
92 (34)
NS
Hypertension, n
121 (53)
133 (50)
NS
Smoking history, n
94 (41)
97 (36)
NS
LDL cholesterol > 3.3 mmol/l
162 (70)
184 (69)
NS
Family history of CAD, n
46 (20)
51 (19)
NS
Prior CABG, n
16 (7)
23 (9)
NS
Prior MI, n
46 (20)
63 (24)
NS
Chronic renal failure
35 (15)
44 (16)
NS
Statin treatment before PCI
120 (52)
136 (51)
NS
Prior left ventricular failure, n
29 (13)
27 (10)
NS
PCI for acute MI, n
57 (25)
74 (28)
NS
PCI for unstable angina, n
37 (16)
58 (22)
NS
PCI for silent myocardial ischemia, n
29 (13)
27 (10)
NS
N
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
P
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Angiographic Baseline Characteristics and Procedural Data
Iodixanol
Ioxaglate
p
267 ± 125
276 ± 120
NS
Peak anti-Xa >0.5 IU/ml, n
224 (97)
259 (97)
NS
Peak anti-Xa > 1 IU/ml, n
67 (29)
72 (27)
NS
Intravenous antiplatelet therapy, n
99 (43)
112 (42)
NS
Planned, n
88 (38)
93 (35)
NS
Rescue, n
11 (5)
19 (7)
NS
23 (10)
29 (11)
NS
One vessel, PCI, n
192 (83)
219 (82)
NS
Two vessel PCI, n
37 (16)
43 (16)
2 (1)
5 (2)
Volume of contrast media (ml)
Bifurcation/ostial lesion, n
Number of vessel PCI per patient
Three vessel PCI, n
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Angiographic Baseline Characteristics and Procedural Data (continued)
Iodixanol
Ioxaglate
p
Failure to cross the lesion, n
6 (3)
10 (4)
NS
Balloon, n
10 (4)
17 (6)
NS
215 (93)
240 (90)
NS
One stent, n
143 (62)
162 (61)
NS
Two stents, n
47 (20)
54 (20)
Three stents
16 (7)
15 (6)
Four stents or more, n
9 (4)
9 (3)
Direct stenting, n
159 (69)
187 (70)
NS
Drug eluting stent, n
69 (30)
72 (27)
NS
Use of intra-aortic balloon pump, n
16 (7)
11 (4)
NS
Treatment device
Stent, n
Number of stent used per patient
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Clinical Events
Iodixanol
Ioxaglate
p
2 (0.8)
0
NS
7 (3)
1 (0.3)
0.05
1 (0.4)
0
NS
0
0
NS
2 (0.8)
0
NS
7(3)
1 (0.3)
0.05
Emergency repeat PCI, n
3 (1.3)
0
NS
Emergency CABG, n
1 (0.4)
0
NS
0
0
NS
11 (4.8)
1 (0.3)
0.005
Procedural events
Cardiac death, n
Non fatal MI or reinfarction, n
Emergency CABG, n
Stroke or systemic thromboembolic event, n
In-hospital events
Cardiac death, n
Non fatal MI or reinfarction, n
Stroke or systemic thromboembolic event, n
Composite outcome, n
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Clinical Events (continued)
Iodixanol
Ioxaglate
p
3 (1.3)
0
NS
7 (3)
1 (0.3)
0.05
Emergency repeat PCI, n
5 (2.2)
1 (0.3)
NS
Emergency CABG, n
1 (0.4)
0
NS
0
0
NS
14 (6)
2 (0.7)
0.002
30-day events
Cardiac death, n
Non fatal MI or reinfarction, n
Stroke or systemic thromboembolic event, n
Composite outcome, n
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Angiographic and Procedural Complications During or Immediately After PCI
Iodixanol
Ioxaglate
p
14 (6)
1 (0.3)
0.0001
Target vessel occlusion, n
12 (5.2)
1 (0.3)
0.003
Side branch (> 2 mm) occlusion, n
2 (0.9)
1 (0.3)
NS
Composite endpoint, n
14 (6)
1 (0.3)
0.0001
Sustained ventricular arrhythmia
2 (0.9)
1 (0.3)
NS
Hypotension with intervention
4 (1.7)
4 (1.5)
NS
0
3 (1)
NS
2 (1)
7 (2.6)
NS
Appearance of a large thrombus, n
Renal failure requiring treatment
Contrast induced nephropathy
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 3
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar
Nonionic (Iodixanol) Contrast in PCI
Conclusions Regarding Ionic Contrast
►Ioxaglate:
 Thrombus-related events significantly less likely.
• In-hospital MACE
• Large thrombus
►Iodixanol:
 Independent predictor of in-hospital MACE.
Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.
Non-Ionic Contrast Prescribing Information
Isovue
Omnipaque
Optiray
Oxilan
Ultravist
Visipaque
Prescribing Information.
Clots, Contrast Media, and Catheterization
Conclusions
► In PCI, ischemic complications are associated with
adverse outcomes
► Aggressive PCI anticoagulation regimens are
effective in reducing ischemic events but increase
bleeding complications
► Active decision-making with regard to the type of
contrast media may:
 Favorably impact rates of ischemic complications
 Not adversely affect rates of bleeding complications
 Obviate the need for aggressive anticoagulation
regimens
 Improve overall PCI outcomes