Young-Hak Kim, MD, PhD on behalf of the PREVENT investigators Preventive Strategies of REnal Insufficiency in Patients with Diabetes Undergoing InterVENTion.

Young-Hak Kim, MD, PhDon behalf of the PREVENT investigators

PPreventive Strategies of reventive Strategies of REREnal nal Insufficiency in Patients with Diabetes Insufficiency in Patients with Diabetes

Undergoing InterUndergoing InterVENTVENTion or Arteriography: ion or Arteriography:

The PREVENT trial The PREVENT trial

Department of Cardiology, University of Ulsan College of MedicineAsan Medical Center, Seoul, Korea

Conflict of InterestConflict of Interest

Nothig to disclose

• 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.

Background

• 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.

Objective

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

SubjectsSubjects

3569 Patients screened3569 Patients screened

189 Randomized to Saline 193 Randomized to Bicarbonate

3146 Excluded

423 Eligible423 Eligible

41 Denied

382 Randomized382 Randomized

12 hrs

PreparationBefore After

48 hrs24 hrs

Contrast Media Exposure

1:1 randomization, open label design 9 cardiac centers in Korea Independent event committee and data management Sponsored by CardioVascular Research Foundation, Seoul, Korea

1:1 randomization, open label design 9 cardiac centers in Korea Independent event committee and data management Sponsored by CardioVascular Research Foundation, Seoul, Korea

Saline Creatinine, GFR

Electrolyte

Study ProtocolStudy Protocol

NAC12 hrs

NAC6 hrs

Bicarbonate

1 hr

Clinical FU to 6 months

Study ProtocolStudy 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 ProtocolStudy 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.

• 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])

Inclusion CriteriaInclusion 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

Exclusion CriteriaExclusion Criteria

Primary Study EndpointPrimary 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 EndpointsSecondary 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 EstimationSample 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 AnalysisStatistical 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.

ResultsResults

Baseline CharacteristicsBaseline CharacteristicsPatients 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) 0.56

IDDM, insulin dependent diabetes; NIDDM, non insulin dependent diabetes; OHA, oral hypoglycemic agent.

Baseline CharacteristicsBaseline Characteristics

Patients Saline(n=189)

Bicarbonate(n=193) P

value

Peripheral Vascular disease 18 (9.5) 20 (10.4) 0.78

Height, cm 162 7.8 162 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.

Patients Saline(n=189)

Bicarbonate(n=193)

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)

Baseline CharacteristicsBaseline Characteristics

AMI, acute myocardial infarction

ProceduresProcedures

Patients Saline(n=189)

Bicarbonate(n=193) 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: >140 mL and > maximal contrast dose (5 X body weight/creatinine)

Medications during HospitalizationMedications 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

ACE, angiotensin converting enzyme

Measures BeforeContrast

AfterContrast 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

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

Changes in Renal FunctionChanges in Renal Function

* Wilcoxon signed rank test

Effect of BicarbonateEffect of Bicarbonate

Primary End Point- Occurrence of CIN -Primary End Point- Occurrence of CIN -

5.3

9.0

0

5

10

15

20

Saline Group Bicarbonate Group

Saline Group Bicarbonate Group

%

10/187

P=0.17

17/188

%

%

Difference in Serum CreatinineDifference in Serum Creatinine

mg/dL

P=0.49 P=0.18

† Mann-Whitney U test

Difference in Estimated GFRDifference in Estimated GFR

mL/min/1.73 ㎡

P=0.18 P=0.48

† Mann-Whitney U test

Rates of DialysisRates of Dialysis

1.12.1

0

5

10

15

20

Saline Group Bicarbonate Group

Saline Group Bicarbonate Group%

2/187

P=0.69

4/188

Effect of BicarbonateAccording to the Contrast Volume

Effect of BicarbonateAccording to the Contrast Volume

16.0%

1.5%

16.7%

6.0%

0%

10%

20%

30%

40%

50%

HCL (+) HCL (-)

Saline (N=187) Bicarbonate (N=188)

P=0.93P=0.058

(8/50)

CIN according to Contrast VolumeCIN according to Contrast Volume

(9/54)

(2/137) (8/134)

* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)

2.0%0.7%

1.9% 2.2%

0%

10%

20%

30%

HCL (+) HCL (-)

Saline (N=187) Bicarbonate (N=188)

P=1.00 P=0.37

(1/50)

Dialysis according to Contrast VolumeDialysis according to Contrast Volume

(1/54) (1/137) (3/134)

* HCL, High Contrast Load: >140 mL and > maximal contrast dose (5Xbody weight/creatinine)

7.9%

3.6%

10.3%8.2%

0%

10%

20%

30%

40%

50%

>150mL ≤150mL

Saline (N=187) Bicarbonate (N=188)

P=0.61 P=0.15

6/76

CIN according to Contrast VolumeCIN according to Contrast Volume

8/78 4/111 9/110

1.3% 0.9%2.6% 1.8%

0%

10%

20%

30%

>150mL ≤150mL

Saline (N=187) Bicarbonate (N=188)

P=1.00 P=1.00

(1/76)

Dialysis according to Contrast VolumeDialysis according to Contrast Volume

(2/78) (1/110) (2/110)

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

Multivariate Predictors of CINMultivariate Predictors of CIN

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

Clinical OutcomesClinical Outcomes

P=1.00

1

* MAE: Cumulative major adverse events

Major Adverse Events at 1 MonthMajor Adverse Events at 1 Month

P=1.00

11

P=1.00

21

5

* MAE: Cumulative major adverse events

8

P=0.45

Major Adverse Events between 1 to 6 monthsMajor Adverse Events between 1 to 6 months

2

P=0.11

23

P=0.25

6

* MAE: Cumulative major adverse events

10

P=0.45

2

P=0.053

3

Major Adverse Events at 6 MonthsMajor Adverse Events at 6 Months

P=0.37

41

• 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.

Conclusion Conclusion

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