REMEDIAL II REnal Insufficiency Following Contrast MEDIA

Administration II TriaL RenalGuard system in high risk patients for contrast

induced acute kidney injury

Carlo Briguori, MD, PhDLaboratoy of Interventional Cardiology

Clinica Mediterranea, Naples - Italy

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

Background

Contrast-induced acute kidney injury (CI-AKI) is a powerful predictor of unfavorable early and late outcome1-3

Several studies showed the advantages of the prophylaxis by sodium bicarbonate solution 4-5

N-acetylcysteine (NAC) 6-7

However, in high risk patients the rate of CI-AKI is still high

1. McCullough PA. J Am Coll Cardiol 2008;51:1419-282. Solomon R. et al. Clin J Am Soc Nephrol 2009;4:1162-11693. Briguori C, et al. Circulation 2010;121:2117-2122.4. Merten GJ et al. JAMA 2004;291:2328-23345. 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

High risk patientsHypotension 5

IABP 5

CHF 5

Age > 75 years 4

Anemia 3

Diabetes 3

Contrast media volume 1 for each 100 cc3

Serum creatinine >1.5 mg/dl

OR

eGFR <60 mlmin1.73 m2

4

2 for 40-60

4 for 20-60

6 for <20

Risk

Score

Risk of CIAKI

Risk of

Dialysis

5 7.5% 0.04%

6 to 10 14% 0.12%

11 to 16

26.1% 1.09%

16 57.3% 12.6%

Mehran R et al J Am Coll CardiolJ Am Coll Cardiol 2004; 44:1393-9

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 that increasing the urine flow rate (≥150 ml/h) reduces the toxic effect of contrast 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 Coll Cardiol 1999;33:403-4112. Weinstein JM et al. Nephron 1992;62:413-4153. Solomon R, et al. N Engl J Med 1994;331:1416-1420.

Background

RenalGuard system

RenalGuard System

RenalGuard Systemclosed loop fluid management system high volume fluid pump high accuracy dual weight measuring systemsingle use intravenous set; urine collection system that interfaces with a standard Foley catheterreal-time display of urine and hydration fluid volumeuser set net fluid gain and fluid bolus administration for patients that require re-hydration prior to and during the procedureautomatic battery back-upautomatic priming of infusion settimely alerts to drain urine bag or to replace the hydration fluid bag.

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)

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)

RenalGuard group

Control group

CI-AKI(sCr ≥0.3 mg/dL at 48 h)

• 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

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

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.

RenalGuard groupRenalGuard group

REMEDIAL II trial

Hydration with normal saline Hydration with normal saline (urine flow (urine flow ≥ 300 ml/h≥ 300 ml/h))

&&NAC (1.5 g/L)NAC (1.5 g/L)

&&limited (0.25 mg/kg) furosemide doselimited (0.25 mg/kg) furosemide dose

Hydration by sodium bicarbonateHydration by sodium bicarbonate(3 ml/Kg i.v. 1 h before (3 ml/Kg i.v. 1 h before

and 1 ml/kg for 6 h after)and 1 ml/kg for 6 h after)&&

NAC 1200 mg BID x 2 & NAC 1200 mg BID x 2 & 1.5 g e.v. during the procedure1.5 g e.v. during the procedure

Sodium Bicardonate &Sodium Bicardonate &AcetylcysteineAcetylcysteine

Uri

ne

flow

rat

e (m

l/h

)

0

100

200

300

400

500

600

0 30 60 90 120 150 180 210 240 270 300 330 360 400

Fole

y Ca

thet

er

Rena

lGua

rd s

yste

mPr

ime

(≤25

0 m

L)

Furo

sem

ide

(0.2

5 m

g/kg

)

Pre-procedure Procedure Post- procedure

Patient ready forprocedure when urine flow rateis ≥300 ml/h

Continuous real-time matched replacement fluid

Time (minutes)

Biomarkers:sCr = baseline, 2, 6, 12, 24 and 48 hourssCyC = baseline, 2, 6, 12, 24 and 48 hoursNGAL = baseline, 2, 6, 12, 24 and 48 hours

RenalGuard group

RenalGuard System

• Primary endpoint:– Rate of CI-AKI, defined as a serum creatinine (sCr) increase 0.3

mg/dLat 48 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

Assessed for eligibility ( n= 806)

Exclusion (n = 512)Not meeting inclusion/exclusion criteria (n = 485 )

Refused to partecipate (n = 27)

Randomized (n = 294)

Patients lost at follow-up (n = 0) Discontinued treatment (n = 2)

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)

Patients analized ( n = 146) Patients excluded from analysis (n = 0)

Patients lost at follow-up (n = 0) Discontinued treatement (n = 0)

Patients analized ( n = 146) Patients excluded from analysis (n = 0)

Enro

llem

ent

Allo

catio

nFo

llow

-up

Anal

ysis

Clinical CharacteristicsControl Group

(N=146)

RenalGuard Group(N=146)

P

Age, yrs (mean SD) 75 9 76 8 0.31

Male, % 103 (70.5%) 88 (60.5%) 0.065

BMI (kg/m2) 29 5 28 5 0.16

Blood pressure (mm Hg) Systolic Diastolic Mean

152±2778±10

103±13

152±2777±13

102±15

0.99 0.76 0.85

LVEF, % (mean SD) 48 10 46 11 0.10LVEDP (mm Hg) 14±7 14±7 0.81Diabetes mellitus 104 (71%) 101 (69%) 0.51Hypertension, % 144 (98%) 143 (98%) 0.95Drugs: ACE inhibitor Calcium channel blocker Angiotensin II receptor inhibitor Diuretics blocker Statins

67 (46%)44 (30%)45 (31%)85 (58%)88 (60%)

111 (76%)

70 (48%)36 (25%)42 (29%)93 (64%)92 (63%)

108 (74%)

0.770.370.770.360.660.73

Biochemical CharacteristicsControl Group

(N=146)

RenalGuard Group(N=146)

P

eGFR (ml/min/1.73 m2) GFR ≤ 30

32 762 (44%)

32 969 (48.5%)

0.830.41

Serum Urea Nitrogen (mg/dL) Baseline after 48 h

78 3170 ± 30

80 3571±35

0.570.84

Serum Sodium (mEq(L) Baseline after 48 h

140 5139± 6

140 3140 ± 5

0.370.87

Serum Potassium (mEq/L) Baseline after 48 h

4.7 0.74.3 ± 0.6

4.6 0.74.2 ± 0.6

0.550.17

Procedural Characteristics

Control Group

(N=146)

RenalGuard Group(N=146)

P

Performed procedure coronary angiography PCI coronary angiography & PCI peripheral procedure

60 (41%)58 (40%)17 (11%)11 (6%)

51 (35%)71 (49%)11 (7.5%)13 (9%)

0.36

Volume of contrast media (ml) Contrast ratio >1

145 7935 (24%)

135 7628 (19%)

0.290.32

13%

72.5%

12.5%0

20

40

60

80

100

120

Risk score

≥5 ≥6-10 ≥11-15 ≥16

2%

Num

ber o

f pati

ents

Distribution of the Risk score

p <0.001

0

500

1000

1500

2000

2500

3000

Control Group RenalGuard group

Urine Volume at 24 hours

Uri

ne

flow

rat

e (m

l/h

)

0

100

200

300

400

500

600

0 30 60 90 120 150 180 210 240 270 300 330 360 400

Fole

y Ca

thet

er

Rena

lGua

rd s

yste

mPr

ime

(223

±45

mL;

rang

e =

50-3

00)

Furo

sem

ide

(14±

8mg;

rang

e =

0-50

)

Pre-procedure Procedure Post- procedure

Time to reach Target urine flow rate58±19 min (30-120)

Continuous real-time matched replacement fluid

Time (minutes)

Biomarkers:sCr = baseline, 2, 6, 12, 24 and 48 hourssCyC = baseline, 2, 6, 12, 24 and 48 hoursNGAL = baseline, 2, 6, 12, 24 and 48 hours

RenalGuard group

7 h & 54 minutes (4.7-11.5 h)

RenalGuard Group

Time (minutes)

15 45 75 105 135 165 195 225 255 285 315 345 375

Vo

lum

e (

ml)

0

500

1000

1500

2000

2500

3000

3500

4000

infusion

urine

RenalGuard Group

0

100

200

300

400

500

600

700

800

900

15 45 75 105 135 165 195 225 255 285 315 345 375

Time (minutes)

Uri

ne

flo

w r

ate

(m

l/h

)

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)

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

Baseline 24 48

Time (hours)

seru

m c

reati

nine

(med

ian)

p = 0.008; F = 4.97

Control group

RenalGuard group

sCr kinetic

0

5

10

15

20

25

Control group RenalGuard group

CI-A

KI (%

)

30/146

16/146

Odds ratio = 0.47; 95% CI= 0.24-0.92 p = 0.025

Primary endpoint

20.5%

11%

Control group (n= 146)

RenalGuard group (n= 146)

P

Changes in creatinine at 48 hours

Increase ≥0.3 mg/dL Increase ≥0.5 mg/dL Increase ≥25% Increase ≥50%

30 (20.7%) 22 (15%) 19 (13%)

11 (7.5%)

16 (11%) 9 (6%)

4 (2.7%) 1 (0.7%)

0.0250.003 0.001 0.003

Changes in cystatin C at 24 hours*

Increase ≥0.3 mg/dL Increase ≥10% Increase ≥15% Increase ≥25%

21 (15.5%) 33 (24%) 23 (17%) 14 (10%)

11 (8.5%) 22 (16%) 17 (12%) 5 (3.5%)

0.07 0.13 0.29 0.04

Changes in cystatin C a 48 hours*

Increase ≥0.3 mg/dL 29 (21%) 16 (12%) 0.045 Increase ≥10% 47 (34%) 29 (22%) 0.027 Increase ≥15% 35 (25.5%) 21 (16%) 0.050 Increase ≥25% 23 (17%) 11 (8.5%) 0.039

Secondary endpoints

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

Time (hours)

seru

m c

ysta

tin C

(med

ian)

Baseline 24 48

Control group

RenalGuard groupp = 0.004; F = 5.52

sCyC kinetic

Secondary endpointEvents rate at 1-month

0123456789

10

Dialysis DeathPulmonary Edema

Cumulative

%

p = 0.031

p = 0.62

p = 1.0

p = 0.52

4.8

0.7 0.7

2.1

4.1 4.1

9.6

6.8

Control Group

RenalGuard Group

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.

REMEDIAL II Investigators• Clinica Mediterranea, Naples

– C. Briguori (P.I.)– A. Focaccio – G. Visconti– B. Golia

• Multimedica IRCCS, Milan– F. Airoldi – D. Tavano– S. Di Biase– S. Bertoli

• University of Ferrara, Ferrara– M. Valgimigli– R. Ferrari

• University of Modena, Modena– G.M. Sangiorgi– M. G. Modena