ARTICLE

Sex differences in IV thrombolysis treatment for

acute ischemic stroke
A systematic review and meta-analysis
Brent Strong, Lynda D. Lisabeth, PhD, and Mathew Reeves, PhD Correspondence

®
Dr. Reeves
Neurology 2020;95:e11-e22. doi:10.1212/WNL.0000000000009733 reevesm@msu.edu

Abstract
Objective
A prior meta-analysis of reports published between 2000 and 2008 found that women were 30%
less likely to receive IV recombinant tissue plasminogen activator (rtPA) treatment for stroke
than men; we updated this meta-analysis to determine if this sex difference persisted.

Methods
We identified studies that reported sex-specific IV rtPA treatment rates for acute ischemic
stroke published between 2008 and 2018. Eligible studies included representative populations
of patients with ischemic stroke from hospital-based, registry-based, or administrative data.
Random effects odds ratios (ORs) were generated to quantify sex differences.

Results
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Twenty-four eligible studies were identified during this 10-year period. The summary un-
adjusted OR based on 17 studies with data on all ischemic stroke patients was 0.87 (95%
confidence interval [CI], 0.82–0.93), indicating that women had 13% lower odds of receiving
IV rtPA treatment than men. However, substantial between-study variability existed. Lower
treatment odds in women were also observed in 7 studies that provided data on the subgroup of
patients eligible for IV rtPA treatment, although the summary OR of 0.95 (95% CI, 0.88–1.02)
was not statistically significant. Examination of time trends across 33 studies published between
2000 and 2018 found evidence that the sex difference had narrowed in more recent years.

Conclusions
Although there is considerable variability in the findings of individual studies, pooled data from
recent studies show that women with acute stroke are less likely to be treated with IV
thrombolysis compared with men. However, the size of this difference has narrowed compared
to studies published before 2008.

From the Undergraduate Professorial Assistantship Program, Honors College (B.S.), and Department of Epidemiology and Biostatistics, College of Human Medicine (M.R.), Michigan
State University, East Lansing; and Department of Epidemiology, School of Public Health (L.D.L.), University of Michigan, Ann Arbor.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

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e12
Glossary
AIS = acute ischemic stroke; CI = confidence interval; OR = odds ratio; rtPA = recombinant tissue plasminogen activator.
Interest in how women are treated following an acute stroke
and the impact of sex differences in care on subsequent out-
comes has grown rapidly in the last 10 years.1–7 The finding of
a sex difference in clinical care or clinical outcomes following
an acute stroke raises the concern that such differences rep-
resent a bias (or disparity) in either access to or delivery of
medical care. However, not all sex differences represent in-
equitable medical care; sex differences can be a result of a host
of legitimate factors that influence eligibility for treatment
and/or patient preferences for treatment. The failure to
completely account for the full range of relevant factors can
result in residual confounding and potentially spurious
associations.
Given that IV thrombolysis remains one of the few evidence-
based medical treatments available for acute ischemic stroke
(AIS), the potential for sex differences in both its utilization
and clinical efficacy has remained of high interest. A prior
meta-analysis that included 18 studies published between
2000 and 2008 found that women had a 30% lower odds of
receiving IV recombinant tissue plasminogen activator (rtPA)
for AIS compared to men.8 Since this time, there have been
a growing number of publications that address the issue of sex
differences in access to and use of IV thrombolysis. Some of
these studies reported a significant sex difference,6,9 while
others did not.10 Given the volume of new studies published
on the topic and the potential that the increased attention
given to the care and treatment of stroke in women might
have changed treatment patterns over the last decade, we
conducted an updated systematic review and meta-analysis to
determine if the use of IV thrombolysis still differed by sex.
Methods
Eligibility criteria and search
We followed the same search strategy to identify potentially
relevant studies that was used in the prior meta-analysis,
which included studies published up to March 2008.8 We
searched MEDLINE, EMBASE, and the ISI Web of Science
databases for relevant articles published between April 2008
and December 2018. We used the same combination of
search terms, which included the following: (1) cerebrovas-
cular accident (MeSH) or “stroke”; (2) “r-tPA” or “tPA” or
“thrombolysis” or “thrombolytics”; and (3) “sex” or “sex
factors” or “sex ratio” or “sex distribution.”8 Relevant studies
were those that reported sex-specific treatment rates of IV
rtPA (thrombolysis) for AIS in typical hospital settings.
Typical hospital settings could include individual community-
based or stroke-specialist centers, regional hospital networks,
hospital systems, or hospital-based stroke registries. Studies
that used hospital billing (administrative) data—such as
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national-level hospital discharge data or Medicare fee-for-
service data—were also eligible. The reference lists of any
systematic or narrative reviews identified in the search were
also screened for additional potentially relevant studies. We
excluded conference abstracts, other unpublished gray liter-
ature, and non-English articles. We used a standard text for
guidance on methodologic aspects of conducting the sys-
tematic review and meta-analysis11 and the PRISMA report-
ing guidelines.12
Study selection and data abstraction
Two authors (B.S., M.R.) screened abstracts and titles for
relevancy and then conducted an independent full-text review
of potentially relevant studies. Studies that met eligibility
criteria then underwent dual data abstraction. Abstracted data
included study design, time period of case enrollment, defi-
nition and size of numerator and denominator populations,
sex-specific treatment rates (%), odds ratios (ORs) describing
the sex difference (both unadjusted and adjusted), 95% con-
fidence intervals (CIs), and any confounders that were ad-
justed for. We also abstracted data describing each study’s
patient population including the mean age and range, sex
proportion, and proportion of minority subjects. If sex-
specific treatment rates or the unadjusted OR of the sex dif-
ference in IV rtPA use was not provided in the publication, we
calculated them when data were available to do so. When
provided, we also abstracted data on patient subgroups eli-
gible for thrombolysis treatment as defined by the combina-
tion of time of arrival, time of treatment, and
contraindications. However, the definition of these eligible
treatment subgroups varied among studies—for example,
“arrive by 2 hours, treat by 3 with no contraindications”13,14 or
“arrive by 4 hours.”9 Disagreements were resolved by con-
ference. In several cases, authors were contacted to ascertain
further information about their data.
Quality scoring
We developed a quality assessment instrument by adapting
items from the Newcastle–Ottawa Scale.15 All eligible studies
were scored (0, 1, or 2, where 2 is best and 0 worst) on the
following 4 criteria: (1) the representativeness of the overall
study population, (2) the number and impact of exclusions
applied to the initial patient cohort, (3) adjustment for po-
tential confounding variables that might affect sex differences
in IV rtPA utilization, (4) the method by which the outcome
(IV rtPA treatment or not) was ascertained. Studies that
provided data specific to the subgroup of patients eligible for
IV rtPA treatment were not scored for criterion 3 (adjust-
ment) because further adjustment among patients already
eligible for thrombolysis is unnecessary. To assess overall
study quality, we aggregated the scores to generate a 0–8 scale
(or 0–6 in the case of studies of eligible subgroups). A more
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 detailed description of the quality assessment instrument
along with examples of the scoring is provided in table e-1
(doi.org/10.5061/dryad.1zcrjdfnc).
In addition to the above quality scoring, we also classified
studies into 1 of 4 groups based on their primary focus.
Studies classified as A were those that had a clear objective to
examine sex differences in IV rtPA utilization. Studies classi-
fied as B examined sex differences in IV rtPA effectiveness but
had no clear objective to study IV rtPA utilization per se.
Studies classified as C focused on IV rtPA treatment more
broadly but had no particular objective to study sex differ-
ences. Studies classified as D examined sex differences in acute
stroke care but had no particular objective to focus on IV rtPA
per se. This classification system was created because studies
examining a hypothesis that is directly related to sex differ-
ences in IV rtPA utilization (i.e., group A) might be expected
to have the most validity, whereas those studies that did not
have any specific objective to study IV rtPA (i.e., group D)
might have the least.
Statistical analysis
The primary outcome measure of interest was the unadjusted
OR comparing the IV rtPA treatment rate in women with that
of men, among all AIS admissions. We conducted all meta-
analyses using the metan command in Stata (StataCorp,
College Station, TX). Due to the variability in study design,
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we only report random effects–based results. Heterogeneity
was summarized using the Cochran Q statistic and the I2
statistic. The metaninf command was used to conduct an
influence analysis to investigate the effect of individual studies
on the summary OR. When available, we also analyzed ad-
justed ORs and ORs calculated among the subgroups of
patients eligible for treatment. If we were only provided a 95%
CI of the OR, we used both the upper and lower bounds of the
CI to estimate the standard error.16 Other prespecified sub-
group analyses included geographic region (North America,
Europe, Asia), study design (hospital-based studies and reg-
istries vs administrative data), quality score (0–8), primary
study focus (groups A–D), and the time period of publication
(2009–2013, 2014–2018). Pairwise comparisons of summary
ORs between subgroups were made using a Z test. To ex-
amine longer-term secular trends, we combined the studies
found in the current search with the 16 studies identified in
the prior meta-analysis (published between 2000 and 2008)8
that provided unadjusted OR estimates of sex differences in IV
thrombolysis use among all AIS admissions. These 33 studies
were then categorized according to date of publication
(i.e., 2000–2004, 2005–2008, 2009–2013, 2014–2018) and
differences were tested using a linear test for trend and pair-
wise Z tests.
Standard protocol approvals, registrations,
and patient consents
Review board approval and informed consent were not
obtained because this research makes use of only published,
de-identified data.
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Data availability
The protocol for this systematic review as well as the data used
in the meta-analysis are available upon request from the
authors. The data supplement is available from dryad (doi.
org/10.5061/dryad.1zcrjdfnc).
Results
The search identified 1,097 initial hits, of which 66 studies
passed the initial relevancy screen and underwent full review
(figure 1). Of these, 31 met eligibility criteria and provided
sufficient data to either abstract or calculate an OR comparing
IV rtPA treatment rates in women with those in men. Seven
studies were excluded because they used the same data source
from a similar time period as another publication (see data
supplement, doi.org/10.5061/dryad.1zcrjdfnc). Thus a total
of 24 studies were included in the final systematic review and
meta-analysis; study characteristics and IV rtPA treatment
rates by sex for the 24 studies are described in tables 1 and 2.
There were 11 hospital-based, 5 registry-based, and 8 ad-
ministrative data studies. Seventeen studies provided data on
treatment rates among all patients with AIS (table 1), 2
studies only provided data for an adjusted OR estimate for all
patients with AIS (table 1), and 7 studies provided data spe-
cific to eligible treatment subgroups (table 2). Individual
studies differed widely in terms of sample size (range
602–605,960 for all AIS) and treatment rates (range
1.5%–27.8% for all patients with AIS and 10.0%–88.0% for
eligible treatment subgroups). The results of the quality as-
sessment scoring and the classification system that reflected
the primary study focus (i.e., groups A–D) are summarized in
table e-2 (doi.org/10.5061/dryad.1zcrjdfnc). Studies differed
widely in terms of quality, with total scores ranging from 1 to 8
with a median of 5. Only 5 (21%) of the 24 studies were
classified as group A, indicating that they had the specific goal
of examining sex differences in IV rtPA utilization. Of the
remaining studies, a total of 3, 9, and 7 studies were classified
as group B, C, or D, respectively.
Seventeen studies provided data on the unadjusted sex dif-
ference among all patients with AIS; the forest plot of the
unadjusted ORs from the 17 studies is shown in figure 2. The
random effects summary unadjusted OR was 0.87 (95% CI,
0.82–0.93), indicating that women had a statistically signifi-
cant 13% lower odds of receiving IV rtPA treatment than men.
However, the Q statistic was highly significant (p < 0.001) and
the I2 statistic was 87.8%, indicating substantial between-
study variability. The influence analysis revealed that none of
the 17 individual studies had a disproportionate effect on the
overall unadjusted OR.
A total of 10 studies provided data on the adjusted OR for the
treatment sex difference among all patients with AIS; 8 of
these came from the pool of 17 studies that reported an
unadjusted OR, while 2 other studies provided data only on
the adjusted OR (table 1). The summary adjusted OR from
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e14
the 10 studies was 0.95 (95% CI, 0.89–1.01) but with con-
siderable between-study heterogeneity (Q p < 0.001, I2 =
74%) (figure 3). Individual factors that were adjusted for
varied among the studies, but most often included age (n =
10), comorbidities (n = 8), stroke severity (n = 7), race/
ethnicity (n = 4), and hospital-related factors (n = 4). A list
of the specific factors adjusted for in each of the 10 studies
is provided in table e-3 (doi.org/10.5061/dryad.1zcrjdfnc).
To further elucidate the effect of adjustment on the ob-
served sex differences among all AIS, we compared the
results of the 8 studies that included both unadjusted and
adjusted data; the unadjusted summary OR of 0.88 (95%
CI, 0.81–0.97, Q p < 0.001, I2 = 90.6%) (figure e-1, doi.org/
10.5061/dryad.1zcrjdfnc) was similar to the adjusted
summary OR of 0.91 (95% CI, 0.87–0.96, Q p = 0.003, I2 =
67.3%) (figure e-2, doi.org/10.5061/dryad.1zcrjdfnc), in-
dicating that adjustment for these various factors made
relatively little difference in the magnitude of the sex
difference.
There were 7 studies that provided data on the subgroup of
patients who were eligible for IV rtPA treatment; the summary
unadjusted OR was 0.95 (95% CI, 0.88–1.02), indicating that the
odds of treatment were still lower for women but that the estimate
was no longer statistically significant within these selected patient
subpopulations. There was only modest between-study hetero-
geneity (Q test p = 0.186, I2 = 31.7%) (figure 4). As previously
Figure 1 PRISMA flow diagram12 including reasons for exclusion of full-text articles
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noted, descriptions of the eligible subgroups differed among
studies (see footnotes, table 2).
Prespecified subgroup and sensitivity analyses
The subgroup analysis that examined studies from different
geographical regions found that sex differences in IV rtPA use
among all patients with AIS were observed both in European
and United States–based studies but not in studies from Asia
(figure e-3, doi.org/10.5061/dryad.1zcrjdfnc). The summary
unadjusted OR for the 6 European studies was 0.82 (95%
CI, 0.78–0.85) with no significant heterogeneity (Q p =
0.350, I2 = 10.3%), and for the 7 United States–based
studies it was 0.85 (95% CI, 0.75–0.96) but with substantial
between study heterogeneity (Q p < 0.001, I2 = 92.9%).
In contrast, the summary OR for the 4 Asian studies was
0.98 (95% CI, 0.94–1.03) with no significant heterogeneity
(Q p = 0.889, I2 = 0%). The summary OR for the Asian
studies was statistically significantly different from the
European (Z test p < 0.001) and United States–based
(Z test p = 0.03) studies.
When the results of the 11 hospital-based and registry-based
studies were compared to the 6 administrative data studies,
the summary unadjusted ORs among all patients with AIS
were similar (0.90 [95% CI, 0.83–0.97] and 0.86 [95% CI,
0.78–0.95], respectively; Z test p = 0.522) (figure e-4, doi.org/
10.5061/dryad.1zcrjdfnc). Both subgroups had either modest
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Table 1 Characteristics of 19 included studies providing sex-specific utilization data among all patients with acute ischemic stroke (AIS) classified according to the type of
data provided: all AIS with unadjusted estimates (n = 17 studies), AIS with only an adjusted estimate provided (n = 2 studies)
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Female rtPA- Female Male rtPA- Male Adjusted

treated Female treatment treated Male treatment estimate
a
Authors Year Country Time Study design cases, n denominator, n rate, % cases, n denominator, n rate, % provided

All AIS unadjusted

estimates (n = 17)

Allen et al.32 2009 United 2004 Multiple- 39 604 6.5 47 630 7.5 Yes
States hospital
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Asdaghi et al.13 2016 United 2010–2014 Registry 2,397 25,059 9.6 2,606 25,543 10.2 Yes
States

Boehme et al.30 2014 United 2004–2011 Multiple- 679 2,372 28.6 706 2,605 27.1 No
States hospital

Clua-Espuny 2015 Spain 2006–2014 Multiple- 53 597 8.9 60 675 8.9 No

et al.10 hospital

de Ridder et al.9 2013 Holland 2003–2005 Multiple- 314 2,778 11.3 382 2,737 14.0 No
hospital

Eriksson et al.22 2010 Sweden 2003–2008 Registry 957 29,506 3.2 1,578 41,199 3.8 Yes

6
Faigle et al. 2017 United 2007–2011 Administrative 7,905 179,664 4.4 7,877 157,537 5.0 Yes
States

Huang et al.34 2010 China 2006 Registry 178 1810 9.8 307 2,972 10.3 Yes

Kunisawa 2014 Japan 2010–2011 Administrative 236 4,389 5.4 321 6,226 5.2 Yes
et al.31
Neurology | Volume 95, Number 1 | July 7, 2020

Łabuz-Roszak 2018 Poland 2009–2015 Administrative 1,565 35,880 4.4 1,690 33,107 5.1 No
et al.39

Lee et al.17 2018 United 2012–2015 Single- 71 456 15.6 113 470 24 No
States hospital

Nagaraja et al.40 2012 United 2006 Multiple- 8 320 2.5 10 282 3.5 No
States hospital

Nardetto et al.41 2017 Italy 2007–2015 Administrative 1,672 31,414 5.3 2012 29,648 6.8 No

Park et al.25 2013 South 2008 Multiple- 190 2,830 6.7 261 3,805 6.9 Yes
Korea hospital

Santalucia 2013 Italy 2011 Registry 41 410 10 62 527 11.8 No

et al.42

Towfighi et al.43 2013 United 1997–2006 Administrative 4,219 332,225 1.3 4,763 273,735 1.7 Yes
States

Continued
e15
 or substantial between-study heterogeneity (I2 = 56.6% and

Studies using primarily administrative data were classified as retrospective designs; studies that used data from medical records or registries (i.e., single-hospital, multiple-hospital, and registry) were classified as prospective
Table 1 Characteristics of 19 included studies providing sex-specific utilization data among all patients with acute ischemic stroke (AIS) classified according to the type of data
I2 = 94.8%, respectively).

Adjusted
estimate
provided

For some studies, the number of treated cases and/or denominators were estimated from the reported treatment rates. Abbreviations: NA = data not available; rtPA = recombinant tissue plasminogen activator.
After combining data from the 16 studies included in the previous

Yes

Yes
No
meta-analysis,8 there were a total of 33 studies that provided data
treatment on the unadjusted OR among all patients with AIS. After cate-
gorizing these studies into 4 time periods according to the date of
rate, %

publication, the pooled results from more recently published

Male

2.7

NA

NA
studies tended to show a smaller sex difference (figure 5). Al-
though the linear test for trend for the summary ORs across the 4
time periods was not statistically significant (p = 0.15), when the
denominator, n

summary ORs for the earlier time periods were compared to the
provided: all AIS with unadjusted estimates (n = 17 studies), AIS with only an adjusted estimate provided (n = 2 studies) (continued)

2014–2018 period (OR, 0.90 [95% CI, 0.84–0.97]), the

2000–2004 estimate (OR, 0.73 [95% CI, 0.67–0.80]) was sig-
107,915

nificantly different (Z test p < 0.001).

2,570

5,862
Male

Finally, among the 17 studies that provided unadjusted data

Male rtPA-

on all patients with AIS, when studies with a quality assessment

cases, n
treated

score of 5 or lower (n = 9) were compared to studies with a score

2,940

of 6 or higher (n = 8), the summary unadjusted ORs were the same

NA

NA

(0.88 [95% CI, 0.81–0.95] and 0.88 [95% CI, 0.78–0.98], re-
spectively) (figure e-5, doi.org/10.5061/dryad.1zcrjdfnc). Both
treatment

subgroups had significant between-study heterogeneity. With

Female

rate, %

respect to the primary study focus, studies classified under

2.7

NA

NA

group A (i.e., specific objective to look at sex differences in IV

rtPA use) found a slightly greater sex difference (summary
unadjusted OR, 0.80 [95% CI, 0.69–0.92]) than studies
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denominator, n

classified as either B or C (summary unadjusted OR, 0.87

[95% CI, 0.78–0.96]) or group D (summary unadjusted OR,
0.96 [95% CI, 0.91–1.02]) (figure e-6, doi.org/10.5061/
Female

91,323

2,707

5,768

dryad.1zcrjdfnc). Only the pairwise difference between group

A and group D was statistically significant (Z test p = 0.02).
Female rtPA-

Discussion
cases, n
treated

2,444

NA

NA

This updated meta-analysis found 24 studies published since

2008 that provided data to address the issue of sex differences
a

Administrative

Administrative
Study design

in IV rtPA treatment among patients with AIS. Although the

results of individual studies varied substantially, the pooled
Multiple-
hospital

unadjusted random effects OR among all patients with AIS,

which was based on data from 17 studies and over 1 million
patients with stroke, indicated that women were less likely to
2011–2014

2000–2012

2009–2013

receive IV thrombolysis treatment compared to men. It is im-

Time

portant to note that the 13% lower relative odds of treatment

observed in these 17 studies reflects modest absolute differences
in treatment rates between women and men; most of the dif-
Country

Thailand

United

United
States

States

ferences were in the range of 0.5%–1.0%, with the largest being

8.4%.17 However, even small absolute differences could translate
into a large number of untreated women, given the high in-
2018

2016

2016
Year

cidence of AIS. Moreover, missed opportunities to deliver IV

rtPA could have greater consequences in women because they
estimate only (n =

have poorer stroke outcomes than men18 but derive at least

Domino et al.33
All AIS: adjusted
Vongmongkol

Zachrison

equivalent treatment benefit.1

et al.44

et al.37
Sauser-
Authors

designs.

Why would a sex difference in IV thrombolysis treatment rates

persist even if the absolute differences are small? One
2)

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Table 2 Characteristics of 7 included studies providing sex-specific utilization data among eligible treatment subgroups
Female rtPA-treated Female Female treatment Male rtPA-treated Male Male treatment
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Author Year Country Time Study design cases, n denominator, n rate, % cases, n denominator, n rate, %

Asdaghi 2016 United 2010–2014 Registry NA NA 87.8 NA NA 88.1

et al.13,a States

de Ridder 2013 Holland 2003–2005 Multiple- 314 755 41.6 382 902 42.4
et al.9,b hospital

Fredwall 2016 United 2010–2013 Single- 119 354 33.6 122 309 39.5
et al.20,c States hospital
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McDermott 2017 United 2009–2012 Multiple- 35 55 63.6 21 35 60.0

et al.35,d States hospital

Messe et al.14,a 2016 United 2003–2011 Registry 23,254 31,219 74.5 23,162 30,479 76.0
States

Rudd et al.21,e 2011 United 2008 Administrative 61 668 9.1 99 937 10.6
Kingdom

Tafreshi 2010 United 2001–2009 Multiple- 148 390 37.9 146 458 31.9
et al.36,f States hospital

Abbreviations: AIS = acute ischemic stroke; NA = data not available; rtPA = recombinant tissue plasminogen activator.
Two studies9,13 provided data on all patients with AIS and eligible subgroups.
a
Eligible patients with AIS (i.e., absence of contraindications or warnings) with arrival within 2 hours and treatment within 3 hours.
b
Patients with AIS with arrival within 4 hours.
c
Eligible patients with AIS (i.e., absence of contraindications or warnings) treated within 4.5 hours.
d
Patients with AIS with arrival within 2 hours and no contraindications.
e
Eligible patients with AIS (i.e., absence of contraindications or warnings) with age <80 years and arrival within 3 hours.
f
Patients with AIS with a “stroke code” and IV rtPA treatment decision in the emergency department.
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e18
Figure 2 Forest plot of unadjusted odds ratio (OR) of IV recombinant tissue plasminogen activator use in women compared
to men in all acute ischemic stroke admissions
Random effects model (n = 17 studies). CI = confidence interval.
explanation is that there are differences in the characteristics
of women and men who present with acute stroke, which for
women includes older age, different comorbidity profiles,
higher stroke severity, and a greater chance of being widowed
or living alone, affecting their eligibility for IV rtPA treatment
and leading to an apparent sex difference in the utilization of
the treatment. One approach to test this hypothesis is to
examine the studies that provide data on eligible treatment
subgroups. Although the definition of what constituted an
eligible treatment subgroup varied across the 7 studies in-
cluded in this meta-analysis, in aggregate, they found only
a very modest and nonsignificant sex difference (summary
unadjusted OR, 0.95). This estimate was smaller than the
nonsignificant difference reported in the original meta-
analysis (summary unadjusted OR, 0.81), which was based
on only 4 studies.8
A detailed accounting of the specific factors that cause the
exclusion of women and men from the pool of patients eligible
for IV rtPA treatment—most notably contraindications and
warnings for IV rtPA and time of arrival—have been the focus
of several studies. For example, data from a population-based
stroke incidence study found no sex differences in eligibility
for IV rtPA treatment, except for severe hypertension on
presentation, which was more common in women.19 Older
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age (i.e., >80 years), which had been traditionally regarded as
a reason to exclude patients from IV thrombolysis therapy, was
found to be an explanation for why more women were excluded
from IV rtPA therapy in 2 of the studies included in this
review.20,21 Although there is no strong evidence that women are
more likely to arrive later to the hospital than men following the
onset of stroke symptoms,1 one study included in this review
found that the later arrival of women to the hospital did explain
their lower use of IV thrombolysis.9 Among the older pop-
ulation, women are much more likely than men to live alone and
this has been identified as a risk factor for late arrival and failure
to receive IV thrombolysis treatment.22,23
Another approach to explain sex differences in IV thrombol-
ysis treatment is to examine the studies that provide adjusted
estimates among the broad population of all patients with AIS.
Overall, statistical adjustment did attenuate the overall sum-
mary OR from 0.87 unadjusted (in 17 studies) to 0.95 ad-
justed (in 10 studies), which suggests that factors such as age
and severity help explain the origins of some of the observed
disparity. However, when the effect of adjustment was ex-
amined only among the 8 studies that provided both un-
adjusted and adjusted estimates, adjustment had a very
modest attenuating effect on the summary ORs (0.88 un-
adjusted vs 0.91 adjusted). Interpretation of the overall effects
Neurology.org/N
 Figure 3 Forest plot of the adjusted odds ratio of IV recombinant tissue plasminogen activator use in women compared to
men in all acute ischemic stroke admissions.

Random effects model (n = 10 studies). CI = confidence interval; OR = odds ratio.

Downloaded from https://www.neurology.org by King Saud Bin Abdulaziz University for Health on 11 March 2024

of statistical adjustment is also complicated by the fact that
many studies did not adjust for socioeconomic factors that
are often different in women with stroke compared to men;
for example, few studies adjusted for health insurance status
(n = 2), education level (n = 2), living alone (n = 2), or
household income (n = 1) (table e-3, doi.org/10.5061/
dryad.1zcrjdfnc).
Another possible explanation for differences in IV throm-
bolysis treatment rates is that the clinical presentation of

Figure 4 Forest plot of the unadjusted odds ratio of IV recombinant tissue plasminogen activator use in women compared
to men among eligible treatment subgroup of patients with acute ischemic stroke

Random effects model (n = 7 studies). See table footnotes for study-specific definitions. CI = confidence interval; OR = odds ratio.

Neurology.org/N Neurology | Volume 95, Number 1 | July 7, 2020 e19

Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Figure 5 Subgroup analysis by publication date (2000–2004, 2005–2008, 2009–2013, 2014–2018)
Downloaded from https://www.neurology.org by King Saud Bin Abdulaziz University for Health on 11 March 2024

Forest plots of the unadjusted odds ratio (OR) of IV recombinant tissue plasminogen activator use in women compared to men in all acute ischemic stroke
admissions. Random effects model (n = 33 studies). CI = confidence interval.

women with acute stroke is different enough from that of men
to affect treatment decision-making. An unusual presentation
of female patients could delay treatment decisions by com-
plicating the confirmation of the diagnosis of AIS or its time of
onset. A recent systematic review of 43 studies that examined
sex differences in the clinical presentation of acute stroke
found a tendency for women to present more often with
nontraditional stroke symptoms (including altered mental
status, generalized weakness, and urinary incontinence) and
concluded that these could contribute to delayed recognition
and treatment.24 Another recent review reached similar con-
clusions regarding the higher prevalence of nontraditional
presenting symptoms in women with stroke.1 Among the
studies included in our meta-analysis, most did not include
details of presenting symptoms in their patient populations.
However, one study did find that women were significantly
more likely to present with altered mental status than men.25
The higher prevalence of stroke mimics, especially in younger
women, can also complicate the timely diagnosis of acute
stroke, and result in errors in determining eligibility for IV
rtPA treatment.26,27
Sex differences in patient preference for IV thrombolysis ad-
ministration is another possible explanation for lower utili-
zation rates in women. A Canadian study of ambulatory
patients that used a series of case scenarios determined that

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Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 women were less likely to accept thrombolysis treatment and
also tended to be less confident and more risk averse in their
decisions compared to men.28 However, a single-center study
from Texas that compared eligible patients who had refused
treatment with eligible patients who had consented to treat-
ment did not find a sex difference in the acceptance of IV
thrombolysis therapy.29
Another plausible explanation for the sex differences observed
in these studies is residual confounding—perhaps there
remains a variable that is either unmeasured or poorly mea-
sured that would explain this sex-based disparity. Studies with
more detailed data on the specific particulars of the clinical
presentation of acute stroke cases are needed to help sort out
the complicated matrix of issues that might explain differences
in eligibility and the use of IV rtPA therapy in women
and men.
There are some limitations to our systematic review and meta-
analysis to consider. First, almost all of the meta-analyses we
conducted found substantial between-study variability, and
some individual studies documented higher unadjusted or
adjusted treatment rates in women compared to men,30–36
although in only one was the difference statistically signifi-
cant.37 This heterogeneity complicates the interpretation of
the summary (pooled) effect estimates, and emphasizes that
the presence and magnitude of any observed sex difference is
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The preponderance of evidence from studies published in
the last 10 years that compare IV thrombolysis treatment
rates in women and men with acute stroke points to lower
treatment rates in women. However, the absolute differences
in treatment rates between women and men were small, and
when compared to articles published more than 10 years ago
the magnitude of the sex difference is smaller on a relative
basis. This treatment disparity appears to be partially
explained by sex differences in eligibility for treatment. The
continued presence of this sex difference calls for further
studies designed to explain its origins, as well as ongoing
surveillance to monitor the magnitude and changes over
time. This is especially important as we move towards
wider implementation of intra-arterial thrombectomy–based
treatments.38
Study funding
No targeted funding reported.
Disclosure
The authors report no relevant disclosures. Go to Neurology.
org/N for full disclosures.
Publication history
Received by Neurology May 16, 2019. Accepted in final form
December 5, 2019.

ultimately study- and population-specific. However, all of the

summary OR estimates we generated were less than 1.0, in- Appendix Authors
dicating that overall treatment rates in women were always
Name Location Contribution
lower than those in men, which justifies our conclusion that
the preponderance of evidence still points to lower treatment Brent Michigan State Database searches, protocol
Strong University, East development, abstraction of data,
rates in women. Second, while subgroup analyses can help Lansing statistical analyses, manuscript
identify the source of between-study heterogeneity, almost all preparation
of the prespecified subgroup analyses we conducted still Lynda University of Review of protocol and draft
showed evidence of significant between-study heterogeneity. Lisabeth, Michigan, Ann manuscript
PhD Arbor
Meta-regression can be used to identify factors that contribute
to between-study heterogeneity,11 but it is best used when Mathew Michigan State Design of the study, protocol
there are a large number of studies with a consistent set of Reeves, University, East development, abstraction of data,
PhD Lansing review of statistical analyses,
study-level factors that are plausibly related to sex-specific manuscript preparation
treatment patterns. Such data were lacking among the rele-
vant studies identified in this review. Third, only 5 studies
were conducted with the specific objective of examining sex References
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