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Contrast Media Safety
Minimizing the Risk of CIN
Bracco Imaging S.p.A. Symposium
Bulgarian Endovascular Course
2011; 09-11 December
Prof. G. Kirova
TOKUDA Hospital Sofia
Physicochemical Properties of CM
 IODINE CONCENTRATION
 CHEMICAL COMPOSITION
Ionic vs Non-ionic
 Monomer vs Dimer

 OSMOLALITY

The lower osmolality of a CM
is, the better its safety profile is
 VISCOSITY
Iodine Concentration
 Milligrams of iodine per milliliters of solution (mgI/ml)
 Provides delivery of an amount of iodine flux in a given period of
time
 Higher Iodine concentration:
 results in markedly improved imaging performance owing to greater
contrast enhancement
 achieves increased iodine delivery at an equivalent injection rate over a
shorter injection time
 improves SNR when critical (e.g. obese patients)
 allows a reduced radiation dose by reducing the voltage required
Iomeron is readily available in a wide variety of Iodine concentrations and volumes for
clinical use; Iomeron 400 is the contrast medium with the highest concentration
available on the market
Bulgarian Endovascular Course 2011
Osmolality
 The number of dissolving particles in a body of solution (mOsm/kg of
water) – high, low, iso
 Low osmolality is a desierable feature for a non-ionic contrast media
 What does this mean?





Less heat & pain
Less fluid shifts
Less hypervolaemic burden
Less effect on blood-brain-barrier
Less deformation of erythrocytes
Compared to all other monomeric CM, Iomeprol possesses the lowest osmolality at
given concentrations
According SPCs of the products
 The resistance of fluid to flow. It is
Viscosity
defined as the force needed to move
water one centimeter (Centipoises,
cP) at 20 degrees C
 Low viscosity is a desiderable
feature for a non-ionic contrast
media




Viscosity is a feature of the final solution
Viscosity determines the resistance of a
fluid to flow
Lower viscosity requires lower pressure to
push a CM through needles and catheters
Viscosity is dependent on
> temperature (pre-heat prior to
injection!)
> CM concentration
> CM molecular structure (dimeric or
monomeric)
Compared to all other non-ionic CM, Iomeprol shows the lowest viscosity at all
concentration
According SPCs of the products
The Ideal Contrast Medium
Molecular Features
Finished Product Features
– Electrically neutral (no
charge)
– Small (low molecular
mass)
– High water solubility
– High hydrophilicity
– Low molecular toxicity
– Low neurotoxicity
– Low osmolality
– Low viscosity
– Sufficient levels of iodine
(concentration)
– Low incidence of reactions
– Low nephrotoxicity
– Broad range of indications
– Minimum presence of
additives in the solution
CM Safety
Bulgarian Endovascular Course 2011
Contrast Media Safety
 Among the safest of all medications
 Adverse events
 Minor: 0.5−5%
 Severe: <0.5% (dyspnea, sudden drop of blood pressure, cardiac arrest,
loss of consciousness)
 Fatal: <1/130,000
 Prevention: not possible for severe Adverse Events (AEs)
 Patients who have had a DAE to an iodinated contrast are
1.7- 3.3 times more likely to have another one
Katayama H.et al; Radiology 1991;178: 363-367
.
General Safety
 The high safety and tolerability of non-ionics has been
clearly demonstrated by numerous clinical studies
 In a large multicentre study on 1918 patients
(Katayama 1994), using all available concentration of
Iomeprol:
 133 patients (5.3%) experienced one or more adverse events,
which were mainly mild or moderate in intensity
 The most frequently reported adverse event was nausea
 The frequency of all other adverse events was less than 1%
Katayama H. Et al; Eur J Radiol 1994; 18;115-119
Schmiedel E ;Eur J. of Radiology 1994; 18 104-108
.
Delayed Adverse Reactions (DAE)
 The literature shows that
non-ionic dimers, such as
iodixanol & iotrolan, are
associated with a higher rate
of DAEs than non-ionic
monomers
 In two separate studies, the
incidence of DAEs with
iodixanol was 3.5-4 times
higher than two widely used
non-ionic monomers
Sutton AGC. Et al; The Journal of Invasive Cardiology
2003;15;133-138
Sutton AGC et al; American Heart Journal, April 2001;141:
677-683
Frequency of the side effects
 Potential risk factors
 Allergic predisposition (22%)



Allergy to foodstuffs
Hypersensitivity to inhalant allergens
Hypersensitivity to CM
 Cardiovascular diseases (45%)
 Kidney diseases (15%)
 High-dose of CM
 Geriatric patients
 Side effects are generally expected to be more frequently
with certain methods of examination (8% for cerebral
angiography)
Bulgarian Endovascular Course 2011
Contrast Induced Nephropathy
“ an acute impairment of renal function that follows an
exposure to radiographic contrast materials, and for which
alternative etiologies for the renal impairment have been
excluded”
Berkseth RO, Kellstrand CM. Medical Clinics of North America.Vol 65. No 2, 1984
CIN - Background
 Contrast
induced nephropathy (CIN) is a common
complication of percutaneous coronary interventions (PCI)
characterized by acute deterioration of renal function after
exposure to contrast media
 CIN is associated with increase morbidity, mortality and
cost after PCI
 Preexisting renal disease with elevated serum creatinine is
unquestionably the most important risk factor in the
development of CIN
Lindsay J. Am J Cardiol. 2004;94:786-789.
Nikolsky E. Am J Cardiol. 2004;94(3):300-305.
Increased creatinine levels
Nephropathy is measured by increase in serum creatinine
within 48-72 hours of contrast exposure.
SCr (Relative) ↑ by ≥ 25%
OR
SCr (Absolute) ↑ by ≥ 0.5mg/dL
From baseline
serum creatinine
Levy EM, et al; JAMA 1996
Effect of baseline Creatitinine
on the frequency of contrastinduced nephropathy after
percutaneous coronary
interventions
Clavijo et al,WHC; AHA-2005
Comparison within groups
* p <0.001 <1.2 vs. ≥ 1.2 mg/dL
CM Volume
 Contrast volumes in excess of
JR Brown et al; Circ Cardiovasc Interv; 2010;3:346
Bulgarian Endovascular Course 2011
the max. allowable contrast
dose threshold linearly increase
the risk for CIN, whereas
contrast volumes below the
threshold hold to a lower
plateau risk of CIN
 Exceeding the max. allowable
contrast dose threshold is
associated with an increased
risk of CIN regardless of
baseline renal function
 Repeated exposure to CM within
72h is associated with an
increase risk of CIN
• Requires ~120 cc contrast
• Timing of second contrast
•Minimum 72 hrs
•Ideally 3-4 weeks
100% CX
100% CX
 Increased N of pts
exposured to iodinated
CM
Circumflex
 800% increase of CT
 390% increase of cardiac
catheterizations
In-hospital Death (%)
CIN and in Hospital Mortality
ARF + Dialysis
35.7%
 Prolonged hospital stay,
increase cost
ARF
7.1%
No ARF
 in-hospital mortality rate
1.1%
0%
10%
20%
McCullough et al. Am J Med 1997; 103-375
Bulgarian Endovascular Course 2011
30%
40%
of 34%
 In-hospital mortality rate
in cases of renal failure
and renal replacement
therapy 62%
Pathophysiology of CIN
 Renal hemodynamic changes (vasoconstriction)
 Direct tubular toxicity of the CM
 Contrast induces a biphasic haemodynamic change in
the kidney
 Initial transient increase
 Followed by prolonged decrease in renal blood flow
 Histologically - cell injury after administration of
contrast media, vacuolisation of renal tubules
Barrett BJ: Contrast nephrotoxicity. J. Am Soc Nephrol 5: 125-137, 1994
Risk Factors for CIN
 Established
 Dehydration
 Pre-existing renal failure
 Diabetes Mellitus
 Large contrast volume
 Repeat contrast in <48
hours
 Class III / IV congestive
heart failure
 Multiple myeloma
 Probable
 Age > 70 yrs
 Concomitant use of loop
diuretics
 Concurrent administration
of drugs which are
nephrotoxic or produce
intra-renal
vasoconstriction.
 Type of Contrast Media
Risk scores for prediction of CIN
Diabetes - any Tx
Age over 70
Multiple vessels treated
Female
IABP use
Acute coronary syndrome
% CIN
SVG treated
60
50
40
30
20
10
0
P<0.0001 χ2 by trend
0 or 1
CrCl < 50 cc/min
•9639 patients
•Multivariate predictors chosen by backward logistic
regression with a entry/leave criteria of 0.1
Mehran et al, JACC 2004
2
3
4
Risk Score
5
6
7 or 8
Contrast Induced Nephropathy (CIN)
 CIN incidence is strongly correlated with the use of large volume of contrast in
renally impaired patients
 Iopamidol and Iomeprol profile in at risk patients has been extensively studied
in CT and Cath Lab:
 In CT procedures:



IMPACT Study
PREDICT Study
ACTIVE + IMPACT Study
 In Cath Lab procedures:




CARE Study
CARE Follow-Up Study
NEPHRIC II
ACC Guidelines
The CARE Study
 Multicenter, randomized, double-blind, parallel group
comparison of Iopamidol 370 and Iodixanol 320 in
diagnostic and interventional cardiac angiography
 414 patients with pre-existing moderate-to-severe chronic
kidney disease undergoing Cath Lab procedures
 Primary CIN end point
 Defined as an absolute increase in SCr ≥ 0.5 mg/dL from baseline to 48 -120
hours after contrast media administration
 Secondary CIN end points
 Incidence of a postdose ≥ 25% increase in SCr
 Incidence of a postdose decrease in eGFR ≥ 25% from baseline
Thomsen HS, Morcos SK, Erley CM, Grazioli L Bonomo, L Ni
Z, Romano L, Investigators Investigative Radiology, pp 170178, Vol. 43 n.3, March 2008
The CARE Study
CIN Rates
TOTAL STUDY POPULATION (N=414)
Postdose Incidence
Iopamidol 370
Group
( N = 204 )
iodixanol 320
Group
( N = 210 )
pValue
Serum creatinine increase > 0.5
mg/dL
9 (4.4%)
14 (6.7%)
“The rate of CIN in high-risk
patients
who0.39undergo
20 (9.8%)
26 (12.4%)
0.44
Serum
creatinine increase
> 25%
cardiac
angiography
or percutaneous
coronary
12 (5.9%)
21 (10.0%)
Estimated GFR decrease > 25%
intervention is not statistically
different 0.15
between
SUBGROUP POPULATION
use of
iopamidol-370
or iodixanol-320.
Therefore,
PATIENTS
WITH
DIABETES AND RENAL IMPAIRMENT
(N=170)
Iopamidol
370
Iodixanol
320 as safely as
iopamidol-370
may
be
used
at
least
pPostdose Incidence
Group
Group
Value
( N = 78high-risk
)
( N clinical
= 92 )
iodixanol-320 in this
setting”
Serum creatinine increase > 0.5
mg/dL
4 (5.1%)
12 (13.0%)
0.11
Serum creatinine increase > 25%
8 (10.3%)
14 (15.2%)
0.37
Estimated GFR decrease > 25%
5 (6.4%)
12 (13.0%)
0.20
Thomsen HS, Investigators Investigative Radiology, pp 170178, Vol. 43 n.3, March 2008
The CARE Follow-Up Study
 Determines comparative ≥1-year adverse events in patients
with and without CIN
 Determines comparative ≥1-year adverse events in patients
with CIN following iodixanol 320 or Iopamidol 370
 Pts undergoing Cath Lab procedures (coronary
angiography, CABG, other revascularization procedures)
 Cystatin C as a better marker for GFR than serum
creatinine: higher sensitivity to detect a reduced GFR than
creatinine determination
Solomon RJ, Mehran R, Natarajan MK, Doucet S, Katholi RE,
Staniloae CS, Sharma SK, Labinaz M, Gelormini JL, Barrett BJ
Clin. J. American Society Nephrology 4/7: pp 1162-1169
2009
The CARE Follow-Up Study
Results: Adverse Events Incidence and CIN
COMPARISON OF INCIDENCE OF ALL EVENTS BETWEEN PATIENTS (N=294) WITH
POSTCONTRAST CIN AND PATIENTS WITHOUT CIN*
Overall CIN Incidence
(%)
SCysC increase  15%
Endpoint
All AEs
CIN Group
Non-CIN
Group
p**
24.8
25/60 (42%)
47/182 (26%)
0.02
SCysC increase  20%
19.4
20/47 (43%)
52/195 (27%)
0.03
SCysC increase  25%
16.1
18/39 (46%)
54/203 (27%)
0.01
SCr increase  0.3 mg/dl
17.3
22/51 (43%)
70/243 (29%)
0.04
* AE,
** P
adverse event
value from c 2 test
Solomon RJ. et al. Clin J Am Soc Nephrol 2009; 4: 1162–
1169
SCr increase of ≥ 0.3 ml/dl and S CystatynC increases ≥ 15%, 20% and 25%
from baseline are associated with a higher rate of long term adverse events
Solomon RJ, Mehran R, Natarajan MK, Doucet S, Katholi RE,
Staniloae CS, Sharma SK, Labinaz M, Gelormini JL, Barrett BJ
Clin. J. American Society Nephrology 4/7: pp 1162-1169
2009
The CARE Follow-Up Study
Results: Adverse Events and Type of Contrast Medium
COMPARISON OF THE INCIDENCE OF ALL AND MAJOR AES BEETWEEN TREATMENTS
(IOPAMIDOL VERSUS IODIXANOL)*
AEs
Total
( n = 294 )
Iopamidol Group
( n = 145 )
Iodixanol Group
( n = 149 )
All Events
92 (31%)
39 (27%)
53 (36%)
No. of events
120
48
72
Person-time of follow-up (yr)
387
198
189
Patients with events (n[%])
Major Events ***
38 (13%)
16 (11%)
22 (15%)
No. of events
45
17
28
Person-time of follow-up (yr)
387
198
189
Patients with events (n[%])
* IRR, comparing iodixanol and iopamidol from Poisson regression model.
** P value from Poisson regression analysis
***Major events: Death, stroke, myocardial infarction, and ESRD requiring dialysis.
IRR (95% CI)
p**
18 (1.1 to 3.0)
0.016
3.2 (1.2 to 8.9)
0.024
The use of iodixanol is associated with a two- to three-fold increase in the
incidence of long term adverse events
Solomon RJ, Clin. J. American Society Nephrology 4/7: 1162-1169; 2009
Take Home Messages
 The CARE Follow-Up Study is a landmark study
 Confirms the link between CIN and a negative long-term prognostic
implications (measured by MACE)
 Confirms that Iopamidol has a statistically lower rate of MACEs
compared to iodixanol
 The CARE results are supported by numerous head-to-
head studies and several published meta-analysis
American College of Cardiology
Guidelines - 2009
 Recently, American College of Cardiology (ACC) has revised its
guidelines with respect to the administration of CM for Percutaneous
Coronary Intervention (PCI) in patients with chronic kidney disease
 After a thorough review of the more recent data available since mid
2007, the authors conclude that:
RECOMMENDATION FOR ANGIOGRAPHY IN PATIENTS WITH CHRONIC KIDNEY DISEASE
2004/2005/2007 Recommendation:2007 PCI
Guidelines Update, Table 9
2009 PCI
Focused Update
Recommendation
“In patients with chronic kidney
disease
undergoing
angiography who are not undergoing
dialysis,
either
“In patients withchronic
chronic kidney
disease undergoing
who are not undergoing chronic dialysis,
an kidney
isosmolar
contrast
mediumangiography
(Level
of evidence: A) or a low“In chonic
disease patients
undergoing
either an isosmolar contrast medium (Level of
angiography, isosmolar contrast agents are indicated
Evidence: A) or a low-molecular-weight contrast
molecular-weight
and are preferred
(Level of Evidence: A)”contrast medium other than Ioxaglate or
medium other than Ioxaglate or Iohexol is indicated
Iohexol is indicated (Level
of evidence:
B)”
(Level of Evidence:
B) “
Kushner FG. Et al.
Journal of the American Heart Association: Circulation,
Volume 120 n.22, pp 2271-2306, December 2009
CIN and key steps for prevention
 Before the procedure
 During the procedure
 Post procedure
Bulgarian Endovascular Course 2011
29
BEFORE THE PROCEDURE
Focus on patient!
 Identify patients at risk:
 Renal Insufficiency


Calculate estimated creatinine clearance (<60 mL/min)
Serum creatinine >1.2 mg/dL
 Diabetes Mellitus; Metabolic Syndrome

Patients with the metabolic syndrome are at increase risk of
developing CIN after percutaneous coronary interventions
Patients in end-stage renal disease who have no remaining natural renal
function are no longer at risk for CIN and may receive LOCM or IOCM
NIDDM
BEFORE THE PROCEDURE
Check patient’s medical history!
 Consider alternative modalities not requiring the CM
administration
 Cease nephrotoxic drugs 24h pre and post examination
 Stop administration of diuretics
 Cease administration of Metformin for 48h following the
examination
 Check for recent Exposure to Contrast Media
IDDM
BEFORE THE PROCEDURE
The optimal hydration regimen to prevent CIN is
unclear at this time
NS (12 + 12 hr)
vs.
Sodium Bicarbonate (2 + 4hr)
vs.
Rapid intra-arterial 5% Dextrose (5 min)
HYDRATE !!!!
DURING THE PROCEDURE
Focus on the procedure!
 Use low or isoosmolar contrast agent
 Limit the dose of contrast to the minimum needed
to obtain diagnostic images
 Avoid hypotension
 Minimize renal cholesterol microembolization
 Know when to stop
POST PROCEDURE
Focus on patient’s care!
 Maintain adequate hydration
 Avoid secondary contrast exposure (at least 72
hrs; ideally 2-3 weeks)
 Monitor renal function (24-72 hrs; peak 7th day)
 Early renal consultation
Thank You For Your Attention
Bulgarian Endovascular Course 2011