Duration of Ischemia Affects

Outcomes Independent of Infarct

Size in Stroke
Ameer E. Hassan

Background

Delays in endovascular reperfusion for patients with large vessel

occlusion stroke are known to worsen outcomes, and the mechanism
is believed to be time-dependent expansion of the ischemic
infarction. In this study, we hypothesize that delays in onset to
reperfusion (OTR) assert an effect on outcomes independent of
effects of final infarct (FI).

Methods

We performed a subgroup analysis from the prospective multicenter

COMPLETE (International Acute Ischemic Stroke Registry With the
Penumbra System Aspiration Including the 3D Revascularization
Device; Penumbra, Inc) registry for 257 patients with anterior
circulation large vessel occlusion who underwent endovascular
therapy with successful reperfusion (modified treatment in cerebral
infarction score 2b/3). FI was measured by Alberta Stroke Program
Early CT score and volume on 24- to 48-hour computed tomography
or magnetic resonance imaging. The likelihood of 90-day good
functional outcome (modified Rankin scale 0–2) was assessed by
OTR and absolute risk difference (ARD) was estimated using
multivariable logistic regressions adjusting for patient characteristics
including FI.
Results

In univariable analysis, longer OTR was associated with a decreased

likelihood of good functional outcome (ARD –3% [95% CI –4.5 to –
1.0]/h delay). In multivariable analysis accounting for FI, the
association between OTR and functional outcome remained
significant (ARD –2% [95% CI –3.5 to –0.4]/h delay) with similar
ARD. This finding was maintained in the subset of patients with FI
imaging using CT only, using Alberta Stroke Program Early CT Score
or volumetric FI measurements, and also in patients with larger
versus smaller FIs.

Conclusions

The impact of OTR on outcomes appears to be mostly through a

mechanism that is independent of FI. Our findings suggest that
although the field has moved toward imaging infarct core definitions
of eligibility for endovascular treatment, time remains an important
predictor of outcome, independent of infarct core.

Abbreviations

AIS acute ischemic stroke

ASPECTS Alberta Stroke Program Early CT Score
EVT endovascular treatment
FI final infarct
IV-tPA intravenous tissue plasminogen activator
LVO large vessel occlusion
mRS modified Rankin scale
OTR onset to reperfusion

Clinical Perspective
What Is New?

In patients with anterior circulation large vessel occlusion acute

ischemic stroke treated with successful endovascular
treatment, rapid reperfusion improved clinical outcomes
independent of its effect on reducing the final infarct volume.

What Are the Clinical Implications?

Prolonged ischemic time asserts an effect on 90-day functional

outcomes that is independent of effects on final infarct
suggesting a mechanism beyond infarct growth.

Although the field has moved toward imaging infarct core

definitions of eligibility for endovascular treatment, time remains
an important predictor of outcome and delays in successful
endovascular treatment may independently worsen clinical
outcome, despite successful reperfusion and small final infarct.

Multiple randomized clinical trials have established the efficacy of

endovascular therapy (EVT) to reduce disability after large vessel
occlusion (LVO) acute ischemic stroke (AIS).1, 2, 3, 4, 5 From these
studies, the benefits of EVT have been shown to be highly
dependent on time, with decreasing likelihood of good outcome with
longer time to reperfusion.6, 7 The pathophysiology behind this
worsening, however, remains incompletely uncharacterized.

At present, the presumed mechanism is expansion of infarct core

over time, at rates depending on the quality of collateral circulation.8,
9 This concept has shifted EVT screening paradigms from the initial

time-based approaches to imaging-based approaches, in which

infarct core serves as the principal criterion. In this new paradigm,
the relative importance of time from symptom onset is minimized. In
support of this approach, final infarct (FI) has been shown to be a
strong predictor of functional outcome and has even served as the
end point in randomized clinical trials.10, 11 Conversely, other studies
found that FI volume explains only a small part of the treatment
effect on functional outcome.12, 13

In this study, we examine a large real-world cohort and assess

whether time from stroke onset to reperfusion (OTR) influences
functional outcomes after accounting for differences in FI among
patients with AIS LVO and successful EVT reperfusion. We
hypothesize that delays in OTR assert an effect on outcomes
independent of effects of FI (Figure 1).

Figure 1. A proposed model for the interactions between onset to reperfusion, final infarct, and
90-day clinical outcomes.

Onset to reperfusion (OTR) is associated with final infarct (FI) and FI has an effect on clinical outcomes.
In this study, we examine the effect of OTR on clinical outcomes after adjusting for the effect of FI.

Methods

Study Design and Study Participants

The data that support the findings of this study are available from
the corresponding author upon reasonable request. We conducted a
post hoc analysis from the prospective cohort COMPLETE
(International Acute Ischemic Stroke Registry With the Penumbra
System Aspiration Including the 3D Revascularization Device;
Penumbra, Inc.) registry.14 The COMPLETE registry collected
performance and safety data on the Penumbra System in a real-
world patient population with AIS secondary to intracranial LVO and
was a prospective, single-arm, multicenter observational registry
from 42 participating sites internationally conducted from July 2018
and March 2020. All patients or their legally authorized
representatives provided signed, informed consent per institutional
review board/ethics committee at each center for participation in the
COMPLETE study.

We included patients 18 years and older with anterior circulation AIS

with LVO and prestroke modified Rankin Scale (mRS) scores 0 to 1,
who underwent EVT within 24 hours of symptom onset and achieved
successful reperfusion at final angiogram (n=302). The EVT
procedure was required to begin within 90 minutes of the last
imaging study and successful reperfusion was defined by a modified
thrombolysis in cerebral infarction score of 2b or higher. If patients
had any comorbid disease or condition expected to compromise
survival or ability to complete follow-up assessments through 90
days, they were not eligible to enroll. We limited the cohort to
patients with documented stroke onset excluding patients with
wake-up stroke (n=25) given our primary exposure was OTR time.
We excluded patients if they had missing information for mRS scores
at 90 days (n=18), time from symptom onset to successful
reperfusion (n=1), and stroke severity (n=1). The final cohort
included 257 patients who were treated with EVT between July 29,
2018, and October 9, 2019, from 35 participating sites.

Clinical Assessment and Outcomes

Baseline stroke severity was assessed using the National Institutes

of Health Stroke Scale score (range, 0–42, with higher scores
indicating greater stroke severity). Baseline Alberta Stroke Program
Early CT Score (ASPECTS) was assessed at baseline graded from 0
to 10, with 1 point subtracted from 10 for any evidence of early
ischemic changes on noncontrast computed tomography. For the
extent of FI, we used 2 measurements from computed tomography
(CT) or magnetic resonance imaging (diffusion-weighted imaging
sequences) obtained at 24 to 48 hours post-EVT. The first
measurement was ASPECTS (FIASPECTS) and the second was infarct
volume (FIVOLUME).15 Volumetric assessments for FIVOLUME were
made by manual region segmentation (OsirixMD, Pixmeo). All
imaging analyses, including ASPECTS, modified thrombolysis in
cerebral infarction, and FI, were recorded by an independent Imaging
Core Lab, blinded to clinical and treatment characteristics.

Stroke onset was determined as the moment of witnessed symptom

or the time last seen well. Intervals from stroke onset were the
studied exposures and included stroke onset to admission, from
onset to arterial puncture, and from onset to first reached successful
reperfusion (OTR). We censored the per-hour analysis at 12 hours
because the data became very dispersed after that time. The
outcome was functional independence at 90 days postprocedure,
defined as a score of 0 to 2 on mRS.

Statistical Analysis

Patient demographic and clinical characteristics were reported by

3time windows (0–180, 181–360, >360 minute) from stroke OTR, for
illustrative purposes. Percentages and median interquartile ranges
(IQRs) were reported for categorical and continuous variables,
respectively and Fisher exact tests and Kruskal–Wallis tests were
used for significant differences across time windows. The
distributions of FIASPECTS and FIVOLUME against 90-day functional
outcomes were calculated using kernel density estimation. Optimal
widths were chosen to minimize the mean integrated squared error
for FIVOLUME measurements, and a bandwidth of 1 was used for
FIASPECTS.
To estimate the effect of time on functional outcome, univariate and
multivariable logistic regressions were performed separately for
onset to admission, onset to arterial puncture, and OTR intervals. We
report unadjusted and adjusted odds ratios and absolute risk
differences in predicted probabilities by hour from logistic
regressions. Predicted probability of the outcome was plotted with
margins plot using time as continuous variable, with 95% CIs.
Logistic regressions were adjusted for demographic and known
prognostic factors including age, sex, stroke severity as baseline
National Institutes of Health Stroke scale, prestroke mRS, location of
occlusion, and FI.10, 16, 17, 18, 19 In the multivariable models, FI was
defined by FIASPECTS in Model 1 and FIVOLUME in Model 2. We
performed several sensitivity analyses. Of note, intravenous tissue-
type plasminogen activator (IV-tPA) was not included as a covariate
because the time dependency of IV-tPA makes this variable highly
correlated with the primary exposure variables (eg, the time
intervals). However, to address whether IV-tPA treatment can
account for time-dependent changes in outcome, we performed a
sensitivity analysis of OTR in the subgroup of patients treated with
IV-tPA. In further sensitivity analysis, we limited the analysis to the
subset of patients with CT imaging for FI, excluding those with
magnetic resonance imaging determinations of FI, to examine the
effect of OTR when imaging modality was kept consistent. We also
assessed the associations of time to reperfusion with functional
outcomes for varying definitions (excellent outcome with mRS 0–1
and fair outcome with mRS 0–3) to address possible threshold
effect, which may be vulnerable to cutoff value of mRS. Then,
additional sensitivity analyses were performed by analyzing the
subsets of patients with larger FI (FIASPECTS < 8) and those with
smaller FI (FIASPECTS 8–10) separately.

Significance levels were set at P < 0.05 for 2-tailed tests. All analyses
were performed using STATA 16.0 (StataCorp, College Station, TX)
and Prism 9 (GraphPad, La Jolla, CA) statistical software.

Results

Characteristics of Patients

Among 257 patients that met inclusion criteria, OTR occurred for 72
(28%) patients within 180 minutes, 110 (43%) patients within 181–
360 minutes, and 75 (29%) patients beyond 360 minutes. Females
accounted for 56% of patients and median age was 71 years (IQR,
61–79). As shown in Table 1, there were no significant differences in
patients’ demographics and vascular risk factors across 3 OTR
windows. Median National Institutes of Health Stroke scale score
was 16 (IQR, 10–20) and greater among those treated early (17 in
≤180 minutes versus 16 in 181–360 minutes versus 14 in
>360 minutes, P=0.045) (Table 1). The majority of patients (72%)
had prestroke mRS 0 and 60% of patients achieved functional
independency at 90 days with higher percentage of patients in
earlier OTR (72% in ≤180 minutes versus 60 in 181–360 minutes
versus 35 in >360 minutes, P=0.01). Mortality rate was 16%, and
there was no significant difference across time windows.

John Wiley & Sons, Ltd.

Table 1. Demographic and Clinical Characteristics of Patients by

Onset-to-Reperfusion Times

Patients,
Onset to reperfusion, min
n (%)
All 0–180 181–360 >360 P
(N=257) (n=72) (n=110) (n=75) value*
144 37 45
Female sex 62 (56.4) 0.58
(56.0) (51.4) (60.0)
Age, median 71 [61– 69 [56– 72 [62– 74 [63–
0.09
[IQR], y 79] 78] 79] 82]
NIHSS, median 16 [10– 17 [13– 14 [9–
16 [11–21] 0.045
[IQR] 20] 22] 18]
Prestroke mRS 0.26
186 51 50
0 85 (77.3)
(72.4) (70.8) (66.7)
21 25
1 71 (27.6) 25 (22.7)
(29.2) (33.3)
mRS at 90 d 0.01
153 52 35
0–2 66 (60.0)
(59.5) (72.2) (54.3)
104 20 40
3–6 44 (40.0)
(40.5) (27.8) (45.7)
Mortality 40 (15.6) 11 (15.3) 15 (13.6) 14 (18.7) 0.66
149 48 25
IV-tPA treatment 76 (69.1) <0.001
(58.0) (66.7) (33.3)
Vascular risk
factors
24 24
Atrial fibrillation 93 (36.2) 45 (40.9) 0.41
(33.3) (32.0)
Cardiovascular 133 37 35
61 (55.5) 0.50
disease (51.8) (51.4) (46.7)
16 16
Diabetes 59 (23.0) 27 (24.5) 0.90
(22.2) (21.3)
181 46 57
Hypertension 78 (70.9) 0.27
(70.4) (63.9) (76.0)
110 24 33
Hyperlipidemia 53 (48.2) 0.14
(42.8) (33.3) (44.0)
Previous 14
44 (17.1) 16 (14.5) 14 (18.7) 0.65
stroke/TIA (19.4)
23 25
Tobacco use 83 (32.3) 35 (31.8) 0.97
(31.9) (33.3)
Primary clot 0.34
location
Carotid T 40 (15.6) 6 (8.3) 20 (18.2) 14 (18.7)
ICA cavernous 5 (2.0) 3 (4.2) 2 (1.8) 0 (0.0)
ICA origin 3 (1.2) 0 (0.0) 2 (1.8) 1 (1.3)
ICA supraclinoid 4 (1.6) 1 (1.4) 3 (2.7) 0 (0.0)
158 52 44
M1 62 (56.4)
(61.5) (72.2) (58.7)
10
M2 42 (16.3) 18 (16.4) 14 (18.7)
(13.9)
ACA/A2 3 (1.2) 0 (0.0) 2 (1.8) 1 (1.3)
M3 2 (0.8) 0 (0.0) 1 (0.9) 1 (1.3)
Parenchymal
hematoma
Type 1 14 (5.4) 2 (2.8) 7 (6.4) 5 (6.7) 0.57
Type 2 6 (2.3) 1 (1.4) 1 (0.9) 4 (5.3) 0.18
Infarct, median
[IQR]
ASPECTS on 9 [7–
8 [7–9] 8 [6–9] 8 [6-9] 0.002
baseline 10]
FIASPECTS at 24– 8 [6.5–
7 [5–8] 7 [5–8] 7 [5–8] 0.03
48 h 9]
5.9 12.3
FIVOLUME at 24 h, 8.2 [3.0– 8.4 [3.9–
[1.4– [2.1– 0.06
cm3 32.3] 32.0]
19.5] 44.5]
mTICI at final
0.32
angiogram
15 23
Grade 2b 66 (25.7) 28 (25.5)
(20.8) (30.7)
15 19
Grade 2c 53 (20.6) 19 (17.3)
(20.8) (25.3)
138 42 33
Grade 3 (53.7) (58.3) 63 (57.3) (44.0)
 Workflow times, median [IQR], min
410
Onset to 133 [65– 47 [33– 139 [94–
[300– <0.001
admission 277] 71] 195]
734]
210 121 490
Onset to arterial 207 [173–
[145– [102– [387– <0.001
puncture 263]
360] 137] 772]
Arterial puncture 25 [16– 18 [13– 28 [17– 28 [18–
<0.001
to reperfusion 39] 29] 41] 46]

IV-tPA was given to 58% of patients, and 33% of patients with the
OTR>360-minute window were also treated with IV-tPA. Note that
the majority of the patients given IV tPA in the late time window
received it at the European sites, following the publication of
randomized trials in support of this approach in 2018.20 More than
half of patients (54%) achieved complete reperfusion (modified
thrombolysis in cerebral infarction score 3). FI was determined by CT
imaging in 174 (68%) and by magnetic resonance imaging in 83
(32%) of the cohort. Median onset to admission was 133 minutes
(IQR, 65–277), median time from admission to arterial puncture was
67 minutes (IQR, 48–88), and median time from puncture to
reperfusion was 25 minutes (IQR, 16–39).

The distribution of FI sizes by volumetric measurements and

ASPECTS is shown in Figure 2. The peaks of these distributions were
largely comparable between patients who went on to functional
independence as well as those with significant disability.

Figure 2. Distributions of FI by FIVOLUME and FIASPECTS and by 90-day disability outcomes.

The optimal width of 2.6 mL was calculated and applied for FIVOLUME and bandwidth of 1 was used for
FIASPECTS. ASPECTS indicates Alberta Stroke Program Early CT Score; FI, final infarct; and mRS,
modified Rankin Scale.

Functional Outcomes by Time Windows and FI

The probability of functional independency decreased by about 3%
(absolute risk difference) per 1-hour delay to reperfusion (Table 2).
This hourly decrease in good outcomes was similar using onset to
admission and onset to arterial puncture metrics as well. After
adjusting for presentation factors including age, sex, stroke severity
as baseline National Institutes of Health Stroke scale, prestroke mRS,
location of occlusion, and additionally for FI (using FIASPECTS in Model
1 and FIVOLUME in Model 2), the effect of OTR on outcomes remained.
The magnitude of the effect was comparable to the unadjusted
analysis after adjusting for FI, with a 2% reduction in likelihood of
good outcome per hour of OTR. Both FIASPECTS and FIVOLUME
definitions resulted in a similar effect of OTR delay, although
FIASPECTS was associated with a slightly larger estimate than
FIVOLUME.

John Wiley & Sons, Ltd.

Table 2. Association of a 1-Hour Treatment Delay with Functional

Independence (mRS 0–2) at 90 Days in Patients Treated With
Endovascular Therapy

Model 1 Model 2
aOR aOR
per 1- aARD, per 1- aARD,
Unadjusted hour % hour %
OR per 1- Unadjusted delay (95% delay (95%
hour delay ARD, % (95% CI)* (95% CI)*
(95% CI) (95% CI) CI)* CI)*
All
(n=257)
0.89 −1.8 0.89 −1.6
0.89 (0.82 −2.8 (−4.4 (0.81 (−3.2 (0.81 (−3.1
OTA
to 0.96) to −1.2) to to to to
0.98) −0.3) 0.99) −0.2)
 0.89 (0.82 −2.7 (−4.5 0.88 −2.0 0.88 −1.8
OTP (0.79 (−3.5 (0.79 (−3.4
to 0.96) to −1.0)
to to to to
0.98) −0.4) 0.98) −0.3)
0.88 −1.9 0.89 −1.8
0.89 (0.82 −2.8 (−4.5 (0.79 (−3.5 (0.79 (−3.3
OTR
to 0.96) to −1.0) to to to to
0.98) −0.4) 0.99) −0.2)
IV-tPA
given
(n=149)†
0.81 0.81
−2.4 −2.3
0.74 (0.61 to −5.8 (−8.9 (0.63 (0.64
OTA (−5.1 (−4.8
0.88) to −2.8) to to
to 0.3) to 0.3)
1.04) 1.04)
0.86 0.87
−1.8 −1.6
0.79 (0.68 −4.6 (−7.5 (0.68 (0.69
OTP (−4.3 (−4.2
to 0.94) to −1.6) to to
to 0.8) to 0.9)
1.08) 1.09)
0.88 0.89
−1.5 −1.3
0.80 (0.69 −4.4 (−7.1 (0.70 (0.72
OTR (−4.0 (−3.7
to 0.94) to −1.6) to to
to 0.9) to 1.1)
1.09) 1.11)
FI by CT
(n=174)‡
0.83 −2.7 0.84 −2.4
0.81 (0.73 to −4.7 (−6.5 (0.72 (−4.4 (0.74 (−4.2
OTA
0.90) to −2.8) to to to to
0.94) −1.0) 0.96) −0.7)
0.80 −3.2 0.81 −3.0
0.80 (0.72 −4.7 (−6.7 (0.69 (−5.1 (0.70 (−4.9
OTP
to 0.90) to −2.8) to to to to
0.92) −1.4) 0.94) −1.0)
0.79 −3.3 0.81 −3.0
0.80 (0.71 to −4.9 (−6.9 (0.68 (−5.2 (0.69 (−5.0
OTR
0.89) to −3.0) to to to to
0.92) −1.4) 0.94) −1.1)
In a subgroup analysis restricted with those received IV-tPA before
EVT, the unadjusted effect of time delay on functional outcome
(4.4% [–7.1 to –1.6]) was greater than in whole cohort (2.8% [–4.5 to
–1.0]). However, in this subset the adjusted effect was not
statistically significant. In a subgroup analysis with FI determined by
CT alone, the effect of OTR on outcomes was greater, with absolute
risk reduction of approximately 3%. (Table 2).

When we tested the association of time to reperfusion with different

functional outcomes, we found the effect of time remained similar for
excellent outcome (mRS 0–1) in both models accounting for
FIASPECTS and FIVOLUME but smaller and statistically insignificant for
fair outcome (mRS 0–3) in a model accounting for FIVOLUME
(Table 3). In patients with smaller FIs (defined as FIASPECTS 8–10), as
well as those with larger FIs (defined as FIASPECTS <8), longer OTR
was associated with a reduced likelihood of functional
independence, as shown in Figure 3. The effect of prolonged OTR on
functional independence showed the same deterioration (likelihood
per hour of delay) for patients with both larger and smaller FIs.

John Wiley & Sons, Ltd.

Table 3. Association of a 1-Hour Treatment Delay with Different

Outcomes at 90 Days in Patients Treated With Endovascular Therapy

Model 1 Model 2
aOR aOR
Unadjusted per per
Unadjusted aARD, aARD,
OR per 1- 1- 1-
ARD, % % %
hour delay hour hour
(95% CI) (95% (95%
(95% CI) delay delay
CI)* CI)*
(95% (95%
CI)* CI)*
Onset to
 reperfusion
0.89 −2.1 0.89 −1.9
0.89 (0.82 −2.8 (−4.7 (0.80 (−3.8 (0.80 (−3.7
mRS 0–1
to 0.97) to −0.9) to to to to
0.99) −0.3) 0.99) −0.2)
0.88 −1.9 0.89 −1.8
0.89 (0.82 −2.8 (−4.5 (0.79 (−3.5 (0.79 (−3.3
mRS 0–2
to 0.96) to −1.0) to to to to
0.98) −0.4) 0.99) −0.2)
0.90 −1.7 0.91
−1.4
0.90 (0.83 −2.2 (−3.8 (0.81 (−3.2 (0.82
mRS 0–3 (−2.9
to 0.98) to −0.5) to to to
to 0.1)
0.99) −0.2) 1.01)

Figure 3. Association between time from onset to reperfusion and probability of functional
independence by final infarct.

Functional independence was defined as mRS score 0–2 at 90 days. Predicted probability was obtained
from logistic regression of outcome on time as a continuous variable, after adjustment for age, sex,
baseline stroke severity (National Institutes of Health Stroke scale), target occlusion location, baseline
mRS, and FIASPECTS. Dashed curve indicates 90% CI. ASPECTS indicates Alberta Stroke Program Early
CT Score; FI, final infarct; and mRS, modified Rankin Scale.

Discussion

In this study of a large, prospective, multicenter international cohort

of patients with LVO AIS treated with EVT, we found that prolonged
ischemic time was associated with less favorable functional
outcomes at 90 days independent of FI. The majority of the effect of
delayed reperfusion on 90-day disability outcomes remained after
adjusting for the effect of FI, with a 2% decrease in likelihood of
good outcomes per 1 hour of delay. This effect was present in
patients with FI measured by CT or magnetic resonance imaging
using ASPECTS or volumetric measurements and preserved in
patients with both smaller and larger FIs. These findings suggest that
delays in successful EVT may affect clinical outcomes via a
mechanism independent of effects on infarct size.
Prior studies have shown that despite advanced imaging selection
and rapid recanalization, the majority of patients with LVO AIS do not
achieve functional independence at 90 days.7 Several studies have
previously showed the association of FI with functional outcomes
after an LVO of the proximal anterior circulation.10, 21, 22, 23 These
studies found that patients treated with EVT had significantly smaller
FIs compared with controls. On the other hand, these reduced infarct
volumes may not fully explain the beneficial effect of EVT on
functional outcomes. In a pooled analysis from 7 randomized
multicenter trials, the HERMES (Highly Effective Reperfusion
Evaluated in Multiple Endovascular Stroke Trials) investigators found
that only 12% of the variance in 90-day mRS could be attributed to a
difference in treatment-reduced FI.13 In our study as well, we
observed FI-independent changes in clinical outcome and then also
show that OTR remains significant. These findings suggest that there
are likely other mechanisms by which OTR affects 90-day functional
outcomes beyond infarct growth.

Several hypotheses could explain this phenomenon. First, the

dichotomization of infarcted versus noninfarcted areas using routine
imaging procedures may miss the extent of functional versus
dysfunctional parenchyma. Moreover, it has been shown that
selective neuronal loss outside the defined infarct, which cannot be
captured with standard imaging techniques, may affect the salvaged
penumbra and hamper functional recovery following reperfusion.24
Another related explanation may be the increased presence of “no-
reflow” phenomena in patients with later OTR. In a recent publication
using the combined EXTEND (Extending the Time for Thrombolysis
in Emergency Neurological Deficits-Intra-Arterial) data sets, later
presentation was significantly associated with this syndrome of
impaired microvascular circulation despite successful upstream
reperfusion, and patients with this no-reflow condition had worsened
outcomes.25 Perfusion imaging was not performed in our data set, to
validate this possibility, but prolonged ischemia leading to increased
rates of endothelial injury, microthrombi, and inflammation may be a
mechanism to explain our findings.

Prior studies have observed a deterioration in likelihood of good

outcomes after EVT with prolonged times from OTR. Our estimate is
smaller than previously reported, and this difference may be due to
the use of FI as opposed to presentation infarct core.7, 26 Much of
the previous description in the literature on the interaction between
OTR and outcome has been in relation to its effect on infarct growth.
The growth rate of infarct core of approximately 2 million neurons
per minute is widely quoted,27 and following the results of the late
window thrombectomy trials, the concept of screening eligible
patients has shifted from the time from onset basis to a more
individualized imaging-based approach.28, 29, 30 In this study on the
other hand, we examined patients after the process of infarct growth
and reperfusion, by focusing on the FI. It is worth noting that we did
not observe a clear correlation between OTR and FI, again
demonstrating that the effects of OTR on final outcome are unlikely
to be fully explained by FI.

Our study has a several limitations. First, our cohort was limited to
patients with successful EVT with modified thrombolysis in cerebral
infarction 2b/3 reperfusion, and as such should not be generalized to
all patients with EVT. We intentionally excluded patients without
substantial reperfusion because successful EVT is one of the most
powerful predictors of 90-day disability outcomes and could
confound FI size as well. In addition, it is possible that infarct growth
continues past the 24–48-hour window used for our FI
determinations. On the other hand, infarct imaging in this time
window is commonly used in clinical practice, and this time window
has been used in prior studies to define FI.13, 31 Also, the majority of
patients in our cohort were treated with OTR <6 hours. This
distribution of OTR, however, is representative of clinical practice
and we had a decent sample size for this OTR compared with
previous studies. We acknowledge that this skew distribution may
extrapolate the results and overestimate the effect of time on
outcomes in the later EVT group. Finally, this analysis does not
consider relative eloquence of the infarcted brain regions, apart from
weighting for eloquence provided in the ASPECTS measurement.

In conclusion, we find that in patients with anterior circulation LVO

AIS treated with successful EVT, prolonged ischemic time asserts an
effect on 90-day disability outcomes that is independent of effects
on FI. In this study, the majority of the reduction in likelihood of good
outcomes with delays in reperfusion was preserved after adjusting
for the effects of FI on outcomes. Our study is limited by the post
hoc nature of the analysis but suggests that longer ischemic time
independently worsens clinical outcome, despite successful
reperfusion. Further study of the mechanisms behind this finding is
warranted

Sources of Funding

This study was funded in part by the American Academy of

Neurology Interventional Neurology Career Development award
(principal investigator: Dr Sheth). The COMPLETE Trial was
sponsored by Penumbra, Inc.

Disclosures

S.A.S. reports personal fees from Penumbra during the conduct of

the study; A.J.Y. reports personal fees from Penumbra during the
conduct of the study; grants from Penumbra, Medtronic, and Stryker,
grants and personal fees from Cerenovus outside the submitted
work, and equity interest in Insera Therapeutics; O.O.Z reports
personal fees and grant from Penumbra during the conduct of the
study. A.E.H reports grants from Penumbra, during the conduct of
the study, personal fees from Medtronic, Microvention, Stryker,
Penumbra, Cerenovus, Genentech, Scientia, Balt, Insera
therapeutics, Proximie, NovaSignal, Vesalio, grants and personal fees
from Viz.ai, grants from Vallley Baptist, outside the submitted work;

Footnotes

*Correspondence to: Sunil A. Sheth, MD, Department of Neurology,

UTHealth McGovern Medical School, 6431 Fannin St, Houston, TX
77030. Email: [email protected]

This manuscript was sent to Dr. Andrei V. Alexandrov, Guest Editor,

for review by expert referees, editorial decision, and final disposition.

References
1 Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma
HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ,
et al. A randomized trial of intraarterial treatment for acute ischemic
stroke. N Engl J Med. 2015; 372:11–20.CrossrefMedlineGoogle
Scholar
2 Bracard S, Ducrocq X, Mas JL, Soudant M, Oppenheim C, Moulin T,
Guillemin F; . Mechanical thrombectomy after intravenous alteplase
versus alteplase alone after stroke (THRACE): a randomised
controlled trial. Lancet Neurol. 2016; 15:1138–
1147.CrossrefMedlineGoogle Scholar
3 Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi
N, Yan B, Dowling RJ, Parsons MW, Oxley TJ, et al. Endovascular
therapy for ischemic stroke with perfusion-imaging selection. N Engl
J Med. 2015; 372:1009–1018.CrossrefMedlineGoogle Scholar
4 Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A,
San Román L, Serena J, Abilleira S, Ribó M, et al. Thrombectomy
within 8 hours after symptom onset in ischemic stroke. N Engl J
Med. 2015; 372:2296–2306.CrossrefMedlineGoogle Scholar
5 Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM,
Albers GW, Cognard C, Cohen DJ, Hacke W, et al. Stent-retriever
thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl
J Med. 2015; 372:2285–2295.CrossrefMedlineGoogle Scholar
6 Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva
P, Yavagal DR, Ribo M, Cognard C, Hanel RA, et al. Thrombectomy 6
to 24 Hours after Stroke with a Mismatch between Deficit and
Infarct. N Engl J Med. 2018; 378:11–21.CrossrefMedlineGoogle
Scholar
7 Saver JL, Goyal M, van der Lugt A, Menon BK, Majoie CB, Dippel
DW, Campbell BC, Nogueira RG, Demchuk AM, Tomasello A, et al.
Time to Treatment with endovascular thrombectomy and outcomes
from ischemic stroke: a meta-analysis. JAMA.2016; 316:1279–
1288.CrossrefMedlineGoogle Scholar
8 Christoforidis GA, Mohammad Y, Kehagias D, Avutu B, Slivka AP.
Angiographic assessment of pial collaterals as a prognostic indicator
following intra-arterial thrombolysis for acute ischemic stroke. AJNR
Am J Neuroradiol. 2005; 26:1789–1797.MedlineGoogle Scholar
9 Olivot JM, Mlynash M, Inoue M, Marks MP, Wheeler HM, Kemp S,
Straka M, Zaharchuk G, Bammer R, Lansberg MG, et al.
Hypoperfusion intensity ratio predicts infarct progression and
functional outcome in the DEFUSE 2 Cohort. Stroke. 2014; 45:1018–
1023.LinkGoogle Scholar
10 Zaidi SF, Aghaebrahim A, Urra X, Jumaa MA, Jankowitz B,
Hammer M, Nogueira R, Horowitz M, Reddy V, Jovin TG. Final infarct
volume is a stronger predictor of outcome than recanalization in
patients with proximal middle cerebral artery occlusion treated with
endovascular therapy. Stroke. 2012; 43:3238–3244.LinkGoogle
Scholar
11 Simonsen CZ, Yoo AJ, Sørensen LH, Juul N, Johnsen SP,
Andersen G, Rasmussen M. Effect of general anesthesia and
conscious sedation during endovascular therapy on infarct growth
and clinical outcomes in acute ischemic stroke: a randomized clinical
trial. JAMA Neurol. 2018; 75(4):470–477.Google Scholar
12 Compagne KCJ, Boers AMM, Marquering HA, Berkhemer OA, Yoo
AJ, Beenen LFM, van Oostenbrugge RJ, van Zwam WH, Roos
YBWEM, Majoie CB, et al. Follow-up infarct volume as a mediator of
endovascular treatment effect on functional outcome in ischaemic
stroke. Eur Radiol. 2019; 29:736–744.CrossrefGoogle Scholar
13 Boers AMM, Jansen IGH, Brown S, Lingsma HF, Beenen LFM,
Devlin TG, Román LS, Heo JH, Ribó M, Almekhlafi MA, et al.
Mediation of the relationship between endovascular therapy and
functional outcome by follow-up infarct volume in patients with acute
ischemic stroke. JAMA Neurol. 2019; 76:194–202.CrossrefGoogle
Scholar
14 Zaidat OO, Fifi JT, Nanda A, Atchie B, Woodward K, Doerfler A,
Tomasello A, Tekle W, Singh IP, Matouk C, et al. Endovascular
treatment of acute ischemic stroke with the penumbra system in
routine practice. Stroke. 2022; 53:769–778.LinkGoogle Scholar
15 Finlayson O, John V, Yeung R, Dowlatshahi D, Howard P, Zhang L,
Swartz R, Aviv RI. Interobserver agreement of ASPECT score
distribution for noncontrast CT, CT angiography, and CT perfusion in
acute stroke. Stroke. 2013; 44:234–236.AbstractGoogle Scholar
16 Koennecke HC, Belz W, Berfelde D, Endres M, Fitzek S, Hamilton
F, Kreitsch P, Mackert BM, Nabavi DG, Nolte CH, et al. Factors
influencing in-hospital mortality and morbidity in patients treated on
a stroke unit. Neurology. 2011; 77:965–972.CrossrefMedlineGoogle
Scholar
17 Adams HP, Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke
WR, Woolson RF, Hansen MD. Baseline NIH Stroke Scale score
strongly predicts outcome after stroke: a report of the Trial of Org
10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;
53:126–131.CrossrefMedlineGoogle Scholar
18 Schiemanck SK, Kwakkel G, Post MW, Prevo AJ. Predictive value
of ischemic lesion volume assessed with magnetic resonance
imaging for neurological deficits and functional outcome poststroke:
a critical review of the literature. Neurorehabil Neural Repair. 2006;
20:492–502.CrossrefMedlineGoogle Scholar
19 Ernst M, Boers AMM, Aigner A, Berkhemer OA, Yoo AJ, Roos YB,
Dippel DWJ, van der Lugt A, van Oostenbrugge RJ, van Zwam WH,
et al. Association of computed tomography ischemic lesion location
with functional outcome in acute large vessel occlusion ischemic
stroke. Stroke. 2017; 48:2426–2433.LinkGoogle Scholar
20 Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y,
Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, et al. MRI-guided
thrombolysis for stroke with unknown time of onset. N Engl J Med.
2018; 379:611–622.CrossrefMedlineGoogle Scholar
21 Albers GW, Goyal M, Jahan R, Bonafe A, Diener HC, Levy EI,
Pereira VM, Cognard C, Yavagal DR, Saver JL. Relationships between
imaging assessments and outcomes in solitaire with the intention for
thrombectomy as primary endovascular treatment for acute ischemic
stroke. Stroke. 2015; 46:2786–2794.AbstractGoogle Scholar
22 Al-Ajlan FS, Goyal M, Demchuk AM, Minhas P, Sabiq F, Assis Z,
Willinsky R, Montanera WJ, Rempel JL, Shuaib A, et al. Intra-arterial
therapy and post-treatment infarct volumes: insights from the
escape randomized controlled trial. Stroke. 2016; 47:777–
781.AbstractGoogle Scholar
23 Boers AMM, Jansen IGH, Beenen LFM, Devlin TG, San Roman L,
Heo JH, Ribó M, Brown S, Almekhlafi MA, Liebeskind DS, et al.
Association of follow-up infarct volume with functional outcome in
acute ischemic stroke: a pooled analysis of seven randomized trials.
J Neurointerv Surg. 2018; 10:1137–1142.CrossrefGoogle Scholar
24 Baron JC, Yamauchi H, Fujioka M, Endres M. Selective neuronal
loss in ischemic stroke and cerebrovascular disease. J Cereb Blood
Flow Metab. 2014; 34:2–18.CrossrefMedlineGoogle Scholar
25 Ng FC, Churilov L, Yassi N, Kleinig TJ, Thijs V, Wu T, Shah D,
Dewey H, Sharma G, Desmond P, et al. Prevalence and significance
of impaired microvascular tissue reperfusion despite macrovascular
angiographic reperfusion (no-reflow). Neurology. 2022;
98(8):e790–e801.CrossrefGoogle Scholar
26 Mulder MJHL, Jansen IGH, Goldhoorn RB, Venema E, Chalos V,
Compagne KCJ, Roozenbeek B, Lingsma HF, Schonewille WJ, van
den Wijngaard IR, et al. Time to endovascular treatment and
outcome in acute ischemic stroke: MR CLEAN registry results.
Circulation. 2018; 138:232–240.LinkGoogle Scholar
27 Saver JL. Time is brain–quantified. Stroke. 2006; 37(1):263–
266.LinkGoogle Scholar
28 von Kummer R. Treatment of ischemic stroke beyond 3 hours: is
time really brain?Neuroradiology. 2019; 61:115–117.CrossrefGoogle
Scholar
29 Puig J, Shankar J, Liebeskind D, Terceño M, Nael K, Demchuk AM,
Menon B, Dowlatshahi D, Leiva-Salinas C, Wintermark M, et al. From
“Time is Brain” to “Imaging is Brain”: a paradigm shift in the
management of acute ischemic stroke. J Neuroimaging. 2020;
30:562–571.CrossrefGoogle Scholar
30 Lu J, Mei Q, Hou X, Manaenko A, Zhou L, Liebeskind DS, Zhang
JH, Li Y, Hu Q. Imaging acute stroke: from one-size-fit-all
tobiomarkers. Front Neurol.2021; 12:697779.Google Scholar
31 Mokin M, Levy EI, Saver JL, Siddiqui AH, Goyal M, Bonafé A,
Cognard C, Jahan R, Albers GW; . Predictive value of RAPID
assessed perfusion thresholds on final infarct volume in SWIFT
PRIME (solitaire with the intention for thrombectomy as primary
endovascular treatment). Stroke. 2017; 48:932–938.LinkGoogle
Scholar