0. Professor of Medicine (Cardiology)
Dye Utilization during CTO Angioplasty: Minimizing, Monitoring and Managing Contrast Induced Nephropathy
Roxana Mehran, MD
Professor of Medicine (Cardiology)
Director, Interventional Cardiovascular Research and Clinical Trials Mount Sinai School of Medicine

1. Roxana Mehran, MD Consulting Fees Abbott Vascular Regado BioSciences
Cardiva Medical, Inc.
Honoraria
Cordis Corporation
The Medicines Company
Grants/Contracted Research
Bristol-Myers Squibb / Sanofi Pharmaceuticals Partnership

2. I intend to reference off label or unapproved uses of drugs or devices in my presentation.

3. Contrast Media During CTO: What are the Issues?
CTO procedures are classified as 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 load 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. 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

5. 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

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

7. YES we Can!! At least try to…
Assess the patient’s risk status before the procedure

8. 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:

9. 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

10. 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

11. MEENA Design Hydration Protocol
353 patients enrolled between January 2006 and January 2007
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
178 patients assigned to sodium bicarbonate
236 patients assigned to sodium chloride
22 excluded
28 excluded
156 evaluable patient
147 evaluable patient
Hydration Protocol
3 mL/kg for 1 hr before the procedure
1.5 mL/kg during and for 4hrs post-procedure
Brar, S et. al., i2/ACC 2007

12. MEENA
p = 0.82
p = 0.97

13. 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

14. N-ACETYLCYSTEINE (NAC)

15. 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 1 ml/kg/h x 24 h
p= 0.01
A prospective randomized trial utilizing the oxygen radical scavenger, acetylcysteine, explored the role of oxidative injury in contrast induced nephropathy. Patients undergoing a contrast CT scan were randomized to usual care or pretreatment with 600 mg bid of acetylcysteine starting 24 hours before the contrast exposure and continuing for 24 hours after the exposure. A marked decrease in the incidence of contrast induced nephropathy (CIN) was noted.
Although the study is very exciting, a number of limitations are worth noting. First, the low dose of contrast and the route of administration (intravenous) make it difficult to extrapolate the positive results to patients receiving 2-3 times as much contrast intraarterially. Second, the marked reduction in the incidence of CIN was associated with an actual decrease in serum creatinine in many patient, a finding difficult to explain based on the presumed mechanism of action of acetylcysteine. Finally, a number of other experiments involving animal models of renal injury have failed to produce such dramatic results using other free oxygen radical scavengers. This may simply mean that animal models don’t mimic human pathophysiology accurately. In any case, until additional studies in other clinical situations confirm the dramatic results found here, it should not be assumed that acetylcysteine is a magic bullet.
Tepel NEJM 2000

16. Relative Risk for Developing CIN after NAC
Review: Acetylcysteine and CIN
Comparison: 01 NAC on CIN
Outcome: 01 CIN
Study or substury
NAC n/N
Control n/N
RR (Random) 95% Cl
Risk Ratio (Random) 95% Cl
Allaqaband et al 8/45 6/ (0.45, 3.12)
Briguori et al 6/92 10/ (0.23, 1.57)
Diaz-Sandoval et al 2/25 13/ (0.04, 0.72)
Durham et al 10/38 9/ (0.55, 2.63)
Goldenberg et al 4/41 3/ (0.30, 5.31)
Gomes et al 8/78 8/ (0.40, 2.53)
Kay et al 4/102 12/ (0.11, 0.96)
Nguyen-Ho et al 9/95 19/ (0.20, 0.89)
Oldemeyer 4/49 3/ (0.30, 5.41)
Pate et al 57/238 50/ (0.82, 1.60)
RAPIDO 2/41 8/ (0.05, 1.05)
Shyu 2/60 15/ (0.03, 0.57)
Fung et al 8/46 6/ (0.49, 3.46)
Total: (95% Cl) (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
0.5 1 2 5 10
Favors treatment
Favors control
Zagler et al. Am Heart J 2006;151:

17. Acetylcysteine for the prevention of Contrast-induced nephropaThy (ACT) Trial:
A Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography
The ACT Trial Investigators
Presenter: Otavio Berwanger (MD; PhD)
Chair - Steering Committe
Sponsor: Ministry of Health-Brazil

18. Concealed Randomization Acetylcysteine 1200mg Matching Placebo
2,308 Patients undergoing an angiographic procedure with at least one of the following risk factors:
Age > 70 years;
Chronic Renal Failure;
Diabetes Mellitus;
Heart Failure or LVEF <0.45;
Shock
ITT
Concealed
Randomization
Acetylcysteine 1200mg
Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure
Matching Placebo
Primary Endpoint: Contrast-induced nephropathy (CIN)
(≥ 25% elevation of serum creatinine above baseline 48h-96h after angiography)
Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of serum creatinine, Side effects

19. Results
Acetylcysteine (N=1172) Placebo (N=1136)
Primary Endpoint

20. Results
Acetylcysteine (N=1172) Placebo (N=1136)
Primary Endpoint

21. Clinical Outcomes at 30 days
Acetylcysteine (N=1172) Placebo (N=1136)
Mortality or need for dialysis

22. Clinical Outcomes at 30 days
Acetylcysteine (N=1172) Placebo (N=1136)
Mortality or need for dialysis

23. Updated Meta-Analysis
All criteria adequate * =
Allocation concealment, double-blind and ITT

24. 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

25. 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 115, (2007)

26. CARE
p = 0.39
p = 0.44
p = 0.15

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!!

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

29. ACIST CVi® Contrast Delivery System

30. Patient Care: Less Contrast Dosage
The use of the ACIST was associated with a 17% to 20% lower average contrast dose per patient.*
- Anne, et al. J Inv Cardiol 2004
{For these next slides, you may want to have the ACIST bibliography readily available as a reference – use the “Selected Publications and Research” brochure, which has the reference listing on the back side. }
* vs traditional hand injection + power injector methods
Anne, et al. J Inv Cardiol 2004

31. Contrast Tracking Information
Contrast Remaining
amount of contrast remaining in the syringe.
Contrast Delivered
running total of the contrast injected during a procedure.
Last Injection
the amount of contrast and the rate of injection for the last injection given.

32. Volume Matters!
76 y.o. female with diabetes, Hgb 11.5 g/dl and eGFR 36 ml/min
CIN risk score is 15 if contrast medium volume is 100 ml
CIN risk is 26%
Dialysis risk is 1%
CIN risk score is >16 if contrast medium volume is 200 ml
CIN risk is 57%
Dialysis risk is 12%

33. 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

34. 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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35. 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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