Iso-Osmolar versus Low-Osmolar Contrast Media in

Reducing Contrast Induced Nephropathy in Patient

with Renal Impairment Undergoing Coronary

Angiography or Intervention.

Thesis submitted for partial fulfillment of master degree in cardiology

By

Emad Saleh Mousa Elgabaili, M,BB.Ch

Supervised by

Prof. Mouhamed Mahmoud Abd Elghany, MD

Professor of cardiology

Faculty of Medicine- Cairo University

Dr. Karim Said Mustafa, MD

Lecturer of cardiology

Faculty of Medicine- Cairo University

Faculty of Medicine

Cairo University

2012

ACKNOWLEDGMENT

Acknowledgment

The ability to achieve this is attributed first and foremost to ALLAH, the Gracious,

who helped us to accomplish this work.

I would like to express my great and deep appreciation and great thanks to

Prof. Dr. Mouhamed abd Elghany for his experienced supervision, valuable advices,

continuous support and encouragement.

Also I am so grateful to Dr. Karim Said Mustafa for his sincere assistance valuable

advice continuous support, advices and limitless help.

My very special thanks go to Dr. Mouhamed Hassan for his bright ideas and help

in the statistical analysis of this work.

My best appreciation and particular thanks to all my friends and colleagues in the

cardiology department-Cairo University for their kind helps.

No wards can be enough to express the extent of my gratitude to my mother, my wife,

and all my family for their limitless patience, lovely support and encouragement through

the duration of my studies.

Emad Saleh

2012

ABSTRACT

ABSTRACT

OBJECTIVES

This study was undertaken to compare the renal safety of iso-osmolar iodixanol vs. low-

osmolar iopromide in patients with chronic kidney disease (CKD) undergoing coronary

angiography and /or intervention.

BACKGROUND

With the growing number of contrast-enhanced procedures being performed for coronary

artery disease management, the safety and efficacy of iodinated contrast media (CM) have

come under increased scrutiny. Contrast-induced nephropathy (CIN) is a common cause of in-

hospital renal failure. A prior meta-analysis and studies was conflicting about the safety of

iodixanol (IOCM) compared with iopromide (LOCM) in reduce the incidence of CIN in

patients with chronic kidney disease (CKD) undergoing coronary interventions.

METHODS

One hundred ten patients with CKD (eGFR ≤ 60 mL/min/1.73m2) were randomized in 1:1

fashion to receive either iso-osmolar contrast agent (iodixanol =55) or low-osmolar contrast

agent (iopromide =55) with proper hydration. Serum creatinine levels were measured at

baseline and 48–72 hours after contrast administration. Contrast-induced nephropathy (CIN)

was defined as an increase in serum creatinine (SCr) ≥25% or 0.5 mg/dL within 72 hr of CM

administration.

ABSTRACT

RESULTS

The overall incidence of CIN expressed as a relative ≥ 25% increase in SCr was

significantly lower in iodixanol group than iopromide group (7patients (12.7%) vs. 17

patients(29.1%), P= 0.035). Similarly when expressed as an absolute ≥0.5 mg/dL increase in

SCr the incidence of CIN was significantly lower in patients who received iodixanol: 8 patients

(14.5%) compared with those who received iopromide: 19 patients (34.5%); P= 0.015. Among

all variables in the study, female gender (HR=0.29; 95% confidence interval 0.1 to 0.7,

P=0.008), use of iopromide (HR=3.59; confidence interval 1.3 to 9.3, P=0.008) and DM

appeared to be associated with higher risk of CIN by >25% and ≥0.5 mg increase SCr from

baseline.

CONCLUSIONS

In patients with impaired renal function undergoing coronary catheterization, use of iso-

osmolar contrast medium, iodixanol is associated with lower risk of contrast induced

nephropathy than the low-osmolar contrast medium, iopromide. Among many clinical and

procedure related variables, only female gender and use of contrast medium iopromide are

associated with increased risk of contrast induced nephropathy.

Key Wards: Renal impairment - Coronary Angiography – iodinated contrast media- Contrast

induced Nephropathy

I

List of abbreviations

American College of Cardiology ACC

Angiotensen Converting Enzyme Inhibitors ACE-I

Acute Coronary Syndrome ACS

American Heart Association AHA

Acute Kidney Disease AKD

Atrial Natriuretic Peptide ANP

Beta Blockers BB

Body Mass Index BMI

Body Surface Area BSA

Coronary Artery Bypasses Grafting CABG

Coronary Artery Disease CAD

Calcium Channel Blockers CCB

Confidence Interval CI

Contrast Induced Nephropathy CIN

Chronic Kidney Disease CKD

Contrast Media CM

Cyclooxygenase 2 COX2

Computed Tomography CT

Diastolic Blood Pressure DBP

Diabetes Mellitus DM

Digital Subtraction Angiography DSA

European Association for Cardio-Thoracic Surgery EACTS

Estimated Glomerular Filtration Rate eGFR

European Society of Cardiology ESC

Ethylene Ediamine Tetra Acetic Acid EDTA

Gram iodine / kilogram gI/kg

Heart Failure HF

High Osmolar Contrast Media HOCM

Hazard Ratio HR

High Viscosity Contrast Media HVCM

II

Iso Osmolar Contrast Media IOCM

Intra Venous IV

Left Ventricle LV

Low Osmolar Contrast Media LOCM

Low Viscosity Contrast Media LVCM

Left Ventricular end Diastolic Pressure LVED

Left Ventricular Ejection Fraction LVEF

Left Ventricular Systolic Pressure LVSP

Major Adverse Cardiac Events MACE

Myocardial Infarction MI

Millipascal seconds into Centipoise mpa-s

Milli-Osmoles per Kilogram Water mOsm/kg H2O

N- Acetyl Cystain NAC

Nitric Oxide NO

Non Steroidal Anti Inflammatory Drugs NSAIDS

Non ST Elevation Myocardial Infarction NSTEMI

New York Heart Association Functional Class NYHA FC

Optimal Medical Therapy OMT

Percutaneous Coronary Intervention PCI

Partial Oxygen Pressure PO2

Peripheral Vascular Disease PVD

Systolic Blood Pressure SBP

Serum Creatinine SCr

ST Elevation Myocardial Infarction STEMI

Unstable Angina UA

Delta Δ

III

Contents

Page

1 I. Introduction and aim of the work…………………………..……….

2 II. Review of literature………………………………………..………..

3 Contrast Agents in Use Today ………………………………….

6 Types of contrast media………………………………………....

17 Contrast induced nephropathy…………………………………..

20 Risk factors of CIN……………………………………………...

32 Mechanism of contrast nephropathy…………………………….

34 Methods of prevention of CIN…………………………………..

51 Future preventive approach……………………………………. .

52 Treatment of patients developed CIN………………...…………

53 I. Patients and methods…………………………………………

57 II. Statistical Analysis……………………………………………

58 III. Results………………………………………………………..

67 IV. Discussion…………………………………………………….

74 V. Limitations……………………………………………………

75 VI. Summary and Conclusions……………………………………

77 VII. Recommendations……………………………………………

78

101

105

VIII. References……………………………………………………

IX. Master Tables…………………………………………………

X. Arabic summary ………………………………………………

List of figures

Figure Page

1. Prototypic structures of contrast media …………………………………………………………. 4

2. Viscosity and osmolality of selected contrast media at 20 °C …………………………………… 5

3. The chemical structure Iopromide……………………………………………………………….. 8

4. The chemical structure of Iodixanol …........................................................................................... 12

5. Risk score for prediction of contrast-induced nephropathy by Mehran et al…………………….. 31

6. Diagram shows proposed pathophysiologic mechanisms of contrast-induced nephropathy…..... 32

7. Rates of Contrast-Induced AKI in a Meta-Analysis of 16 Trials of Iso-Osmolar Iodixanol…… 47

8. Forest Plot of RR of CI-AKI…………………………………………………………………….. 48

9. Algorithm for Management of Patients Receiving Iodinated Contrast Media …………………. 50

10. Incidence of CIN in both study groups.……………………………………………………….. 65

11. Change in SCr in both study groups…………………………………………………………… 65

12. Change in eGFR in both study groups.………………………………………………………… 66

IV

List of Tables

Tables Page

Table .1 Classification of select contrast media* used for cardiac procedures.…………………… 6

Table .2 Risk factors for contrast-medium nephropathy ………………………………………….. 20

Table .3 Recommendations for prevention of contrast-induced nephropathy (ESC/EACTS

GUIDELINES)…………………………………………………………………………………….. 49

Table .4 Baseline characteristic……………………………………………………………………. 58

Table .5 Procedural data…………………………………………………………………………… 60

Table .6 Changes in SCr and eGFR in both study groups…………………………………………. 62

Table .7 Predictors of CIN using the relative 25% definition ………………………………………… 63

Table .8 Predictors of CIN using the ≥ 0.5 mg/dl definition ………………………………………….. 64

V

1

Introduction and Aim of the work

Introduction

Over the past several decades, coronary angiography (CA) has undergone tremendous

growth. It remains the gold standard for identification and diagnosis of coronary stenosis

due to coronary artery disease (CAD).

CA has several indications and also has some reported complications. Among these

reported complications is the contrast induced nephropathy (CIN).

Several methods and strategies were used aiming at preventing this unpleasant

complication with it's consequences. These efforts included, Identification of risk factors,

hydration forced dieresis, use of drugs such as vasodilators and, N-acetylcysteine, and

choice of the type of the contrast media.

The aim of this study

1) - Compare between the iso-osmolar CM iodexanol with the low-osmolar CM

iopromide in prevention of CIN in patients with CKD.

2) - Identification of the predictors for deterioration of renal function after coronary

catheterization.

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2

Contrast angiography

Introduction

Diagnostic and interventional cardiac angiography has undergone tremendous growth over

the past several decades. Iodinated contrast media (CM) are utilized in an estimated 80 million

diagnostic and interventional cardiovascular and non-cardiovascular procedures worldwide;

annually (1)

. A great deal of this growth has been facilitated through an increased ability to

perform these procedures safely. This would have not been possible without the design and

development of several generations of intravascular contrast agents (2)

.

Contrast enhanced x-ray imaging remains essential to the diagnosis and treatment of many

types of cardiac and vascular diseases. Despite the rapid advancement in less invasive imaging

technique, only traditional angiography provides a high resolution, real time, dynamic view of

vascular structures (3)

.

Historical Background:

Soon after the discovery of X-rays by Roentgen, it was recognized that iodine was radio-

opaque. The attenuation of X-rays by iodine-containing media during radiographic

examinations resulted in the name “contrast” media. In 1901, Marcel Guerbet, Professor of

Toxicology at the School of Pharmacy in Paris, developed Lipiodol, the first organic contrast

compound. (4)

However, it was not until 1921–1922 that this iodinated oil compound was used

in radiology procedures, following myelography studies by Jacques Forestier and Jean-

Athanase Sicard. (5)

In 1928, Moses Swick developed the first water-soluble iodinated CM

suitable for intravenous use. After his initial attempts to find a soluble and stable CM

compound, Swick and colleagues went on to develop a number of more effective, safer

compounds.(6)

The first use of CM in cardiac catheterization was by Sven- Ivar Seldinger,(7)

a

young radiologist working at the Karolinska Clinic in Stockholm in 1956. By that time, the

forerunner of contemporary CM containing a tri-iodinated benzene ring compound (sodium

diatrizoate) had been produced.

REVIEW

3

Early CM was ionic, monomeric and high osmolar. In 1968, the first nonionic, monomeric,

low-osmolar CM, metrizamide, was developed by a Swedish radiologist, Torsten Almen, in an

effort to improve the safety profile of CM.(6)

He believed that the dissociation of ionic CM in

solution and the resulting effects on the osmolality of the solution were primarily responsible

for their untoward hemodynamic effects. Since metrizamide was unstable in solution, other

low-osmolar CM was developed. One of the first stable low-osmolar CM, ioxaglate, was

marketed in the United States (8)

in 1985. More recently, nonionic, dimeric, iso-osmolar CM

were developed in an attempt to further reduce their osmolality to that approaching plasma.

However, the dimeric structure of these agents resulted in a substantial increase in their

viscosity (9)

.

Contrast Agents in Use Today:

Contrast media differ significantly with regard to their physical and biochemical

properties.

Physicochemical Properties of Contrast Media

Contrast media have traditionally been classified by their physical and biochemical

properties, including structure, ionicity, osmolality and viscosity (10)

. Although intimately

related, these properties are distinct and are best discussed separately.

Structure is related to the number of benzene rings per molecule. The basic structure of all

currently used CM consists of a 2, 4, 6 tri-iodinated benzene ring. The structural composition of

iodinated CM is either a single tri-iodinated benzene ring (monomer) or 2 bound benzene rings

(dimer). Monomers and dimers can be either ionic or nonionic depending on their side chain

constituents.

Ionicity refers to the conjugation of the benzene ring structure (anion) with a non-radio-

opaque cation resulting in a water-soluble compound. Ionic monomeric CM dissociate (ionize)

in solution (i. e., in the bloodstream) into 1 anion and 1 cation, resulting in an iodine-to-particle

ratio of 3:2 (3 iodine atoms for 2 ions). Nonionic monomeric CM consist of tri-iodinated

benzene rings with hydrophilic hydroxyl groups and organic side chains placed at the 1, 3, 5

REVIEW

4

positions, which do not ionize in solution, resulting in an iodine to particle ratio (11)

of 3:1.

Dimeric CM can be composed of either 2 bound nonionic monomers or a bound nonionic and

ionic monomer, resulting in iodine-to particle ratios of 6:1 and 6:2, respectively. The iodine-to-

particle ratio and the concentration of iodine-bearing molecules in solution affect the osmolality

and amount of radio-opacity of a given CM, respectively. Based upon these differences in

structure and ionicity, iodinated CM are often grouped into 4 major categories: ionic

monomers, nonionic monomers, ionic dimers, and nonionic dimers (12)

. The chemical structures

of these prototypic CM are illustrated in figure 1.

Figure .1 Prototypic structures of contrast media (13).

REVIEW

5

Osmolality refers to the concentration of osmotically active particles in a solution. The

normal osmolality of blood is 280–295 mOsm/kg H2O. Contrast media used in cardiovascular

procedures are often referred to as high osmolar (HOCM, typical osmolality 1400–2016

mOsm/kg H2O), low osmolar (LOCM, typical osmolality 600–844 mOsm/kg H2O) or

isosmolar (290mOsm/kg H2O).(13)

Viscosity refers to the intrinsic resistance of a material to changing form and is determined

primarily by the chemical structure of CM, differences in organic side chain composition,

iodine concentration and temperature. Factors, such as molecular size and complexity of side

chains, may lead to steric hindrance of bond torsion angles, restricting rotation and resulting in

a more rigid molecule with higher viscosity. In general, viscosity is directly related to particle

size and inversely related to osmolality. As with osmolality, CM may be categorized as high

viscosity CM (HVCM) or low-viscosity CM (LVCM). The viscosities of select currently

available CM for iodine concentrations used in cardiac catheterization and percutaneous

coronary intervention (PCI) vary widely from 15.7–26.6 mPa.s at 20˚C (13)

. The relationship

between viscosity and osmolality of select LOCM is summarized in figure 2.

Figure .2 Viscosity and osmolality of selected contrast media at 20 °C (13)

.

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6

Types of Contrast Media

The properties of select CM used in cardiac procedures are summarized in table 1.

Table .1 Classification of select contrast media* used for cardiac procedures (13).

Ionic monomers include diatrizoate, iothalamate, metrizoate and ioxithalamate and were

the first class of CM agents (11)

. These agents are HOCM. Due to their high osmolality, ionic

monomers result in a number of side effects and now account for less than 3% of intravascular

CM used.

Nonionic monomers include iohexol, iopamidol, ioversol, iopromide and ioxilan (11)

.

These agents are LOCM and are available in iodine concentrations of 240–370 mgI/ml.

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7

The viscosities of nonionic monomers vary widely, depending upon their specific chemical

structure as well as iodine concentration. Ioxilan is unique due to a small hydrophobic region

within its hydrophilic side chain that leads to molecular aggregation and a reduction in the

number of osmotically active particles in solution (14)

. This results in the lowest osmolality

(695mOsm/kg H2O) and viscosity (16.3 mPa.s at 20˚C) of the nonionic monomers; thus,

ioxilan is classified as a LOCM and LVCM.

Ionic dimers available are limited to ioxaglate. Ioxaglate, like ioxilan, is a balanced LOCM

(600 mOsm/kg H2O) and LVCM (15.7 mPa.s at 20˚C) at the 320 mgI/ml concentration (13)

.

Nonionic dimers available include only iodixanol at present. Iotrolan, another nonionic

dimer, was previously withdrawn from the Japanese and European markets due to late adverse

reactions (11)

. Iodixanol is an iso-osmolar CM (290 mOsm/ kgH2O), but its large, bulky

molecular structure also makes it a HVCM (26.6 mPa.s at 20˚C). The result is a CM with the

lowest osmolality but the highest viscosity of the available CM. In addition, the high viscosity

associated with iodixanol limits its usable iodine concentration to 270–320 mgI/mL (13)

.

REVIEW

8

Examples of Low-osmolar, nonionic contrast agent and Isosmolar,

nonionic contrast agents

Low-osmolar, nonionic contrast agent (ULTRAVIST®) :- (15)

Proprietary Name:

ULTRAVIST 240, ULTRAVIST 300, ULTRAVIST 370

Non-proprietary Name: Iopromide

ULTRAVIST is a non-ionic monomeric contrast medium containing iopromide as the

active ingredient.

DESCRIPTION

ULTRAVIST® (iopromide) Injection is a nonionic, tri iodinated, water soluble x-ray

contrast agent for intravascular administration. The chemical name for iopromide is 1, 3-

Benzenedicarboxam-ide, N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5[(methoxyacetyl)amino]

-N-methyl. (Figure 3)

Iopromide has a molecular weight of 791.12 (iodine content 48.12%). CAS No.: 73334-07-

3 Chemical Formula: C18H24I3N3O8 (15)

.

Figure.3 The chemical structure Iopromide.

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9

Pharmacology

Pharmacodynamic Properties

Iopromide, which is the contrast-giving substance in the ULTRAVIST formulation, is a

derivative of tri iodinated is ophthalic acid in which the firmly bound iodine absorbs the X-

rays.

Pharmacokinetics

Distribution

Following intravascular administration, ULTRAVIST is very rapidly distributed in the

extracellular space, the half- life being 3 minutes.

Plasma protein binding with a concentration of 1.2 mg I /ml is 0.9 ± 0.2%. It is unable to

cross the intact blood-brain barrier but a small amount does cross the placental barrier (rabbit).

Five minutes after an intravenous bolus injection of ULTRAVIST 300, 28 ± 6 % of the dose

was found in the total plasma volume, irrespective of the size of the dose.

Following intrathecal administration, maximum iodine concentrations of 4.5% of the

administered dose per total plasma volume were observed after 3.8 hours (16)

.

Metabolism

No metabolites were detected in human following the administration of the clinically

relevant doses of ULTRAVIST (16)

.

Elimination

The elimination half-life in patients with normal kidney function is approximately 2 hours,

irrespective of the dose. Under the doses recommended for diagnostic purposes, filtration of

ULTRAVIST is exclusively glomerular.

Renal excretion is approximately 18 % of the dose within 30 minutes post injection,

approximately 60 % within 3 hours post injection, and 92 % within 24 hours post injection. The

total clearance was 110 and 103 mL/min. at the lower (150 mg I/mL) and at the higher dose

(370 mg I/mL) levels, respectively.

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10

After lumbar myelography, ULTRAVIST is almost completely excreted renally within 72 hr

with a prolonged half-life. Major deviations of the plasma half-life have been observed (17)

.

Characteristics in patients

In end stage renal failure patients, non-ionic contrast media can be eliminated by dialysis.

Elimination in patients with impaired liver function is not affected because only 1.5 % of the

dose is excreted in faeces after 3 days.

The influence of iopromide on clotting, fibrinolysis, complement activation and erythrocyte

morphology has been minimal (17)

.

Indications

ULTRAVIST 240/300/370 is used as a diagnostic tool, in intravascular use and use in body

cavities. Contrast enhancement in computerized tomography (CT), arteriography and

venography, intravenous/intra-arterial digital subtraction angiography (DSA), intravenous

urography, ERCP, arthrography and examination of other body cavities.

ULTRAVIST 240: is also used for intrathecal diagnosis.

ULTRAVIST 370: is used especially for angiocardiography.

ULTRAVIST 300/370: are not used for intrathecal diagnosis (17)

.

Contraindications

ULTRAVIST (iopromide) should not be administered to patients with known

hypersensitivity or previous reaction to iodinated contrast media or any excipients. Immediate

repeat myelography, in the event of technical failure, is contraindicated because of over dosage

considerations.

Hysterosalpingography must not be performed during pregnancy or in the presence of

acute inflammatory processes in the pelvic cavity (17)

.