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Carlo Briguori , MD, PhD Laboratoy of Interventional Cardiology Clinica Mediterranea , Naples - Italy

REMEDIAL II RE nal Insufficiency Following Contrast MEDIA Administration II Tria L RenalGuard system in high risk patients for contrast induced acute kidney injury. Carlo Briguori , MD, PhD Laboratoy of Interventional Cardiology Clinica Mediterranea , Naples - Italy.

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Carlo Briguori , MD, PhD Laboratoy of Interventional Cardiology Clinica Mediterranea , Naples - Italy

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  1. REMEDIAL II REnal Insufficiency Following Contrast MEDIA Administration II TriaLRenalGuard system in high riskpatientsforcontrastinduced acute kidneyinjury Carlo Briguori, MD, PhD Laboratoy of Interventional Cardiology ClinicaMediterranea, Naples - Italy

  2. I, Carlo Briguori DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. Disclosure Statement of Financial Interest

  3. Background • Contrast-induced acute kidney injury (CI-AKI) is a powerful predictor of unfavorable early and late outcome1-3 • Severalstudiesshowed the advantages of the prophylaxis by • sodium bicarbonate solution 4-5 • N-acetylcysteine (NAC) 6-7 • However, in high riskpatients the rate of CI-AKI isstill high 1. McCullough PA. J Am CollCardiol 2008;51:1419-28 2. Solomon R. et al. Clin J Am Soc Nephrol 2009;4:1162-1169 3. Briguori C, et al. Circulation 2010;121:2117-2122. 4. Merten GJ et al. JAMA 2004;291:2328-2334 5. Briguori C, et al. Circulation 2007;115:1211-1217. 6. Tepel M et al. N Engl J Med 2000;343:180-184. 7. Trivedi H, et al. Am J Med 2009;122:874 e9-15

  4. High risk patients Mehran R et al J Am CollCardiol2004; 44:1393-9

  5. Background • Creating and maintaining a high urine output is beneficial to prevent kidney damage. This high urine flow rate, indeed, should allow the body to rapidly eliminate contrast, reducing its toxic effects. • Data from the PRINCE study indicate thatincreasing the urine flow rate (≥150 ml/h) reduces the toxiceffectofcontrast media 1 • A forced diuresis regime is usually achieved by high dose of furosemide which may be deleterious, potentially due to a negative fluid balance 2,3 1. Stevens MA et al. J Am CollCardiol 1999;33:403-411 2.Weinstein JM et al. Nephron 1992;62:413-415 3. Solomon R, et al. N Engl J Med 1994;331:1416-1420.

  6. Background • The RenalGuardTM automated hydration matching system (PLC Medical System, Inc.) was developed in order to achieve precise real-time high volume fluid balance using a closed loop hydration monitoring and infusion system

  7. RenalGuard system Resnic F. et al. J Am CollCardiol2009 53: A36

  8. RenalGuard System

  9. RenalGuard System • closed loop fluid management system • high volume fluid pump • high accuracy dual weight measuring system • single use intravenous set; urine collection system that interfaces with a standard Foley catheter • real-time display of urine and hydration fluid volume • user set net fluid gain and fluid bolus administration for patients that require re-hydration prior to and during the procedure • automatic battery back-up • automatic priming of infusion set • timely alerts to drain urine bag or to replace the hydration fluid bag.

  10. Purpose • We performed a prospective, randomized study comparing the prophylactic effectiveness of 2 different strategies for preventing CI-AKI: • Sodium Bicarbonate plus N-Acetylcysteine (Control Group) • Hydration with RenalGuard system (RenalGuard Group)

  11. REMEDIAL II • DESIGN: Prospective, randomized, double-arm, multicenters clinical study Elective contrast media administration in patients at high risk for CI-AKI (risk score ≥11 and/or eGFR≤30 ml/min/1.73 m2) Control group RenalGuard group CI-AKI (sCr ≥0.3 mg/dL at 48 h)

  12. Hypothesis: Reduction in the primary endpoint from 25% in the Control group to 10% in the RenalGuard group Sample size: A total of 266 patients (133 each group) will be necessary to gave the study 90% power and a significance level <0.05 Sample size

  13. Inclusion criteria • Age 18 y • Chronic kidney disease • High risk for CI-AKI: • eGFR ≤30 ml/min/1.73 m2 and/or • Mehran score ≥ 11

  14. Exclusion criteria • Primary or rescue PCI • Pregnancy • Recent (≤ 7 days) contrast media exposure • Chronic dialysis and/or history or previous dialysis • multiple myeloma • pulmonary edema • acute myocardial infarction • Administration of theophylline, dopamine, mannitol, or fenoldopam or sodium bicarbonate.

  15. REMEDIAL II trial Sodium Bicardonate & Acetylcysteine RenalGuard group Hydrationbysodiumbicarbonate (3 ml/Kg i.v. 1 h before and 1 ml/kg for 6 h after) & NAC 1200 mg BID x 2 & 1.5 g e.v.during the procedure Hydrationwithnormal saline (urine flow ≥ 300 ml/h) & NAC (1.5 g/L) & limited (0.25 mg/kg) furosemide dose

  16. RenalGuard group Pre-procedure Procedure Post- procedure 600 • Biomarkers: • sCr = baseline, 2, 6, 12, 24 and 48 hours • sCyC = baseline, 2, 6, 12, 24 and 48 hours • NGAL = baseline, 2, 6, 12, 24 and 48 hours 500 Foley Catheter RenalGuard system Prime (≤250 mL) 400 Furosemide (0.25 mg/kg) Urine flow rate (ml/h) 300 200 Continuous real-time matched replacement fluid 100 0 0 30 60 90 120 150 180 210 240 270 300 330 360 400 Time (minutes) Patient ready for procedure when urine flow rate is ≥300 ml/h

  17. RenalGuard System

  18. Primary endpoint: Rate of CI-AKI, defined as a serum creatinine (sCr) increase 0.3 mg/dLat48 hours Secondary endpoints: an increase in the sCr concentration 25% and 0.5 mg/dl at 48 hours after contrast exposure changes in the serum cystatin C (sCyC) concentration at 24 and 48 hours after contrast exposure the rate of acute renal failure requiring dialysis the rate of in-hospital, and 1 month major adverse events (MAE), including a) death, b) renal failure requiring dialysis, and c) acute pulmonary edema changes in the serum and urine NGAL concentrations at 2, 6, 12, 24 and 48 hours after contrast exposure Endpoints

  19. Assessed for eligibility ( n= 806) Exclusion (n = 512) Not meeting inclusion/exclusion criteria (n = 485 ) Refused to partecipate (n = 27) Enrollement Randomized (n = 294) • Patients allocated in the RenalGuard group (n = 147) • Received allocated treatment (n = 146) • Did not receive the allocated treatment (n =1) • Patients allocated in the Control group (n = 147) • Received allocated treatment (n = 146) • Did not receive the allocated treatment (n= 1) Allocation Patients lost at follow-up (n = 0) Discontinued treatement (n = 0) Patients lost at follow-up (n = 0) Discontinued treatment (n = 2) Follow-up Analysis Patients analized ( n = 146) Patients excluded from analysis (n = 0) Patients analized ( n = 146) Patients excluded from analysis (n = 0)

  20. Clinical Characteristics

  21. Biochemical Characteristics

  22. Procedural Characteristics

  23. Distributionof the Risk score 120 100 72.5% 80 Number of patients 60 40 20 2% 13% 12.5% 0 ≥5 ≥6-10 ≥11-15 ≥16 Risk score

  24. 3000 p <0.001 2500 2000 1500 1000 500 0 Control Group RenalGuard group Urine Volume at 24 hours

  25. RenalGuard group Pre-procedure Procedure Post- procedure 7 h & 54 minutes (4.7-11.5 h) 600 • Biomarkers: • sCr = baseline, 2, 6, 12, 24 and 48 hours • sCyC = baseline, 2, 6, 12, 24 and 48 hours • NGAL = baseline, 2, 6, 12, 24 and 48 hours 500 400 Foley Catheter RenalGuard system Prime (223±45 mL; range = 50-300) Urine flow rate (ml/h) Furosemide (14±8mg; range = 0-50) 300 200 Continuous real-time matched replacement fluid 100 0 0 30 60 90 120 150 180 210 240 270 300 330 360 400 Time (minutes) Time to reach Target urine flow rate 58±19 min (30-120)

  26. 4000 3500 3000 2500 infusion Volume(ml) 2000 1500 urine 1000 500 0 15 45 75 105 135 165 195 225 255 285 315 345 375 Time (minutes) RenalGuard Group

  27. 900 800 700 600 500 400 300 200 100 0 15 45 75 105 135 165 195 225 255 285 315 345 375 RenalGuard Group • Mean urine flow rate: • 352±131 ml/h • Target reached in 93% • of patients (416±19 ml/h) • Below the target in 7% • of patients (117±48 ml/h) Urine flow rate (ml/h) Time (minutes)

  28. sCrkinetic 2.4 2.2 2.0 1.8 serum creatinine (median) 1.6 1.4 Control group 1.2 p = 0.008; F = 4.97 RenalGuard group 1.0 Baseline 24 48 Time (hours)

  29. 30/146 16/146 Primaryendpoint Odds ratio = 0.47; 95% CI= 0.24-0.92 p = 0.025 25 20.5% 20 15 CI-AKI (%) 11% 10 5 0 Control group RenalGuard group

  30. Secondaryendpoints

  31. sCyCkinetic 2.4 2.2 2.0 1.8 serum cystatin C (median) 1.6 1.4 Control group 1.2 p = 0.004; F = 5.52 RenalGuard group 1.0 Baseline 24 48 Time (hours)

  32. Control Group RenalGuard Group Secondaryendpoint Events rate at 1-month p = 0.52 9.6 10 9 8 6.8 7 p = 0.031 p = 1.0 6 4.8 % 5 4.1 4.1 4 p = 0.62 3 2.1 2 0.7 0.7 1 0 Dialysis Pulmonary Edema Death Cumulative

  33. Conclusions The RenalGuard therapy, including hydration with normal saline plus high dose of NAC controlled by the RenalGuard system in combination with limited (0.25 mg/kg) dose of furosemide, is an effective renoprotective strategy for patients at high- risk for CI-AKI.

  34. Clinica Mediterranea, Naples C. Briguori (P.I.) A. Focaccio G. Visconti B. Golia REMEDIAL II Investigators • University of Ferrara, Ferrara • M. Valgimigli • R. Ferrari • Multimedica IRCCS, Milan • F. Airoldi • D. Tavano • S. Di Biase • S. Bertoli • University of Modena, Modena • G.M. Sangiorgi • M. G. Modena

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