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Interventional Cardiology

Iodinated Contrast MediaA Safety Review

R a m a n D u s a j , M D 1 a n d J o n a t h a n S R e i n e r, M D 2
1. Fellow, Cardiology; 2. Professor of Medicine and Director, Cardiac Catheterization Laboratories, George Washington University Medical Center, Washington DC

Abstract
Iodinated contrast media (CM) are administered to millions of patients every year, yet controversy continues to exist regarding the safety of the
various agents. Iodinated CM are either ionic or non-ionic, and vary in their osmolality relative to plasma. It is generally accepted that first-generation
ionic, high-osmolality CM (HOCM) are less well tolerated than non-ionic, low-osmolar CM (LOCM). However, whether there are differences in safety
among the remaining classes or individual CM, particularly with regard to nephrotoxicity and ischemic complications, remains controversial. Many
clinical studies and meta-analyses have compared the safety of the various CM and, depending on the patient population and study design,
conflicting results have often been obtained. However, strong trends are emerging to indicate that, with regard to nephrotoxicity and adverse cardiac
events, little if any differences exist among the majority of LOCM and between LOCM and the one available iso-osmolar contrast medium (IOCM).
Herein we review the data regarding the tolerability, nephrotoxicity, and thrombotic risks associated with the use of iodinated CM.

Keywords
Contrast media, contrast-induced nephropathy, major adverse cardiac events (MACE), myocardial infarction
Disclosure: Raman Dusaj, MD, has no conflicts of interest to declare. Jonathan S Reiner, MD, is a speaker for Eli Lilly and Bracco Diagnostics and a consultant for Cordis, Abbott
Vascular, and Merck.
Received: August 14, 2009 Accepted: September 4, 2009
Correspondence: Jonathan S Reiner, MD, Division of Cardiology, George Washington University Medical Center, Washington, DC 20037, US. E: jreiner@mfa.gwu.edu

The rapid development of percutaneous coronary and peripheral

vascular interventional technologies, as well as non-invasive computed
tomography (CT)-based imaging systems, has led to a dramatic increase
in the number of patients receiving intravenous or intra-arterial contrast
media (CM). It has been estimated that more than 80 million doses
(8 million litres) of contrast material are administered worldwide
each year.1 While relatively uncommon, adverse events can occur
following the administration of contrast, including both nuisance
reactions (e.g. nausea, urticaria) and potentially severe complications
(e.g. contrast-induced nephropathy [CIN] and thrombotic events). In this
article we review the evidence regarding the occurrence of adverse
effects following iodinated CM administration.

Pharmacology of Iodinated Contrast Media

Various CM possess different formulations and are generally stratified
into four categories based on whether they are ionic or non-ionic and
monomeric or dimeric (see Table 1).2 While the viscosity and osmolality
of these agents vary, all have iodine concentrations between 270 and
400mg/ml, which is sufficient to provide adequate radiographic
opacification.3 The first-generation agents (e.g. diatrizoate meglumine,
iothalamate) were hyperosmolar ionic monomers with osmolalities
approximately five to six times that of plasma. It is now generally
accepted that the immediate side effects observed with the use of these
agents relate to the ionicity and high osmolality of these drugs relative to

TOUCH BRIEFINGS 2009

plasma. In an effort to improve the tolerability of these agents, the

osmolality was lowered by making the molecules non-ionic. The next
generation of contrast agents developed were therefore non-ionic
monomers, now referred to as low-osmolality CM (LOCM), because they
possess considerably lower osmolality than the first-generation agents,
although they are still hyperosmolar relative to plasma. These
agents include iohexol (Omnipaque), iopamidol (Isovue), ioversol
(Optiray), and iopromide (Ultravist). Another approach to reducing
osmolality was to develop dimeric molecules, essentially two
tri-iodinated CM molecules joined together. One low-osmolar ionic dimer
was developed (ioxaglate, Hexabrix) and one iso-osmolar non-ionic
dimer (iodixanol, Visipaque). In general, non-ionic CM are better tolerated
than ionic CM: a review of the US Food and Drug Administration (FDA)
database revealed a significantly higher overall incidence of adverse
reactions per million examinations following administration of ionic CM
compared with non-ionic CM (193.8 versus 44.4; p<0.00001).4 However,
the relative differences in the incidence of more severe reactions among
the various agents have been more controversial.

Contrast-induced Nephropathy
Contrast-induced nephropathy, typically defined as an absolute increase
in serum creatinine (SCr) of 0.5mg/dl or a relative rise in SCr
concentration 25% within the first 1224 hours following contrast
administration without alternative explanation,5 is an ominous event in

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Interventional Cardiology
Table 1: Iodinated Contrast Media
Structure and Properties
Contrast
Generic
Name
Diatrizoate,

Medium
Trade
Name
Renografin,

Ionicity

Chemical
Structure

Class

Osmolality
(mOsm/kg)*

Ionic

Monomer

HOCM

1,5001,860

Iothalamate, Conray,
Ioxitalamate Telebrix
Ioxaglate

Hexabrix

Ionic

Dimer

LOCM

~600

Iohexol

Omnipaque

Non-ionic

Monomer

LOCM

521695

Iopamidol

Isovue

Non-ionic

Dimer

IOCM

290320

Ioversol

Optiray

Iopromide

Ultravist

Iodixanol

Visipaque

HOCM = high-osmolality contrast medium; LOCM = low-osmolality contrast medium;

IOCM = iso-osmolality contrast medium.
*With a concentration of 300320mg/ml.

Incidence of contrast-induced
nephropathy(%)

Figure 1: Incidence of Contrast-induced Nephropathy in

Patients with Chronic Kidney Disease Receiving the
Low-osmolality Contrast Media Iohexol and Iopamidol and
the Iso-osmolality Contrast Media Iodixanol in Various
Prospective Studies 12

of >0.5mg/dl following administration of LOCM was 0.61 (95% confidence

interval [CI] 0.480.77) times that of HOCM. For patients with pre-existing
renal failure, this OR was 0.5 (CI 0.360.68), while in patients without
prior renal failure it was 0.75 (CI 0.521.1).

p<0.001

40
35

p<0.001

30
25
20
15
10
5
0

22%

10%

11%

Iohexol
Omnipaque
844mOsm/kg

Iodixanol
Visipaque
290mOsm/kg

Iopamidol
Isovue
796mOsm/kg

p = not significant

cardiology patients and its occurrence is a potent predictor of mortality. In

a prospective trial of 439 patients with chronic kidney disease (SCr
1.8mg/dl) undergoing coronary angiography and intervention, an
increase in SCr 25% was associated with an increase of both in-hospital
mortality (17.0 versus 3.9%; p<0.01) and one-year mortality (43.3 versus
20.1%; p<0.001).6 In a larger retrospective analysis of 7,586 patients
undergoing coronary intervention at the Mayo Clinic, CIN was a strong
predictor of in-hospital death with an odds ratio (OR) of 10.8 (p<0.0001),
and was second only to pre-procedure shock (OR=12.1).7 In patients for
whom CIN requires treatment with dialysis, in-hospital mortality increases
even further: in a study of 1,826 patients undergoing coronary
intervention, in-hospital mortality was 35.7% in patients who developed
CIN and required dialysis, 7.1% in patients who developed CIN but did not
require dialysis, and 1.1% in patients who did not develop CIN
(p=0.0000001). Moreover, in this large group of patients, survival at two
years in dialyzed patients was only 18.8%.8 In the 12-month follow-up data
from the Cardiac Angiography in Renally Impaired Patients (CARE) study,9
the incidence of negative outcomes was increased in patients who
developed CIN compared with those who did not, including adverse
events (i.e. death, stroke, myocardial infarction [MI], and end-stage renal
disease [ESRD] requiring dialysis), as well as percutaneous coronary

98

intervention (PCI), coronary artery bypass grafting (CABG), other

revascularization procedure, cardiac arrest, congestive heart failure (CHF),
pulmonary edema, or need for permanent pacing. Due to the potentially
serious consequences of CIN, multiple studies were conducted in the
1990s to investigate whether the incidence of CIN could be reduced by
the use of a LOCM. Overall, these studies found that compared with
high-osmolality CM (HOCM), the incidence of CIN is reduced in patients
receiving LOCM, and that this reduction is most striking in patients with
pre-existing chronic kidney disease.1016 In a trial by Rudnick et al.16 in
which 1,196 patients were randomized to receive the non-ionic LOCM
iohexol or the ionic agent diatrizoate meglumine, differences in the
incidence of CIN were demonstrated only in patients with chronic kidney
disease with or without diabetes. In patients with a baseline SCr
>1.4mg/dl, an increase in SCr of >1mg/dl was demonstrated in 7.2% of
patients receiving the LOCM versus 15.8% of those receiving the
high-osmolality agent. This effect was more pronounced if the patients
had coexisting diabetes: 11.8% developed CIN with LOCM versus 27%
with HOCM.16 The largest pool of data comparing the relative
nephrotoxicity of high- versus low-osmolality agents in patients with
pre-existing chronic kidney disease is found in a meta-analysis by
Barrett.17 In this analysis of 25 clinical trials, the pooled OR for a rise in SCr

As use of LOCM results in fewer immediate adverse effects and less

commonly results in CIN compared with HOCM, the former have become
the preferred agents for most arterial and venous imaging. More
controversial has been the issue of whether there is a difference in the
incidence of CIN among the newer-generation contrast agents. Much of
the controversy was generated by the Nephrotoxicity in High-Risk Patients
Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media
(NEPHRIC) trial published in 2003 by Aspelin et al.18 The NEPHRIC study
was a small trial that enroled 129 patients with chronic kidney disease
and diabetes and randomized the patients to the iso-osmolar CM
(IOCM) iodixanol or the LOCM iohexol. Baseline SCr in the study ranged
from 1.5 to 3.5mg/dl and CIN was defined as an increase in SCr of at least
0.5mg/dl. CIN occurred in 3% of patients given iodixanol versus 26% of
those who received iohexol.18 Although this initial study found a lower
incidence of CIN in patients treated with iodixanol, several more
recent, larger trials with different comparator agents failed to show an
advantage for iodixanol. In fact, in 2005 a meta-analysis of 17 primary
studies including a total of 1,365 patients was published12 that suggested
that among LOCM, iohexol significantly increased the risk for CIN, while
there was no difference between other LOCM and the IOCM iodixanol
(see Figure 1).
In the 2008 Visipaque Angiography/Interventions with Laboratory
Outcomes in Renal Insufficiency (VALOR) trial, 337 patients with stable
chronic kidney disease undergoing coronary angiography were
randomized to receive the IOCM iodixanol or the LOCM ioversol.19 The
VALOR investigators found no difference in the overall incidence of CIN
in the iodixanol subjects compared with the ioversol subjects (21.8
versus 23.8%; p=0.78). However, in the subset of patients with diabetes,
CIN was significantly lower in the iodixanol compared with the ioversol

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Iodinated Contrast MediaA Safety Review

In addition to the choice of contrast agent, the route of administration

may affect the risk for developing CIN: intra-arterial administration of CM
is believed to be associated with an increased incidence of CIN. Several
recent studies have evaluated the relative risk for CIN in patients receiving
IOCM and LOCM intravenously. The Impaired Patients Undergoing
Computed Tomography (IMPACT) study from 2006 compared CIN rates
following intravenous administration of the LOCM iopamidol and the IOCM
iodixanol in 166 patients with stable moderate to severe chronic kidney
disease undergoing contrast-enhanced CT of the liver or peripheral
arteries.21 None of the patients receiving iopamidol and two of 76 patients
receiving iodixanol demonstrated an absolute increase in SCr 0.5mg/dl.
In the Patients With Renal Impairment and Diabetes Undergoing
Computed Tomography (PREDICT) study, Kuhn et al. compared the rates of
CIN after intravenous administration of iopamidol and iodixanol in 263
patients with both moderate to severe chronic kidney disease and
diabetes.22 Increases in the SCr of 25% occurred in seven patients (5.6%)
in the iopamidol group and six (4.9%) in the iodixanol group (p=1.0) in this
high-risk population similar to those included in the NEPHRIC trial. The
conclusion of these studies is that when administered intravenously,
the rate of CIN is low and similar for the IOCM iodixanol and the LOCM
iopamidol, even in patients at highest risk for CIN. Finally, in a recent metaanalysis of 25 randomized trials (including both intravenous and intraarterial administration) comparing iodixanol with various LOCM, iodixanol
did not significantly reduce the risk for CIN (relative risk [RR] 0.80; 95% CI
0.611.04).23 However, in this meta-analysis, patients with intra-arterial
administration and renal insufficiency who received iohexol did have a
greater risk for CIN than those treated with iodixanol (RR 0.38; 95% CI
0.210.68), while this difference was not observed when LOCM other than
iohexol were analyzed.

Figure 2: Results from the Cardiac Angiography in Renally

Impaired Patients Trial
Contrast-induced nephropathy (%)

subjects (12.9 versus 22.4%; p=0.01). The CARE trial published by

Solomon et al. in 2007 is the largest of these comparative CIN studies,
enroling 482 patients with chronic kidney disease undergoing coronary
angiography or percutaneous intervention. Patients were randomized to
either the LOCM iopamidol or the IOCM iodixanol.20 This trial contained a
large cohort of patients with diabetes (n=170). The primary end-point of
the study was the incidence of CIN (post-dose SCr increase of 0.5mg/dl
over baseline). Overall, CIN occurred in 4.4% of patients treated with
iopamidol and 6.7% of patients treated with iodixanol (p=0.39) (see Figure
2). Unlike in the VALOR trial, the use of iodixanol was not associated with
lower CIN rates in the diabetic population (13.0% of patients after
iodixanol and 5.1% after iopamidol; p=0.11). When long-term (over
one-year) follow-up data on 294 patients who participated in the CARE
trial were independently evaluated, the rate of long-term adverse events
was found to be higher in individuals with CIN.9 In addition, it was found
that randomization to the LOCM iopamidol was associated with a reduced
incidence of both CIN and major adverse events (death, stroke, MI, and
ESRD requiring dialysis) compared with iodixanol (11 versus 15%; p=0.02),
suggesting once again that IOCM are not safer for high-risk patients
undergoing cardiac angiography.

18

p=0.11

16
14
12
10

p=0.39

p=0.45

6
4
2
0

Total Population

Patients without diabetes Patients with diabetes

Iopamidol-370

Iodixanol-320

Incidence of contrast-induced nephropathy (increase in SCr of 0.5mg/dl from baseline) in the

total population and subgroups of patients without and with diabetes.20

Table 2: Incidence of Major Adverse Cardiac Events

with Ionic and Non-ionic Contrast Media from a
Meta-analysis of 10 Contrast Media Trials 3
MACE
Emergent CABG, n (%)

Ionic CM (n=3,230)
36 (1.1)

Non-ionic CM (n=3,164)
41 (1.3)

Myocardial infarction, n (%)

99 (3.1)

94 (3.0)

Cardiac death, n (%)

14 (0.4)

14 (0.4)

MACE = major adverse cardiac events; CM = contrast media; CABG = coronary artery
bypass graft.

properties of iodinated CM. Robertson noted that clot formation in

syringes proceeded more quickly following administration of non-ionic
versus ionic CM;24 however, other reports produced conflicting results
concerning the procoagulant effect of CM or whether ionic and
non-ionic agents differ in their prothrombotic properties.2527
In the 1990s, a total of 10 randomized trials were performed comparing
ionic and non-ionic CM in patients undergoing coronary angioplasty. In
the first, Lembo and colleagues found no difference in the incidence of
hospital complications (MI, emergency CABG or death) in 913 patients
randomized to receive either non-ionic iopamidol or ionic diatrizoate
meglumine.28 Six additional trials2934 compared the ionic CM ioxaglate
with either iopamidol or iohexol, both non-ionic CM. In all of these
trials, in-laboratory thrombotic events, recurrent ischemic events,
recatheterization, and subacute recoil were reduced in patients
receiving the ionic CM ioxaglate. However, at the time these trials were
performed, glycoprotein IIb/IIIa receptor inhibitors (e.g. abciximab) and
coronary stenting were not routinely used, and thus these results may
not be relevant to current clinical practice.

Thrombotic Events

In 1999, Schrader et al. performed a large, multicenter, randomized trial in

which the ionic agent ioxaglate was compared with the non-ionic agent
iomeprol in 2,000 patients undergoing coronary angioplasty.35 In this trial,
stenting was performed appropriately and the investigators found no
difference in the rate of major ischemic complications after administration
of either CM (emergency bypass surgery: 0.8 versus 0.7%; MI: 1.8 versus
2.0%; and cardiac death during hospital stay: 0.2 versus 0.2%).

After case reports of adverse thrombotic events during or after

diagnostic or therapeutic proceduresranging from observation of wire
thrombus to frank angiographically visible thrombiwere reported in
the 1980s, concern developed about the potential prothrombotic

In 2000, two additional large trials comparing non-ionic and ionic CM

were performed: the European Visipaque In PTCA (VIP) trial36 and the US
Contrast Media Utilization in High-risk PTCA (COURT) trial.37 The results of

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Interventional Cardiology
the VIP trial, a randomized comparison of non-ionic iodixanol and ionic
ioxaglate in 1,411 patients undergoing coronary intervention in the
setting of stable or unstable angina, were consistent with those of
the trial by Schrader et al.: no significant difference was found in major
adverse cardiac events (MACE) at 30 days (non-ionic iodixanol versus
ionic ioxaglate: 6.3 versus 5.2%; p=0.42).36 Furthermore, no significant
differences were found in peri-procedural events: abrupt closure
occurred in 2.6% of patients receiving non-ionic iodixanol versus 3.4%
of those receiving ionic ioxaglate (p=0.39). However, the incidence of
CM-related adverse events was higher with the ionic ioxaglate than with
the non-ionic iodixanol, with the difference being significant in terms of
both cardiac-related adverse reactions (3.5 versus 1.0%; p=0.002) and
hypersensitivity reactions (2.5 versus 0.7%; p=0.007).
In the COURT trial, a randomized , double-blind trial of 856 high-risk
patients undergoing coronary intervention, a significant difference in
MACE at two-day follow-up was seen with the non-ionic iodixanol
compared with the ionic ioxaglate (5.4 versus 9.5%, respectively;
p=0.027); however, when the 30-day composite MACE rates were
compared, the difference between iodixanol and ioxaglate was no
longer significant (9.1 versus 13.4%; p=0.07).37 The significant difference
seen two days after the procedure could be attributed to a significant
reduction in the incidence of non-fatal MI with iodixanol versus
ioxaglate (eight versus 18; p=0.05) and in-hospital abrupt closure
(three versus 10; p=0.05). However, in the subgroup treated with
abciximab (n=345), the two-day difference in MACE rates was no longer
observed (10.5% with iodixanol versus 11.5% with ioxaglate; p=0.77).
The largest data set addressing the issue of non-ionic versus ionic
contrast agents with regard to MACE comes from a meta-analysis of 10
randomized trials. In this analysis of over 6,000 patients, the overall
incidence of MACE was equivalent following administration of non-ionic
and ionic agents (4.7 and 4.6%, respectively).3 Specifically, no differences
were found between non-ionic and ionic CM in the incidence of
emergent bypass surgery (1.3 versus 1.1%), MI (3.0 versus 3.1%), and
cardiac death (0.4% with both types of CM) (see Table 2).
Data evaluating differences in the incidence of MACE following
administration of IOCM compared with LOCM are similarly
unconvincing. The Visipaque (iodixanol) versus Isovue (iopamidol) in
Cardiac Complications (VICC) trial38 compared the IOCM iodixanol with
the LOCM iopamidol in 1,276 patients undergoing PCI. The majority of
patients received glycoprotein IIb/IIIa receptor inhibitors, and stents
were placed as appropriate. After 30 days, no difference was found in
the overall MACE rate (iopamidol 14.1% versus iodixanol 12.2%; p=0.32);

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100

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however, the incidence of MI was lower with iodixanol (5.3 versus 9.4%;
p=0.005), whereas repeat catheterization was less frequent with
iopamidol (1.0 versus 2.5%; p=0.05). In-hospital MACE was increased in
the iopamidol arm of the study, a result driven primarily by the higher
incidence of non-Q-wave MI in the iopamidol group (7.5 versus 3.4% in
the iodixanol group).38 The lack of difference in the overall MACE by 30
days appears related to the significant increase in re-catheterization and
late PCI in the iodixanol group.
Certain study design issues with the VICC trial must be taken into
account when evaluating the results of this study. First, baseline and
post-procedure laboratory tests, including biomarker tests, were not
mandatory, and 27.9% of iopamidol patients and 13.6% of iodixanol
patients subsequently found to have a non-Q-wave MI did not have a
baseline creatine kinase MB (CK-MB) determination.38 Consequently, it
cannot be excluded that several of the non-Q-wave MI events responsible
for the significant difference in the in-hospital MACE rate were present
prior to cardiac catheterization and therefore were not related to the
procedure. The second potential limitation of the VICC study relates to
the study design. In the VICC trial, subjects who had undergone diagnostic
angiography with any contrast agent could enter the trial without any
washout period and be randomized to a different contrast agent for their
PCI procedure. Consequently, it cannot be excluded that the recorded
incidence of MACE, particularly the in-hospital MACE, was influenced by
previous administration of a CM other than the one to which the patient
was randomly assigned. In fact, if patients who received a mixture of
contrast agents were eliminated from the analysis (approximately
one-third of all patients), there was no statistically significant difference
between iopamidol and iodixanol in terms of in-hospital or 30-day MACE,
although the rate of re-PCI was still higher in the iodixanol group.

Conclusion
Non-ionic CM are clearly better tolerated by patients than ionic CM, but
the difference among agents regarding CIN or thrombotic adverse
events is more complex. There is solid evidence that use of LOCM
results in less nephrotoxicity in high-risk patients with pre-existing
chronic kidney disease and diabetes compared with the first-generation
ionic HOCM. Differences in the risk for CIN among the non-ionic agents
are more subtle, and multiple randomized trial and meta-analyses do
not support a difference in the incidence of CIN between the IOCM
iodixanol and any of the LOCM, with the possible exception of iohexol.
When comparing ionic with non-ionic agents, there does not appear to
be a significant difference in clinically significant thrombotic events; nor
is there a difference in MACE when comparing IOCM with LOCM. n

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