2. STROKE MANAGEMENT STRATEGIES
Neurorehabilitation
Drug development
Robotics
Cortical stimulation
Stem cell therapies
V. Neuroprotection and Repair
Anti-excitability
Anti-inflammatory
Anti-apoptosis
Promote repair
Neuroplasticity
Recovery
3. RISK FACTORS
The risk of recurrent stroke or TIA is high but can be mitigated with appropriate
secondary stroke prevention.
5 factors—BP,
diet,
physical inactivity,
smoking
abdominal obesity-
accounted for 82% and 90% of the population-attributable risk for ischemic and
hemorrhagic stroke in the INTERSTROKE study (Global and regional effects of
potentially modifiable risk factors associated with acute stroke
in 32 countries).
Global Burden of Disease Study showed that 90.5% of the global burden of
stroke was attributable to modifiable risk factors
4. TABLE 65.1 Risk Factors for Ischemic Stroke
Nonmodifiable Modifiable
Age
Gender
Race
Family
history
Genetics
Arterial hypertension
Transient ischemic attacks
Prior stroke
Asymptomatic carotid bruit/stenosis
Cardiac disease
Aortic arch atheromatosis
Diabetes mellitus
Dyslipidemia
Cigarette smoking
Alcohol consumption
Increased fibrinogen
Elevated homocysteine
Lack of physical activity
Low serum folate
Elevated anticardiolipin antibodies
Oral contraceptive use
Obesity
5. 1. HYPERTENSION
TABLE 65.2 ACC/AHA 2017 Guideline for the Management of High Blood Pressure in Secondary
Stroke Prevention in Adult Patients
Population BP Goal Agents and Timing of Therapy
Adult with
stroke or TIA SBP <130
• Thiazide-type diuretic (preferably a
long-acting agent), ACE-I or ARB. or in
DBP <80 long term) Combination
• Restart anti-HTN medication a few days after
the index event for patients previously on
medication
• For patients not previously on drugs with
established BP >140 mm Hg or DBP > 90 mm
Hg start therapy a few days after event
• For patients not previously treated with SBP
<140 mmHg or DBP <90 mm Hg the benefit of
anti-HTN drugs is less clear
AHA/ASA 2021 GUIDELINES ON STROKE PREVENTION
6. 2. DYSLIPIDEMIA
Dyslipidemia is a recognized risk factor for ischemic stroke.
Ischemic stroke risk increases with increasing serum cholesterol, and the
reduction in stroke risk associated with 3-hydroxy, 3-methyl-glutaryl
coenzyme A reductase inhibitor (statin) therapies is related to reduction in
LDL.
Lipid-lowering agents may slow atherosclerotic plaque progression and may
even cause plaque regression.
7. TRAILS
1. The Myocardial Ischemia Reduction with Aggressive Cholesterol
Lowering (MIRACL) showed a 50% relative risk reduction in stroke
among high-risk coronary disease patients
2. The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
(ASCOT-LLA) study demonstrated a favorable trend for fatal and nonfatal
stroke, with a 27% RRR in patients at low risk for coronary events
3. The Heart Protection Study (HPS) of patients at high risk with DM, coronary
artery disease, or other atherosclerotic vascular disease showed an overall
reduction in stroke risk
8. A Comparison of Two LDL Cholesterol Targets
after Ischemic Stroke
P. Amarenco, J.S. Kim, J. Labreuche, H. Charles, J. Abtan, Y. B£jot, L. Cabrejo,J.-K. Cha, G. Ducrocq, M. Giroud, C. Guidoux,
C. Hobeanu, Y.-J. Kim, B. Lapergue, P.C. Lavall^e, B.-C. Lee, K.-B. Lee, D. Leys, M.-H. Mahagne,
E. Meseguer, N. Nighoghossian, F. Pico, Y. Samson, I. Sibon, P.G. Steg, S.-M. Sung, P.-J. Touboul, E. Touz6, O. Varenne, £.
Vicaut. N. Yelles. and E. Bruckert. for the Treat Stroke to Target Investigators*
5.TREAT
STROKE TO
TARGET
BACKGROUND
The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and
ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after
stroke has not been well studied
METHODS
In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3
months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-
target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had
evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of
major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid
revascularization, or death from cardiovascular causes.
RESULTS
A total of2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The
mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65
mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial
was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point
occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95%
confidence interval, 0.61 to 0.98; P=0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly
between the two groups.
CONCLUSIONS
After an ischemic stroke or TIA with evidence of atherosclerosis, patients
who had a target LDL cholesterol level of less than 70 mg per deciliter had a
lower risk of subsequent cardiovascular events than those who had a target
range of 90 mg to 110 mg per deciliter.
10. Clopidogrel with Aspirin in Acute Minor Stroke
CHANCE TRIAL
2013
BACKGROUND
Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke.
Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than
aspirin alone.
METHODS
In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned
5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with
clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin
at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All
participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary
outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis.
Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random
effect.
RESULTS
Stroke occurred in 8.2%> of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin
group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred
in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of
hemorrhagic stroke was 0.3% in each group.
CONCLUSIONS
Among patients with TIA or minor stroke who can be treated within 24
hours after the onset of symptoms, the combination of clopidogrel and
aspirin is superior to aspirin alone for reducing the risk of stroke in the
first 90 days and does not increase the risk of hemorrhage.
11. Platelet-
Oriented
Inhibition in
New TIA
and Minor
Ischemic
Stroke
(POINT)
trial 2018
Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a
minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a
reduction in the risk of recurrent stroke. We tested this combination in an international population.
METHODS
In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of
600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone.
The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the
risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic
vascular event, at 90 days.
RESULTS
A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had
been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated
with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic
events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus
placebo (hazard ratio, 0.75; 95% confidence interval [Cl],
0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients
(0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% Cl, 1.10 to
4.87; P=0.02).
CONCLUSIONS
In patients with minor ischemic stroke or high-risk TIA, those who received a
combination of clopidogrel and aspirin had a lower risk of major ischemic events but
a higher risk of major hemorrhage at 90 days than those who received aspirin alone.
12. Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke
An Exploratory Analysis of the THALES Randomized Clinical Trial 2020
IMPORTANCE Pnor trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute
Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial,
but results have not been reported separately, raising concerns about safety and efficacy in this subgroup.
OBJECTIVE To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health
Stroke Scale [NIHSS] score of 4 to 5).
DESIGN. SETTING, AND PARTICIPANTS The THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and
December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less
severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with
NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021.
INTERVENTIONS Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after
symptom onset. All patients received aspinn,
300 to 325 mg. on day 1 followed by aspirin. 75 to 100 mg. daily on days 2 to 30. Patients were observed for 30 additional days.
MAIN OUTCOMES AND MEASURES The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe
bleeding.
RESULTS In total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke
group. 1293 (39.0%) were female, and the mean (SD) age was 645 (10.8) years: of those in the less severe stroke group. 2518 (37.7%) were
female, and the mean (SD) age was 64.8 012) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129
of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio. 0.84:95% Cl.
0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and
5.7% (190 of 3312) for those in the placebo group (hazard ratio. 0.82; 95% Cl, 0.66-1.01) (Pfor interaction = .88). Severe bleeding occurred in
8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16
patients
CONCLUSIONS AND RELEVANCE In this study, patients with a
moderate ischemic stroke had consistent benefit from ticagrelor
plus aspirin vs aspirin alone compared with patients with less
severe ischemic stroke, with no further increase in the risk of
intracranial bleeding or other severe bleeding events.
13. ABSTRACT
Background In patients with a minor ischaemic stroke or transient ischaemic attack (TIA), separate
trials have shown that dual antiplatelet therapy with clopidogrel plus aspirin (cJopidogrel—aspirin) or
ticagrelor plus aspirin (ticagrelor-aspirin) are more effective than aspirin alone in stroke secondary
prevention. However these two sets of combination have not been directly compared. Since clopidogrel
was less effective in stroke patients who were CKP2C79loss-of-function (LOF) allele carriers, whether
ticagrelor-aspirin is clinically superior to clopidogrel— aspirin in this subgroup of patients with stroke is
unclear. Aim To describe the rationale and design considerations of the Clopidogrel in High-risk
patients with Acute Nondisabling Cerebrovascular Events (CHANCE-2) trial.
Design CHANCE-2 is a randomised, double-blind, doubledummy, placebo-controlled, multicentre trial
that compares two dual antiplatelet strategies for minor stroke or TIA patients who are CYP2C19 LOF
allele carriers: ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily on days 2-90)
or clopidogrel (300 mg loading dose on day 1 followed by 75 mg daily on days 2-90), plus open-label
aspirin with a dose of 75-300 mg on day 1 followed by 75 mg daily on day 2-21. All will be followed for
1 year. Study outcomes The primary efficacy outcome is any stroke (ischaemic or haemorrhagic)
within 3 months and the primary safety outcome is any severe or moderate bleeding event within 3
months.
Discussion The CHANCE-2 trial will evaluate whether ticagrelor-aspirin is superior to
clopidogrel—aspirin for minor stroke or TIA patients who are CYP2C19 LOF allele
carriers
CHANCE 2 TRIAL (ONGOING)
16. ECASS III TRIAL .
Werner Hacke, M.D., N/larkku Kaste. M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Divalos, M.D., Donata Guidetti, M.D., Vincent Larrue, M.D., Kennedy
R. Lees, M.D., Zakaria Medeghri, M.D.,
Thomas Machnig, M.D., Dietmar Schneider, M.D., Rudiger von Kummer, M.D., Nils Wahlgren, M.D.,
and Danilo Toni, M.D., for the ECASS Investigators*
ABSTRACT
BACKGROUND
Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after
the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
METHODS
After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic
stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was
disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at
all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point w^as a global outcome analysis of four
neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
RESULTS
We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of
alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval
[CD, 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% Cl, 1.00 to 1.65;
P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for
symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%,
respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
CONCLUSIONS
As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours
after the onset of symptoms significantly improved clinical outcomes in patients with acute
ischemic stroke; alteplase was more frequently associated with svmptomatic intracranial
hemorrhage.
17. Intensive blood pressure reduction with intravenous
thrombolysis therapy for acute ischaemic stroke
(ENCHANTED): an international, randomised, open-label
blinded-endpoint, phase 3 trial
.
Interpretation Although intensive blood pressure lowering is safe,
the observed reduction in intracranial haemorrhage did not lead to
improved clinical outcome compared with guideline treatment.
These results might not support a major shift towards this treatment
being applied in those receiving alteplase for mild-to-moderate
acute ischaemic stroke. Further research is required to define the
underlying mechanisms of benefit and harm resulting from early
intensive blood pressure lowering in this patient group.
18. Tenecteplase versus Alteplase before Thrombectomy
EXTEND-1A TNK TRIAL
METHODS
We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or
middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose
of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per
kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was
reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus
at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by
superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no
neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral
hemorrhage.
RESULTS
Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The
primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated
with alteplase (incidence difference, 12 percentage points;
95% confidence interval [Cl], 2 to 21; incidence ratio, 2.2; 95% Cl, 1.1 to 4.4; P=0.002 for
noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than
alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% Cl, 1.0 to 2.8;
P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group.
CONCLUSIONS
Tenecteplase before thrombectomy was associated with a higher
incidence of reperfusion and better functional outcome than
alteplase among patients with ischemic stroke treated within 4.5
hours after symptom onset.
20. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset
WAKE-UP TRIAL
BACKGROUND
Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if ' it can be ascertained that the time
since the onset of symptoms was less than 4.5 hours. 1 We sought to determine whether patients with stroke with an unknown
time of onset ! and features suggesting recent cerebral infarction on magnetic resonance imaging i (MRI) would benefit from
thrombolysis with the use of intravenous alteplase.
I
METHODS I
In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either
intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging
but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which • indicated that the stroke had
occurred approximately within the previous 4.5 hours, i We excluded patients for whom thrombectomy was planned. The
primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic
disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. 1 A secondary outcome was the likelihood that
alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).
RESULTS
The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of
these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days
was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group
(adjusted odds ratio, 1.61; 95% confidence interval [Cl], 1.09 to 2.36; P=0.02). The median score on the modified Rankin
scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% Cl, 1.17 to
2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38;
95% Cl, 0.92 to 12.52;
P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group
(odds ratio, 4.95; 95% Cl, 0.57 to 42.87; P=0.15).
CONCLUSIONS
In patients with acute stroke with an unknown time of onset, intravenous
alteplase guided by a mismatch between diffusion-weighted imaging and
FLAIR in the region of ischemia resulted in a significantly better functional
outcome and numerically more intracranial hemorrhages than placebo at 90
days.
21. Thrombolysis Guided by Perfusion Imaging up to 9 HoursEXTEND
BACKGROUND
The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within
4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may
be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on
imaging.
METHODS
We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic
stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion
imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between
4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the
midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on
which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary
outcome was adjusted for age and clinical severity at baseline.
RESULTS
After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss
of equipoise after the publication of positive results from a previous trial. A total of 113 patients
were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome
occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo
group (adjusted risk ratio, 1.44; 95% confidence interval [Cl], 1.01 to 2.06; P=0.04). Symptomatic
intracerebral hemorrhage occurred in 7 patients (62%) in the alteplase group and in 1 patient (0.9%)
in the placebo group (adjusted risk ratio, 7.22; 95% Cl, 0.97 to 53.5; P=0.05). A secondary ordinal
analysis of the distribution of scores on the modified Rankin scale did not show a significant
between-group difference in functional improvement at 90 days.
CONCLUSIONS
Among the patients in this trial who had ischemic stroke and
salvageable brain tissue, the use of alteplase between 4.5 and
9.0 hours after stroke onset or at the time the patient awoke
with stroke symptoms resulted in a higher percentage of
patients with no or minor neurologic deficits than the use of
placebo. There were more cases of symptomatic cerebral
hemorrhage in the alteplase group than in the placebo group.
22.
23. MECHANICAL
THROMBECTOMY
The stroke physician community witnessed a major “breakthrough” in acute stroke
therapeutics when the results of the first of the many positive trials, “MR CLEAN,”
were published showing a significant absolute benefit in favor of mechanical
thrombectomy in patients with large vessel occlusion (LVO).
Based on the initial studies, the American Stroke Association amended the 2013
guidelines in 2015 to include mechanical thrombectomy as the standard of care in
patients with LVO presenting within six hours. Thereafter, the investigators of
ESCAPE, SWIFT PRIME, REVASCAT, THRACE, and PISTE concluded the same.
The horizon was further expanded when two major landmark trials, DAWN and
DEFUSE 3, established the benefit of mechanical thrombectomy in the delayed
window period in a select group of patients. It further led to the inclusion of the
delayed window period treatment strategies in the 2018 guidelines.
24. Multicenter
Randomized
Clinical Trial of
The NEW ENGLAND
JOURNAL of MEDICINE
ESTABLISH HD IN 1*12 JANUARY 1, 201S VOL 372 NO. 1
A Randomized Trial of Intraarterial Treatment for Acute
Ischemic Stroke
BACKGROUND
Endovascular
Treatment for
Acute Ischemic
Stroke in the
Netherlands (MR
CLEAN)
In patients with acute ischemic stroke caused by a proximal intracranial arterial
occlusion, intraarterial treatment is highly effective for emergency revascularization.
However, proof of a beneficial effect on functional outcome is lacking.
METHODS
We randomly assigned eligible patients to either intraarterial treatment plus usual
care or usual care alone. Eligible patients had a proximal arterial occlusion in the
anterior cerebral circulation that was confirmed on vessel imaging and that could be
treated intraarterially within 6 hours after symptom onset. The primary outcome was
the modified Rankin scale score at 90 days; this categorical scale measures
functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The
treatment effect was estimated with ordinal logistic regression as a common odds
ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio
measured the likelihood that intraarterial treatment would lead to lower modified
Rankin scores, as compared with usual care alone (shift analysis).
RESULTS
We enrolled 500 patients at 16 medical centers in the Netherlands (233 assigned to
intraarterial treatment and 267 to usual care alone). The mean age was 65 years
(range, 23 to 96), and 445 patients (89.0%) were treated with intravenous altcplase
before randomization. Retrievable stents were used in 190 of the 233 patients
(81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was
1.67 (95% confidence interval [CD, L21 to 2.30). There was an absolute difference
of 13.5 percentage points (95% Cl, 5.9 to 21.2) in the rate of functional
independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6%
vs. 19.1%). There were no significant differences in mortality or the occurrence of
symptomatic intracerebral hemorrhage.
In patients with acute ischemic stroke caused by a proximal intracranial occlusion
of the anterior circulation, intraarterial treatment administered within 6 hours after
stroke onset was effective and safe.
25. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PAAlone
in Stroke SWIFT-PRIME
BACKGROUND
Among patients with acute ischemic stroke due to occlusions in the proximal ante- ' rior intracranial
circulation, less than 40% regain functional independence when ' treated with intravenous tissue
plasminogen activator (t-PA) alone. Thrombectomy N with the use of a stent retriever, in addition to
intravenous t-PA, increases reperfu- < sion rates and may improve long-term functional outcome. .
METHODS (
We randomly assigned eligible patients with stroke who were receiving or had re- , ceived intravenous
t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the
use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had
confirmed occlusions in the proximal anterior intracranial circulation and an absence of large
ischemic-core lesions.
The primary outcome was the severity of global disability at 90 days, as assessed by . means of the
modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]).
i
RESULTS I
The study was stopped early because of efficacy. At 39 centers, 196 patients under- < went
randomization (98 patients in each group). In the intervention group, the median time from qualifying
imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the
procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at
90 days over the entire range of scores on the modified Rankin scale (PcO.OOl). The rate of functional
independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the
control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day
mortality (9% vs. 12%, P=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P=0.12).
In patients receiving intravenous t-PA for acute
ischemic stroke due to occlusions in the proximal
anterior intracranial circulation, thrombectomy with
a stent retriever within 6 hours after onset improved
functional outcomes at 90 days
26. Randomized Assessment of Rapid
Endovascular Treatment of Ischemic Stroke ESCAPE TRIAL
BACKGROUND
Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90
days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid
endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core,
a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation.
METHODS
We randomly assigned participants to receive standard care (control group) or standard care plus endovascular
treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal
intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a
large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded.
Workflow times were measured against predetermined targets. The primary outcome was the score on the
modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to
calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on
the modified Rankin scale than would control care (shift analysis).
RESULTS
The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom
238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention
group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional
independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in
the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95%
confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs.
19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in
intervention group and 2.7% of participants in control group (P=0.75).
CONCLUSIONS
Among patients with acute ischemic stroke with a proximal
vessel occlusion, a small infarct core, and moderate-to-good
collateral circulation, rapid endovascular treatment improved
functional outcomes and reduced mortality
27. Thrombectomy within 8 Hours after SvmDtom Onset in
Ischemic Stroke
REVASCAT TRIAL
We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke
in a trial embedded within a population-based stroke reperfusion registry.
METHODS
During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206
patients who could be treated within 8 hours after the onset of symptoms of acute
ischemic stroke to receive either medical therapy (including intravenous al-teplase when
eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy
group) or medical therapy alone (control group). All patients had confirmed proximal
anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all
study patients, the use of alteplase either did not achieve revascularization or was
contraindicated. The primary outcome was the severity of global disability at 90 days, as
measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]).
Although the maximum planned sample size was 690, enrollment was halted early
because of loss of equipoise after positive results for thrombectomy were reported from
other similar trials.
RESULTS
Thrombectomy reduced the severity of disability over the range of the modified Rankin
scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [Cl],
1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90
days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% Cl, 1.1 to 4.0). At 90 days, the rates
of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and
the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively
(P=0.60). Registry data indicated that only eight patients who met the eligibility criteria
were treated outside the trial at participating hospitals.
Among patients with anterior circulation stroke who could be treated
within 8 hours after symptom onset, stent retriever thrombectomy reduced
the severity of poststroke disability and increased the rate of functional
independence.
28. DELAYED WINDOW PERIOD: HOW WIDE IS THE
WINDOW?
To address the question if patients could be treated in the later time
windows, two landmark thrombectomy trials, namely DAWN and
DEFUSE 3, were conducted.
Until these two trials, it was believed that time was one of the most
crucial factor in determining the outcome following MT
late window trials included only those patients who had a small core
and were slow progressors.
based on the above two trials, the American Stroke Association
recommended MT in selected patients with AIS within 6 to 16 hours
of last known normal who have LVO in the anterior circulation and
meet other DAWN or DEFUSE 3 eligibility criteria.
29. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch
between Deficit and Infarct
BACKGROUND
The effect of endovascular thrombectomy that is performed more than 6 hours after the
onset of ischemic stroke is uncertain. Patients with a clinical deficit that is
disproportionately severe relative to the infarct volume may benefit from late
thrombectomy.
METHODS
We enrolled patients with occlusion of the intracranial internal carotid artery or proximal
middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who
had a mismatch between the severity of the clinical deficit and the infarct volume, with
mismatch criteria defined according to age (<80 years or £80 years). Patients were
randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to
standard care alone (the control group). The coprimary end points were the mean score
for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death]
to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0,
1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores
indicating more severe disability) at 90 days.
RESULTS
A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and
99 to the control group. At 31 months, enrollment in the trial was stopped because of the
results of a prespecified interim analysis. The mean score on the utility-weighted
modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with
3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible
interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional
independence at 90 days was 49% in the thrombectomy group as compared with 13% in
the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to
44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial
hemorrhage did not differ significantly between the two groups (6% in the thrombectomy
group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%,
respectively; P=1.00).
Among patients with acute stroke who had last been known to be well 6 to 24
hours earlier and who had a mismatch between clinical deficit and infarct,
outcomes for disability at 90 days were better with thrombectomy plus
standard care than with standard care alone.
DAWN TRIAL
30. Presenting 6 to 24 hours after they were last known to be well
Clinical infarct mismatch was defined as mismatch between
the volume of the ischemic core on CT perfusion imaging and
clinical deficit as measured by National Institutes of Health
Stroke Scale (NIHSS) and categorized according to the age as
follows:
1) Age ≥ 80 y; NIHSS ≥ 10; Ischemic core <21 mL
2) Age < 80 y, NIHSS ≥ 10; Ischemic core <31 mL
3) Age <80 y, NIHSS ≥ 20; 31≤ Ischemic core<51 mL
DAWN TRIAL
31. Thrombectomy for Stroke at 6 to 16 Hours with
Selection by Perfusion Imaging
BACKGROUND
Thrombectomy is currently recommended for eligible patients with stroke who are
treated within 6 hours after the onset of symptoms.
METHODS
We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in
patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not
yet infarcted. Patients with proximal middle-cerebral-artery or intemal-carotid-artery occlusion, an initial infarct size of
less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more
were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy
group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the
modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90.
RESULTS
The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone
randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus
medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of
functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of
patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%,
P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group
(P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial
hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18).
CONCLUSIONS
Endovascular thrombectomy for ischemic stroke 6 to 16 hours
after a patient was last known to be well plus standard medical
therapy resulted in better functional outcomes than standard
medical therapy alone among patients with proximal middle-
cerebral-artery or intemal-carotid-artery occlusion and a region
of tissue that was ischemic but not yet infarcted.
DEFUSE3 TRIAL
32. presenting 6 to 16 hours after they were last known to be well,
with a region of tissue on imaging that was ischemic but not yet
infarcted and fulfilling the criteria for target mismatch (TMM) as
follows:
1) Ischemic core volume (by CT perfusion imaging) <70 mL
2) Mismatch ratio ≥ 1.8
3) an absolute volume of potentially reversible ischemia
(penumbra) of 15 ml or more
DEFUSE 3 TRIAL
33.
34. Endovascular Thrombectomy with or without Intravenous
Alteplase in Acute Stroke DIRECT-MT TRIAL
BACKGROUND
In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering
intravenous alteplase before endovascular thrombectomy.
METHODS
We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular
thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke.
Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were
randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-
alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9
mg per kilogram of body weight, administered within 4.5 hours after symptom onset
(combination-therapy group). The primary analysis for non inferiority assessed the between-
group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms]
to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the
adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary
outcomes, including death and reperfusion of the ischemic area.
RESULTS
Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-
alone group and 329 assigned to the combination-therapy group.
Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and
endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio,
1.07; 95% confidence interval, 0.81 to 1.40; P=0.04 for non inferiority) but was associated with
lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%)
and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the
thrombectomy-alone group and 18.8% in the combination-therapy group.
CONCLUSIONS
In Chinese patients with acute ischemic stroke from large-
vessel occlusion, endovascular thrombectomy alone was
noninferior with regard to functional outcome, within a 20%
margin of confidence, to endovascular thrombectomy
preceded by intravenous alteplase administered within 4.5
hours after symptom onset.
36. CRYTOGENIC STROKE
Cryptogenic stroke comprises up to 33% of all ischemic strokes.
It is a heterogeneous group because it includes patients with multiple high-risk
causes and those with no cause identified.
majority of cryptogenic strokes appear embolic in nature-led to the refined
definition of embolic stroke of undetermined source (ESUS).
ESUS is a subset of cryptogenic stroke and refers to an embolic-appearing
stroke for which no high-risk cause has been determined despite a thorough
diagnostic workup (including at least 24 hours of cardiac rhythm monitoring)
.
ESUS patients are heterogeneous, including some with later atrial fibrillation
and some with nonstenotic carotid plaques
37. If this diagnostic testing has not yielded a high-risk cause, detailed evaluation
needed:
1. Extended cardiac monitoring:
EMBRACE (Event Monitor Belt for Recording Atrial Fibrillation After a
Cerebral Ischemic Event): detection of 30 seconds of AF was achieved in
3.2% of patients with usual care(including an electrocardiography and inpatient
cardiac telemetry) and 16.1% of those who wore an extended cardiac monitor.
(30-day cardiac event monitor)
CRYSTAL-AF (Cryptogenic Stroke and Underlying AF) 1.4% of
patients were found to have AF within 6 months while 8.9% of those in the
insertable cardiac monitor group were found to have AF. At 3 years of
follow-up, detection of AF exceeded 30%.
38. 2. Transesophageal echocardiography (TEE):
• TEE provides more detailed imaging than transthoracic echocardiography
especially of the left atrium, left atrial appendage, valvular structures, and
the arch of the aorta.
• examine for the presence of left atrial/ atrial appendage thrombus, atrial
myxoma, fibroelastoma, or vegetation.
• It may also be used if PFO is suspected or further detail is required on its
morphology.
• TEE is reserved for patients the below the age of 60 as the yield of this test
is low above that threshold.
39. 3. Hypercoagulability testing:
should be considered in a person with no other candidate cause
identified especially if they have a history of arterial thrombotic events
elsewhere or a family history of arterial thrombotic events.
4. Other:
MRI with T1 fat-suppressed sequences (to examine for arterial
dissection not visible on previous testing), diagnostic cerebral angiography,
and cerebrospinal fluid testing (if cerebral vasculitis or reversible cerebral
vasoconstriction are suspected) or genetic testing (if an inherited stroke
syndrome is suspected).
Additional considerations include emerging putative associations with ESUS
including occult malignancy, the carotid web,
and nonstenotic carotid atherosclerosis within the early phases of a patient’s
diagnostic workup.
40. Ischemic stroke or TIA
24-hour cardiac
monitoring
Vascular
imaging
Echocardiography Neuroimaging
L J
ESUS
(non-lacunar)
Prolonged cardiac
monitoring
CRYPTOGENIC STROKE
No cardioembolic mechanisms
No large vessel stenosis >S0%
No small vessel occlusion* No
other causes
ARCADIA DEFINITION FOR
LACUNAR STROKE
Both criteria should be met:
1) Subcortical (Including pons and
mtdbrain) Infarct In the distribution
of small penetrating arteries.
2) <1.5 cm on CT or T2-MRI.
or <2.0 cm on DWI MRI
Lacunar
Atrial cardiopathy or
systemic embolism
Yes No
Carotid Complex Nonstenotic
Web aortic plaque carotid plaque PFO
Occult or
known
cancer
Atrial Cardiopathy
ARCADIA0«f INITION fOR A TRIAL CAR
OTOPATHY (any of the following)
1} PTFV1>5000 mV/rm on 12 lead ECG
2) Serum NT proBNP >2 SO pg/ml
3) Left atrial diameter index
>3 cm/mJ on echocardiogram
Antiplatelet agents
Statins
Anticoagulants
Cancer therapy
Antiplatelet agents and wait
for ARCADIA & ATTICUS
Antiplatelet agents
Statins
41. The distinction between ESUS and lacunar cryptogenic stroke is sometimes
challenging.
ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in
Prevention After Cryptogenic Stroke) randomized clinical trial
provide a simple and clinically sound criteria.
According to the ARCADIA criteria, lacunar cryptogenic strokes are those
involving subcortical cerebral territories of small penetrating arteries,
including the pons and midbrain.
The established size of lacunar infarcts is <1.5 cm on CT or T2-MRI or
<2.0 cm on diffusion-weighted imaging MRI.
Embolic infarcts are those involving the cerebral cortex, multiple small
subcortical infarcts occurring simultaneously in the same or different
vascular territories, lateral medullary infarcts, or cerebellar infarcts.
43. • one of the most common cause of ischemic stroke worldwide, causing up to
50% of ischemic strokes in Asia
• high risk of recurrence
• WASID study (Warfarin-Aspirin Symptomatic Intracranial Disease)
evaluated patients with a stroke or TIA in the previous 90days due to
intracranial stenosis of 50% to 99% and found a 19% risk of recurrent
ischemic stroke at 2 years, with 75% occurring in the distribution of the
stenotic artery.
44. Antithrombotic Treatment
mainstay of management for secondary prevention in ICAD.
Anticoagulants- tested in the WASID trial found not effective;
patients treated with warfarin to a goal INR 2 to 3 had a similar rate of stroke
recurrence than those on aspirin but a higher rate of
major hemorrhagic events and death.
DAPT - standard of care for the initial 3 months after an index event.
SAMMPRIS trial (Stenting Versus Aggressive Medical Therapy for
Intracranial Arterial Stenosis),
enrolled a higher risk population with 70% to 99% stenosis within 30 days on
stroke onset treated with aspirin
and clopidogrel, and a similar high-risk cohort from WASID, suggested that
DAPT for 90 days was superior to aspirin in preventing recurrence in this
earlier period. (THALES and CHANCE trial also)
45. Cilostazol-based regimens of DAPT for ICAD.
CATHARSIS (Cilostazol-Aspirin Therapy Against Recurrent Stroke With
Intracranial Artery Stenosis Study) no benefit of cilostazol plus aspirin versus
aspirin alone
open-label CSPS trial (Cilostazol Stroke Prevention Study for Antiplatelet
Combination), which compared cilostazol plus aspirin or clopidogrel versus
aspirin or clopidogrel alone in patients 8 to 180 days after symptom onset did
find a lower risk of recurrent ischemic stroke
TOSS-2 trial (Trial of Cilostazol in Symptomatic Intra- cranial Arterial
Stenosis II) DAPT with cilostazol plus aspirin versus clopidogrel plus aspirin
was tested in the which enrolled patients with ICAD within 2 weeks; there was
no difference in stroke recurrence in the territory of the symptomatic vessel at 7
months with either regimen.
DAPT did not increase hemorrhagic complications in ICAD studies.
46. Vascular Risk Factor Control
RISK FACTORS- Poorly controlled cholesterol and low-density lipoprotein,
elevated blood pressure (BP) inadequate physical activity
PREVENTION- High-dose statins, engage in at least moderate regular
physical activity, and achieve a systolic BP of <130 mmHg.
BUT the early post- stroke management of BP after an ICAD-related stroke
has not been well studied, and smaller trials have suggested
potential higher risk of aggressive BP control in the early window,
particularly in those with hemodynamic impairment.
47. Revascularization
Endovascular approaches to ICAD - tested in 2 randomized clinical trials with
negative results.
SAMMPRIS trial evaluated high-risk patients with symptoms within 30 days
(median 7 days) with high-grade stenosis and randomized patients to intensive
medical therapy with or without angioplasty and stenting with a self-expanding
stent. It found a greater rate of stroke and death at 30 days of 14.7% in the
intervention arm versus 5.3 in the medical
treatment arm, with no delayed benefit was observed in long-term outcomes
VISSIT trial (Vitesse Stent Ischemic Therapy) utilizing a balloon-mounted stent
found a higher periprocedural risk with endovascular therapy.
angioplasty and stenting should not be recommended as initial treatment of
symptomatic ICAD.
49. Atherosclerotic carotid artery disease : major causes of ischemic stroke and TIA,
accounting for about 10% of cases.
primarily at the carotid bifurcation, involving the distal common and the
proximal internal carotid artery.
previous trials showed: robust benefit of carotid endarterectomy for severe (70%-
99%) stenosis, moderate stenosis (50%-69%), no demonstrable benefit below
50% stenosis.
Early surgery, with revascularization performed within 2 weeks of the last
symptomatic event, is now recommended.
50. • Regarding choice of revascularization procedure, CEA is currently
performed more than CAS, with CEA accounting for >80% of procedures
in a previous national study
• several trials found a lower complication rate with CEA (1.3% rate of
stroke/death) compared to carotid artery stenting (CAS; 8.3%).
• CAS has been associated with a higher complication rate above age 70
years.
• CEA has been associated with a lower rate of periprocedural stroke but a
higher rate of periprocedural myocardial infarction in relation to CAS.
51. Transcarotid artery revascularization (TCAR)- newer revascularization
option
• In this procedure, there is direct access achieved in the common carotid
artery and flow reversal is instituted.
• lower stroke/death rate with TCAR compared to transfemoral CAS.
• ROADSTER 2 (Safety and Efficacy Study for Reverse Flow Used During
Carotid Artery Stenting Procedure 2) registry, the 30-day stroke/death rate
was 5.0% in symptomatic patients and 1.4% in asymptomatic patients.
• No randomized trial comparing TCAR with either CEA or CAS.
• Despite growing enthusiasm for TCAR, the American Heart Association
and American Stroke Association secondary prevention guidelines felt that
the efficacy of TCAR for symptomatic patients is not well established
53. Full spectrum of cerebral SVD includes
• covert cerebral SVD detected incidentally on brain neuroimaging,
• SVD-related clinical presentations with lacunar stroke,
• cognitive decline or dementia,
• mood or physical dysfunction.
Markers of SVD on brain imaging are white matter hyperintensities,
cerebral microbleeds (CMBs), lacunes, and enlarged perivascular
spaces.
54. Antithrombotic Agents in the Context of Ischemic Stroke
Related to SVD
SPS3 trial (Secondary Prevention of Small Subcortical Stroke) of 3020 patients
with lacunar ischemic stroke (mean age 63 years), long-term dual versus single
antiplatelet therapy increased bleeding and death without reducing recurrent
stroke.
The pathological findings in SVD are arteriolosclerosis, lipohyalinosis,
fibrinoid necrosis in which thrombi may not be relevant. So, the usefulness of
antiplatelet agent such as aspirin may be challenged.
the general guidance for noncardioembolic secondary stroke prevention and
the use of antiplatelet therapy also applies for stroke caused by SVD.
55. • In patients with SVD, the balance between the prevention of a recurrent
occlusive event versus the risk of ICH is a major concern.
In a systematic review, cilostazol decreased recurrent ischemic stroke,
hemorrhagic stroke, deaths, systemic bleeding. To date, the usefulness of
cilostazol in non-Asian population in ischemic stroke related to SVD
remains uncertain.
• The 2021 European Stroke Organization guidelines on covert cerebral SVD
concluded that in patients with covert SVD (ie, who did not have any clinical
stroke) antiplatelet agents cannot be recommended to reduce the risk of
future stroke, major adverse cardiovascular events or cognitive decline.
56. Other Pharmacological Interventions BP
Management
In patients with SVD, intensive management of BP is probably the most
effective way to prevent both ischemic and hemorrhagic events as well as
cognitive decline.
Statins
Statins are recommended in secondary prevention guidelines with no evidence
of different effects in lacunar ischemic stroke as hyperlipidemia does not play
an important role in the development of SVD
Lifestyle
physical activity may play an important role in secondary stroke prevention.
58. Table 1. Short-Term and Long-Term Secondary Prevention Strategies With Cardioembolic Stroke Causes
Short-term management Long-term management
ATRIAL FIBRILLATION Oral anticoagulation (prefer DOACs over warfarin)
Oral anticoagulation (prefer DOACs
over warfarin)
Optimal initiation timing is unknown, but reasonable to start 2-14 d from stroke
Left atrial Appendage Occlusion as an alternative to oral
anticoagulation
Avoid bridging with heparin or low molecular weight heparin Avoid concomitant antiplatelet therapy unless strong indication
ATRIAL CARDI- Antiplatelet therapy Antiplatelet therapy
OPATHY Cardiac monitoring to look for AF
Anticoagulation if AF is found on cardiac monitoring
PFO Antithrombotic therapy PFO closure in patients meeting criteria
for positive PFO trials
Thorough investigation including cardiac monitoring to look for competing stroke
mechanisms Antithrombotic therapy in patients not meeting criteria for
positive PFO trials
59. INFECTIVE ENDO- Intravenous antibiotics Warfarin for mechanical heart valve
CARDITIS
Avoid anticoagulation Anticoagulation for concomitant AF
Consideration of surgery Preventative measures to reduce the risk of transient bacteremia
RECENT MYOCAR- Antiplatelet therapy Antiplatelet therapy
DIAL INFARCTION
Cardiac monitoring to look for AF Warfarin for persistent LV thrombus
TTE with Definity or Cardiac MRI to look for LV thrombus
Warfarin for at least 3 mo for LV thrombus
Warfann for at least 3 mo for anterior STEMI with apical
hypokinesis
60. i i IUOIO
LV DYSFUNCTION Antiplatelet therapy Antiplatelet therapy
Cardiac monitoring to look for AF Warfarin for persistent LV thrombus
TTE with Definity or cardiac MRI to look for LV thrombus Anticoagulation treatment if AF is found
Warfann for at least 3 mo for LV thrombus (reasonable Consider anticoagulation with warfarin
to start 4-14 d from stroke) or DOAC patients with EF <15%
Consider anticoagulation with warfann or DOAC patients with EF <15%
RHEUMATIC VAL-
Anticoagulation, preferably with warfarin,
particularfy if
Anticoagulation, preferably with
warfarin
VULAR DISEASE concomitant AF particularly if concomitant AF
Cardiac monitoring to look for AF if not present on initial assessment
Consider valve surgery
Consider initiation at 4-14 d from ischemic stroke
Avoid bridging with heparin or low molecular weight heparin
CARDIAC TUMORS Antithrombotic therapy Antithrombotic therapy
Cardiac monitoring to look for AF if not present on initial Anticoagulation with DOAC or warfann
assessment if concomitant AF
Consider surgical resection when safe from stroke standpoint
61. Stroke
88%
■ INTRACEREBRAL HEMORRHAGE
■ SUBARACHNOID HEMORRHAGE
■ ISCHEMICSTROKE
Ischemic Stroke
■ CARDlOEMBOUC
■ CRYPTOGENIC
LARGE ARTERY
■ OTHER
Cryptogenic Stroke
50%
Figure 1. Conceptual representation of
ischemic stroke subtypes.
Percentages arc approximate ard arc informed
by KoJomirsky-Rabas ct al36 ard Gardcrcr ct
aJ. 'T Precise percentages will ccpcnd on
extent of testirg ard patient populations.
Ischemic stroke subtype ccfiritors arc
informed by the TOAST (Trial o’* Org 10172 m
Acute Stroke Treatment) classification
scheme38 urlcss otherwise incicatcd. ES'JS
indicates embolic stroke of undetermined
source.
50%
■ ESUS
■ NON-ESUS
62. 5.4. Cardioembolism
5.4.1. Atrial Fibrillation
Recommendations for AF
Referenced studies that support recommendations are summarized in online
COR LOE Recommendations
1 A
1. In patients with nonvalvular AF and stroke or TIA, oral anticoagulation (eg,
apixaban, dabi-gatran, edoxaban, rivaroxaban, or warfann) is recommended
to reduce the risk of recurrent stroke.
1 B-R
2. In patients with AF and stroke or TIA, oral anticoagulation is indicated to reduce
the risk of recurrent stroke regardless of whether the AF pattern is paroxysmal,
persistent, or permanent.
1 B-R
3. In patients with stroke or TIA and AF who do not have moderate to severe mitral
stenosis or a mechanical heart valve, apixaban, dabi-gatran, edoxaban, or
rivaroxaban is recommended in preference to warfarin to reduce the risk of
recurrent stroke.
1 B-NR
4. In patients with atrial flutter and stroke or TIA, anticoagulant therapy similar to
that in AF is indicated to reduce the risk of recurrent stroke
63. 1 C-EO
5. In patients with AF and stroke or TIA, without moderate to severe
mitral stenosis or a mechanical heart valve, who are unable to
maintain a therapeutic INR level with warfarin, use of dabigatran,
rivaroxaban, apixaban, or edoxaban is recommended to reduce
the risk of recurrent stroke.
2a B-NR
6. In patients with stroke at high risk of hemorrhagic conversion in
the setting of AF, it is reasonable to delay initiation of oral
anticoagulation beyond 14 days to reduce the risk of ICH/20-*31
2a C-EO
7. In patients with TIA in the setting of nonvalvu-lar AF, it is
reasonable to initiate anticoagulation immediately after the index
event to reduce the risk of recurrent stroke.
64. 5.4.2. Valvular Disease
Recommendations for Valvular Disease
Referenced studies that support recommendations are summarized in online
COR LOE Recommendations
1 B-R
1. In patients with ischemic stroke or TIA and valvular AF
(moderate to severe mitral stenosis or any mechanical
heart valve), warfarin is recommended to reduce the risk of
recurrent stroke or TIA
1 C-LD
2. In patients with a mechanical mitral valve and a history of
ischemic stroke or TIA before valve replacement, aspirin
(75-100 mg/d) is recommended in addition to warfarin with
an I NR target of 3.0 (range, 2.5-3.5) to reduce the risk of
thrombosis and recurrent stroke or TIA
1 C-EO
3. In patients with ischemic stroke or TIA and native aortic or
nonrheumatic mitral valve disease (eg, mitral annular
calcification or mitral valve prolapse) who do not have AF
or another indication for anticoagulation, antiplatelet
therapy is recommended to reduce the risk of recurrent
stroke or TIA.
1 C-EO
4. In patients with a bioprosthetic aortic or mitral valve, a
history of ischemic stroke or TIA before valve replacement,
and no other indication for anticoagulation therapy beyond
3 to 6 months from the valve placement, long-term therapy
with aspirin is recommended in preference to long-term
anticoagulation to reduce the risk of recurrent stroke or
TIA.
65. Figure 3. Recommended antithrombotic regimen in patients with history of ischemic stroke or transient ischemic attack (TIA) and different
valvular heart disease conditions.
Colors correspond to Class of Recommendation in Table 3. Abx indicates antibiotics; AF, atrial fibrillation; AV, aortic valve; AVD, aortic valve disease;
DOAC, direct oral anticoagulant; MAC, mitral annular calcification; MS, mitral stenosis; MV, mitral valve; MVD, mitral valve disease; MVP, mitral valve
prolapse; and VHD, valvular heart disease. 'Definition of valvular AF. t Includes MAC and MVP. * Rheumatic and nonrheumatic AVD. increase the target
international normalized ratio by 0.5, depending on bleeding risk.
