Preventive Strategies of REnal
Insufficiency in Patients with Diabetes
Undergoing InterVENTion or Arteriography:
The PREVENT trial
Young-Hak Kim, MD, PhD
on behalf of the PREVENT investigators
Department of Cardiology, University of Ulsan College of Medicine
Asan Medical Center, Seoul, Korea
Conflict of Interest
Nothig to disclose
Background
• Contrast-Induced Nephropathy (CIN):
- Common cause of hospital acquired renal failure.
- Occurs in less than 1% of general population.
- Occurs in up to 50% of patients with chronic
renal insufficiency, especially if diabetes is present.
• Diabetic nephropathy and chronic kidney disease
are the most common risk factors for the
development of CIN.
Background
•
•
Recent small scale studies suggested that hydration
with sodium bicarbonate may be more protective than
sodium chloride alone in the prevention of CIN.
However, in the recent meta-analysis, the effectiveness
of sodium bicarbonate treatment remains uncertain due
to the heterogeneity in outcomes across studies.
Ann Intern Med. 2009;151:631
•
In particular, there are a few data about its
effectiveness for patients with diabetes mellitus.
Objective
• To determine if sodium bicarbonate is superior
to sodium chloride for preventing CIN in diabetic
patients with mild to moderate chronic kidney
dysfunction who are undergoing coronary and/or
endovascular intervention or angiography.
Subjects
3569 Patients screened
3146 Excluded
423 Eligible
41 Denied
382 Randomized
189 Randomized to Saline
193 Randomized to Bicarbonate
187 Included in primary contrast-induced
nephropathy analysis
2 Excluded because did not have
laboratory data after angiography
188 Included in primary contrast-induced
nephropathy analysis
5 Excluded because did not have
laboratory data after angiography
189 Included in 30-day clinical FU
188 Included in 6-month clinical FU
193 Included in 30-day clinical FU
192 Included in 6-month clinical FU
Study Protocol
Clinical FU
to 6 months
Contrast Media Exposure
Before
Preparation
After
Saline
Creatinine, GFR
Electrolyte
Bicarbonate
12 hrs
NAC




1 hr
NAC
6 hrs
12 hrs
24 hrs
48 hrs
1:1 randomization, open label design
9 cardiac centers in Korea
Independent event committee and data management
Sponsored by CardioVascular Research Foundation, Seoul, Korea
Study Protocol
•
•
•
•
Bicarbonate group: Sodium bicarbonate 154mEq/L: 3
mL/kg for 1 hour prior, decreased to 1 mL/kg/hr during and
6 hours after the procedure.
Saline group: Isotonic saline 0.9% NaCl: 1 mL/kg/hr for 12
hours before and 12 hours after.
All patients received oral N-acetylcysteine 1200 mg twice
daily for 2 days, prior to procedure.
If ejection fraction < 45%, hydration rate was reduced to
0.5mL/kg/hr in both arms.
Study Protocol
•
•
•
•
Serum creatinine was measured on days 1 and 2 post
angiography.
For all patients, creatinine levesls were assessed until any
increase of renal resolved or reached a new baseline of
renal function.
All patients who developed CIN were asked to return
around 1 month for repeat measurement of creatinine.
All study participants received idixanol (Visipaque, 320mg
iodine/mL, Amersham), a non-ionic, dimeric iso-osmolar
contrast medium.
Inclusion Criteria
•
•
•
Age>18 years, no upper limits,
Diabetes treated with insulin or oral hypoglycemic agents,
Serum creatinine ≥ 1.1mg/dL, and
resting estimated glomerular filtration rate (GFR)
< 60 ml/min per 1.73 m2 by Modification of Diet in Renal
Disease formula (1.863 x serum creatinine level -1.154 x
age -0.203 x [0.742 if female])
Exclusion Criteria
•
•
•
•
•
•
•
•
•
•
•
•
Serum creatinine ≥ 8 mg/dL
Resting estimated GFR < 15 ml/min/1.73 m2
End stage renal disease on hemodialysis
Multiple myeloma
Pulmonary edema
Uncontrolled hypertension (systolic BP >160mmHg or
diastolic BP>100mmHg)
Acute STEMI undergoing primary PCI
Emergent coronary angioplasty or angiography
Recent use of contrast agent within 2 days
Allergic reaction to contrast
Pregnancy
Allergic to following medication : theophylline, dopamine,
mannitol, fenoldopam, N-acetylcysteine
Primary Study Endpoint
• Occurrence of CIN within 48 hours after contrast
exposure.
• CIN was defined as an increase of serum
creatinine >25% or absolute increase of serum
creatinine  0.5mg/dL within 48 hours after
coronary and/or endovascular intervention or
angioplasty
Secondary Endpoints
• Secondary Endpoint
: Death (all-cause)
: Myocardial infarction
: Stroke
: Dialysis including hemofiltration
at 30 days, between 1 month and 6 months, and
6 months after contrast exposure.
Sample Size Estimation
•
•
Study sample size was calculated on the basis of
a power analysis assuming that 10% of sodium
chloride group and 2% of the sodium bicarbonate
group would develop contrast induced
nephropathy.
With a power of 90% and 2-sided α of 0.05, 368
patients with complete data would be required to
detect a statistically significant difference.
Statistical Analysis
•
•
•
The categorical variables were presented as
number (percentage) and were compared using
chi-square or Fisher exact test.
The continuous variables were presented as
median (interquartile range) and were compared
using Mann-Whitney U test.
To identify independent predictors of CIN,
multivariate logistic regression test was performed
with fixed 7 covariates.
Results
Baseline Characteristics
Patients
Age (yr)
Female gender
Saline
(n=189)
Bicarbonate
(n=193)
P
value
67.5 (62-72)
68.5 (63-73)
0.30
54 (28.6)
57 (29.5)
0.84
Diabetes mellitus, type
IDDM
NIDDM
0.53
9 (4.8)
12 (6.2)
180 (95.2)
181 (93.8)
Treatment modalities
0.56
OHA
121 (64.0)
129 (66.8)
Requiring insulin
68 (36.0)
64 (33.2)
Hypertension
151 (79.9)
149 (77.2)
0.49
Hyperlipidemia
63 (33.3)
72 (37.3)
0.42
Current smoker
29 (15.3)
36 (18.7)
0.56
IDDM, insulin dependent diabetes; NIDDM, non insulin dependent diabetes; OHA, oral hypoglycemic agent.
Baseline Characteristics
Patients
Saline
(n=189)
Bicarbonate
(n=193)
Peripheral Vascular disease
18 (9.5)
20 (10.4)
0.78
Height, cm
162  7.8
162  7.8
0.56
Weight, kg
67  9.7
66  9.1
0.16
BMI, kg/m2
25.4  3.3
25.1  3.0
0.31
Systolic BP
131  17
132  18
0.67
Diastolic BP
75  12
75  11
0.72
74  13
76  12
0.07
P
value
Blood pressure, mmHg
Heart rate, /min
BMI, body mass index; BP, blood pressure; GFR, glomerular filtration rate.
Baseline Characteristics
Saline
(n=189)
Bicarbonate
(n=193)
P
value
1.5 (1.3-1.7)
1.5 (1.3-1.9)
0.49
Baseline estimated GFR
46 (37-53)
46 (34-53)
0.58
LVEF (%)
60 (50-65)
58 (48-64)
0.84
Patients
Baseline creatinine, mg/dL
0.22
Clinical indication (%)
Silent ischemia
39 (20.6)
41 (21.2)
Stable angina
80 (42.3)
102 (52.8)
Unstable angina
58 (31.2)
41 (21.2)
11 (5.8)
9 (4.7)
AMI
AMI, acute myocardial infarction
Procedures
Saline
(n=189)
Bicarbonate
(n=193)
Contrast volume, mL
120 (79-223)
113 (80-220)
0.89
High contrast load *
50 (26.5)
54 (28.0)
0.74
Angiogram alone
96 (50.8)
97 (50.3)
PCI
89 (47.1)
86 (44.6)
Peripheral angioplasty
3 (1.6)
9 (4.7)
PCI & peripheral angioplasty
1 (0.5)
1 (0.5)
Patients
P
value
Procedures
* High Contrast Load: >140 mL and > maximal contrast dose (5 X body weight/creatinine)
Medications during Hospitalization
Patients
Saline
(n=189)
Bicarbonate
(n=193)
ACE inhibitor
43 (22.8)
32 (16.6)
0.25
Angiotensin receptor blocker
86 (45.5)
84 (43.5)
0.70
Calcium channel blocker
114 (60.3)
120 (62.2)
0.71
Beta blocker
103 (54.5)
103 (53.4)
0.92
Diuretics
69 (36.5)
60 (31.1)
0.26
Statin
125 (66.1)
138 (71.5)
0.63
ACE, angiotensin converting enzyme
P
value
Changes in Renal Function
Before
Contrast
After
Contrast
P value*
Serum Creatinine, mg/dL
1.61  0.47
1.61  0.76
<0.001
Estimated GFR, mL/min/1.73m3
44.3  10.11
47.6  16.16
0.001
Serum Creatinine, mg/dL
1.67  0.52
1.72  0.77
0.022
Estimated GFR, mL/min/1.73m3
43.2  11.7
45.9  17.5
0.014
Measures
Sodium Chloride group
Sodium Bicarbonate group
* Wilcoxon signed rank test
Effect of Bicarbonate
Primary End Point
- Occurrence of CIN Saline Group
Bicarbonate Group
% 20
P=0.17
15
9.0 %
10
5.3 %
5
10/187
17/188
Saline Group
Bicarbonate Group
0
Difference in Serum Creatinine
mg/dL
P=0.49
P=0.18
† Mann-Whitney U test
Difference in Estimated GFR
mL/min/1.73 ㎡
P=0.18
P=0.48
† Mann-Whitney U test
Rates of Dialysis
Saline Group
%
Bicarbonate Group
20
15
P=0.69
10
5
1.1
0
2/187
Saline Group
2.1
4/188
Bicarbonate Group
Effect of Bicarbonate
According to the Contrast Volume
CIN according to Contrast Volume
Saline (N=187)
Bicarbonate (N=188)
50%
40%
30%
20%
P=0.93
16.0%
P=0.058
16.7%
(2/137)
10%
(8/50)
(9/54)
(8/134)
6.0%
1.5%
0%
HCL (+)
HCL (-)
* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)
Dialysis according to Contrast Volume
Saline (N=187)
Bicarbonate (N=188)
30%
20%
P=1.00
P=0.37
10%
(1/50)
(1/54)
2.0%
1.9%
(1/137)
0.7%
(3/134)
2.2%
0%
HCL (+)
HCL (-)
* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)
CIN according to Contrast Volume
Saline (N=187)
Bicarbonate (N=188)
50%
40%
30%
P=0.61
P=0.15
20%
10%
7.9%
10.3%
8.2%
3.6%
0%
6/76
8/78
>150mL
4/111
9/110
≤150mL
Dialysis according to Contrast Volume
Saline (N=187)
Bicarbonate (N=188)
30%
20%
P=1.00
10%
(1/76)
1.3%
(2/78)
P=1.00
(1/110)
2.6%
0.9%
(2/110)
1.8%
0%
>150mL
≤150mL
Multivariate Predictors of CIN
Variables
Odds
ratio
95% CI
P
value
Contrast amount
(mL)
1.005
1.002, 1.009
0.003
LV ejection fraction
(%)
0.961
0.929, 0.995
0.026
From 7 covariates including age, sex, contrast amount, procedural type,
LV ejection fraction, randomization, and body mass index
Clinical Outcomes
Major Adverse Events at 1 Month
P=1.00
1
* MAE: Cumulative major adverse events
P=1.00
1
1
P=1.00
1
2
Major Adverse Events
between 1 to 6 months
P=0.11
P=0.45
P=0.25
2
5
* MAE: Cumulative major adverse events
3
2
8
Major Adverse Events at 6 Months
P=0.053
P=0.45
P=0.37
2
6
* MAE: Cumulative major adverse events
1
4
3
10
Conclusion
• In patients with diabetic nephropathy who
received coronary or endovascular
angiography or intervention, hydration with
sodium bicarbonate before or after contrast
exposure was not superior to hydration with
sodium chloride for the prevention of CIN.
Thank You !!
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