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 !! www.summitMD.com