Dr. Vijay Kunadian MBBS, MD, MRCPSenior Lecturer and Consultant Interventional Cardiologist

Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University&

Freeman Hospital, Newcastle upon Tyne

SAFETY IN THE CATH LABHow to Minimise Contrast Toxicity

I DO NOT HAVE ANY CONFLICT OF INTEREST TO DECLARE

Contrast Media in Cath Lab

• In the UK 231, 510 coronary angiography procedures per year and 87, 676 PCI procedures per year are carried out.

Definition and Incidence

• Contrast-­‐induced nephropathy (CIN):– A rise in serum creatinine by either ≥0.5 mg/dL or by ≥25% from baseline

within the first 2–3 days after contrast administration

• Incidence of CIN: – Ranges from 0.6% to 2.3%.

• CIN rate may be as high as 50% in the presence chronic renal insufficiency and diabetes mellitus.

Mechanisms of CIN

• Ischemia/hypoxemia– Contrast media reduces renal blood

flow, particularly in the medulla of the kidney.• Inhibition of NO synthesis

• Cell toxicity– CM are taken up by renal tubule cells

and interfere with mitochondria, leading to the release of stimuli for the cell to undergo apoptosis.

CIN – The Problem

• CIN is the third most common cause of acute renal failure in hospitalized patients.

• Nearly all cases reflect mild transient impairment of renal function.

• 7% require temporary dialysis or progress to end-­‐stage renal disease.

• 13%-­‐50% of patients will require permanent renal replacement therapy.

In-­‐hospital mortality is extremely high (37-­‐39%) in patients requiring dialysis after PCI.

Circulation. 2002;;105(19):2259–2264.

Risk Factors for CIN

Patient-­‐related Risk Factors• Renal insufficiency• Diabetes mellitus with

renal insufficiency• Age• Volume depletion• Hypotension• Low cardiac output• Class IV CHF• Other nephrotoxins• Renal transplant• Hypoalbuminemia (<35 g/l)

Procedure-­‐related Risk Factors• Multiple contrast media injection

within 72 hrs• High volume of contrast media• High osmolality of contrast

media

Contrast Volume

• Contrast volume (from 100 mL to 800 mL) may increase the risk of CIN, depending mainly on patient characteristics, clinical scenarios, and CIN definition.

• In one trial, the cutoff dose of contrast below which there were no cases of acute renal failure requiring dialysis after coronary intervention was 100 mL.

• However, in patients with both chronic renal insufficiency and diabetes mellitus, even less than 100 mL of contrast agent may cause CIN.

Am J Med. 1990;;89(5):615–620.Am J Med. 1997;;103(5):368–375.

RiskScore

Riskof CIN

Risk ofDialysis

≤ 5 7.5% 0.04%

6 to 10 14.0% 0.12%

11 to 16 26.1% 1.09%

≥ 16 57.3% 12.6%

Mehran et al. JACC 2004;;44:1393-­1399.

Hypotension

IABP

CHF

Age >75 years

Anemia

Diabetes

Contrast media volume

Risk Factors5

5

5

4

3

3

Integer Score

1 for each 100 cc3

Scheme to Define CIN Risk Score

Serum creatinine > 1.5mg/dl 4

eGFR <60ml/min/1.73 m22 for 40 – 604 for 20 – 406 for < 20

eGFR < 60ml/min/1.73 m2 =186 x (SCr)-­1.154 x (Age)-­0.203X (0.742 if female) x (1.210 if African American)

Calculate

OR

Prognostic significance of the proposed risk score for CIN extended to prediction of 1-­year mortality.

CIN Risk Score & 1-­‐year Mortality

31.2 33.3

15.5

5.51.9 2.0

5.7

13.5

0

5

10

15

20

25

30

35

Low Moderate High Very High

1-­year mortality

Risk Groups:Risk Score: ≤5 6 to 10 11 to 15 ≥16

Mehran et al. JACC 2004;;44:1393-­1399.

Red bars = development dataset Blue bars = validation dataset

Tested Therapies so far….

Pharmacologic strategiesHydration BeneficialNa bicarbonate May be beneficial Furosemide May be harmfulMannitol May be harmfulN-­‐acetylcysteine Inconsistent dataDopamine No benefitFenoldopam No benefitTheophylline Inconsistent dataCa channel block Inconsistent dataACEI/ARB Inconsistent dataANP No benefitProstaglandin E1 May be beneficialStatins May be beneficial

Non-­‐pharmacologic strategiesHemodialysis Inconsistent dataHemofiltration May be beneficialBenephit™ May be beneficialRenalGuard® May be beneficial

N-­‐Acetylcysteine-­‐NAC2,308 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

I T T

ConcealedRandomization

Acetylcysteine 1200mg Orally Twice Daily for 2 Doses

Before and 2 Doses After Procedure

I T T

Matching Placebo

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

Circulation 2011 Sep 13;;124(11):1250-­9.

N-­‐Acetylcysteine ACT-­‐Results

X

Circulation 2011 Sep 13;;124(11):1250-­9.

N-­‐Acetylcysteine ACT-­‐Results

Circulation 2011 Sep 13;;124(11):1250-­9.

X

Mueller, C. et al. Arch Intern Med 2002;;162:329-­336.

Hydration with 0.9% Saline

Hydration with 0.9% Saline

Mueller, C. et al. Arch Intern Med 2002;;162:329-­336.1 mL/kg of body weight per hour for 24 hours

Early Hydration with Sodium Bicarbonate

Maioli M et al. Circ Cardiovasc Interv 2011;;4:456-­462

Patients underwent primary PCI

Sodium Bicarbonate

RenalGuard System

No inadvertant volume depletion. Loading dose of 250 mL saline IV fluids matched in ‘real time’ to urine output. Low dose furosemide 0.25-­0.5 mg/kg

RenalGuard group

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

&NAC (1.5 g/L)

&limited (0.25 mg/kg) furosemide dose

Hydration by sodium bicarbonate(3 ml/Kg i.v. 1 h beforeand 1 ml/kg for 6 h after)

&NAC 1200 mg BID x 2 &

1.5 g e.v. during the procedure

Sodium Bicardonate &Acetylcysteine

REMEDIA II Trial

Circulation. 2011 Sep 13;;124(11):1260-­9

Clinical Characteristics

Control Group(N=146)

RenalGuard Group(N=146)

P

Age, yrs (mean ± SD) 75 ± 9 76 ± 8 0.31Male, % 103 (70.5%) 88 (60.5%) 0.065BMI (kg/m2) 29± 5 28 ± 5 0.16Blood pressure (mm Hg)SystolicDiastolicMean

152±2778±10103±13

152±2777±13102±15

0.99 0.760.85

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 inhibitorCalcium channel blockerAngiotensin II receptor inhibitorDiureticsb blockerStatins

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

Circulation. 2011 Sep 13;;124(11):1260-­9

Uri

ne fl

ow r

ate

(ml/h)

0

100

200

300

400

500

600

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

Foley Catheter

Rena

lGua

rd sy

stem

Prim

e (≤25

0 mL)

Furosemide (0.25 mg/kg)

Pre-­‐procedure Procedure Post-­‐ procedure

Patient ready forprocedure when urine flow rate is ≥300 ml/h

Continuous real-­‐time matched replacement fluid

Time (minutes)

Biomarkers:ÄsCr = baseline, 2, 6, 12, 24 and 48 hoursÄsCyC = baseline, 2, 6, 12, 24 and 48 hoursÄNGAL = baseline, 2, 6, 12, 24 and 48 hours

RenalGuard group

Circulation. 2011 Sep 13;;124(11):1260-­9

p <0.001

0

500

1000

1500

2000

2500

3000

Control Group RenalGuard group

Urine Volume at 24 hours

Circulation. 2011 Sep 13;;124(11):1260-­9

0

5

10

15

20

25

Control group RenalGuard group

CI-­‐AKI (%

)

30/146

16/146

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

20.5%

11%

Primary endpoint

Circulation. 2011 Sep 13;;124(11):1260-­9

NSTEMI patients with CKDundergoing urgent coronary angiography

(n=73)

Randomized (n=174)

Intention-­to-­treat sample

Allocated to control group

(n=85)

Allocated toFMH group(n=89)

2 patients excluded(withdrawal of elective coronary angiography and acute pulmonary

edema during hydration)

analyzed (n=83)per-­protocol sample

2 patients excluded(failure to insert Foley catheter)

analyzed (n=87)per-­protocol sample

Stable CKD patients undergoing elective coronary angiography

(n=101)

Marenzi G. et al. JACC Interv 2012

Consecutive CKD patients (eGFR<60ml/min/1.73m2) undergoing coronary angiography between September 1, 2008 and September 15, 2010

MYTHOS

0

5

10

15

20

25

30

35

40

Overall Elective angiography Urgent angiography

CIN incidence (%)

18%

4.6% 4%

10%

5%

32%

N=83 N=87 N=52 N=48 N=31 N=39

P=0.005RR = 0.29

(95% CI 0.10-­0.85) Control group

FMH groupP=0.44

RR = 0.42 (95% CI 0.10-­1.82)

P=0.003RR = 0.16

(95% CI 0.04-­0.58)

Marenzi G. et al. JACC Interv 2012

MYTHOS

CARE

Design• DESIGN: Prospective,

randomized, double-­blind, parallel-­group, multi-­center clinical evaluation iopamidol-­370 and iodixanol-­320

• OBJECTIVE: To compare the incidence of CIN between iopamidol-­370 and iodixanol-­320

• PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration

482 patients enrolled between July 2005 and June 2006 in 25 clinical site in North America

14 patients withdrew consent

468 assigned to a treatment arm

236 patients assigned to Iodixanol-­320

230 patients assigned to Iopamidol-­370

204 evaluable patient

Solomon, RJ et. al., Circulation 115, 3189 (2007)

210 evaluable patient

26 excluded

26 excluded

CARE

p = 0.39 p = 0.44 p = 0.15

Solomon, RJ et. al., Circulation 115, 3189 (2007)

Summary

• CIN is one of the most important independent predictors of poor outcome post PCI

• CIN remains a frequent source of acute renal failure and is associated with increased morbidity and mortality, and higher resource utilization

• Several factors predispose patients to CIN

• Preventive measures pre procedure, as well as careful post procedure management should be routine in all patients

How to minimise CIN

1. Matched Hydration

2. Discontinue nephrotoxic drugs (NSAIDS, antibiotics, etc)

3. Limit contrast agent volume

4. Low-­‐osmolar/iso-­‐osmolar agents preferable

5. RenalGuard appears promising…...