high rates of death and disability, ranging up to 73%.1–5
Patients with acute ischemic stroke (AIS) are treated
with intravenous thrombolysis (IVT) within 4.5 hours
of symptom onset as recommended by American Heart
Association/American Stroke Association guidelines.6
However, previous trials, including the National Institutes
of Neurological Disorders and Stroke thrombolysis study
and the Prolyse in Acute Cerebral Thromboembolism II
trial, have excluded patients presenting with AIS associ-
ated with IE.1,4,7 The issue is further complicated by the
fact that the diagnosis of IE may not be evident at the
time of the acute ischemic event. Case reports of patients
treated with IVT in the setting of AIS caused by IE have
shown mixed results.2,7,8 We sought to determine the rates
and outcomes of AIS patients with IE treated with IVT
using nationally representative data.
erebral ischemic events are highly prevalent in patients
with infective endocarditis (IE) and associated with
We used data files from the Nationwide Inpatient Sample from 2002
to 2010. We used the International Classification of Disease, Ninth
Revision, Clinical Modification for ischemic stroke, IE, and the use of
thrombolysis to identify patients. Outcomes were defined as rates of
post-thrombolytic intracerebral hemorrhage (ICH) and favorable out-
come (discharge disposition of home/self-care). Univariate and multi-
variate analyses were performed to determine the effect of IE on rates
of post-thrombolytic ICH and favorable outcome among survivors.
For the complete methodology of our study, refer to the Methods in
the online-only Data Supplement.
There were 222 patients (mean age 59±18 years; 46% women)
who were treated with IVT for AIS secondary to IE and 134 048
patients (mean age 69±15 years; 49% women) who were
treated for AIS without IE (Table). The rate of post-throm-
bolytic ICH was significantly higher in patients with IE com-
pared with non-IE AIS patients (20% versus 6.5%; P=0.006).
There was a significantly lower rate of favorable outcome in
the IE group (10% versus 37%; P=0.01) when compared with
the non-IE AIS treated group. The length of hospital stay was
significantly longer among thrombolytic-treated patients with
IE (P=0.006) and the mean hospital charges were significantly
higher (P=0.01). Refer to our Results in the online-only Data
Supplement for further analysis.
Background and Purpose—Cerebral ischemic events are highly prevalent and associated with high rates of death and
disability in patients with infective endocarditis (IE). However, the role of thrombolysis in these patients remains unclear.
We sought to determine the rates and outcomes of acute ischemic stroke patients with IE treated with intravenous
Methods—We determined the rates of post-thrombolytic intracerebral hemorrhage and favorable outcome among acute
ischemic stroke patients with IE treated with IVT. Patients were identified using Nationwide Inpatient Sample data from
2002 to 2010. We compared the rates of various outcomes with ischemic stroke patients without IE treated with IVT.
Results—There were 222 patients (mean age 59±18 years; 46% women) who were treated with IVT for acute ischemic
stroke associated with IE and 134 048 patients (mean age 69±15 years; 49% women) who were treated for stroke without
IE. The rate of post-thrombolytic intracerebral hemorrhage was significantly higher in patients with IE compared with
those without IE (20% versus 6.5%; P=0.006). There was a significantly lower rate of favorable outcome in the IE group
(10% versus 37%; P=0.01).
Conclusions—High rates of post-thrombolytic intracerebral hemorrhage and low rates of favorable outcome mandate
caution in using IVT in acute ischemic stroke patients with IE. (Stroke. 2013;44:2917-2919.)
Key Words: endocarditis ◼ outcomes assessment ◼ stroke ◼ thrombolytic therapy
Thrombolysis for Ischemic Stroke Associated With
Results From the Nationwide Inpatient Sample
Ganesh Asaithambi, MD; Malik M. Adil, MD; Adnan I. Qureshi, MD
Received March 25, 2013; final revision received June 17, 2013; accepted July 3, 2013.
From the Zeenat Qureshi Stroke Research Center (G.A., M.M.A., A.I.Q.), University of Minnesota, Minneapolis, MN.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
Correspondence to Ganesh Asaithambi, MD, Department of Neurology, University of Minnesota, 420 Delaware St, SE, MMC 295, Minneapolis, MN.
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.001602
by guest on October 29, 2015 by guest on October 29, 2015 by guest on October 29, 2015 by guest on October 29, 2015 by guest on October 29, 2015 by guest on October 29, 2015 http://stroke.ahajournals.org/http://stroke.ahajournals.org/http://stroke.ahajournals.org/ http://stroke.ahajournals.org/http://stroke.ahajournals.org/ http://stroke.ahajournals.org/ Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from
2918 Stroke October 2013
Anderson et al9 noted in their study that 35% of stroke patients
with IE died during their acute admission, and a total of 52%
died within 1 year. With this high rate of mortality among
patients with AIS associated with IE, it is important to deter-
mine whether current performance of thrombolysis for AIS
is beneficial within this unique group of patients. Current
American Heart Association/American Stroke Association
guidelines do not exclude eligible AIS patients with IE from
The use of thrombolytics is controversial because of high
rates of spontaneous hemorrhagic transformations of infarc-
tions among patients with IE.3,4,8 The high rate is partly attrib-
uted to concurrent existence of mycotic aneurysms with
subsequent rupture. Other potential pathogeneses include
the presence of pyogenic arteritis, microabscesses, immune
complex–mediated arteritis, and infiltration of meningeal
We found that the rates of post-thrombolytic ICH were sig-
nificantly higher and the rates of favorable outcomes were sig-
nificantly lower within the IE group when compared with the
non-IE group. Recent case reports have shown variable rates
of favorable and unfavorable outcomes associated with IVT
use in patients with AIS associated with IE.2,7,8 Our study had a
relatively large number of patients with IE and, therefore, was
devoid of biases introduced by patient referral patterns and
socioeconomic factors within catchment areas seen in single
center studies. The precision of estimates may be higher in
our study for post-thrombolytic ICH and favorable outcomes.
In the absence of a randomized comparison between throm-
bolytic and nonthrombolytic treatment among AIS patients
with IE, thrombolytic treatment cannot be prohibited in this
group of patients. The results do support a cautious approach
with careful risk–benefit analysis on a case-by-case basis. The
results also emphasize the need for early diagnosis of IE in
AIS patients given the prognostic significance among throm-
bolytic-treated patients. In patients with concurrent fever and
leukocytosis, documentation of endocardial involvement by
auscultation and emergent echocardiography may identify
such patients in the acute setting when results of blood cul-
tures may not be available.
We recognize that our study has certain limitations.
Inaccuracies with coding can affect patient identification
and result in underestimation of proportion of patients in the
groups created for comparison. International Classification
of Disease, Ninth Revision, Clinical Modification codes for
ischemic stroke (when listed as primary diagnosis) and throm-
bolysis have high specificity but moderate sensitivity and, thus,
underestimate the prevalence.10 The procedure code 99.10
does not differentiate between various thrombolytic agents and
approaches, and it is possible that some patients may not be
treated with IV alteplase. Furthermore, we cannot comment on
the appropriateness of use and protocol violations. Although
the accuracy of International Classification of Disease, Ninth
Revision, Clinical Modification code for IE is unknown, a rela-
tively high-positive predictive value is expected because the
codes are necessary for reimbursement of posthospitalization
IV antibiotic treatment. However, the criteria used for diagno-
sis may be varied between institutions. We are also unable to
determine the severity of neurological deficits, baseline func-
tioning of patients, and underlying location (lacunar versus non-
lacunar) and cannot exclude the possibility that IE patients had
more severe deficits and preexisting disability. We were able to
ascertain presence of ICH using International Classification of
Disease, Ninth Revision, Clinical Modification codes, but were
unable to categorize ICH based on severity. Although a formal
outcome scale was not used, the use of discharge home as an
outcome has a negative predictive value of 95% for modified
Rankin scale scores ≥2 at 3 months.11 Our data were derived
from several institutions, including rural, urban teaching,
and urban nonteaching hospitals. Institutional characteristics,
such as availability of dedicated neuro-critical care and stroke
services, can lead to differences in patient outcomes and our
results may be underrepresenting the care and outcomes at
comprehensive stroke centers. The difference in length of stay
must be interpreted with caution because of several posthospi-
talization factors, such as need for postdischarge IV antibiotic
treatment and bed availability at destination.
Table. Interventions and Outcomes of Acute Ischemic Stroke Patients Treated With
Intravenous Thrombolysis With or Without Infective Endocarditis
Patients With IE Patients Without IEP Value
Mean age (SD) in y
Mean length of stay in d (SD)
66 220 (49)
29 095 (21.7)
49 572 (37)
Mean hospital charges in $ (SD)120 192 (96 692)
70 045 (75 642)0.01
ICH indicates intracerebral hemorrhage; and IE, infective endocarditis.
by guest on October 29, 2015 http://stroke.ahajournals.org/Downloaded from
Asaithambi et al Thrombolysis in Infective Endocarditis 2919
The high rate of ICH and low rates of favorable out-
come mandate caution in using IVT in AIS patients asso-
ciated with IE. Endovascular treatment may be evaluated
in future studies because of lower thrombolytic doses and
concurrent angiographic assessment of medium-sized
Dr Qureshi has received funding from the National Institutes
of Health U01-NS062091-01A2 (medication provided by EKR
Therapeutics), American Heart Association Established Investigator
Award 0840053 N, and Minnesota Medical Foundation, Minneapolis,
Minnesota. The other authors have no conflicts to report.
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stent technology for removal of a large septic embolus in the middle
cerebral artery. World Neurosurg. 2012;77:591.e1–591.e5.
2. Bhuva P, Kuo SH, Claude Hemphill J, Lopez GA. Intracranial hemor-
rhage following thrombolytic use for stroke caused by infective endocar-
ditis. Neurocrit Care. 2010;12:79–82.
3. Dababneh H, Hedna VS, Ford J, Taimeh Z, Peters K, Mocco J et al.
Endovascular intervention for acute stroke due to infective endocarditis.
Neurosurg Focus. 2012;32:E1.
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5. Sonneville R, Mirabel M, Hajage D, Tubach F, Vignon P, Perez P et al.
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Thrombolysis for Ischemic Stroke Associated with Infective Endocarditis: Results
from the Nationwide Inpatient Sample
Ganesh Asaithambi, MD1,2
Malik M. Adil, MD1
Adnan I. Qureshi, MD1,2
From the Zeenat Qureshi Stroke Research Center1 and Department of Neurology2 at
the University of Minnesota, Minneapolis, MN.
Ganesh Asaithambi, MD
Department of Neurology
University of Minnesota
420 Delaware St., SE
Minneapolis, MN 55455
The Nationwide Inpatient Sample (NIS) is the largest all-payer database in the
United States and derives the data from 20% of non-federal hospitals. By using
appropriate sampling weights, national estimates can be derived. The database contains
information on patients’ demographic and clinical characteristics, in-hospital procedures,
hospital characteristics, and discharge outcomes. A summary of the NIS can be found at
We used the International Classification of Disease, 9th Revision, Clinical
Modification (ICD-9-CM) primary diagnosis codes 433-437.1 to identify patients
admitted with ischemic stroke. We identified patients who received IV thrombolysis
using ICD-9-CM procedure code 99.10. Subsequently, patients with IE were identified
using ICD-9-CM secondary diagnosis code 421. Study variables analyzed were patient’s
age, gender, race/ethnicity, and co-morbidities including diabetes mellitus, hypertension,
atrial fibrillation, heart failure, and end-stage renal disease. Outcomes were defined as
rates of post-thrombolytic intracerebral hemorrhage (ICH, ICD-9-CM code 430-432) and
favorable outcome (discharge disposition of home/self-care).
We performed chi-square test for categorical and t-test for continuous
variables to identify differences in demographic and clinical characteristics and
outcome variables of thrombolytic treated patients with or without IE. We
compared the rates of various outcomes with ischemic stroke patients (without IE)
treated with IV thrombolysis. Multivariate analyses were performed to determine
the effect of IE on rates of post-thrombolytic ICH and favorable outcome among
survivors. Potential confounders included variables that were identified as
significant in univariate analysis. All analyses were performed using SAS 9.1
software (SAS Institute, Cary, NC).
The IE group was significantly younger than the non-IE group (59±18 years
versus 69±15 years, p=0.02) but had lower proportion of patients with atrial fibrillation
(15% versus 31%, p=0.03). Baseline and clinical characteristics can be found in
Supplemental Table I. In the multivariate analysis, higher rates of post-thrombolytic ICH
and lower rates of favorable outcomes were seen in AIS thrombolytic treated patients
associated with IE after adjusting for age and atrial fibrillation (Supplemental Table II).
Trends by year for intravenous (IV) thrombolytic use and incidence of post-
thrombolytic ICH among those with or without IE can be found in Supplemental
Table III. We found that there was a significantly higher rate of post-thrombolytic
ICH among those with a diagnosis of IE.
We also examined the potential effect of patients’ payer statuses as a confounder
for the outcome “discharge home/self-care.” For example if a patient was “self pay” as
opposed to having insurance and would have benefited from a discharge location other
than home, a discharge disposition of home may not mean a favorable outcome.
However, there is not a significant difference in payer statuses between the two groups
(Supplemental Table IV).
Supplemental Table I: Baseline and clinical characteristics of acute ischemic stroke
patients treated with intravenous thrombolysis with or without infective
Patients with IE
Mean age (SD) in
Women (%) 103 (46)
White 124 (56)
African American 40 (18)
Other 58 (26)
Hypertension 140 (63)
Diabetes mellitus 33 (15)
Dyslipidemia 10 (4.5)
Atrial fibrillation 34 (15)
Supplemental Table II: Multivariate analysis comparing outcomes for acute
ischemic stroke patients treated with intravenous thrombolysis with or
without infective endocarditis.
Favorable outcome 0.2 (0.05-
Post-thrombolytic ICH 4.1 (1.7-9.8)
Abbreviations: AF=atrial fibrillation; IE=infective endocarditis.
Supplemental Table III: Number of patients with and without infective
endocarditis who received intravenous thrombolysis and rates of post-
thrombolytic intracerebral hemorrhage from 2002-2010 by year.
Patients with IE
Year # receiving IV
2002 16 0
2003 5 0
2004 5 0
2005 30 15 (50)
2006 22 4 (18.2)
2007 5 0
Patients without IE
0.02 59 (18)
66220 (49) 0.7
0.6 39 (17)
30 (13.5) 1390 (1) 0.08
Adjusted for age and AF
Patients without IE
# receiving IV
Rate of ICH Rate of ICH
Abbreviations: IE=infective endocarditis; ICH=intracerebral; IV=intravenous.
Supplemental Table IV: Payer status of patients with or without
infective endocarditis receiving thrombolysis.
Abbreviations: HMO=health maintenance organization; IE=infective endocarditis.
0.08 111 (50.2)
75 (34) 34821 (26) 0.3
35 (15.8) 9720 (7.3) 0.2
Ganesh Asaithambi, Malik M. Adil and Adnan I. Qureshi
the Nationwide Inpatient Sample
Thrombolysis for Ischemic Stroke Associated With Infective Endocarditis: Results From
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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