Stroke

CLINICAL AND POPULATION SCIENCES

Thrombolysis for Acute Ischemic Stroke in

Patients With Premorbid Disability: A Meta-
Analysis
Benjamin Beland , MD*; Fouzi Bala , MD, MSc*; Aravind Ganesh, MD, DPhil

BACKGROUND: Randomized controlled trials for the use of alteplase in acute ischemic stroke have excluded or had little
representation of patients with prestroke disability, and the benefit of alteplase in this population remains uncertain. We
performed a systematic review and meta-analysis to examine the outcomes of thrombolysis in patients with premorbid
disability.

METHODS: We performed a systematic review in accordance with the Meta-Analysis of Observational Studies in Epidemiology
guidelines and retrieved studies reporting intravenous thrombolysis (IVT) in patients with prestroke disability (modified Rankin
Scale score, 3–5) with acute ischemic stroke, either compared with untreated patients or treated patients without premorbid
disability. The primary outcome was the return to premorbid disability at 90 days. Secondary outcomes included rate and odds
ratio of favorable functional outcome at 90 days (modified Rankin Scale score 0–2 or return to premorbid modified Rankin
Scale), symptomatic intracerebral hemorrhage (sICH), and 90-day mortality.

RESULTS: Eight articles were included involving 103 988 patients. Patients with disability treated with IVT had better odds of
returning to baseline function compared with those who did not receive IVT (odds ratio, 7.26 [95% CI, 2.51–21.02]). Mortality
and rates of sICH were not significantly different between patients with disability treated with IVT and those not treated,
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although there were numerically more sICHs in the IVT group. Return to baseline function was not significantly different
between patients with and without prestroke disability (odds ratio, 1.46 [95% CI, 0.75–2.83]). The rates of sICH were not
significantly different in patients with and without premorbid disability. However, mortality was 3× higher in patients with
premorbid disability than in those without premorbid disability (38.2% versus 12.6%).

CONCLUSIONS: The use of IVT in patients with disability was associated with better outcomes compared with patients who did
not receive IVT without statistically significant added risks of sICH or mortality. When compared with those without disability,
there was no significant difference in the return to baseline function or sICH. High-quality data comparing treated versus
untreated patients with premorbid disability are needed to clarify this issue.

REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021240499.

GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: cerebral hemorrhage ◼ humans ◼ ischemic stroke ◼ meta-analysis ◼ stroke

S
ince the original randomized controlled trials of
the use of recombinant tissue-type plasminogen
activator (alteplase) in the 1990s,1 there has been
widespread adoption of thrombolysis with alteplase as
a safe and effective therapy for acute ischemic stroke.2
However, the benefit of thrombolysis remains uncertain
in patients living with disability before their stroke (pre-
morbid disability). This is because randomized controlled

Correspondence to: Aravind Ganesh, MD, DPhil, Department of Clinical Neurosciences, University of Calgary, HMRB Room 103, 3280 Hospital Dr NW, Calgary, AB
T2N 4Z6. Email aganesh@ucalgary.ca
*B. Beland and F. Bala contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.038374.
For Sources of Funding and Disclosures, see page 3063.
© 2022 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2022;53:3055–3063. DOI: 10.1161/STROKEAHA.121.038374 October 2022   3055

 Beland et al
CLINICAL AND POPULATION
Nonstandard Abbreviations and Acronyms
SCIENCES
aOR adjusted odds ratio
IST3 Third International Stroke Trial
IVT intravenous thrombolysis
mRS modified Rankin Scale
OR odds ratio
sICH symptomatic intracranial hemorrhage
tPA tissue-type plasminogen activator
trials of thrombolysis have excluded or had significant
underrepresentation of patients with premorbid disabil-
ity.3 In part, this relates to the primary outcome measures
in these trials, which have generally been dichotomously
defined as favorable versus unfavorable based on the
patients’ 90-day modified Rankin Scale (mRS) score,
with mRS score 0 to 1 or 0 to 2 generally considered
excellent or good outcomes, respectively. Therefore,
patients living with premorbid disability, defined variably
as an mRS score ≥2 or ≥3 before their stroke, are by
definition unable to achieve a favorable outcome since
acute stroke therapies can at best return such patients
to their premorbid level of function.
Given the lack of definitive data from randomized con-
trolled trials to inform their care, it is unsurprising that
patients with premorbid disability are often excluded
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from thrombolysis in routine practice.4 Besides, registry
data show that patients with premorbid disability have
worse prognosis, with higher mortality and disability.5
Analyses of large patient registries in the United King-
dom have shown that there was an increase in poor
outcomes in terms of length of stay, discharge destina-
tion, complications, and mortality, as well as higher health
care costs for every point increase on prestroke mRS.5,6
Importantly, the American Heart and Stroke Association
guidelines for thrombolysis for acute ischemic stroke do
not explicitly suggest that preexisting disability is a con-
traindication to thrombolysis; “therapy with IV alteplase
for acute stroke patients with preexisting disability (mRS
score, >2) may be reasonable, but decisions should take
into account relevant factors such as quality of life, social
support, place of residence etc.”7 In contrast, the Euro-
pean Stroke Organization guidelines suggest that all
patients presenting within 4.5 hours who are otherwise
eligible should receive thrombolysis even if they expe-
rience multimorbidity, frailty, or prestroke disability8 but
acknowledge that the quality of evidence is very low and
the strength of the recommendation is weak.8
That being said, such data do not exclude a beneficial
role for alteplase in these patients. The Oxford Vascular
Study demonstrated that for each increment of additional
poststroke disability in patients with premorbid disability,
there were higher health care and social care costs and
higher rates of institutionalization during a 5-year period.6
3056   October 2022
Thrombolysis With Premorbid Disability
In this regard, it seems reasonable to consider that many
patients who live with disability would likely consider a
return to their previous functional status as a personally
favorable outcome after stroke. In the absence of high-
quality randomized controlled trial data, observational
studies of thrombolysis in patients with premorbid dis-
ability may help inform their care by providing relevant
data on the safety and outcomes of thrombolysis, par-
ticularly on their rates of return to premorbid function. A
synthesis of such data is presently lacking.
Therefore, we performed a systematic review and
meta-analysis of outcomes with thrombolysis in patients
with premorbid disability.
METHODS
Search Strategy and Inclusion Criteria
This meta-analysis is compliant with the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses guidelines9
and was written according to the Meta-Analysis of Observational
Studies in Epidemiology guidelines.10 The study was registered
at PROSPERO (unique identifier: CRD42021240499).
We searched Medline and Ovid-Embase for studies
reporting thrombolysis or best medical treatment in adult
patients with acute ischemic stroke with and without premor-
bid disability, from inception to July 26, 2021. No language
or date restriction was applied. Studies were included if they
met the following criteria: (1) randomized or observational
studies of adult patients with premorbid disability (using an
inclusive definition, mRS score 3–5); (2) presenting with
acute ischemic stroke treated with thrombolysis; and (3) with
a minimum of 10 patients. We excluded case reports and in
vitro/animal studies.
The complete search algorithm that was used in Medline
and Ovid-Embase is available in the Supplemental Material.
Reference lists of included articles were examined to identify
studies that may have been missed during the initial search.
The titles and abstracts were screened by 2 authors (F.B.
and B.B.), and full texts of eligible studies were retrieved for
inclusion. Conflicts about study inclusion at both screening and
full-text review stages were resolved by a third reviewer (A.G.).
The data supporting this meta-analysis are available from
the corresponding author upon reasonable request.
Data Extraction
Two authors performed the data extraction (F.B. and B.B.),
which was then cross-checked by a third author (A.G.). We col-
lected the following data: study design, sample size and defini-
tion of premorbid disability, raw data, and adjusted odds ratios
(aORs) with their 95% CIs for outcomes of interest, including
functional outcome measured by mRS score at 90 days, return
to premorbid mRS at 90 days, rate of symptomatic intracranial
hemorrhage (sICH), and mortality at 90 days.
Outcomes
The primary outcome was the rate of return to premorbid dis-
ability at 90 days. Secondary outcomes included the rate of
favorable functional outcome at 90 days defined as mRS score
Stroke. 2022;53:3055–3063. DOI: 10.1161/STROKEAHA.121.038374
 Beland et al
0 to 2 or return to premorbid mRS, the rate of sICH defined by
each study, and 90-day mortality.
Statistical Analyses
Rates and their corresponding 95% CIs were calculated for
all outcomes using random-effects models (Der Simonian
and Laird method). Heterogeneity was assessed using the
Higgins index (I2).
Additionally, we computed the effect estimates (odds ratios
[ORs] and their 95% CIs) of all outcomes by analyzing the
event rates in studies reporting data in intravenous thromboly-
sis (IVT) patients with premorbid disability (mRS score, 3–5)
versus without (mRS score, 0–2). Subsequently, we performed
adjusted analyses for each outcome by pooling the aOR of
patients with versus without premorbid disability in studies pro-
viding these data.
As a sensitivity analysis, we repeated the meta-analyses
using the Hartung-Knapp-Sidik-Jonkman method, and the
results were similar, and, therefore, we only reported the results
of the Der Simonian and Laird method.
Statistical tests were 2 sided, and P<0.05 was considered
statistically significant. Analyses were performed with the STATA
Statistical Software Release 17 for Windows (StataCorp LP).
Assessment of Study Quality and Risk of Bias
Two reviewers (F.B. and B.B.) independently assessed each
study using the Quality in Prognosis Studies tool,11 and dis-
agreement was resolved by a third reviewer (A.G.). The tool
consists of 6 domains: study participation, study attrition, prog-
nostic factor measurement, confounding measurement, out-
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come measurement, and statistical analysis and reporting. Risk
of bias for each domain was rated as low, moderate, or high
following detailed instructions.
Risk of publication bias was assessed using funnel plots,
and we planned to test for funnel plot asymmetry (Egger linear
regression test) for a given outcome if at least 10 studies were
available for analysis.12
RESULTS
Included Studies
The initial search resulted in 3006 articles. After
removal of duplicates and title and abstract screening,
91 articles remained for full-text review and 8 were
finally included in the systematic review13–20 (Figure 1).
Among the 8 included studies, 5 compared outcomes
between patients with (premorbid mRS score, 3–5)
versus without premorbid stroke disability (premorbid
mRS score, 0–2) treated with IVT and were included
in the meta-analysis. One study20 compared patients
with premorbid mRS score 2 to 4 to patients with
premorbid mRS score 0 to 1 and was excluded from
the meta-analysis to avoid heterogeneity in outcomes
estimates. We found 2 studies13,14 comparing patients
with premorbid disability treated with IVT to premor-
bidly disabled patients receiving medical management;
however, their data were not pooled as the timing of
Stroke. 2022;53:3055–3063. DOI: 10.1161/STROKEAHA.121.038374
Thrombolysis With Premorbid Disability
the mRS assessment was not comparable between
CLINICAL AND POPULATION
the two (90-day mRS in one and discharge mRS in
another). Among the studies that were not included
SCIENCES
was an article comparing thrombolysis in a mobile
stroke unit to conventional hospital care for patients
with preexisting disability.21 Although this article dis-
cussed outcomes in patients with disability who were
treated with thrombolysis, it was comparing 2 systems
of thrombolysis and as such did not fit our criteria.
Four of the studies were observational retrospective
cohorts13,14,16,20 while the remaining 4 were prospective
cohort, 3 of which were multicenter.15,17,18
Baseline Characteristics
Among the 103 988 patients included, sex data were
available for 103 594 patients, and 46 936 were women
(45.3%). Compared with those without premorbid dis-
ability, patients with premorbid disability were older and
more frequently women (58.3% versus 44.6%). The
main characteristics of included studies are summarized
in Table 1. Adjudication of the prestroke mRS scores was
estimated based on an understanding of the patient’s
prestroke function, and the 90-day mRS score was
either determined by visit to a physician, telephone con-
sultation with study personnel,17 or it was not described
by the authors.13–17,19,20
Studies Comparing Treated Patients With
Premorbid Disability to Treated Patients Without
Premorbid Disability
We included 5 studies comparing thrombolysis outcomes
in patients with premorbid disability (prestroke mRS score,
3–5; n=5263) versus those without premorbid disability
(prestroke mRS score, 0–2; n=97 905).15–19 Three stud-
ies reported return to baseline mRS data in both groups
(premorbid mRS score, 3–5 versus 0–2).15,17,19 We found
that 38.4% of patients with premorbid disability returned
to their initial level of function (Figure S1) compared
with 29.3% of patients without premorbid disability, with
a pooled unadjusted OR of 1.46 ([95% CI, 0.75–2.83]
I2=86.9%; Figure 2; Table 2). Adjusted point estimates
of return to baseline level of function were not available
in any study.
Four studies reported data for the favorable outcome
in both groups.15–18 Of patients with premorbid disability,
41.2% achieved favorable outcome (mRS score 0–2 or
return to baseline mRS) compared with 55.7% of patients
without disability, with a pooled unadjusted OR of 0.53
([95% CI, 0.40–0.71] I2=82.4%; Figure 2; Table 2). How-
ever, when adjusted for age, sex, and various stroke risk
factors, the analysis of the data available from 3 studies
suggested no significant difference between groups for
favorable outcome (aOR, 0.89 [95% CI, 0.58–1.37]; Fig-
ure 3; Table S1).15,17,18
October 2022   3057
 Beland et al
CLINICAL AND POPULATION
SCIENCES
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Figure 1. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart for study selection.
Alteplase indicates recombinant tissue-type plasminogen activator.
Symptomatic Intracranial Hemorrhage
Data regarding sICH were available from 5 included
studies.15–19 The rates of sICH were 6.6% (Figure S2)
versus 4.3% in patients with and without premorbid
disability, respectively, with a pooled unadjusted OR
of 1.57 ([95% CI, 1.14–2.16] I2=48.6%; Figure 2;
Table 2). In the analysis that was adjusted for demo-
graphic and stroke risk factors, the OR became non-
significant (aOR, 1.03 [95% CI, 0.87–1.23], 4 studies;
Figure 3; Table S1).15,17–19
Mortality at 90 Days
All included studies reported mortality data at 90 days.
The rates of mortality were 3× higher in patients with
premorbid disability than in those without premorbid dis-
ability (36.4% versus 12.6%; Figure S3). The pooled
unadjusted OR was 4.03 ([95% CI, 3.11–5.23] I2=73.3%;
3058   October 2022
Thrombolysis With Premorbid Disability
Figure 2; Table 2) and remained significant in the analy-
sis adjusted for sex, age, and stroke risk factors (aOR,
2.27 [95% CI, 1.81–2.85], 3 studies; Figure 3; Table S1).
Studies Comparing Treated Versus Untreated
Patients With Premorbid Disability
Whereas we were most interested in studies comparing
treated (ie, with thrombolysis) versus untreated patients
with premorbid disability, we only found 2 studies that
fit in this category. A retrospective analysis by Merlino
et al13 compared return to prestroke mRS, mortality, and
sICH in 110 patients with prestroke mRS of 3 or 4 who
either received IVT (n=36) or who did not receive IVT
(n=74). Those treated with IVT had better odds of return-
ing to baseline function compared with those who did not
receive IVT (OR, 7.26 [95% CI, 2.51–21.02]). Mortality at
3 months was not significantly different between groups
Stroke. 2022;53:3055–3063. DOI: 10.1161/STROKEAHA.121.038374
 Beland et al Thrombolysis With Premorbid Disability

Table 1. Summary of the Data Extracted From the Studies

CLINICAL AND POPULATION

Definition of premorbid Return to Favorable
disability and control Age % baseline mRS, outcome, n sICH, n 90-d mortal-

SCIENCES
Author Year groups n (median) Male n (%) (%) (%) ity, n (%)
Caruso et al13 2020 3–5 23 … … … … 2 (14) 3 (13)
0–2 259 … … … … 3 (25) 2 (0.7)
Cooray et al 12
2020 3–5 4566 78 42.3 1745 (38) … 53 (1.2) 1102 (31)
0–2 83 528 71 33.9 19 385 (23) … 1062 (1.3) 8214 (23)
Foell et al16 2003 3–5 14 76 … 5 (36) 5 (36) 1 (7.1) 7 (50)
0–2 98 71 … 41 (41) 41 (41) 2 (2.0) 13 (13)
Gensicke et al 15
2015 3–5 489 71 57.4 … 193 (40) 23 (4.8) 189 (39)
0–2 6941 84 33.9 … 4190 (60) 308 (4.5) 845 (12)
Karlinski et al14 2014 3–5 171 75 41.5 … 43 (34) 19 (11.7) 61 (43)
0–2 7079 … 42.2 … 2702 (38) 380 (5.4) 1034 (14)
Zhang et al17 2018 2–4 140 82 40.7 35 (25) … 60 (42.9) (35.7)
0–1 680 71 57.9 169 (25) … 77 (11.3) (12.8)
Gumbinger et 2019 IVT+ 15 317 74.3 51 … … … …
al11*
IVT− 37 424 … … … …
Merlino et al10* 2019 IVT+ 36 86.0 22.2 … 24 (66.7) 2 (5.6) 9 (25)
IVT− 74 79.6 50.4 … 27 (36.5) 0 (0) 16 (21.6)

IVT indicates intravenous thrombolysis; mRS, modified Rankin Scale; and sICH, symptomatic intracranial hemorrhage.
*Studies not included in the meta-analysis.

(25% and 21.6%, P=0.6, for IVT and no IVT, respec-
tively). The rates of sICH were 5.6% versus 0% for IVT
and no IVT, respectively (P=0.1).
Another analysis by Gumbinger et al14 compared the
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(Figure S1). The 2 studies that are included in the dis-
cussion and not in the meta-analysis were both consid-
ered to have moderate risk of bias.
Funnel plot assessment and funnel plot asymmetry

rates of returning to prestroke mRS or mRS score 0 to 1
at the time of discharge with and without the use of IVT
in patients with preexisting disability. The ORs favored
IVT for return to prestroke mRS or mRS score 0 to 1
in all subgroups with prestroke mRS from 0 to 4. Spe-
cifically, the use of IVT in patients with prestroke mRS
2, 3, and 4 had OR of 1.42 (95% CI, 1.16–1.73), 1.57
(1.24–1.99), and 1.60 (1.13–2.27), respectively. The OR
for death during hospital stay that was adjusted for age,
sex, and various stroke risk factors was not statistically
significant for prestroke mRS score 2 to 5 but was sig-
nificantly lower for those treated with IVT with prestroke
mRS score of 0. There were no comments on the rate
of sICH in this study. Note that this study only exam-
ined outcomes at discharge rather than at 90 days, so
we were unable to pool it along with the study by Merlino
et al for meta-analyses.
Study Heterogeneity
Significant heterogeneity (P≤0.10) was found for all the
outcomes in the unadjusted analyses except for sICH.
Quality of Included Studies
Using the Quality in Prognosis Studies tool, 2 of the 8
included studies were deemed to have an overall low risk
of bias, 4 had a moderate risk, and 2 had a high risk
tests were not performed as there were fewer than 10
included studies per outcome.
DISCUSSION
Our systematic review of 8 observational studies included
103 988 patients. Two studies found that patients with
disability had better OR of returning to baseline function
and favorable outcomes when treated with IVT compared
with not being treated with IVT. Importantly, 3-month mor-
tality was not significantly different between treated and
untreated groups in 1 study despite a numerical increase
in the rate of sICH (0% versus 5% for no IVT versus IVT,
respectively). In another study, the ORs were in favor of
the use of IVT for favorable outcomes in all subgroups
with prestroke mRS from 0 to 4. We also found that a
comparable proportion of patients with premorbid dis-
ability returned to their baseline level of functioning at
90 days with the use of alteplase, compared with those
without disability (37.2% and 29.3%, respectively; no sig-
nificant adjusted difference). There was, however, a sub-
stantial increase in 90-day mortality in treated patients
with premorbid disability than in those without premorbid
disability (38.2% versus 12.6%).
Given the favorable rates of return to prestroke mRS
achieved with thrombolysis in these observational stud-
ies, we believe that our results support the use of IVT in
selected patients with disability as opposed to withholding

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 Beland et al Thrombolysis With Premorbid Disability
CLINICAL AND POPULATION
SCIENCES
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Figure 2. Forest plots with pooled unadjusted odds ratio from random-effects model in patients with versus without premorbid
disability.
Return to baseline modified Rankin Scale (mRS) at 90 d (A); favorable outcome (mRS score 0–2 or return to baseline mRS at 90 d; B); symptomatic
intracranial hemorrhage (C); mortality at 90 d (D). pRS indicates prestroke modified Rankin Scale; and sICH, symptomatic intracranial hemorrhage.

IVT, with the important caveat that there were only 2 het- results did indicate higher mortality among patients with
erogeneous studies that compared treated and untreated prestroke disability receiving IVT compared and those
patients with premorbid disability. That being said, our without disability. However, attributing this higher mortality

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 Beland et al Thrombolysis With Premorbid Disability

Table 2. Unadjusted Pooled Outcomes for Stroke Patients better understand acute stroke treatment in this group.21,22

CLINICAL AND POPULATION

With and Without Premorbid Disability Treated With Intrave- The Oxford Vascular Study demonstrated that for each
nous Thrombolysis
increment of additional poststroke disability, there were

SCIENCES
Outcome No. of studies Pooled OR* 95% CI higher health care and social care costs and higher rates
Return to baseline mRS at 90 d 3 1.46 0.75–2.83 of institutionalization over a 5-year period among individu-
Favorable outcome at 90 d 4 0.53 0.40–0.71 als with preexisting disability.6 If the use of IVT for acute
sICH 5 1.57 1.14–2.16 stroke treatment can help patients with premorbid disabil-
Mortality at 90 d 5 4.03 3.11–5.23
ity return to their prestroke functional state, this may help
improve both clinical and long-term economic outcomes
Favorable outcome defined as mRS score 0 to 2 or not worsening of the base-
line mRS score. mRS indicates modified Rankin Scale; OR, odds ratio; and sICH,
in this population. Such improvement would need to be
symptomatic intracranial hemorrhage. verified with data from treatment registries of clinical trials.
*Results are from unadjusted analyses using random-effects models. In our meta-analysis, the OR for the absence of disabil-
ity accumulation was not significantly different between
to IVT itself does not seem prudent, given the absence of those who had premorbid disability and those who did not
mortality data showing differences between treated and (OR, 1.46 [95% CI, 0.75–2.83]), although only 3 studies
untreated patients with prestroke disability. were available for analysis. This would suggest that the
According to the US Administration on Aging, cen- effect of IVT is independent of whether someone has pre-
sus data suggest that 19% of Americans over the age existing disability or not. Again, this highlights the flaw that
of 65 years have some form of disability, the majority of is associated with using strict dichotomous definitions of
which was described as difficulty getting around (40%) favorable outcome (eg, mRS score 0–2, alone) and how it
or difficulty with cognition (27%).22 The prevalence of is not appropriate in patients with premorbid disability as it
patients living with a preexisting disability is expected to sets an unattainable and unjust bar of success.
increase, as a result of increased life expectancy with Our meta-analysis showed similar data in terms of rates
chronic conditions, which underscores the imperative to of sICH when compared with large international stroke
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Figure 3. Forest plots with pooled

adjusted odds ratio from random-
effects model in patients with versus
without premorbid disability.
Favorable outcome (modified Rankin Scale
[mRS] score 0–2 or return to baseline
mRS at 90 d; A); mortality at 90 d (B);
symptomatic intracranial hemorrhage (C).
sICH indicates symptomatic intracranial
hemorrhage.

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 Beland et al
trials, such as IST-3 (Third International Stroke Trial).23 The
CLINICAL AND POPULATION
rates of sICH with alteplase were comparable between
the results of our meta-analysis and the results obtained in
SCIENCES
IST3; 6.1% and 4.3% in patients with and without premor-
bid disability, respectively, and 7% in IST3. At 6 months, the
mortality was 27% in IST3, and our meta-analysis shows
a mortality rate at 90 days of 38.2% in patients with pre-
existing disability. The root cause of this discrepancy in
mortality between those with disability and those without
is unclear. It may be that despite the similar rates of sICH,
those with disability have a higher mortality owing to the
comorbidities that gave rise to their disability. This points
to a need for a high-quality comparison of treated versus
untreated patients with preexisting disability in order to
better understand whether there is a treatment-related
excess mortality risk. Interestingly, patients with premorbid
disability who have undergone endovascular thrombec-
tomy for acute ischemic stroke have also been shown to
have higher mortality compared with those without dis-
ability in 2 cohort studies with comparable rates to what
we describe in our results; 39.6% to 40.3% and 14.1%
to 14.3%, respectively.24,25 A meta-analysis of endovas-
cular thrombectomy in patients with preexisting disability
also showed similar findings where patients with disability
had higher pooled ORs of return to baseline mRS than
those without disability (OR, 1.82 [95% CI, 1.02–3.24]).26
Patients with disability who received EVT had higher odds
of returning to baseline function at 90 days compared with
those treated with medical management alone (OR, 2.37
Downloaded from http://ahajournals.org by on May 26, 2024
[95% CI, 1.39–4.04]; P=0.001).26
Our systematic review and meta-analysis were per-
formed on 8 articles that were retrospective series and
were likely subject to both a selection bias and a publica-
tion bias. Given that stroke guidelines caution the use of
tPA (tissue-type plasminogen activator) in patients with
disability, many patients with disability were likely denied
tPA and thus not included in this analysis. For those arti-
cles that compared IVT to no IVT in patients with disability,
there were likely unmeasured or unadjusted confounders
influencing why certain patients were not given throm-
bolysis. The inclusion of favorable outcome in our meta-
analysis as it is defined (mRS score 0–2 or return to
baseline disability) certainly influenced the result of the
meta-analysis because those with preexisting disability
are realistically not going to achieve mRS score 0 to 2
after their stroke and would be relatively disadvantaged
compared with those without disability who would still
achieve favorable outcome even if their mRS score wors-
ens (eg, going from mRS score 0 to mRS score 2 would
still allow them to achieve favorable outcome when it is
defined this way). However, we included this outcome
because it was reported in 4 of the 8 studies14,17–19 we
retrieved and is commonly reported in stroke literature
in general. Moreover, despite the disadvantage, patients
with preexisting disability achieved favorable outcome in
41.2% of cases. Solely examining return to premorbid
3062   October 2022
Thrombolysis With Premorbid Disability
state is also problematic since this is more challenging
for patients without prestroke disability to achieve (eg,
a patient with prestroke mRS score 0 would need to
be totally free of any symptoms poststroke to fulfill that
outcome). The adjudication of prestroke mRS scores in
the studies was based on a retrospective assessment
of the patient’s level of functioning, which may be sub-
ject to recall bias. Additionally, the studies did not clearly
describe the acquisition of poststroke mRS; therefore;
there may be nonuniformity in these estimates. Another
consideration is the limitation in interrater reliability of
mRS scores even among trained professionals.27 Impor-
tantly, the mRS was not originally intended for the evalu-
ation of prestroke disability, and an analysis examining
the validity of prestroke mRS found only modest correla-
tion with other markers of prestroke function.5
The need for randomized clinical trial evidence for
the safety and efficacy of thrombolysis (be it alteplase
or newer agents like tenecteplase) for acute stroke in
patients with preexisting disability cannot be overstated.
The population is aging, and with it, the prevalence of dis-
ability is also likely to increase. Stroke physicians will face
the issue of treating patients with acute stroke in whom
there is preexisting disability more frequently and there
will be increased need to draw upon high-quality evidence
in this area. Such evidence need not take the form of a
trial dedicated to patients with premorbid disability; rather,
future trials of thrombolysis in ischemic stroke (such as tri-
als comparing tenecteplase to alteplase) would just need
to consider opening enrollment to patients with premorbid
disability. Using more inclusive primary outcome measures
(such as an ordinal analysis of the mRS, avoidance of mRS
score 5–6, or return to prestroke state) would facilitate the
inclusion of such patients.
CONCLUSIONS
Our meta-analysis showed that in patients with pre-
morbid disability presenting with acute ischemic stroke
who otherwise are eligible for IVT, 38.4% return to their
baseline level of functioning compared with 29.3% of
patients without premorbid disability without a significant
increase in sICH. However, this is weighed against a
higher 90-day mortality. The results of our meta-analysis
suggest that IVT could benefit selected patients with
preexisting disability. While there is an enduring need for
high-quality clinical trial evidence to answer this ques-
tion, our aggregate data can help inform the expecta-
tions of stroke physicians, patients, and families about
the outcomes that may be achievable with thrombolysis
in patients with premorbid disability.
ARTICLE INFORMATION
Received December 13, 2021; final revision received April 29, 2022; accepted
May 6, 2022.
Stroke. 2022;53:3055–3063. DOI: 10.1161/STROKEAHA.121.038374
 Beland et al
Affiliation
Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.
Acknowledgments
We would like to thank Hayley Chato for designing the graphic abstract for this
article.
Sources of Funding
None.
Disclosures
Dr Bala is supported by La Société Française de Neuroradiologie (Bourse de
recherche Anne Bertrand SFNR) et La Société Française de Radiologie (Bourse
de Recherche Alain Rahmouni SFR-CERF). Dr. Ganesh reports membership in
editorial boards of Neurology, Neurology: Clinical Practice, and Stroke; research
support from the Rhodes Trust, Wellcome Trust, Canadian Institutes of Health
Research, Canadian Cardiovascular Society, Sunnybrook Research Institute
INOVAIT Program, and Alberta Innovates; consultation fees from Figure 1, MD
Analytics, CTC Communications Corp, MyMedicalPanel, and Atheneum; stock
options from SnapDx, TheRounds.com, and Advanced Health Analytics (AHA
Health, Ltd); and a provisional patent application (US 63/024,239) for a system
for delivery of remote ischemic conditioning or other cuff-based therapies. The
other author reports no conflicts.
Supplemental Material
Search Strategy
Table S1
Figure S1
PRISMA Checklist
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