1. Contrast Awareness: Why and When Do we Worry?
Roxana Mehran, MD
Professor of Medicine (Cardiology) and Health Evidence Policy
Director of Interventional Cardiovascular Research and Clinical Trials The Icahn School of Medicine at Mount Sinai, New York, NY
Chief Scientific Officer
Cardiovascular Research Foundation, New York, NY
Cardiovascular Research Technology - CRT
February 23-26, 2013
Washington, DC

2. Roxana Mehran, MD
Consulting: AstraZeneca, Johnson and Johnson, Merck and Company, Inc., and Abbott Laboratories
Grant Support: Bristol-Myers Squibb, Sanofi, The Medicines Company, Lilly and Daiichi Sankyo
Honoraria: Regado Bio-Sciences

3. Contrast Media During CTO: What are the Issues?
CTO procedures are one of the most complex and time consuming procedures in IC
Most CTO procedures require dual injection for complete visualization of the vessel to enhance success
Contrast volume in these procedures are usually twice or more than the routine PCI procedures
Patients with CTO are usually more complex, with more co-morbidities which will increase the risk of contrast Induced- acute kidney injury (CI- AKI)
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4. Contrast-induced Nephropathy: In-hospital Mortality
% In-hospital Death
P<0.001
In-hospital mortality is especially high in pts requiring dialysis.
McCullough et al. Am J Med. 1997;

5. Contrast-Induced Nephropathy: Resource Utilization
Endpoint (%)
Patients
P-value
With CIN
Without CIN
Hospital length of stay (days)
<0.001
ICU length of stay (days)
<0.0001
Need for hemodialysis (%) 12
Iakovou I et al. J Am Coll Cardiol. 2002;39:2A.

6. 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]) x (Age-0.203x (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

7. Contrast-Induced Nephropathy
Definition
New onset or exacerbation of renal dysfunction after contrast administration in the absence of other causes:
increase by > 25% or absolute  of > 0.5 mg/dL
from baseline
serum creatinine
There is a variety of definitions of RCN, the most common being an increase of serum creatinine greater than 0.5 mg/dl or increase by >25% of baseline creatinine within 24–48 hours following exposure to contrast without other identifiable causes of ARF.
The time course of contrast-induced renal failure is predictable. It occurs within 24–48 hours after exposure, with a typical peak creatinine after 3–5 days and a return to baseline or near baseline in 1 to 2 weeks.
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

8. Can we Prevent CIN?
How to prevent CIN?

9. YES we Can!! Or at least try to…
Assess the patient’s risk status before the procedure

10. Scheme to Define CIN Risk Score
Risk Factors
Integer Score
Hypotension 5
IABP 5
CHF 5
Risk Score
Risk of CIN
Risk of
Dialysis
≤ 5
7.5%
0.04%
6 to 10
14.0%
0.12%
11 to 16
26.1%
1.09%
≥ 16
57.3%
12.6%
Age >75 years 4
Anemia 3
Diabetes 3
Calculate
Contrast media volume
1 for each 100 cc3
Serum creatinine > 1.5mg/dl 4
Recently, CIN risk score was developed and validated based on the analysis of large prospectively created database. You may see that risk of CIN may be as high as 57% and risk of dialysis maybe as high as 12% in pts with multiple risk factors. OR
2 for 40 – 60
4 for 20 – 40
6 for < 20
eGFR <60ml/min/1.73 m2
eGFR < 60ml/min/1.73 m2 =
186 x (SCr) x (Age)-0.203
X (0.742 if female) x (1.210
if African American)
Mehran et al. JACC. 2004;44:

11. Tips to Prevent CIN
Assess the patient’s risk status before the procedure
Hydrate all patients as tolerated for as long as possible but at least two- four hours before procedure- may require to bring the patient in the night before for careful/gentle hydration in those with CHF

12. Optimal Hydration 0.9% NS vs 0.45% NS3
0.9% Saline
0.45% Sodium Chloride
P=.04 2
P=.93
Incidence, %
P=.35 1 CN
Mortality
Vascular
Mueller et al Arch Intern Med 2002

13. Sodium Bicarbonate Hydration
p = 0.82
p = 0.97
Brar S, et al. JAMA 2009

14. Create and maintain high urine output
RenalGuardTM for CI-AKI prevention is designed to:
Create and maintain high urine output
Prevent contrast agents from clogging tubules
Limit toxin exposure in kidneys
Automated matched fluid replacement in real-time to reduce side effects associated with over- or under-hydration
We believe PLC’s new technology Renal Guard accomplishes this challenge – High urine flow with matched fluid replacement for C-I-N prevention.
Renal Guard keeps the tubules clear and reduces exposure to contrast toxins through high urine flow. The Renal Guard therapy includes a replacement of fluid volume precisely matched to each patient, ensuring the optimal C-I-N prevention without the risk of over or under-hydration.
US: Investigational device. Limited by Federal Law to investigational use. 23 23

15. MYTHOS Study
Consecutive CKD patients (eGFR<60ml/min/1.73m2) undergoing coronary angiography between September 1, 2008 and September 15, 2010
157 pts
Elective
Procedures
n= 94
Urgent (<24 hrs)
procedures
(NSTEMI)
n= 63
RenalGuard
n=80
Standard i.v. hydration
(1 ml/kg/hr)
for 12 hrs before and
after procedure
n=77
Primary end point: CIN (>0.5 mg/dl or >25% sCr increase during first 72 hrs)
Secondary end points: In-hospital MACE (acute pulmonary edema,
cardiogenic shock, MI, need for RRT, severe arrhythmias, and death)
Bartorelli A. JACC Int

16. Incidence of CIN Controls % RenalGuard 25% -80% -69% 16% -60% 10% 6%
P=0.03
25%
RenalGuard
P=0.028
-80%
-69%
16%
P NS
-60%
10%
Added the patient numbers at the top of each column 6% 5% 4%
All patients
NSTEMI
Elective
procedures 25 25

17. REMEDIAL II REnal Insufficiency Following Contrast MEDIA Administration II TriaL RenalGuard system in high risk patients for contrast induced acute kidney injury
Carlo Briguori, MD, PhD
Laboratoy of Interventional Cardiology
Clinica Mediterranea, Naples - Italy 26

18. Assessed for eligibility (n=806)
Exclusion (n=512)
Not meeting inclusion/exclusion criteria (n=485 )
Refused to partecipate (n=27)
Enrollement
Randomized (n=294)
Patients allocated in the RenalGuard group (n=147)
Received allocated treatment (n=146)
Did not receive the allocated treatment (n=1)
Patients allocated in the Control group (n=147)
Received allocated treatment (n=146)
Did not receive the allocated treatment (n=1)
Allocation
Patients lost at follow-up (n=0)
Discontinued treatment (n=2)
Patients lost at follow-up (n=0)
Discontinued treatement (n=0)
Follow-up
Analysis
Patients analized (n=146)
Patients excluded from analysis (n=0)
Patients analized (n=146)
Patients excluded from analysis (n=0) 27 27

19. Primary endpoint Odds ratio = 0.47; 95% CI= 0.24-0.92 p = 0.025 20.5%
30/146 15
CI-AKI (%)
11% 10
16/146 5
Control group
RenalGuard group

20. A study to evaluate the safety and efficacy of the RenalGuard System when compared with standard care in the prevention of contrast induced nephropathy in the catheterization laboratory RGS001D Version 4.1 – 14 April 2011
© PLC Medical Systems, Inc.

21. STUDY PROCEDURES RENALGUARD RANDOMIZATION CONTROL
Baseline Blood
(prior to therapy)
Foley Cath
RG Match Hydration
Hydration Bolus
(NS mls)
NAC per protocol
Lasix Dose
(0.3 mg/Kg)
Visipaque or Isovue
Additional Lasix
( if needed)
RG Matched Hydration
(for 4 hrs post last administration
of contrast)
Blood Draw/urine post procedure
(2- 4 post last contrast)
Urine output monitoring
( from hour 4 to hour 6)
NAC per site protocol
3 ml/Kg/hr Bicarb
hydration
(x 60 min prior to
cath)
1 ml/Kg/hr Bicarb
1 ml/Kg/hr saline hydration
(for 6 hours post cath)
Patient monitoring
RANDOMIZATION
CONTROL
RENALGUARD
Approx 90 min prior
Approx 60 min prior
During Cath
Post Catheterization
© PLC Medical Systems, Inc, Company Confidential

22. Tips to Prevent CIN
Assess the patient’s risk status before the procedure
Hydrate all patients as tolerated for as long as possible but at least two- four hours before procedure- may require to bring the patient in the night before for careful/gentle hydration in those with CHF
Choose low-osmolar contrast media and monitor the volume

23. CARE
Design
482 patients enrolled between July 2005 and June 2006 in 25 clinical site in North America
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
14 patients withdrew consent
468 assigned to a treatment arm
230 patients assigned to Iopamidol-370
236 patients assigned to Iodixanol-320
26 excluded
26 excluded
204 evaluable patient
210 evaluable patient
Solomon RJ et al. Circulation. 2007;115,3189.

24. CARE
p = 0.39
p = 0.44
p = 0.15

25. Tips to Prevent CIN
Assess the patient’s risk status before the procedure
Hydrate all patients as tolerated for as long as possible but at least two- four hours before procedure- may require to bring the patient in the night before for careful/gentle hydration in those with CHF
Choose low-osmolar contrast media and monitor the volume!!

26. Columbia University CTO Experience N=390
(ml)
Contrast Volume
Min. 43 – Max.1120 ml
P=0.68

27. Tips to Prevent CIN
Assess the patient’s risk status before the procedure
Hydrate all patients as tolerated for as long as possible but at least two- four hours before procedure- may require to bring the patient in the night before for careful/gentle hydration in those with CHF
Choose low-osmolar contrast media and monitor the volume!!
Follow the patient post procedure with repeat creat ( 24 hours, hrs with PMD) and continue hydration for 12 hours

28. Conclusions (1)
CTO procedures are usually in the most complex patients and are the most time consuming and require the largest volume of contrast media than most coronary procedures.
CI- AKI 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
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29. Conclusions (2) Limit contrast agent volume
Hydration pre-PCI (12 hours recommended)
D/C nephrotoxic drugs (NSAIDS, antibiotics, etc)
NO ROLE for n-acetylcysteine !!
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
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