Young-Hak Kim, MD, PhD

1
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
2
Conflict of Interest

• Nothig to disclose

3
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.

4
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. 2009151631
• In particular, there are a few data about its
  effectiveness for patients with diabetes
  mellitus.

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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.

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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 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
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Study Protocol
Clinical FU to 6 months
Contrast Media Exposure
Before
After
Preparation
Saline
Creatinine, GFR
Electrolyte
Bicarbonate
12 hrs
48 hrs
24 hrs
12 hrs
1 hr
6 hrs
NAC
NAC

• 11 randomization, open label design
• 9 cardiac centers in Korea
• Independent event committee and data management
• Sponsored by CardioVascular Research Foundation,
  Seoul, Korea

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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 lt 45, hydration rate was
  reduced to 0.5mL/kg/hr in both arms.

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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.

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Inclusion Criteria

• Agegt18 years, no upper limits,
• Diabetes treated with insulin or oral
  hypoglycemic agents,
• Serum creatinine 1.1mg/dL, and
• resting estimated glomerular filtration rate
  (GFR)
• lt 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)

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Exclusion Criteria

• Serum creatinine 8 mg/dL
• Resting estimated GFR lt 15 ml/min/1.73 m2
• End stage renal disease on hemodialysis
• Multiple myeloma
• Pulmonary edema
• Uncontrolled hypertension (systolic BP gt160mmHg
  or diastolic BPgt100mmHg)
• 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

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Primary Study Endpoint

• Occurrence of CIN within 48 hours after contrast
  exposure.
• CIN was defined as an increase of serum
  creatinine gt25 or absolute increase of serum
  creatinine ? 0.5mg/dL within 48 hours after
  coronary and/or endovascular intervention or
  angioplasty

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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.

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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 a of 0.05, 368
  patients with complete data would be required to
  detect a statistically significant difference.

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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.

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Results
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Baseline Characteristics
Patients Saline (n189) Bicarbonate (n193) 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) 0.56
IDDM, insulin dependent diabetes NIDDM, non
insulin dependent diabetes OHA, oral
hypoglycemic agent.
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Baseline Characteristics
Patients Saline (n189) Bicarbonate (n193) P value
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
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
BMI, body mass index BP, blood pressure GFR,
glomerular filtration rate.
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Baseline Characteristics
Patients Saline (n189) Bicarbonate (n193) P value
Baseline creatinine, mg/dL 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
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) 41 (21.2)
AMI 11 (5.8) 9 (4.7)
AMI, acute myocardial infarction
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Procedures
Patients Saline (n189) Bicarbonate (n193) P value
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) 1 (0.5)
High Contrast Load gt140 mL and gt maximal
contrast dose (5 X body weight/creatinine)
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Medications during Hospitalization
Patients Saline (n189) Bicarbonate (n193) 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
ACE, angiotensin converting enzyme
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Changes in Renal Function
Measures Before Contrast After Contrast P value
Sodium Chloride group
Serum Creatinine, mg/dL 1.61 ? 0.47 1.61 ? 0.76 lt0.001
Estimated GFR, mL/min/1.73m3 44.3 ? 10.11 47.6 ? 16.16 0.001
Sodium Bicarbonate group
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
Wilcoxon signed rank test
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Effect of Bicarbonate
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Primary End Point- Occurrence of CIN -

P0.17


17/188
10/187
25
Difference in Serum Creatinine
mg/dL
P0.49
P0.18
Mann-Whitney U test
26
Difference in Estimated GFR
mL/min/1.73 ?
P0.48
P0.18
Mann-Whitney U test
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Rates of Dialysis

P0.69
2/187
4/188
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Effect of BicarbonateAccording to the Contrast
Volume
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CIN according to Contrast Volume
P0.93
P0.058
(2/137)
(8/134)
(8/50)
(9/54)
HCL, High Contrast Load gt140 mL and gt maximal
contrast dose (5Xbody weight/creatinine)
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Dialysis according to Contrast Volume
P1.00
P0.37
(1/50)
(1/54)
(3/134)
(1/137)
HCL, High Contrast Load gt140 mL and gt maximal
contrast dose (5Xbody weight/creatinine)
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CIN according to Contrast Volume
P0.61
P0.15
6/76
8/78
9/110
4/111
32
Dialysis according to Contrast Volume
P1.00
P1.00
(2/78)
(2/110)
(1/76)
(1/110)
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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
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Clinical Outcomes
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Major Adverse Events at 1 Month
P1.00
P1.00
P1.00
1
1
1
2
1
MAE Cumulative major adverse events
36
Major Adverse Events between 1 to 6 months
P0.11
P0.45
P0.25
5
8
2
2
3
MAE Cumulative major adverse events
37
Major Adverse Events at 6 Months
P0.053
P0.45
P0.37
6
10
2
3
4
1
MAE Cumulative major adverse events
38
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.

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