Download Influence of a Nonionic, Iso-Osmolar Contrast Medium

Influence of a Nonionic, Iso-Osmolar Contrast Medium
(Iodixanol) Versus an Ionic, Low-Osmolar Contrast Medium
(Ioxaglate) on Major Adverse Cardiac Events in Patients
Undergoing Percutaneous Transluminal Coronary Angioplasty
A Multicenter, Randomized, Double-Blind Study
Michel E. Bertrand, MD; Enrique Esplugas, MD; Jan Piessens, MD; Wenche Rasch, PhD;
for the Visipaque in Percutaneous Transluminal Coronary Angioplasty [VIP] Trial Investigators
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
Background—The potential merits and disadvantages of the use of ionic or nonionic contrast media in patients undergoing
percutaneous transluminal coronary angioplasty (PTCA) have been the subjects of controversy. The present study was
designed to evaluate the possible influence of both types of contrast media on major adverse cardiac events (MACE)
in patients undergoing PTCA.
Methods and Results—In a randomized, parallel-group, double-blind study, 1411 patients received either iodixanol (a
nonionic, iso-osmolar contrast medium) or ioxaglate (an ionic, low-osmolar contrast medium) during PTCA. A
standardized anticoagulation regimen was followed. Patients were monitored in the hospital for 2 days and followed-up
at 1 month. The primary end point, a composite of MACE (death, stroke, myocardial infarction, coronary artery bypass
grafting, and re-PTCA) after 2 days, occurred in 4.3% of the total population, with no statistically significant difference
between groups (iodixanol, 4.7%; ioxaglate, 3.9%; P50.45). Further, between 2-day and 1-month follow-ups, no
significant difference (P50.27) existed between the groups in the rates of MACE. Hypersensitivity reactions (P50.007)
and adverse drug reactions (P50.002) were significantly less frequent in the iodixanol group. The only significant
predicting factors for the occurrence of MACE were dissection/abrupt closure and country.
Conclusions—No significant differences were observed between the iodixanol and ioxaglate groups with regard to MACE,
although hypersensitivity and adverse drug reactions were significantly less frequent in patients who received iodixanol.
(Circulation. 2000;101:131-136.)
Key Words: contrast media n angioplasty n angiography n stents
T
he potential merits and disadvantages of ionic versus
nonionic contrast media during percutaneous transluminal coronary angioplasty (PTCA) and the influences of these
media on clinical outcome are controversial.1– 8 Thrombosis
and vessel dissection may influence the clinical outcome after
coronary angioplasty, a procedure that invariably damages
the endothelium and produces varying degrees of medial
injury. It has been suggested that ionic contrast media may be
advantageous in this setting because they can act as anticoagulants and inhibitors of platelet aggregation, whereas nonionic contrast media do not have these effects.1– 8 However,
results from preclinical studies are equivocal.9 –20 In addition,
clinical data are limited, and no study has shown an increase
in major adverse cardiac events (MACE) after the administration of nonionic compared with ionic contrast media.
Therefore, we designed a large-scale clinical study to evalu-
ate the possible effects of an ionic (ioxaglate) and a nonionic
(iodixanol) contrast medium on clinical outcome and MACE
in patients undergoing PTCA. The primary end point was a
composite of MACE, defined as death, stroke, myocardial
infarction (MI), and the need for coronary artery bypass
grafting (CABG) or repeated PTCA (re-PTCA). The study
population was composed of patients who had stable or
unstable angina or silent ischemia.
Methods
Study Design
A multicenter, parallel-group, randomized, double-blind study was
conducted in 32 centers in 5 European countries (Belgium, France,
Spain, Sweden, and The Netherlands). It was designed to compare
the effects of the nonionic, iso-osmolar contrast medium iodixanol
320 mg per I/mL (Visipaque, Nycomed Imaging AS) and the ionic,
Received March 17, 1999; revision received July 7, 1999; accepted July 28, 1999.
From the Division of Cardiology, Lille University Heart Institute, Lille, France (M.E.B.); Hospital de Bellvitge Princeps D’Espanya, Barcelona (E.E.);
Nycomed Amersham, Oslo, Norway; and Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium (J.P.).
Correspondence to M.E. Bertrand, MD, Division of Cardiology, Lille University Heart Institute, Boulevard du Professeur Leclercq, Lille, France.
E-mail [email protected]
© 2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
131
132
Circulation
January 18, 2000
low-osmolar contrast medium ioxaglate 320 mg I/mL (Hexabrix,
Guerbet SA) in patients undergoing PTCA. Intracoronary stenting
was allowed, and it was classified as planned or unplanned. The aim
of the study was to assess the influence of the choice of contrast
medium and of other clinical and procedural factors (eg, clinical
presentation, age, sex, and stenting condition) on the occurrence of
MACE after PTCA. Anticoagulation was standardized and monitored during the procedure by repeated measurements of the activated clotting time (ACT). The patients were randomized to receive
1 of the 2 contrast media, which were placed in identical vials to
achieve double blinding. The local ethics committees and the
national regulatory authorities of each institution and country approved the protocol. Informed written consent was obtained from
each patient before enrollment in the trial.
TABLE 1.
Baseline Clinical Characteristics
Iodixanol
(Nonionic; n5697)
Ioxaglate
(Ionic; n5714)
61.6610.6
62.3610.2
Age, y
Male, %
Weight, kg
78.2
76.2
75.9612.2
76.2612.4
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Height, cm
168.268.6
168.068.6
Diabetes, %
20.2
15.8
Current smokers, %
23.2
22.1
Former smokers, %
35.0
36.3
Obesity, %
20.1
20.2
Patients
Family history of CAD, %
30.7
26.3
Between November 21, 1996, and September 22, 1997, 1541 patients
$18 years of age who had stable (Canadian Cardiovascular Society
functional classification) or unstable angina (Braunwald’s classification system) or silent ischemia and who were undergoing PTCA
were enrolled in the study. Exclusion criteria were recent (,7 days)
acute MI, unprotected left main stenosis, or the need for oral
anticoagulation with antivitamin K. Patients were also excluded if
they had contraindications to heparin, aspirin, or ticlopidine therapy
or to iodinated contrast media. Patients who had received iodinated
contrast media within the 18 hours before PTCA were not included
to minimize the possible influence of nonstudy contrast media on the
results. The use of rotablator, directional atherectomy, or pretreatment with glycoprotein IIb/IIIa receptor inhibitors was not allowed.
Left ventricular ejection fraction was required to be .35%. In a few
centers, recruitment of patients was performed before diagnostic
catheterization, and trial contrast medium was then used for that
purpose to ensure identical contrast media throughout the procedures. Among the 1541 patients enrolled, 81 did not have PTCA, 27
had major protocol violations (the majority due to an ejection
fraction ,35% or to the presence of a recent MI), 26 were excluded
because they received a mixture of different contrast media, 3 were
excluded due to loss of their case report form or contrast medium
vials, and 7 were excluded for .1 of the above-mentioned reasons.
Of the 1411 patients who constituted the per-protocol population,
697 received iodixanol and 714 received ioxaglate.
All patients received heparin, and all but 4 received an antiplatelet
agent ($100 mg of aspirin and/or ticlopidine). An intravenous bolus
of heparin (10 000 IU) was administered at the start of the procedure.
The ACT was measured 5 minutes after the first injection of heparin,
and further heparin was given if necessary to maintain the ACT
above 250 or 300 s (depending on the apparatus used). If PTCA
lasted .1 hour, ACT was recorded again, and additional heparin was
given when required. ACT was measured again at the end of the
procedure. Ticlopidine was given to patients after stent implantation
or if otherwise indicated (eg, allergy to aspirin). Overall, 68.6% of
patients received ticlopidine either before, as routine medication, or
before/during/after PTCA. All other medications and procedures
were at the discretion of the investigator.
Prior MI, %
19.1
18.5
Prior PTCA, %
16.1
14.7
Prior CABG, %
7.1
6.7
History of allergy/hypersensitivity, %
4.7
5.7
Unstable angina
51.9
49.3
Stable angina
38.3
40.1
Silent ischemia
9.5
10.1
Follow-Up
Procedural and safety outcomes were recorded for all patients during
the hospital stay (2-day follow-up). The primary end point was a
composite of MACE during the 2-day follow-up period (2-day
MACE); it was defined as death, stroke, Q-wave or non-Q-wave MI
(NQWMI), and CABG and/or emergency re-PTCA at the target
lesion or in the target vessel. The definition of a NQWMI was an
increase in serum creatine kinase (CK) to twice the upper normal
reference range limit or more, coupled with an increase in the
CK-isoenzyme MB fraction. An independent end point classification
committee evaluated CK for all patients to determine NQWMI cases.
This independent end point classification committee, which consisted of 3 cardiologists, also evaluated, in a blinded fashion, all
reported MACE-2 day cases. The committee’s decision was based on
information from the case report form, ECGs, vital signs, laboratory
test results (pre- and post-PTCA), and films/videos from the PTCA
Indication for PTCA*, %
Data are mean6SD unless otherwise indicated. CAD indicates coronary
artery disease.
*0.4% were reported as “unknown.”
procedure. In addition to the in-hospital follow-up, the patients were
contacted by telephone (by the investigator or a study nurse) 1 month
after discharge from the hospital to ascertain if they had been
rehospitalized due to MACE. The end point classification committee
did not evaluate occurrence of MACE between the 2-day and
1-month follow-ups.
Statistical Analysis
To assess the influence of contrast media and other factors on the
occurrence of 2-day MACE, the factors were individually evaluated
through odds ratio (OR) estimates and their associated 95% confidence intervals (single-factor analyses). Testing OR deviations from
1 was done through the 2-tailed likelihood x2 test; P#0.05 was
considered statistically significant. In addition, an exploratory multiple logistic regression analysis was performed based on the results
of the single-factor analysis to identify the predictors for 2-day
MACE; it took into account possible interactions between factors.
Other adverse events, including hypersensitivity reactions, were
compared between contrast media groups at 2 days and at 1 month
using the x2 test.
The comparability of the 2 contrast media groups with regard to
baseline characteristics was assessed through the dependency of the
primary end point on each baseline characteristic. For each baseline
characteristic, the x2 P value for testing independence between the
baseline characteristic and primary end point was calculated per
contrast medium group; P,0.05 indicates dependency. In cases
where dependency is found, a large difference in the baseline
characteristics between the contrast media groups might then have
unwanted effects on the comparability of the groups.
Results
Baseline Characteristics
The baseline clinical characteristics of the study population
are presented in Table 1 and were similar in both contrast
media groups. The indications for PTCA and the location of
the treated lesions did not differ between the groups. Baseline
angiographic characteristics are given in Table 2. No signif-
Bertrand et al
TABLE 2. Baseline Angiographic Characteristics and
Procedural Outcomes
Iodixanol vs Ioxaglate for Cardiac Events
TABLE 3.
133
MACE at 2-Day Follow-Up
Iodixanol
(Nonionic; n5697)
Ioxaglate
(Ionic; n5714)
P
33 (4.7%)
28 (3.9%)
0.45
Death
0
2
NS
Stroke
2
1
NS
35.0
Q-wave MI
3
3
NS
24.8
25.6
NQWMI
24
17
0.24
CABG
1
1
NS
Baseline
84.4611.3
84.9611.8
Re-PTCA
3
4
NS
Post-PTCA
15.5618.5
14.6616.3
Baseline
5.2
4.9
Post-PTCA
2.4
2.1
Iodixanol
(Nonionic; n5697)
Ioxaglate
(Ionic; n5714)
LAD
44.1
39.4
RCA
31.1
Cx
Primary lesion location, %
Stenosis, primary lesion, %*
Thrombus, all lesions, %
Abrupt closure, all lesions, %
Dissection, all lesions, %
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Intracoronary stent, total, %
2.6
3.4
36.9
40.3
During hospital stay (2 days)
was not statistically significant (P50.18) (Table 2). Implantation of intracoronary stents was similar in both groups:
59.8% in the iodixanol group and 60.9% in the ioxaglate
group. The implantation rate varied from 36.0% in the
country with the lowest stent implantation rate (France) to
76.9% in the country with the highest rate (Belgium).
59.8
60.9
Planned
23.5
22.1
Primary End Point
Not planned
33.6
35.4
On the basis of the intention-to-treat population (1538 patients, 765 in iodixanol group and 773 in ioxaglate group),
which consisted of all enrolled patients but the 3 who had a
lost case report form or contrast medium vials, the primary
end point (2-day MACE) occurred in 4.2%, with no statistically significant differences between the iodixanol and the
ioxaglate groups (4.6% versus 3.8%, respectively; P50.42).
Among the MACE, NQWMI was the most frequent complication (2.7%). The analysis of the per-protocol population
(1411 patients) showed similar results (Table 3). No statistically significant differences existed between the iodixanol
and the ioxaglate groups (4.7% versus 3.9%; P50.45).
Among the 2-day MACE, NQWMI was the most frequent
complication (2.9%). The majority (76%) of these patients
had a .4-fold increase in CK values. Two cardiac deaths
occurred during the 2-day follow-up period, both in the
ioxaglate group. The 2-day MACE rate varied among the
centers, from 0% to 18.2% among those completing their
inclusion. One center enrolled only 7 patients and reported 2
patients with 2-day MACE. Patients who underwent stent
implantation had a 4.6% chance of developing 2-day MACE;
the chance was 3.3% when stenting was planned and 5.3%
when it was unplanned. The rate for nonstented patients was
3.9%.
Table 4 shows the ORs with 95% confidence intervals for
potential predictive factors of the occurrence of 2-day
MACE. Results from the single-factor analyses showed that
only dissection/abrupt closure (P,0.001) and country
(P50.005) were significant predictors of the occurrence of
2-day MACE. The presence of the most severe kind of lesion,
type C, was borderline with respect to its significance as a
predictor (P50.06). As shown in Table 4, contrast medium,
sex, age, clinical condition of the patient, and stenting
condition were not significant predictors for the occurrence of
2-day MACE. The multifactorial analysis gave similar
results.
Planned and not planned†
Total contrast dose, mL
2.7
211.5699.3
3.4
228.06108.5
Data are mean6SD unless otherwise indicated. LAD indicates left anterior
descending coronary artery; RCA, right coronary artery; and Cx, circumflex
coronary artery.
*Mainly based on visual assessment.
†Both planned and unplanned stent(s) were implanted.
icant relationships existed between the baseline characteristics listed in Tables 1 and 2 and 2-day MACE. Specifically,
for presence of diabetes and family history of coronary artery
disease, the 2 factors for which frequencies between the
contrast medium groups deviated most, the probability values
for testing of independence were all .0.74. Hence, these
random deviations had no influence on the rate of 2-day
MACE in the contrast media groups.
The majority of the patients underwent single-vessel PTCA
(73.0% versus 71.1%, iodixanol group versus ioxaglate
group). A total of 23% of the patients (22.2% in the iodixanol
group versus 23.4% in the ioxaglate group) had 2-vessel
PTCA, whereas the remaining patients underwent 3-vessel
PTCA. Glycoprotein IIb/IIIa receptor inhibitors were given
during or after the PTCA procedure in 23 patients (12
iodixanol and 11 ioxaglate) who had abrupt closure, stent
occlusion, or coronary dissection.
Procedural Outcome
The percent diameter stenosis at baseline and after PTCA are
reported in Table 2. No difference in percent residual stenosis
existed between the 2 groups immediately after PTCA. The
proportion of angiographically identifiable thrombus (visual
assessment) before and after PTCA was similar in both
contrast media groups (all lesions included) (Table 2). The
rates of abrupt closure (all lesions) occurring during the
procedure did not differ significantly between groups
(P50.39). Procedure-related dissections were reported somewhat less frequently in patients allocated to the iodixanol
group compared with the ioxaglate group, but the difference
One-Month Follow-Up
Similarly, in the per-protocol population, no statistically
significant differences between the 2 groups were observed
134
Circulation
TABLE 4.
January 18, 2000
ORs, Confidence Intervals, and P Values
Dissection or AC
TABLE 5.
OR
95% Confidence Interval
P
5.4
3.1–9.3
,0.001
0.34
0.16–0.78
Country*
Spain
Adverse events
Total no. of adverse events
Belgium
0.52
0.26–1.04
The Netherlands
1.2
0.46–2.9
Sweden
1.6
0.73–3.6
Type C lesion
1.7
0.98–3.1
0.06
Unplanned stent
1.4
0.85–2.4
0.17
Female
1.4
0.82–2.5
0.20
Planned stent
0.69
0.36–1.3
0.26
—
0.005
CM-related, uncertain
Clinical condition†
0.42
0.13–1.4
Stable angina
0.79
0.46–1.4
—
0.28
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Unstable angina
Age, y‡
,50
1.7
0.71–4.1
50–70
1.3
0.63–2.6
1.2
0.73–2.0
Adverse drug reactions
CM-related, certain
France
Silent ischemia
Adverse Events in Patients
—
0.35
Hypersensitivity reactions
Iodixanol
(Nonionic;
n5697)
Ioxaglate
(Ionic;
n5714)
P
192 (27.5%)
197 (27.6%)
0.98
309
304
69 (9.9%)
85 (11.9%)
0.23
0.002
7 (1.0%)
25 (3.5%)
62 (8.9%)
60 (8.4%)
5 (0.7%)
18 (2.5%)
0.007
Types of hypersensitivity reactions
Anaphylactic shock
0
1
Rash/urticaria/pruritus
5
12
Coughing/throat tightness
0
2
Rigor*
0
1
Fever
0
1
Vomiting*
0
1
Flushing
0
1
Data are no. of patients unless otherwise indicated. CM indicates contrast
medium.
*Same patient.
.70
Contrast medium,
iodixanol§
0.45
AC indicates abrupt closure.
*Other countries are compared with France.
†Clinical conditions are compared with unstable angina.
‡Ages are compared with age .70.
§Iodixanol is compared with ioxaglate.
(P50.27) with regard to rehospitalization due to MACE
during the period between the 2-day and 1-month follow-up.
The number of patients hospitalized for each event in each
group (iodixanol/ioxaglate) are as follows: cardiac death
(2/0), stroke (1/0), Q-wave MI (2/0), NQWMI (1/1), CABG
(2/1), and Re-PTCA (6/7). In total, 23 patients (1.6%) were
rehospitalized during this time period, 2.0% in the iodixanol
group and 1.3% in the ioxaglate group. These events were not
validated by the end point classification committee. Combining MACE noted at 2-day follow-up and those occurring
between the 2-day to 1-month follow-ups showed no statistically significant difference between the iodixanol and ioxaglate groups (6.3% versus 5.2%; P50.42).
Adverse Events
The percentage of patients reporting $1 adverse event during
the 2-day follow-up, including MACE, was similar in the 2
groups (27.5% versus 27.6%; Table 5). Chest pain was the
most common event reported; this was followed by hypotension, hematoma at the puncture site, nausea or vomiting, and
bradycardia. As seen in Table 5, patients randomized to the
ioxaglate group had an increased risk (P50.002) of experiencing adverse events that were classified by the investigators
as having a certain relationship to the contrast medium. These
were mainly nausea, vomiting, and rash. When pooling
contrast media–related adverse events and events having an
uncertain relationship to contrast media, the overall adverse
drug reaction frequencies were 9.9% in the iodixanol group
and 11.9% in the ioxaglate group (P50.23). Among the most
common adverse drug reactions with an uncertain relationship to contrast medium were hypotension, bradycardia, chest
pain, and hematoma.
Patients randomized to receive the ionic contrast medium
ioxaglate had an increased risk of developing hypersensitivity
reactions (P50.007) (Table 5). A total of 23 patients had such
reactions, 5 (0.7%) in the iodixanol group and 18 (2.5%) in
the ioxaglate group.
Discussion
Although nonionic contrast media are better tolerated than
ionic contrast media, their potential merits and disadvantages
in patients undergoing interventional procedures have been a
controversial subject.1–7 Studies in vitro have demonstrated
differences in vascular biocompatibility between the isoosmolar nonionic contrast medium iodixanol and the ionic
contrast medium ioxaglate.9 –18 Although both contrast media
display anticoagulant and antiplatelet properties in this setting, such effects are more marked with ioxaglate.19,20 However, iodixanol is the most biocompatible, particularly with
regard to cultured endothelium21 and vascular smooth muscle.22 Data on collagen- or tissue factor–induced arterial
thrombus formation in native blood and blood including
clinically relevant doses of aspirin and heparin were recently
published.23,24 They demonstrate no significant effects of
iodixanol, ioxaglate, or the nonionic contrast medium iohexol
on thrombin-driven (tissue factor) or platelet-driven (collagen) thrombus formation. Previously published clinical studies on intravascular thrombotic events and outcomes were
limited, and the patient populations studied were relatively
small at the time the trials were conducted. A recent exception is the study reported by Schräder et al.25 Therefore, it was
Bertrand et al
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necessary to perform a large-scale, blinded, well-controlled
study, with objective “hard” end points.
The major finding of this multicenter study was that no
difference was found in MACE between the nonionic isoosmolar and the ionic low-osmolar contrast media after both
2 days and 1 month. These results agree with the recently
reported single-center trial performed by Schräder et al.25 In
this randomized study comparing the nonionic iomeprol
(Iomeron, Bracco-Byk-Gulden) to the ionic ioxaglate in a
large series of 2000 patients, no differences were found with
regard to angiographic or clinical end points. Fewer than 20%
of their patients had unstable angina, and glycoprotein IIb/IIIa
receptor inhibitors were not used. However, the present
study’s results differ from those reported in a single-center
study by Grines et al.4 They compared ioxaglate and the
low-osmolar, nonionic contrast medium iohexol (Omnipaque,
Nycomed Imaging AS) in 211 patients with acute MI and
unstable angina undergoing PTCA. Their conclusion was that
the use of the ionic contrast medium ioxaglate reduced the
risk of ischemic complications, both acutely and at 1-month
follow-up. Results from recently published studies on the
effects of iohexol, iodixanol, and ioxaglate on vessel-wall
biocompatibility and on arterial thrombus formation23,24 do
not support the findings of Grines et al.4 However, it is
difficult to directly compare the results from the present study
with those from Grines et al,4 because many essential
differences exist between the studies. We think that the main
reasons for discrepancies in results are that the present study
included a much larger patient population (it was a multicenter study, with '7 times as many patients), patients with
acute MI were excluded, adjuvant anticoagulation was strictly
controlled, and intracoronary stenting was done according to
current practice. Finally, the nonionic contrast medium was
different in the 2 studies; the present study used the new
iso-osmolar iodixanol.
With regard to predictive factors for the occurrence of
MACE, only the procedure-related factors dissection and
abrupt closure were significant, in addition to country
(P50.45 for contrast medium). Regarding the procedural
aspects, we noted no difference between the 2 groups in
thrombus, abrupt closure, or dissection. However, the identification of thrombus is based on angiographic assessment,
and it is well known that angiography has a poor sensitivity
for the detection of thrombus.
This study reflects the present situation in Western Europe
regarding the implantation of intracoronary stents. On average, 60% of the patients were stented, but the country-tocountry variation was large (from 36.0% to 76.9%). This
variation is due to international differences in reimbursement
systems rather than to angiographic indications.
Our results confirm that hypersensitivity and adverse drug
reactions related to contrast medium injection are less frequent after the administration of nonionic contrast medium26 –31 (Table 5). These reactions were independent of the
volume of contrast media injected, which was similar in both
groups (Table 2).
Schräder et al25 concluded that nonionic contrast medium
minimized the risk of allergic reactions in patients undergoing intervention, and Gertz et al31 recommended that nonionic
Iodixanol vs Ioxaglate for Cardiac Events
135
contrast medium should be used in patients undergoing
cardiac angiography to minimize allergic reactions, especially
in patients with known allergies. This recommendation is
now also valid for patients undergoing PTCA.
Study Limitations
The implantation of intracoronary stents is increasing, both in
Europe and worldwide. During the planning phase of the
study, we anticipated an average stenting rate of '40% of
patients. The results showed an '20% higher rate of stenting,
and this fact might have contributed to the lower MACE rates
reported than was expected. The study was planned with a 6%
anticipated MACE rate. However, the lower rate of 4.3% seen
at the completion of the study did not affect the study’s ability
to detect a difference between the contrast media groups,
because the observed contrast group OR of 1.2 is well within
the confidence limits specified in the study protocol.
Only the 2-day MACE were evaluated by the independent
end point classification committee, and this should be considered when looking at the overall results, which combine
the MACE reported after 2 days with those reported after 1
month. In total, 1541 patients were enrolled, but 1411 were
included in the per-protocol population. However, the fact
that the intention-to-treat population results were in accordance with the per-protocol population results regarding
MACE indicates that the exclusion of these patients had no
influence on the results.
In total, 32 centers participated in the trial, and the individual
centers enrolled 2 to 112 patients. The disparity between the
number of enrolled patients could have influenced the final
results, but due to stratification by center, the comparison
between the 2 contrast medium groups was unbiased.
The use of glycoprotein IIb/IIIa receptor inhibitors was not the
current practice at the enrolling centers, and it was not allowed
as a preparation to intervention. Only 23 patients (1.6%) received this type of medication during or after PTCA.
Conclusions
No statistically significant differences were found between
the iso-osmolar, nonionic contrast medium iodixanol and the
low-osmolar, ionic contrast medium ioxaglate on the occurrence of MACE, either at the 2-day follow-up or during the
1-month follow-up period. In addition, the rate of abrupt
closure was similar in both groups.
Thus, we can conclude that in patients, including those
with both stable and unstable angina, receiving iodixanol, no
increase in major cardiac complications occurs when compared with those patients given ioxaglate. Furthermore, hypersensitivity and adverse drug reactions classified as certainly related to contrast medium occurred significantly less
frequently in patients receiving iodixanol.
Appendix
Investigators
France: M. Bertrand, Hôpital Cardiologique, Lille; X. Faverau,
Center Médico-Chirurgical, Le Chesnay; P. Aubry, Hôpital Bichat,
Paris; J.L. Guermonprez, Hôpital Broussais, Paris; M.-C. Morice,
Hôpital Privé de Massy, Massy; P. Besse, Hôpital Haut Leveque,
Pessac; G. Grollier, Center Hôspitalier Universitaire de Caen, Caen;
P.-D. Crochet, Hôpital Laënnec, St. Herblain; A. Cribier, Hôpital
136
Circulation
January 18, 2000
Charles Nicolle, Rouen; P. Dupouy, Hôpital Henri Mondor, Créteil;
J. Boschat, Hôpital de la Cavale Blanche, Brest; K. Khalifé, Hôpital
Notre Dame de Bon Secours, Metz.
The Netherlands: H. Suryapranata, Ziekenhuis De Weezenlanden,
Zwolle; J.J.R.M. Bonnier, Catharina Ziekenhuis, Eindhoven.
Belgium: G. Heyndrickx, Onze Lieve Vrouw Ziekenhuis, Aalst;
C. Hanet, Cliniques Universitaires St Luc, Bruxelles; F. Van den
Branden, Middelheim Ziekenhuis, Antwerpen; M. Vrolix, St. Jan
Ziekenhuis, Genk; J.H. Piessens, Universitair Ziekenhuis Gasthuisberg, Leuven; Y. Taeymans, Universitair Ziekenhuis, Gent; V.
Legrand, Center Hospitalier Universitaire, Liège; J. Dekeyser, Hôpital Civil, Jumet; P. Lafontaine, Clinique St Jean, Bruxelles.
Spain: C. Macaya, Hospital Universitario San Carlos, Madrid; E.
Garcma-Fernández, Hospital General Gregorio Marañón, Madrid; E.
Esplugas and J. Mauri, Hospital de Bellvitge Princeps D’Espanya,
Barcelona; A. Betriu and A. Serra, Hospital Clinic I Provincial,
Barcelona; A. Iñiguez, Clı́nica Nuestra Señora de la Concepción,
Madrid; C. Morı́s, Hospital General de Asturias, Oviedo; T. Colman,
Hospital Marqués de Valdecilla, Santander; M. Gómez-Recio, Hospital de la Princesa, Madrid.
Sweden: L. Grip, Sahlgrenska Sjukhuset, Göteborg.
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
Acknowledgments
We would like to thank all the investigators for their efforts during
their participation in this multicenter trial. We also wish to thank Mr
Trond Haider for the statistical analysis.
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Influence of a Nonionic, Iso-Osmolar Contrast Medium (Iodixanol) Versus an Ionic,
Low-Osmolar Contrast Medium (Ioxaglate) on Major Adverse Cardiac Events in Patients
Undergoing Percutaneous Transluminal Coronary Angioplasty: A Multicenter,
Randomized, Double-Blind Study
Michel E. Bertrand, Enrique Esplugas, Jan Piessens and Wenche Rasch
for the Visipaque in Percutaneous Transluminal Coronary Angioplasty [VIP] Trial Investigators
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Circulation. 2000;101:131-136
doi: 10.1161/01.CIR.101.2.131
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