La prevenzione della nefropatia da contrasto nel paziente cardiologico. Carlo Guastoni U.O. Nefrologia Ospedale Civile di Legnano

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1 La prevenzione della nefropatia da contrasto nel paziente cardiologico. Carlo Guastoni U.O. Nefrologia Ospedale Civile di Legnano

2 CIN (CI-AKI) definition Both clinical studies and ESUR definition (Thomsen H. Curr. Opin. Urol. 2007; 17: 70) Increase in serum creatinine (scr) 0.5 mg/dl and/or 25% from baseline within 3 days of CM exposure The absence of other causes (e.g. atheromatous embolic disease, ischemia, other nephrotoxins, etc.) Stage I AKIN definition CIN definition scr. increase Increase in scr 0.3 mg/dl or 0.3mg/dL 150 to 200 % from baseline (Metha R. Crit.Care 2007) Solomon R. Clin. JASN 2009 Mitchell A. Clin JASN 2010 Briguori C. Circulation 2010

3 2010; 121: % CyC increase 24 hours vs. Scr. increase 0.3 mg/dl 48 hours 410 patients undergoing either coronary or peripheral angiogr. and/or angioplasty Diabetes 39 % GFR 41 ± 10 ml/min

4 CIN incidence following CM administration CIN incidence % < 30 3 GFR ml/min i.a.+ckd+ diabetes i.a. + CKD only } calculated by Mc Cullough from studies published before 2003 J. Cardiov. Med i.a. in 5 RCT studies ( ) (diab %); 2 studies in 3 (diab %) 2- i. v. in 4 studies ( ) (diabetes %) 3- i. v. in 1 study (2010) (diabetes 32%)

5 Possible explanation for risk reduction of CIN 90 s Arterial 00 s Arterial today Venous - Lower CM dose: ± ± ± 19 ml - Better preventive strategies for intra - arterial CM administration (Bicarbonate infusion?, NAC?) - Lower patient related risk in i.v. patients

6 Renal medullary ischemia Direct cytotoxic effect CIN pathogenesis Procedure related risk CM dose Intra-arterial infusion Increased vasoconstriction Decreased renal functional reserve Patient predisposing risk conditions. Pre-existing renal failure.diabetes. Effective or relative volume depletion. Aging. Decreased cardiac output. Cirrhosis. Atherosclerosis/Hypertension. Anemia. NSAIDs. Cyclosporine

7 CIN is a paradigm of combined hypoxic and toxic renal parenchymal injury, conceivably mediated by ROS Vasoconstriction Renal reserve NO Angiot ET-1 Caspase HIF Heyman S. Invest. Radiol. 2010; 45: 188

8 Loss of kidney function and mortality after reversible CIN 78 patients after PCI All patients with CIN (N 10; 13 %) had return to baseline levels by 7 days. egfr 36±7 ml/min/1.73m2 16±15 ml/min/1.73m2 Patients with CIN had higher mortality 31±15 ml/min/1.73m2 Patients with CIN had greater loss of kidney function than those without CIN: 20 vs 6 ml/ min (p=0.02). Goldenberg I. Am. J. Nephrol. 2009

9 12 mo.death / dialysis OR multivariate Analysis. 440 pts.

10 Hydration is effective in CIN prevention ESUR GUIDELINES: ml/kg/h 3-12 hours pre and hours post CM What are the best solution for hydration? Normal saline or Na Bicarbonate?

11 Effects of Hydration in CIN prevention Hydration Contrast-induced renal medullary ischemia Direct cytotoxic effect Volume expansion Forced diuresis CM intratubular dilution Acute tubular necrosis following exposure to the contrast agent

12 RenalGuard System

13 RenalGuard system 53: A36 Resnic F. et al. J Am Coll Cardiol 2009

14 MYTHOS Protocol RenalGuard Continuous Infusion of Matched Replacement Saline Nurse monitors patient and record data every 30 min. i.v. furosemide* (0.5 mg/kg) 48±16 min 30 min. >300 ml/h of UO) 4 hours 250 ml i.v. saline PRE-PROCEDURE PROCEDURE POST-PROCEDURE * In 20% of pts additional furosemide (0.5 mg/kg) was required TCT 2010

15 MYTHOS STUDY- CIN incidence 72 h after CM 157 pts. mean bas. GFR 39 ± 10 ml/min. Furosemide bolus 0.5 mg/kg. Diuresis 826±342 ml/h for 4 hours % P= % P=0.03 Controls RenalGuard 20 16% -69% -80% P NS 15-60% % 6% 10% 4% 0 All patients NSTEMI Elective procedures TCT 2010

16 154 mmol/l % CIN (scr >25%) 13.6% P< pts with (GFR ml/ min) undergoing coronary procedures, periph. angio., or CT scan % 3 ml/kg/h for 1 h before and 1 ml/kg/h for 6h after contrast exposure 0 Sodium Chloride (n=59) Sodium Bicarbonate (n=60) Merten GJ. et al. JAMA 2004

17 Subjects and methods - 18 papers included in the final analysis (9 abstracts) 3055 patients following both intra-arterial and i.v. CM administration. NAC present in 10 trials; Merten protocol in 9 trials trials regarding only coro. and periph. angiography - CKD inclusion (scr. > 1.2 or GFR < 60): all but two trials (2674)

18 Results pre hydration for 1 h. Bolus before CM Lower CIN incidence with BIC. hydration (9.6% vs 13.5%) (p=0.001) Aggregate effect: RR 0.66 ( ) Heterogeneity 52 % (p=0.005)

19 Am. J. Cardiol 2011 Nabic. vs. Saline 154 MEq/L infusion Intravenous bolus injection 0.5 ml /kg as soon as possible followed by 1 ml /Kg/hour for 6 hours 59 patients with maen bas. egfr 40 ± 11 ml/min CIN incidence 3.3 % vs 27.6 % (p = 0.01)

20 Tepel M. NEJM 2000; 343: pt.; scr. 2.4 ± 1.3 Saline 0.45 % hydration 1 ml/kg for 12 hours pre e post TAC with LOCM. Oral NAC 600 mg. twice/day pre and post CM

21 Trivedi H. Am. J. Med. 2009: 122: 874 Am. J. Med. 2009; 122: 874 NAC dose mg/d. 16 RCT; 1677 patients Mean scr mg/dl. scr mg/dl. in 9 studies Mean CM dose 150 ± 40 ml (81 346) OR 0.46 ( ) OR random effect 0.52 ( ). Good methodological quality. No publication bias (p=0.34). No statistical heterogeneity (34 %) (p=ns)

22 2,308 Patients undergoing an angiographic procedure with at least one of the following risk factors: Age > 70 years; Chronic Renal Failure; Diabetes Mellitus; Heart Failure or LVEF <0.45; Shock ACT TRIAL AHA 2010 Berwanger O. et al Concealed Randomization Acetylcysteine 1200mg Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure ITT Matching Placebo ITT Primary Endpoint: Contrast-induced nephropathy (CIN) ( 25% elevation of serum creatinine above baseline 48h-96h after angiography) Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of serum creatinine, Side effects

23 Primary Endpoint Results

24 Adherence to study drug 1 st dose 2 nd dose 3 rd dose 4 th dose Hydration before procedure Compliance and Co-interventions Acetylcysteine (1172) Placebo (1136) 99.0% 97.6% 96.4% 95.6% 99.4% 97.3% 96.1% 94.9% NaCl 0.9% - 1ml/Kg/h 6 h 47.1% 47.5% NaCl 0.9% - any scheme 94.3% 94.3% Bicarbonate 5.1% 4.6% Hydration after procedure NaCl 0.9% - 1ml/Kg/h 6 h 52.3% 54.8% NaCl 0.9% - any scheme 71.2% 74.1% Bicarbonate 28.8% 28.5% Contrast High/low/iso-osmolar (%) 22.0/ 75.0 / / 74.3 / 2.9 Volume (ml) 100 (70 to 130) 100 (70 to 130)

25 Baseline Characteristics Acetylcysteine (1172) Placebo (1136) Age yr 68.0 ± ± 10.4 Female sex 38.0% 39.3% Patients fulfilling inclusion criteria Chronic Renal Failure* 15.4% 16.0% Diabetes mellitus 61.2% 59.7% Heart failure 9.9% 9.2% Shock 0.3% 0.2% History of hypertension 13.5% 13.9% Coronary diagnostic angiography 67.1% 68.7% Percutaneous coronary intervention 30.1% 28.5% Estimated creatinine clearance 60.2 (45.4 to 84.5) 61.4 (45.2 to 83.3) * Serum creatinine >1.5mg/dL (stable measurements)

26 Take home message on Bicarbonate and NAC prevention for CIN. To give or not to give? Bicarbonate seems to be more effective than normal saline for short-duration prehydration protocol (Primary PCI and/or in absence of previous renal function data) Given its favorable side effect profile,the use of daily high dose NAC ( 2400 mg) (oral or i.v.) seems reasonable in risk patients undergoing CM administration

27 CRRT in high risk patients (GFR<30 ml/min.) Marenzi et al. 2 RCT (Am. J. Med NEJM 2003) CVVH pre (6 h.) + post (18-24 h.) 120 pts. post (18-24 h.) + hydr. 12 h. pre Control Hydration 12 h. pre 86 pts h. post RR 0.22 ( ) vs control CIN 3 % within 3 days after CM Guastoni et al. Prospective study (W.C.N 2009) CVVH post (6h.) + hydr. 12 h. pre 23 pts hydr. 24 h. post + NAC 1200 x 2 (3 days) CIN 9 % 48 h. after CVVH

28 Casistica Legnano-Magenta 41 pazienti GFR bas ± 7 Età 73.7 ± 8.8 Diabete 52 % CHF 28 % FE 47.1 ± 10.5 % Dose MDC 120 ± 10.5 ml scr 25 % % scr 0.5 mg/dl 48 h. post CVVH vs. pre %

29 REMEDIAL II trial Briguori C. Sodium Bicardonate & Acetylcysteine ACC 2011 RenalGuard group 146 patients 146 patients Hydration by sodium bicarbonate (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 Hydration with normal saline (urine flow 300 ml/h) & NAC (1.5 g/l) & limited (0.25 mg/kg) furosemide dose Mean CM volume 145 ± 77 ml Laboratory of Interventional Cardiology CLINICA MEDITERRANEA NAPLES

30 Remedial II Biochemical Characteristics Diabetes 70 % egfr (ml/min/1.73 m 2 ) GFR 30 Serum Urea Nitrogen (mg/dl) Baseline after 48 h Serum Sodium (meq(l) Baseline after 48 h Serum Potassium (meq/l) Baseline after 48 h Control Group (N=146) 32 ± 7 62 (44%) 78 ± ± ± 5 139± ± ± 0.6 RenalGuard Group (N=146) 32 ± 9 69 (48.5%) 80 ± 35 71± ± ± ± ± 0.6 P ACC 2011

31 RenalGuard group Pre- procedure Procedure Post- procedure h & 54 minutes ( h) Urine flow rate (ml/h) Foley Catheter RenalGuard system Prime (223±45 ml; range = ) ConDnuous real- Dme matched replacement fluid Time (minutes) ACC 2011

32 Primary endpoint 48 hours SCr 0.3 mg/dl CI- AKI (%) % 30/146 Odds rado = 0.47; 95% CI= p = % 16/ Control group RenalGuard group ACC 2011

33 Hydration NAC Na bic. CVVH Renal Guard McCullough PA, Sandberg KR. Rev Cardiovasc Med 2003