Transcript Hexabrix - Guerbet

HEXABRIX
Hexabrix
clinical studies
and the renal function
Philippe HAVARD
J-P Barraud
Why do we care about the kidneys ?
Hexabrix US training 2008 part3
The Nephron
Cortex
Outer Medulla
(outer and inner stripes)
Inner Medulla
Hexabrix US training 2008 part3
The Renal Function
Normal human kidneys
receive
circa 1700 liters of
blood/day

900 liters of plasma

circa 180 liters/day
cross Bowman's
capsule

only 1-1.5 liter/day is
excreted
Hexabrix US training 2008 part3
Target = the Medulla
Oxygen Consumption / Oxygen Supply Ratio
Kidney
8%
Skin
15%
Brain
34%
Skeletal Muscle
34%
Heart
65%
Renal Outer Medulla
79%
Brezis M et al, in "The Kidney", 4th edition, Brenner BM, Rector FC eds, WB Saunders, 1991
Hexabrix US training 2008 part3
ACUTE RENAL FAILURE
Deterioration of renal function
over a period of hours to days, resulting in the
failure to excrete nitrogenous waste products
and to maintain fluid and electrolyte homeostasis
Brezis M et al. The Kidney. Brenner and Rector, eds. WB Saunders Co, 1991
Hexabrix US training 2008 part3
Complexity and Accuracy of
Various Measures of Renal Function
Scale of the State University of New York Medical School (0 to 5)
Procedure
Complexity
Accuracy
Inulin clearance
5
5
Isotope clearance
4
4
Creatinine clearance
3
3
Plasma
disappearance
(isotope or other)
3
3
Serum creatinine
level
1
2
Blood urea nitrogen
1
0.5
Hexabrix US training 2008 part3
Becker JA, Radiology, 1991;179:337-338
SERUM CREATININE
Normal Values:
•Adult: 70 – 100 µmol/l (0.8 – 1.1 mg/dl)
•Newborn: 25 – 30 µmol/l (0.30 – 0.35 mg/dl)
•Children < 5 years: 35 – 44 µmol/l (0.4 – 0.5 mg/dl)
Hexabrix US training 2008 part3
SERUM CREATININE does not reflect abnormal renal
Serum creatinine concentration
(mg/100ml)
function until after GFR has been reduced to at least 50% of baseline
20
Relationship between GFR and serum
creatinine concentration.
15
Representative changes (arrow 1)
and in acute or chronic renal failure (arrow 2)
10

5

0
0
25
50
75
100
GFR = Glomerular Filtration Rate (% of Normal)
Hexabrix US training 2008 part3
Creatinine Clearance
Normal Values: > 80 ml/min
But its measurement is
difficult
and lengthy (24hrs)
Hexabrix US training 2008 part3
A useful estimate of Creatinine Clearance
without the need of collecting 24 hrs Urine
The Nephron Information Center
Calculator available at: ttp://www.nephron.com/preESRDcalc.html
Hexabrix US training 2008 part3
Two patients with same serum
creatinine level = 110 µmol/l (1.2 mg/dl)
Patient A: man, 30 years old, 90 kg
 Creatinine clearance = 110 ml/mn
Patient B: woman, 80 years old, 65 kg
 Creatinine clearance = 40 ml/mn
Hexabrix US training 2008 part3
The MDRD Equation (Modification of
Diet in Renal Disease study group) …
… for the calculation of the glomerular fitration rate:
GFR = 170 (Scr)-0.999 * (Age)-0.176 * (BUN)-0.17 * Albumin)0.318 * [0.762 if
patient is female] * [1.180 if patient is black]
Levey AS et al. Ann Intern Med 1999; 130: 461-470
Calculator available at: http://medcalc3000.com/GFREstimate.htm
Hexabrix US training 2008 part3
Contrast medium-induced acute renal failure,
aka Contrast Induced Nephropathy (CIN): Definition(s)
Lack of consensus  difficulty in comparing the incidences
• Proportional rise in serum creatinine
- 25%
- 50% over baseline
• Absolute rise in serum creatinine
•By 0.5 mg/dl (44.2 µmol/l)
•By 1.0 mg/dl (88.4 µmol/l)
• etc.
• Combination of the two
• Few studies with creatinine clearance test
• One to 5 days after contrast exposure
Hexabrix US training 2008 part3
ARF IIo to contrast (CIN) & In-Hospital Mortality
50
40
Odds ratio of dying = 5.5
after adjustement of comorbid conditions
30
34 %
20
10
7%
0
No ARF
ARF
183 pts with ARF vs. 174 paired subjects matched for age and
SCr, from 16,248 pts who underwent contrast procedures
Subjects who died: sepsis, bleeding, delirium, respiratory failure, etc.
Deaths from renal causes were rare
Hexabrix US training 2008 part3
Levy et al JAMA 1996; 245: 1489-1494
Contrast Nephropathy after PCI
Cumulative 1-Year Mortality
40%
37%
33.5%
30%
20%
10%
15%
16.5%
18%
0-10%
10-25%
0%
Change
25-50%
<0%
>50%
% Increase in Serum Creatinine
Gruberg et al. JACC 2000; 36: 1542-1548
Hexabrix US training 2008 part3
Change
1-Year Event-free Survival in patients with
pre-existent chronic renal insufficiency
Clinical Outcome
P<0.001
Event-Free Survival
100%
86%
80%
60%
62%
40%
20%
Renal function deterioration
No increase in creatinine
0%
0
1
2
Hexabrix US training 2008 part3
3
4
5
6
7
Time (Months)
8
9
Gruberg et al. JACC 2000; 36: 1542-1548
10
11
12
Meta-analysis of contrast induced nephrotoxicity:
high versus low osmolar contrast media
39 trials – 5146 patients
CIN in 7% of all patients
CIN in 30% of chronic renal
function impaired (CRI) patients
0.8
Relative risk of CIN
Contrast induced nephropathy
(CIN): Serum creatinine increase
> 0.5 mg/dl after administration
of contrast media
1
0.6
0.4
0.2
0
High Osm
Barret BJ, Carlisle EJ J Am Soc Nephrol 92
Barret BJ, Carlisle EJ Radiology 1993;188:171-178
Hexabrix US training 2008 part3
Low Osm
Meta-analysis of the relative
nephrotoxicity of HOCM and LOCM
On average, LOCM cause a statistically
significant smaller decline in renal function than
HOCM
A larger difference is observed in patients with
pre-existing renal failure
«The available data suggest that ioxaglate may
reduce the risk of contrast nephropathy to at least
the same extent as occurs with non-ionic LOCM »
Barret BJ, Carlisle EJ Radiology 1993;188:171-178
Hexabrix US training 2008 part3
No difference between Hexabrix® and
Visipaque in non-at-risk patients referred for
cardio-angiography
Creatinine
clearance
(ml/min)
Baseline
- 24 – 0 h
0 – 24 h
24 – 48 h
Visipaque
( n=34)
93 + 34
82 + 35*
96 + 30
(- 12%)
(+ 3%)
Hexabrix®
( n=38)
85 + 29
78 + 19
86 + 34
(- 8%)
(+ 1%)
*p < 0.05 versus baseline
No significant difference on SCr, urinary enzymes, albumin excretion and
2-microglobulin release. One patient in each group with decrease
in GFR > 25% (reversible in both cases)
Hexabrix US training 2008 part3
Andersen PE et al. Clin Radiol 1993; 48: 268-272
Hexabrix® versus non-ionic monomers
Prospective, randomized, double-blind comparison of Hexabrix®, Omnipaque
(iohexol) and Isovue (iopamidol) in 478 patients who underwent peripheral
angiography (252 IA and 226 IV) during a 6-month period
Mean increase in SCR
(µmol/l) (72 hours)
N patients
Hexabrix®
13.2
161
Omnipaque
22.1
158
Iopamiron
19.4
159
«Ioxaglate was consistently the least nephrotoxic of the three agents»
For all CM, mean Serum Creatinine increase:
IA: 20.54 µmol/L,
IV: 14.57 µmol/L,
Non-renal failure: 10.53 µmol/l
Renal failure: 40.45 µmol/l,
Campbell DR et al. J Can Assoc Radiol 1990;41:133-137
Hexabrix US training 2008 part3
p = 0.08
p < 0.001
NEPHRIC Trial
126 diabetic patients with mild renal insufficiency.
Randomized Baseline SCr: 1.5 and 1.6 mg/dl
Peak increase (J0 to J 3)
Iodixanol
Iohexol
n = 62
n = 64
Mean (mg/dl)
0.13 + 0.22
0.55+ 0.98
Minimum
0.08
0.36
Maximum
0.18
0.85
Aspelin P et al. NEJM 2003; 348: 491-499
Hexabrix US training 2008 part3
NEPHRIC Trial
ARF Criteria
Contrast Medium
N (Patients)
2
Iodixanol
Peak > 0.5 mg/dl
Iohexol
16
Iodixanol
0
Iohexol
9
Peak > 1.0 mg/dl
Aspelin P et al. NEJM 2003; 348: 491-499
Hexabrix US training 2008 part3
NEPHRIC Trial: Editorial
"Although the results of the study by Aspelin are encouraging,
one should not conclude that iodixanol is the answer to contrastagent-induced acute renal dysfunction"
"Yet, since previous clinical studies have yielded conflicting
results, there is a reason to believe that future studies of
iodixanol may provide conflicting data as well"
Carl M Sandler
Univ of Texas Houston Medical School
New Engl J Med 2003; 348: 551-553
Note:the conclusions of further studies disagreed with the results of NEPHRIC;
VALOR (vs Optiray), CARE (vs Isovue),
CONTRAST (vs IOMERON), RECOVER (vs Hexabrix), ICON (vs Hexabrix)….
Hexabrix US training 2008 part3
RECOVER: NEPHRIC CONFIRMED ?
Hexabrix US training 2008 part3
RECOVER: Summary
Prospective & Randomized single center clinical trial in Korea comparing
Hexabrix 320 vs. Visipaque 320
Patients with Renal Insufficiency (CrCl < 60 ml/min) undergoing coronary
angiography with or without percutaneous coronary intervention
Hydration: 1 ml/kg/h of half diluted saline at least 8 hours before and after
procedure
Primary endpoint: Contrast Induced Nephropathy (relative increase in
SCr from baseline > 25% OR absolute increase of > 0.5 mg/dl [44.2 µmol/]
during day 1 and 2
Secondary endpoints:
Proportion of patients showing an increase in SCr > 0.5 mg/dl [44.2
µmol/] or > 1 mg/dl [88.4 µmol/]
Mean peak increase in serum creatinine
Conclusion: Iodixanol less nephrotoxic than ioxaglate in patients wih
renal impairment undergoing coronary angiography.
Hexabrix US training 2008 part3
Jo SH et al., JACC, 2006, vol 48, n°5.
RECOVER does not «confirm »
the general conclusion of NEPHRIC
Criteria used in NEPHRIC and RECOVER: increase in SCr > 0.5 mg/dl [44.2 µmol/] within 3 days
Signicant Difference: p = 0,002
30
26
25
% Patients
Visipaque
(Iocm)
20
15
Not Significant
Hexabrix
(Locm)
8,9
10
3,6
5
3
Omnipaque
(Locm)
0
RECOVER
Jo SH et al., JACC, 2006, vol 48, n°5.
Hexabrix US training 2008 part3
NEPHRIC
Aspelin P. et al., NEJM, 2003, VOL. 348, NO.6
RECOVER: Primary endpoint
CIN : Relative increase in SCr from baseline > 25% OR absolute increase of >
0.5 mg/dl [44.2 µmol/] during days 1 and 2
Significant difference of CIN, BUT difference of age !
P = 0.010
No difference of ARF !
70
60
50
40
30
Visipaque
P = 0.021
20
Not Significant
Hexabrix
10
0
Primary
endpoint:
% CIN
Hexabrix US training 2008 part3
Age of
patients
(years)
= Acute renal failure
(Number of requiring hemodyalisis
ARF
patients)
Jo SH et al., JACC, 2006, vol 48, n°5.
RECOVER: Our conclusions
Differences between Visipaque and Hexabrix
Observed according to the primary endpoint
Which can be explained
 by the setting (1/2 isotonic saline)
 by the age of the patient groups.
No difference between Visipaque and Hexabrix
observed according
to the secondary endpoints
to the number of patients requiring hemodyalisis
RECOVER does not confirm NEPHRIC !
Hexabrix US training 2008 part3
ICON: Study Overview
Multi-center, double-blinded, randomized pilot study
Patients with stable chronic renal failure undergoing
percutaneous coronary diagnostic or interventional
procedures using contrast media
Study Goal:
To compare the nephrotoxicity of the ionic, lowosmolar contrast agent ioxaglate (Hexabrix 320)
with the nonionic, isosmolar contrast agent
iodixanol (Visipaque 320)
Mehran R, TCT 2006
Hexabrix US training 2008 part3
The ICON Trial (CRF NY)
145 patients
with renal insufficiency undergoing angiography
Hydrate
Randomize
Ioxaglate
Iodixanol
n=74 Double Blind N=71
Primary endpoint
Peak Increase in Serum Creatinine from Day 0- 3
Hexabrix US training 2008 part3
Mehran R, TCT 2006
Secondary Endpoints
Frequency of peak increase in creatinine
serum concentrations of ≥ 0.50 mg/dL from
baseline
Frequency of peak increase of ≥ 1 mg/dL from
baseline
Frequency of peak increase of ≥ 0.50 mg/dL or
≥ 25% from baseline
Mehran R, TCT 2006
Hexabrix US training 2008 part3
Demographics
ioxaglate
(N=74)
iodixanol
(N=71)
p value
71.3 ± 12.3
71.5 ± 9.9
0.89
Female gender
12.2 %
12.7 %
1.00
History of CAD
78.4 %
76.1 %
0.84
Stable Angina
25.7 %
39.4 %
0.11
Unstable Angina
32.4 %
29.6 %
0.72
Prior MI
39.2 %
43.7 %
0.62
Prior CABG
25.7 %
35.2 %
0.28
Prior PCI
38.4 %
50.7 %
0.18
History of Smoking
51.4 %
70.4 %
0.03
Peripheral Vasc Disease
20.3 %
32.4 %
0.13
CVA (Stroke or TIA)
13.5 %
21.1 %
0.27
Cr Clearance cc/min
46±19
45±14
0.65
49.27 ± 12.24
51.16 ± 11.98
0.37
Age
LV Ejection Fraction (%)
Hexabrix US training 2008 part3
Mehran R, TCT 2006
Demographics
Ioxaglate
(N=74)
Iodixanol
(N=71)
p
Hypertension
86.5 %
88.7 %
0.80
Hyperlipidemia
78.4 %
85.9 %
0.28
Diabetes Mellitus
40.5 %
50.7 %
0.25
Insulin Controlled
16.2 %
14.1 %
0.82
Prior Expo. To Contrast
74.3 %
74.6 %
1.00
Previous CIN
1.4 %
2.8 %
0.61
Mehran R, TCT 2006
Hexabrix US training 2008 part3
Serial Change of Creatinine
mg/dL
Ioxaglate
Iodixanol
4,0
P=0.25
P=0.86
P=0.62
P=0.38
3,0
1,93
2,0
1,86
1,80
1,80
1,79
1,89
2,13
1,99
1,0
Baseline
12 Hours
24 Hours
Mehran R, TCT 2006
Hexabrix US training 2008 part3
48-72 Hours
Summary
The ICON study included very complex patients, susceptible to CIN,
with high rates of diabetes mellitus (46%), hypertension (82%), and
CHF (26%), undergoing PCI in 72% of cases (average contrast dose
>200cc).
The two groups had similar baseline demographics, received similarly
large contrast load and were treated with similar procedures and
adjunctive medications.
To protect from CIN, n-AC was used in 72% of patients and mean 3.7L
of hydration were given to patients.
During the catheterization, more than half of patients (51% in Ioxaglate
group and 56% in Iodixanol group) received ≥ 200cc of contrast
agents.
Hexabrix US training 2008 part3
Mehran R, TCT 2006
Conclusions of ICON
As compared to ioxaglate, iodixanol was not associated with a
significant reduction of serum creatinine increase after coronary
catheterization or PCI (primary end point of this study), in patients with
Chronic Kidney Disease.
The incidence of creatinine increase of absolute 0.5mg/dL or relative
25% was not significantly different between the two groups.
A similar efficacy regarding the change of creatinine was consistently
observed between the two groups, independent from the presence of
diabetes mellitus or the volume of contrast media used.
Hexabrix US training 2008 part3
Mehran R, TCT 2006
The Swedish Registers Study
Hexabrix US training 2008 part3
The Swedish Registries: a series of oral
presentations and one publication
Methodology (Lagerqvist et al. ESC 2005)
Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
from all centres performing PCI and/or coronary angiography in Sweden
Questionnaire sent to all centres regarding type and amount of CM used,
time point of starting with this CM and what CM they changed from.
In 2002: 4 centers were using ioxaglate, 10 iodixanol and none iohexol
During the period where the 3 CM were in use (1990-2002), a total of 52,526
patients were treated w/ PCI and/or coronary angiography
(Ioxaglate: 22,294 pts, Iodixanol: 24,085 pts and Iohexol: 6,147 pts)
Diagnosis of renal insufficiency: Hospital Discharge Register
Definition of renal insufficiency: ICD-9 and ICD-10
Lagerqvist et al. ESC 2005
Persson et al. CIRSE, 2005
Liss et al. ECR 2006 Published in Kidney International 2006
Hexabrix US training 2008 part3
Background Characteristics
Variable
Ioxaglate
(Hexabrix)
Iodixanol
(Visipaque)
Iohexol
(Omnipaque)
P-value
N
22,294
24,085
6,147
Age
63.8 +10.6
64.2 + 11.2
62.3 + 10.6
< 0.001
Female gender
(%)
30.8
30.2
28.4
< 0.001
Previous PCI (or
angio) (%)
25.1
33.1
24.9
< 0.001
Indication
STEMI
Unstable CAD (%)
Stable CAD (%)
Other (%)
< 0.001
5.3
35.2
44.4
15.1
9.5
41.4
36.3
12.8
6.3
26.9
56.1
10.7
PCI (%)
48.4
56.7
62.1
< 0.001
Previous renal
failure (%)
0.80
1.29
0.78
< 0.001
Hexabrix US training 2008 part3
Lagerqvist B. et al. ESC 2005
Rehospitalizations w/Renal Failure Diagnosis
Variable
Ioxaglate
(Hexabrix)
Iodixanol
(Visipaque)
Iohexol
(Omnipaque)
N patients
22,294
24,085
6,147
43 (0.2%)
125 (0.6%)
200 (0.9%)
79 (0.3%)
269 (1.1%)
428 (1.8%)
5 (0.1%)
35 (0.6%)
61 (1.0%)
< 0.001
< 0.001
< 0.001
4 (0.02%)
19 (0.1%)
36 (0.2%)
9 (0.04%)
52 (0.2%)
87 (0.4%)
2 (0.03%)
8 (0.1%)
15 (0.2%)
ns
< 0.001
< 0.001
Main or
secondary
diagnosis
Within 1 week
Within 3 months
Within 1 year
P-value
Main diagnosis
Within 1 week
Within 3 months
Within 1 year
Lagerqvist B. et al. ESC 2005
Hexabrix US training 2008 part3
Multivariate Analysis of the Risk of Rehospitalization with a
Renal Failure Diagnosis Compared to the Risk w/Iodixanol
(compensated for the co-factors and stratified to the year of procedure)
Renal Failure
Diagnosis
N patients *
Hazard ratio
95% CI
P-value
vs. Iodixanol
22,428
21,074
5,148
1
0.62
0.70
(0.52 – 0.74)
(0.54 – 0.91)
< 0.001
< 0.001
22,428
21,074
5,148
1
0.60
0.64
(0.41 – 0.89)
(0.37 – 1.12)
0.011
0.12 (NS)
Main or Secondary
Diagnosis
Iodixanol
Ioxaglate
Iohexol
Main Diagnosis
Iodixanol
Ioxaglate
Iohexol
*: Number of patients for whom compensation could be performed.
Hexabrix US training 2008 part3
Lagerqvist B. et al. ESC 2005
Conclusion of the Swedish Registry
Study
Data from the official SCAAR and Swedish official hospital discharge
registries
Doubled incidence of re-hospitalization with a renal failure
diagnosis in hospitals using iodixanol (Visipaque)
compared to ioxaglate (Hexabrix) or iohexol (Omnipaque) within one
year post-procedure
After statistical compensation for differences in baseline clinical
characteristics, these differences remained
Need for further studies
Lagerqvist B. et al. ESC 2005
Hexabrix US training 2008 part3
Study of the Swedish Coronary Angiography and
Angioplasty and Hospital Discharge Registers
Renal failure in 57 925 patients undergoing coronary
procedures using iso-osmolar or
low-osmolar contrast media.
P Liss, PB Persson, P Hansell and B Lagerqvist
Kidney International 2006; 70:1811-1817
Hexabrix US training 2008 part3
Rehospitalizations with Renal Failure Diagnosis
2000 - 2003
Variable
ioxaglate (Hexabrix)
iodixanol (Visipaque)
P-value
N patients
12,440
45,485
NS
50 (0.4%)
71 (0.6%)
97 (0.8%)
339 (0.7%)
551 (1.2%)
753 (1.7%)
< 0.001
< 0.001
< 0.001
2 (0.02%)
4 (0.1%)
10 (0.2%)
33 (0.07%)
74 (0.2%)
141 (0.3%)
0.022
< 0.001
< 0.001
0 (0.0%)
3 (0.02%)
9 (0.1%)
10 (0.02%)
52 (0.1%)
87 (0.2%)
0.098
0.009
0.010
Main or secondary diagnosis
Within 1 week
Within 1 month
Within 3 months
Main diagnosis
Within 1 week
Within 1 month
Within 3 months
Start of dialysis
Within 1 week
Within 1 month
Within 3 months
Hexabrix US training 2008 part3
Liss B. et al. Kidney International 2006; 70:1811-1817
Renal failure
primary diagnosis
Total of primary
and secondary
diagnoses
Dialysis
Liss P et al.
Kidney International
2006; 70:1811-1817
Hexabrix US training 2008 part3
Patients with
previously
prevalent
renal failure
Total renal failure
after switch in
one hospital from
Hexabrix (ioxaglate)
to Visipaque
(iodixanol)
Renal failure
up to 10 years
and more.
The Swedish register study: outcome of...
Liss et al; Kidney international (2006) 70, 1811-1817
Hexabrix US training 2008 part3
The Swedish register study: outcome for
patients with previous renal failure
Hexabrix US training 2008 part3
Liss et al; Kidney international (2006) 70, 1811-1817
Outcome in a hospital which
switched from ioxaglate to iodixanol
2.1%
P < 0.001
0.7%
Hexabrix US training 2008 part3
Liss et al; Kidney international (2006) 70, 1811-1817
Renal failure in 57 925 patients undergoing
coronary procedures using iso-osmolar or
low-osmolar contrast media.
Conclusion:
« In this study, we find no indication that the
use of the iso-osmolar CM iodixanol results
in less damage to the kidney than use of the
higher osmolar CM ioxaglate.
In fact, the contrary seems to be the case. »
Liss P et al. Kidney International 2006; 70:1811-1817
Hexabrix US training 2008 part3
Main message 
Hexabrix® poster on
the Guerbet booth
at EuroPCR 07 and
EuroPCR 08
Hexabrix US training 2008 part3
Hexabrix® - positioning
In patients for whom stenting is considered
The « belts and braces » contrast to ensure an
optimal outcome
Hexabrix® is the product of choice because of its
unique anti-clotting properties and
good renal tolerance.
Hexabrix US training 2008 part3
Thank you for your attention !
Hexabrix US training 2008 part3