iso-osmolar versus low-osmolar contrast media in … versus low-osmolar contrast media in reducing...
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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.
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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).
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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)
.
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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)
.