0. 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

1. Conflict of Interest
Nothig to disclose

2. 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.
CIN is the 3rd most common cause of hospital acquired renal failure
Occurs in less than 1% of general population
Occurs in "only" 5.5% of patients with renal insufficiency
But, occurs in 50% of patients with both renal insufficiency and diabetes mellitus 2

3. 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.

4. 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.

5. Subjects 3569 Patients screened 423 Eligible 382 Randomized
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
189 Included in 30-day clinical FU
188 Included in 6-month clinical FU
188 Included in primary contrast-induced nephropathy analysis
5 Excluded because did not have laboratory data after angiography
193 Included in 30-day clinical FU
192 Included in 6-month clinical FU

6. Study Protocol Before After Preparation
Clinical FU
to 6 months
Contrast Media Exposure
Before
After
Preparation
Saline
Creatinine, GFR
Bicarbonate
Electrolyte
12 hrs
1 hr
6 hrs
12 hrs
24 hrs
48 hrs
NAC
NAC
1:1 randomization, open label design
9 cardiac centers in Korea
Independent event committee and data management
Sponsored by CardioVascular Research Foundation, Seoul, Korea

7. 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.

8. 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.

9. 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 x age x [0.742 if female])

10. 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

11. 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

12. 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.

13. 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.

14. 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.

15. Results

16. Baseline Characteristics
Patients
Saline
(n=189)
Bicarbonate
(n=193) P
value
Age (yr)
67.5 (62-72)
68.5 (63-73)
0.30
Female gender
54 (28.6)
57 (29.5)
0.84
Diabetes mellitus, type
0.53
IDDM
9 (4.8)
12 (6.2)
NIDDM
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) OK
IDDM, insulin dependent diabetes; NIDDM, non insulin dependent diabetes; OHA, oral hypoglycemic agent.

17. Baseline Characteristics
Patients
Saline
(n=189)
Bicarbonate
(n=193) P
value
Peripheral Vascular disease
18 (9.5)
20 (10.4)
0.78
Height, cm
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
Blood pressure, mmHg
Systolic BP
131  17
132  18
0.67
Diastolic BP
75  12
75  11
0.72
Heart rate, /min
74  13
76  12
0.07 OK
BMI, body mass index; BP, blood pressure; GFR, glomerular filtration rate.

18. Baseline Characteristics
Patients
Saline
(n=189)
Bicarbonate
(n=193) P
value
Baseline creatinine, mg/dL
1.5 ( )
1.5 ( )
0.49
Baseline estimated GFR
46 (37-53)
46 (34-53)
0.58
LVEF (%)
60 (50-65)
58 (48-64)
0.84
Clinical indication (%)
0.22
Silent ischemia
39 (20.6)
41 (21.2)
Stable angina
80 (42.3)
102 (52.8)
Unstable angina
58 (31.2)
AMI
11 (5.8)
9 (4.7) OK
AMI, acute myocardial infarction

19. Procedures Patients Bicarbonate (n=193) P value Saline (n=189)
Contrast volume, mL
120 (79-223)
113 (80-220)
0.89
High contrast load *
50 (26.5)
54 (28.0)
0.74
Procedures
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) OK
* High Contrast Load: >140 mL and > maximal contrast dose (5 X body weight/creatinine)

20. Medications during Hospitalization
Patients
Saline
(n=189)
Bicarbonate
(n=193) P
value
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 OK
ACE, angiotensin converting enzyme

21. Changes in Renal Function
Measures
Before
Contrast
After
P value*
Sodium Chloride group
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
Sodium Bicarbonate group
1.67  0.52
1.72  0.77
0.022
43.2  11.7
45.9  17.5
0.014 OK
* Wilcoxon signed rank test

22. Effect of Bicarbonate

23. Primary End Point - Occurrence of CIN -%
P=0.17 % %
10/187
17/188

24. Difference in Serum Creatinine
mg/dL
P=0.49
P=0.18
† Mann-Whitney U test

25. Difference in Estimated GFR
mL/min/1.73 ㎡
P=0.18
P=0.48
† Mann-Whitney U test

26. Rates of Dialysis %
P=0.69
2/187
4/188

27. Effect of Bicarbonate According to the Contrast Volume

28. CIN according to Contrast Volume
P=0.93
P=0.058
(2/137)
(8/134)
(8/50)
(9/54)
* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)

29. Dialysis according to Contrast Volume
P=1.00
P=0.37
(1/50)
(1/54)
(1/137)
(3/134)
* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)

30. CIN according to Contrast Volume
P=0.61
P=0.15
6/76
8/78
4/111
9/110

31. Dialysis according to Contrast Volume
P=1.00
P=1.00
(1/76)
(2/78)
(1/110)
(2/110)

32. 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 OK
From 7 covariates including age, sex, contrast amount, procedural type,
LV ejection fraction, randomization, and body mass index

33. Clinical Outcomes

34. Major Adverse Events at 1 Month
P=1.00
P=1.00
P=1.00 1 1 1 1 2
* MAE: Cumulative major adverse events

35. Major Adverse Events between 1 to 6 months
P=0.11
P=0.45
P=0.25 2 5 3 2 8
* MAE: Cumulative major adverse events

36. Major Adverse Events at 6 Months
P=0.053
P=0.45
P=0.37 2 6 1 4 3 10
* MAE: Cumulative major adverse events

37. 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.

38. Thank You !!