Does the application of X-ray contrast agents impair the clinical effect of intravenous recombinant tissue-type plasminogen activator in acute ischemic stroke patients?
ABSTRACT Experimental data suggest a negative interaction between x-ray contrast agents and fibrinolytic efficacy of recombinant tissue-type plasminogen activator (rtPA). We hypothesized that the application of a contrast agent before intravenous thrombolysis with rtPA reduces its clinical efficacy in acute ischemic stroke.
We retrospectively studied consecutive ischemic stroke patients receiving contrast agents for computed tomography angiography before intravenous treatment with rtPA. We compared functional outcomes with an historical control group from the Canadian Alteplase for Stroke Effectiveness Study who did not receive contrast agents before thrombolysis with rtPA. Primary end point was favorable functional outcome at 90 days defined as modified Rankin Scale scores 0 to 2. We performed logistic regression analysis and a propensity score matching analysis to estimate the effect size of contrast agent use as a negative predictor of outcome.
We identified 111 patients for the computed tomography angiography and 1119 patients for the control group. Proportions of favorable functional outcome were 47.7% (53/111 patients) for the computed tomography angiography group and 49.5% (542/1094 patients) for the control group (P=0.77). Adjusted probabilities for favorable outcome were 0.48 (95% CI, 0.37-0.58) and 0.51 (95% CI, 0.47-0.54), respectively. Contrast use was associated with reduced odds of favorable outcome (OR, 0.62(;) 95% CI, 0.38-0.99). Propensity score matching suggested a larger effect size (OR, 10.0%; 95% CI, 0.5%-19.3%).
Our study did not show a significant negative clinical effect of x-ray contrast agents applied before intravenous thrombolysis with rtPA. However, to confirm a possible small negative interaction between contrast agents and rtPA, additional experimental and prospective clinical studies are needed.
- SourceAvailable from: Frank L Silver[show abstract] [hide abstract]
ABSTRACT: Intravenous tissue-type plasminogen activator can be beneficial to some patients when given within 3 hours of stroke onset, but many patients present later after stroke onset and alternative treatments are needed. To determine the clinical efficacy and safety of intra-arterial (IA) recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours' duration caused by middle cerebral artery (MCA) occlusion. PROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled, multicenter, open-label clinical trial with blinded follow-up conducted between February 1996 and August 1998. Fifty-four centers in the United States and Canada. A total of 180 patients with acute ischemic stroke of less than 6 hours' duration caused by angiographically proven occlusion of the MCA and without hemorrhage or major early infarction signs on computed tomographic scan. Patients were randomized to receive 9 mg of IA r-proUK plus heparin (n = 121) or heparin only (n = 59). The primary outcome, analyzed by intention-to-treat, was based on the proportion of patients with slight or no neurological disability at 90 days as defined by a modified Rankin score of 2 or less. Secondary outcomes included MCA recanalization, the frequency of intracranial hemorrhage with neurological deterioration, and mortality. For the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25% for the r-proUK group and 27% for the control group. The recanalization rate was 66% for the r-proUK group and 18% for the control group (P<.001). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06). Despite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.JAMA The Journal of the American Medical Association 01/2000; 282(21):2003-11. · 29.98 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The incidence of contrast-induced nephropathy was examined in 1,075 patients receiving routine CT angiography and CT perfusion brain imaging at a single institution. Fifty-two patients had a creatinine rise of > or =0.5 mg/dL. In four patients (0.37%), the administration of IV contrast medium possibly contributed to renal failure. Two patients (0.19%) received temporary hemodialysis during hospitalization. The incidence of contrast nephropathy in neurovascular patients is low.Neurology 05/2005; 64(10):1805-6. · 8.25 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Minimal research has evaluated the renal safety of emergent computed tomography angiography (CTA) procedures, consecutive contrast medium application, and the long-term outcome in acute stroke patients. We investigated the incidence of contrast-induced renal impairment in these populations. We retrospectively reviewed patients with acute stroke syndrome who received a CTA of the brain with or without the neck within 24 hours from onset of symptoms. All creatinine results and additional conventional angiography findings were recorded. With a positive history of renal disease, contrast administration was delayed until creatinine results were available. Radiocontrast nephropathy (RCN) was defined as a >/=25% increase in serum creatinine from the baseline value up to 5 days after CTA. Four hundred eighty-one patients were reviewed, and 224 met the inclusion criteria. There were 7 of 224 (3%) who fulfilled the criteria for RCN. A number of patients underwent emergent CTA without knowledge of their creatinine value; 2 of 93 (2%) developed RCN. There were 36 patients who received an additional digital subtraction angiogram, and none of these developed subsequent RCN. No patients required dialysis, and 9 of 68 (13%) had a >25% increase in their creatinine levels at a late (>30 days) follow-up. Overall, these results illustrate that there is a low incidence of RCN in acute stroke patients undergoing emergency CTA.Stroke 09/2007; 38(8):2364-6. · 6.16 Impact Factor
Does the Application of X-Ray Contrast Agents Impair the
Clinical Effect of Intravenous Recombinant Tissue-Type
Plasminogen Activator in Acute Ischemic Stroke Patients?
Imanuel Dzialowski, MD; Volker Puetz, MD; Alastair M. Buchan, Prof; Andrew M. Demchuk, MD;
Michael D. Hill, MD; for the Calgary Stroke Program
Background and Purpose—Experimental data suggest a negative interaction between x-ray contrast agents and fibrinolytic
efficacy of recombinant tissue-type plasminogen activator (rtPA). We hypothesized that the application of a contrast
agent before intravenous thrombolysis with rtPA reduces its clinical efficacy in acute ischemic stroke.
Methods—We retrospectively studied consecutive ischemic stroke patients receiving contrast agents for computed
tomography angiography before intravenous treatment with rtPA. We compared functional outcomes with an historical
control group from the Canadian Alteplase for Stroke Effectiveness Study who did not receive contrast agents before
thrombolysis with rtPA. Primary end point was favorable functional outcome at 90 days defined as modified Rankin
Scale scores 0 to 2. We performed logistic regression analysis and a propensity score matching analysis to estimate the
effect size of contrast agent use as a negative predictor of outcome.
Results—We identified 111 patients for the computed tomography angiography and 1119 patients for the control group.
Proportions of favorable functional outcome were 47.7% (53/111 patients) for the computed tomography angiography
group and 49.5% (542/1094 patients) for the control group (P?0.77). Adjusted probabilities for favorable outcome were
0.48 (95% CI, 0.37–0.58) and 0.51 (95% CI, 0.47–0.54), respectively. Contrast use was associated with reduced odds
of favorable outcome (OR, 0.62;95% CI, 0.38–0.99). Propensity score matching suggested a larger effect size (OR,
10.0%; 95% CI, 0.5%–19.3%).
Conclusions—Our study did not show a significant negative clinical effect of x-ray contrast agents applied before
intravenous thrombolysis with rtPA. However, to confirm a possible small negative interaction between contrast agents
and rtPA, additional experimental and prospective clinical studies are needed. (Stroke. 2012;43:00-00.)
Key Words: acute stroke ? CT ? thrombolysis
stroke centers worldwide. NCCT can exclude intracerebral
hemorrhage and allows an inclusive diagnosis of ischemic
stroke before initiation of intravenous (IV) thrombolysis in
many cases. Multimodal computed tomography techniques
are increasingly used to determine intra- and extracranial
arterial status and to determine cerebral perfusion parame-
ters.1,2Moreover, intra-arterial (IA) interventions seem prom-
ising to improve recanalization rates and clinical outcomes3
and are currently tested in a large phase III clinical trial.4
All of these evolving techniques require the application of
x-ray contrast agents. Widely used contrast agents used in CT
diagnostics are typically iodinated, nonionic, and iso- or
low-osmolar. The traditional safety concern regarding these
contrast agents is the development of radio-contrast nephrop-
n acute ischemic stroke, noncontrast computed tomogra-
phy (NCCT) is the preferred imaging modality in most
athy, which has recently been shown to occur at very low
rates in the setting of acute ischemic stroke.5,6Other effects of
radiographic contrast agents, such as negative change in the
Hgb-O2 dissociation curve,7changes in arterial caliber, hy-
perkalemia,8and blood-brain barrier disruption9are all sug-
gestive of adverse pharmacological properties that remain
largely unexplored in the clinical setting.
A less recognized concern is a possible interaction between
x-ray contrast agents and thrombolysis.10Experimental data
from the cardiology literature suggest that contrast agents
markedly delay the onset of thrombolysis of recombinant
tissue-type plasminogen activator (rtPA), streptokinase, and
urokinase.11In coronary thrombosis in dogs, rtPA-induced
reperfusion was significantly delayed in the presence of both
ionic and nonionic iodinated contrast agents.12Whereas in
current cardiology clinical practice, the interaction between
Received January 25, 2012; accepted February 16, 2012.
From the Department of Clinical Neurosciences (I.D., V.P., A.M.D., M.D.H.), University of Calgary, Calgary Stroke Program, Canada; Department
of Neurology (I.D., V.P.), Dresden University Stroke Centre, Technical University Dresden, Dresden, Germany; Department of Geratology (A.M.B.),
University of Oxford, Oxford, UK.
Correspondence to Imanuel Dzialowski, MD, Dresden University Stroke Centre, Department of Neurology, Technical University Dresden,
Fetscherstrasse 74, 01307 Dresden, Germany. E-mail firstname.lastname@example.org
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.orgDOI: 10.1161/STROKEAHA.112.651737
by guest on April 11, 2012 http://stroke.ahajournals.org/Downloaded from
contrast agents and fibrinolysis is negligible because of
prevailing mechanical recanalization techniques, it might
play an important rule for acute ischemic stroke.
We retrospectively studied whether the application of x-ray
contrast agents impairs the effectiveness of IV rtPA on
improved functional outcome in acute ischemic stroke pa-
tients to decide whether a prospective observation is
Materials and Methods
With approval of our institutional ethics review board, we used a
retrospective cohort design to study consecutive patients with acute
ischemic stroke who received x-ray contrast agent to perform a CT
angiography (CTA) before IV thrombolysis with rtPA. We compared
their functional outcomes with an historical control group of patients
who did not receive x-ray contrast agents for CTA before standard
IV thrombolysis, ie, patients from the Canadian Alteplase for Stroke
Effectiveness Study (CASES).13
Patients Receiving CTA Before Thrombolysis
We analyzed consecutive patients (April 2002–September 2006)
who received CTA for acute ischemic stroke at a single tertiary care
stroke center. All patients were retrospectively documented in a CTA
database that contains clinical baseline data, including the National
Institute of Health Stroke Scale (NIHSS) score and the modified
Rankin Scale (mRS) score; these were documented prospectively on
admission. In cases where these scores were unavailable, they were
derived retrospectively. Patients were regularly seen at 90 days
poststroke for clinical follow-up and the mRS score was prospec-
tively recorded. Missing functional outcome data were imputed
from the discharge mRS using the last-score-carried-forward
principle. To qualify for our analysis, patients had to be treated
with IV rtPA within 6 hours from symptom onset. Exclusion
criteria were a premorbid mRS score ?3 and any primary or
additional IA intervention.
All patients were examined with standard NCCT followed by
CTA of the circle of Willis and optional CTA of the neck. The
decision to perform a CTA was made at the discretion of the treating
stroke neurologist and did not follow an institutional protocol.
Overall, CTA was only sporadically performed at the beginning of
the study period and evolved to frequent/routine use in potential rtPA
patients at the end of the study period. CTA was usually ordered to
confirm the presence and determine the site and thrombus burden of
an arterial occlusion. At the discretion of the treating stroke neurol-
ogist and neuroradiologist, this information might have been used to
initiate additional (IV/IA) or primary endovascular therapy. Target
patients usually presented with a proximal intracranial arterial
occlusion without signs of extensive early ischemic changes on
We performed standard NCCT on a multislice CT scanner (GE
Medical Systems or Siemens Medical Solutions) using 170 mV, 120
mAS with 5-mm slice thickness. Coverage was from skull base to
vertex with continuous axial slices parallel to the orbitomeatal line.
CTA was performed with a helical scan technique. We obtained
acquisitions after a single bolus IV injection of 90 to 120 mL of the
iodinated, nonionic, low-osmolar contrast agent ioversol (Optiray-
320) into an anticubital vein at 3 to 5 mL/s. Image acquisition was
autotriggered by the appearance of contrast media in the ascending
aorta. Minimum coverage was from foramen magnum to centrum
semiovale with 0.6-mm to 1.0-mm slice thickness.
Control Group: CASES Patients
Detailed methods and results from the CASES study have been
published previously.13In brief, the CASES study was a prospective
observational cohort study assessing the safety and effectiveness of
IV rtPA for acute ischemic stroke. The study was mandated by the
federal government as a condition of licensure of rtPA for the
treatment of acute stroke in Canada. Over 2.5 years (1999–2001), a
total of 1135 consecutive patients were enrolled at 60 centers across
Canada. Each center obtained Institutional Review Board approval
as required for the data collection protocol. Functional outcomes
were collected at 90 days after stroke using mRS score. Patients in
CASES did not receive contrast agents before IV thrombolysis.
Those few patients who received x-ray contrast agents for combined
IV/IA therapy were excluded from this analysis.
For both groups, we assessed the presence and extent of early
ischemic changes by applying the Alberta Stroke Program Early CT
Score (ASPECTS) to all baseline NCCT by 3-reader consensus.
Readers were blinded to all clinical information except for symptom
side. Accordingly, day-1 NCCT scans were assessed for the presence
of parenchymal hematoma type 1 (PH-1) and type 2 (PH-2) using the
We report data using standard descriptive statistics. Our primary end
point was favorable functional outcome at 90 days, defined as mRS
scores 0 to 2. Comparisons of proportions were made using Fisher’s
exact test. We compared proportions of favorable functional out-
comes at 90 days between the CTA and control group and adjusted
for common baseline confounders (age, baseline NIHSS score,
history of diabetes, onset-to-treatment time, prethrombolysis anti-
platelet therapy). We developed multivariate logistic regression
models including the variables age, sex, history of diabetes mellitus,
baseline NIHSS score, onset-to-treatment time, baseline ASPECTS
score, and antiplatelet treatment to predict favorable functional
outcome at 90 days. Subsequently, we used propensity score match-
ing to estimate the effect size of performing a CTA on the prediction
of functional outcome. Variables used to predict the propensity score
were age, sex, history of diabetes mellitus, baseline NIHSS score,
onset-to-treatment time, and baseline ASPECTS score. The propen-
sity scores were then used to match cases using stratified matching
and nearest-neighbor matching, simulating a randomized controlled
We identified 111 patients for the CTA group and 1119
patients for the control group. Patients receiving CTA before
thrombolysis tended to be more severely affected (P?0.065)
and showed more extensive signs of ischemia on NCCT
(P?0.049) than did patients in the control group (Table 1).
Although patients in the CTA group received rtPA up to 6
hours from onset, the average onset-to-treatment time was
only 5 minutes longer in the CTA group compared with the
control group (P?0.21). Remaining baseline characteristics
did not differ among groups, apart from a higher proportion
of prethrombolysis antiplatelet therapy in the control group
Unadjusted proportions of patients who had a favorable
functional outcome were 47.7% (53/111 patients) for the
CTA group and 49.5% (542/1094 patients) for the control
group (P?0.77). After adjustment for baseline confounders,
probabilities for favorable functional outcome were 0.477
(95% CI, 0.37–0.58) for the CTA group and 0.513 (95% CI,
0.47–0.54) for the control group. In the subgroup of patients
who received rtPA within 3 hours from onset, probabilities
were unchanged (0.485 versus 0.515, respectively).
In multivariate logistic regression analysis, performance of
CTA was associated with reduced odds of favorable func-
tional outcome (OR, 0.62; 95% CI, 0.38–0.99; Table 2).
Additional independent predictors of functional outcome
were age, baseline NIHSS score, history of diabetes, baseline
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ASPECTS, and onset-to-treatment time. Antiplatelet therapy
did not affect the proposed relationship.
Using propensity score matching, we found that the CTA
group was less likely to achieve a favorable functional
outcome, with an average treatment effect size of 10.0%
(95% CI, 0.5%–19.3%) using stratified matching and 9.3%
(95% CI,4.8%–23.4%) using nearest-neighbor matching.
In the CTA group, we found 8 parenchymal hematomas
(7.2%), of which 3 hematomas (2.7%) were judged as PH-2.
In the control group, of 884 follow-up NCCT scans available
for interpretation, 100 parenchymal hematomas (11.3%) were
diagnosed, and 47 hematomas (5.3%) were classified as
PH-2. No statistically significant difference in parenchymal
hematomas (P?0.401) or PH-2 (P?0.473) was observed.
In our study, we did not find evidence confirming our
hypothesis that the beneficial effect of IV rtPA is reduced in
acute stroke patients who received CTA before thrombolysis.
Patients who received CTA were 3% less likely to be
functionally independent at 3 months compared with an
historical control group; however, this effect was not statis-
tically significant. Propensity score analysis, simulating a
randomized controlled trial, suggested a negative effect of
performing a CTA with an absolute effect size of 10%,
though precision of this estimate was low. In multivariate
analysis, performing a CTA before IV thrombolysis was a
weak independent negative predictor of favorable functional
outcome. So overall, our data does not rule out a small
magnitude negative biological effect of radio-contrast media.
We regard this observation as hypothesis generating and
requiring confirmation. Only a few experimental and clinical
studies have assessed the effects of contrast agents on
thrombolysis. Over 2 decades ago, cardiologists began a
debate about the interaction of x-ray contrast agents and
blood function. Robertson and colleagues observed blood clot
formation in angiographic syringes containing nonionic con-
trast media.15When coronary thrombolysis was introduced
into clinical practice, experimental studies examined the
interaction with contrast agents.11,16–18Dehmer and col-
leagues demonstrated that fibrinolysis with streptokinase,
urokinase, or rtPA was markedly delayed in the presence of
ionic or nonionic contrast agents. This effect was dose-
dependent, but already occurred at clinically relevant drug
concentrations.11In experimental coronary thrombosis in
dogs, Pislaru et al showed that reperfusion after standard
thrombolysis with rtPA was significantly delayed after injec-
tion of different ionic or nonionic contrast agents.12In
addition, coronary reocclusion was observed more frequently
in dogs receiving contrast agents compared with saline
controls. A possible explanation for the failure of clot lysis is
that contrast agents alter the assembly and structure of fibrin,
thereby makingclots more
drugs.19,20Another mechanism for disturbed clot lysis seems
to be the inhibition of plasminogen activation.21
Nonionic contrast agents usually can be visualized by CTA
or CT perfusion imaging during their first pass through the
brain vasculature, and parenchyma with minimal delay after
contrast injection. Under normal conditions and as evidenced
by CT perfusion studies, there is a rapid and almost complete
washout of contrast after the first bolus pass.22This first
phase of contrast flooding and washout is followed by a
second phase of recirculation. For the nonionic contrast agent
ioversol, which was used in our study, elimination half-life is
about 1 to 2 hours. Thus, depending on the interval from
contrast application to rtPA treatment, effective IA cerebral
contrast concentration might be very low. In the setting of a
complete intracranial arterial occlusion, however, it seems
likely that some contrast material gets trapped intra-arterially
proximal to and within the occlusive clot. This hypothetical
mechanism would allow for a later interaction with fibrino-
lytics at the occlusive site.
Our study relates the existing knowledge on interactions
between thrombolysis and contrast agents application to the
setting of acute ischemic stroke therapy. The potentially
decreased chance for independent functional outcome in
patients having received contrast agents before thrombolysis
Table 1. Baseline Characteristics
Age, mean?SD (y)
Men, n (%)
Hx antiplatelet therapy, n (%)
Atrial fibrillation, n (%)
Hypertension, n (%)
Hyperlipidemia, n (%)
CAD, n (%)
Diabetes, n (%)
Dominant hemispheric stroke
NIHSS score, median, (IQR)
OTT (mean?SD; min)
OTT ?3 h, n (%)
ASPECTS ?7, n (%)
CTA indicates computed tomography angiography; Hx, history of; CAD,
coronary artery disease; NIHSS, National Institute of Health Stroke Scale Score;
IQR, interquartile range; OTT, onset-to-treatment-time; ASPECTS, Alberta
Stroke Program Early CT Score.
Statistical test for group comparisons: *two-sample t test, †Fisher exact test,
‡Mann-Whitney U test.
Days in Multivariate Analysis
Predictors of Favorable Outcome (mRS 0–2) at 90
ORP Value95% CI
NIHSS baseline (per point increase)
Age (per year increase)
ASPECTS (per point increase)
OTT (per minute increase)
mRS indicates modified Rankin Scale; CTA, computed tomography angiog-
raphy; NIHSS, National Institute of Health Stroke Scale Score; Hx, history of;
ASPECTS, Alberta Stroke Program Early CT Score; OTT, onset-to-treatment
Dzialowski et alInteraction of Contrast Agents and rtPA
by guest on April 11, 2012http://stroke.ahajournals.org/Downloaded from
in our study may be caused by the proposed interaction
between contrast agents and rtPA; this results in reduced
degree and rate of arterial recanalization. However, we
cannot exclude the possibility that other effects of contrast
agents may be relevant for these outcome differences. For
example, contrast agents, especially the ionic type, are known
to cross the blood-brain barrier in acute ischemia and might
have a toxic effect on ischemic brain tissue.23–26In addition,
IA contrast injections in acute ischemic stroke patients may
increase the risk of intracerebral hemorrhage.27Similar rates
of parenchymal hematomas between the CTA and control
groups in our study, however, do not suggest a substantial
effect on postthrombolysis hemorrhagic transformation. In
this regard, our study confirms a recent observation that IV
contrast application does not seem to increase the risk for
intracerebral hemorrhage after thrombolysis.28
A possible interaction between contrast agents and rtPA is
relevant given that, in acute ischemic stroke, CT imaging
studies requiring contrast agent application (ie, CTA and CT
perfusion imaging) often precede IV thrombolysis with rtPA.
In addition, many stroke centers perform endovascular acute
stroke thrombolysis with rtPA, a procedure that repeatedly
uses contrast agents. The Prolyse in Acute Cerebral Throm-
boembolism (PROACT) II trial randomized acute stroke
patients to IA application of prourokinase plus heparin or to
heparin alone after angiographic confirmation of a middle
cerebral artery occlusion; it showed improved functional
outcomes at 3 months compared with controls. Hence, this
trial demonstrated benefit of IA thrombolysis despite re-
peated contrast agent application. However, the recanaliza-
tion rate remained suboptimal (66% Thrombolysis in Myo-
cardial Infarction grade 2 and 3) and this trial used
prourokinase rather than rtPA.3Such an interaction would
also be relevant for current stroke thrombolysis trials that
require the application of contrast agents for identification of
an arterial occlusion on CTA (Desmoteplase in Acute Ische-
mic Stroke III and IV studies) or digital subtraction angiog-
raphy (Interventional Management of Stroke III [IMS]
Study).4The IMS III study is a prospective, multicenter,
randomized open label trial that compares the efficacy of
combined IV and endovascular recanalization versus IV rtPA
alone. Because this trial allows performing a CTA before
thrombolysis, this subset of data might be used to study
prospectively the effect of contrast agents on efficacy of
thrombolysis. A recent systematic review compared recana-
lization rates in anterior circulation stroke patients that were
exposed versus not exposed to different iodinated contrast
agents before standard thrombolysis.29The authors did not
find a significant difference in pooled proportions for recan-
alization (53% [95% CI, 36%–70%) versus 61% [95% CI,
52%–71%]) and concluded that a randomized trial would
require at least 240 subjects, but likely a much higher
Our study has several limitations. First, we retrospectively
compared 2 nonrandomized stroke cohorts. Although our
study design was pragmatic, it would be ideal to have
concurrent controls. Patients in the CTA group tended to be
more severely affected and showed larger infarctions at
baseline. Although we adjusted for baseline imbalances,
differences in functional outcome might simply reflect base-
line differences between the 2 groups. Our results might
therefore be subject of a type II error. For this reason, we
performed a propensity score analysis that aimed to simulate
a randomized trial. Second, only a limited number of prog-
nostically relevant factors were available and were included
in our model that might have influenced 3-month outcomes:
baseline characteristics such as premorbid mRS score and
blood glucose level; data on clinical course and interventions
between hospital admission and day 90, such as carotid artery
stenting or endarterectomy, and infections. Given that we
have compared 2 average stroke populations, these latter
factors should be balanced. The comparison of a multicenter
with a monocentric patient cohort, however, might have
introduced systematic differences, such as different second-
ary prevention and rehabilitation strategies.
Third, patients in our historical control group were studied
several years earlier than were patients in the CTA group
(1999–2001 versus 2002–2006), thus potentially resulting in
differences of functional outcomes caused by secular trends
in general stroke care. Fourth, the control group may have
contained patients with nonischemic symptom etiology and,
thus, favorable clinical course, as no vascular imaging was
performed. In addition, we were not able to compare recan-
alization rates, as no follow-up vascular imaging was per-
formed in most of the CTA and control patients. Fifth, the
individual decision to order a CTA might have introduced a
selection bias to our CTA cohort. Furthermore, the CTA
results might have changed patient management, eg, triggered
IA intervention or early carotid revascularization. Finally, our
results may not be generalizable to contrast agents other than
Optiray (ioversol), which was applied in our stroke center.
Other x-ray contrast agents have other chemical and pharma-
cological properties and may have differing interactions with
thrombolysis. Similarly, we do not know whether other
plasminogen activators (eg, prourokinase, desmoteplase, te-
necteplase) might show different properties in combination
with x-ray contrast agents. For example, Parsons et al
demonstrated a significantly better major vessel recanaliza-
tion with tenecteplase compared with alteplase (10/15 versus
7/29; P?0.01) in acute stroke patients selected with multi-
modal CT imaging.30
Our study did not show a significant negative clinical effect
of x-ray contrast agents applied before IV thrombolysis with
rtPA. However, to confirm a possible small negative interac-
tion between contrast agents and rtPA, additional experimen-
tal and prospective clinical studies are needed. Until addi-
tional data are available, the potential diagnostic advantage of
performing a CTA in acute stroke patients may outweigh the
risks of iodinated contrast agent application.
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Dzialowski et alInteraction of Contrast Agents and rtPA
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