Stroke

Research Review
Making Education Easy Issue 27 - 2017

In this issue: Welcome to the 27 th

issue of Stroke Research Review.
The first article in this issue used real-world data to assess the effectiveness and safety of three NOACs versus
warfarin in patients with nonvalvular AF and previous stroke or TIA. The findings suggest all NOACs were no worse
>>Effectiveness and safety of 3 than warfarin in respect to ischaemic stroke, ICH, or major bleeding risk. A small single centre retrospective chart
NOACs versus warfarin in patients review study found no significant differences in haematoma expansion between patients on NOACs and those
with nonvalvular AF and previous on warfarin. However, the study was not powered to determine differences between the three NOACs assessed.
stroke or TIA A paper exploring cerebral microbleeds and functional outcome after stroke thrombolysis concluded increasing
cerebral microbleed burden is associated with increased risk of ICH and poor 3- to 6-month functional outcome.
>>Secondary vs primary stroke A systematic review and meta-analysis reported antiplatelet pretreatment was not associated with a higher risk of
symptomatic ICH and worse 3-month functional outcome in acute ischaemic stroke patients treated with intravenous
prevention in AF alteplase. This study provides reassurance that thrombolysis should not be withheld in those acute stroke patients
already on antiplatelet therapy
>>CMBs and functional outcome A study comparing outcomes between monitored anaesthesia care and general anaesthesia for vertebrobasilar
after stroke thrombolysis stroke endovascular therapy concluded monitored anaesthesia care is feasible and appears to be as safe and
effective as general anaesthesia. The final article assessed the utility of CT perfusion for selection of patients
>>Intracerebral haemorrhagic for endovascular therapy up to 18 hours after symptom onset. In patients with target mismatch, reperfusion was
associated with higher odds of favourable clinical response. The authors also report the association did not differ
expansion in patients using between patients treated within 6 hours and those treated>6 hours after symptom onset. The article highlights
NOACs vs patients using warfarin access to rapid CT perfusion results to guide decision-making is a significant frontline issue.
I hope you find the research in this issue useful to you in your practice and I look forward to your comments and
>>SVD score and risk of recurrent feedback.
stroke Kind Regards,
Dr Robert Henderson
>>Antiplatelet pretreatment robert.henderson@researchreview.com.au
and outcomes in intravenous
thrombolysis for stroke Effectiveness and safety of apixaban, dabigatran, and rivaroxaban versus
>>Cardiovascular events in patients warfarin in patients with nonvalvular atrial fibrillation and previous
stroke or transient ischemic attack
with OSA and the impact of CPAP
Authors: Coleman CI, et al
therapy Summary: This study compared three non-vitamin K antagonist oral anticoagulants (NOACs) to warfarin in nonvalvular
atrial fibrillation (AF) patients with a previous history of stroke/transient ischaemic attack (TIA). The cohorts included
>>PSC protocol for suspected stroke apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208).
by large-vessel occlusion and The authors concluded neither apixaban nor dabigatran reduced the combined primary end point of ischaemic stroke
improved outcomes or intracranial haemorrhage (ICH) and had no significant effect on major bleeding versus warfarin. Rivaroxaban
reduced the combined end point of ischaemic stroke or ICH without an effect on major bleeding.
>>MAC vs GA for vertebrobasilar Comment: The US MarketScan administrative claims database (actually two databases) seem to keep a
stroke endovascular therapy record of everything. When combined with high-level data trawling you can answer many research questions.
This study confirms what we already knew that the NOACs are no worse than warfarin. Approximately 20%
>>CT perfusion to predict response of patients were receiving low dose NOAC. The authors caution on trying to compare the individual NOACs
(which is what we really want to know) and highlight that a retrospective analysis of claims has many limitations.
to recanalisation in ischaemic
stroke Reference: Stroke 2017 Aug;48(8):2142-2149
Abstract
Abbreviations used in this issue:
AF = atrial fibrillation; CMB = cerebral microbleed;

Stroke
CPAP = continuous positive airway pressure;
CSC = comprehensive stroke centre; CT = computed tomographic;
GA = general anaesthesia; ICH = intracerebral haemorrhage;
MAC = monitored anaesthesia care; mRS = modified Rankin Scale;
NIHSS = National Institutes of Health Stroke Scale;
Research Review
TM

NOAC = non-vitamin K antagonist oral anticoagulant;

OSA = obstructive sleep apnoea; PSC = primary stroke centres;
SVD = small vessel disease; TIA = transient ischaemic attack.

Independent commentary by Robert Henderson, staff neurologist at Royal Brisbane & Womens Hospital where
Claim CPD/CME points Click here for more info. he has worked as a stroke neurologist in a busy Stroke Unit for 10 years, alongside a specific research interest in Motor
Follow RESEARCH REVIEW Australia on Twitter now Neurone Disease. He is active in acute stroke management at the Wesley Hospital in Brisbane.His stroke interest arose

@ neuroreviews from a fellowship with Dr Henry Barnett in Canada, evolved with a neurocritical care focus at the Mayo Clinic with
Dr Eelco Widjicks, and has continued with stroke clinical trials, and an interest in the autonomic involvement after stroke.
Visit https://twitter.com/neuroreviews

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Secondary versus primary stroke Microbleeds, cerebral hemorrhage, and functional outcome after
prevention in atrial fibrillation: stroke thrombolysis: Individual patient data meta-analysis
Insights from the Darlington atrial Authors: Charidimou A, et al
fibrillation registry Summary: The study cohort included 1,973 patients with acute ischaemic stroke treated with intravenous
Authors: Mazurek M, et al tissue-type plasminogen activator from 8 centres. The crude prevalence of cerebral microbleeds (CMBs)
Summary: The researchers assessed AF stroke prevention was 526 of 1,973 (26.7%). A total of 77 of 1,973 (3.9%) patients experienced symptomatic intracerebral
strategies in a community cohort of 105,000 patients from haemorrhage (ICH), 210 of 1806 (11.6%) experienced parenchymal haematoma within the ischaemic
11 general practices in Darlington, England. Of the 2,259 area, and 56 of 1720 (3.3%) experienced parenchymal haematoma remote from the ischaemic area.
(2.15%) patients identified with AF 18.9% constituted a The authors concluded increasing CMB burden category was associated with the risk of symptomatic ICH
secondary prevention cohort. They reported secondary (P=0.014), parenchymal haematoma within the ischaemic area (P=0.013), and parenchymal haematoma
prevention, antithrombotic treatment was guideline adherent remote from the ischaemic area (P<0.00001). They also noted 5 and >10 CMBs independently predicted
in 56.3%, 18.9% were overtreated, and 24.8% undertreated; poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10-3.12; P=0.020; and odds
corresponding proportions for primary prevention were ratio: 3.99; 95% confidence interval: 1.55-10.22; P=0.004, respectively).
49.5%, 11.7%, and 38.8%, respectively. One-year stroke
Comment: CMBs is a hot topic with a number of articles in the last month, including this one from experts
rates were 8.6% and 1.6% for secondary and primary
in this area. It is nice to see evidence and the conclusion above is what you would expect. More than
prevention, respectively (P<0.001); corresponding all-cause
5 CMBs is bad and more than 10 is worse (but more than 10 CMB is actually quite uncommon 2%).
mortality rates were 9.8% and 9.4%, respectively (P=0.79).
The strength of this study is the large sample number from many centres. The result is helpful if you
The researchers also reported lack of antithrombotic treatment
know there are microbleeds on prior imaging, but it doesnt really answer the frontline question with
guideline adherence was associated with increased stroke
the acute stroke patient: ie. the authors acknowledge there is a need to know the risk versus benefit
risk for primary prevention. For secondary prevention lack
ratio of intravenous thrombolysis in relation to microbleeds and randomised trials of pre-treatment
of guideline adherence was associated with increased risk
microbleed imaging evaluation versus standard imaging.
of recurrent stroke and all-cause death.
Reference: Stroke 2017 Jul 18. pii: STROKEAHA.116.012992
Comment: We know AF is common with increasing
Abstract
age. What about those patients who dont choose
anticoagulation therapy? Despite a risk profile, only
50% of patients with AF are prescribed anticoagulation.
The authors also reference a study where 12% of the
population wouldnt choose anticoagulation even if it was
100% effective. The study highlights that the benefit of
anticoagulation is greatest in those with prior stroke with
guideline adherence leading to both reduced stroke and
all-cause mortality. The study provides some practical
data for undertreatment/overtreatment and cautions
Rehabilitation
with overtreatment, although this is complex with similar Research Review TM

all-cause mortality to those optimally treated.

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Reference: Stroke 2017 Aug;48(8):2198-2205 subscription to receive Rehabilitation Research Review.
Abstract

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 Stroke Research Review
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Intracerebral hemorrhagic expansion occurs in patients using
non-vitamin K antagonist oral anticoagulants comparable with
patients using warfarin
Authors: Melmed KR, et al
Summary: This single centre retrospective chart review study assessed patients admitted with
ICH and compared outcomes with and without haematoma expansion. Out of 814 patients admitted
9 were identified with recent NOAC use and 18 were matched controls on warfarin. The group
found no significant differences in National Institutes of Health Stroke Scale (NIHSS) or ICH score
on presentation between patients on NOACs and those on warfarin. They reported 4 out of the
9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated haematoma expansion, with
no significant difference. There were also no significant differences in modified Rankin Scale (mRS)
on discharge between groups.
Comment: Haemorrhagic extension with NOACs is common and it is similar to warfarin. This is a
small retrospective case-series and was not powered to determine differences between the three
NOACs, which would be practically helpful, along with practical protocols for reversal. A true timeline
of when haemorrhagic expansion occurs after acute stroke in this population would be also helpful.
Reference: J Stroke Cerebrovasc Dis 2017 Aug;26(8):1874-1882
Abstract
Total small vessel disease score and risk of recurrent stroke:
Validation in 2 large cohorts
Authors: Lau KK, et al
Summary: These investigators validated the total small vessel disease (SVD) score by determining
its prognostic value for recurrent stroke. Two independent prospective studies were conducted; one
comprising predominantly Caucasian patients with TIA/ischaemic stroke (n = 1,028) and one with
predominantly Chinese patients with ischaemic stroke (n = 974). Cerebral MRI was used to assess
lacunes, microbleeds, white matter hyperintensities, and perivascular spaces. In 2,002 patients with
TIA/ischaemic stroke a higher score was associated with an increased risk of recurrent ischaemic
stroke and ICH. A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischaemic stroke
subtypes. Including burden of microbleeds and white matter hyperintensities and adjusting the cutoff
of basal ganglia perivascular spaces potentially improved predictive power for ICH, but not for recurrent
ischaemic stroke on internal validation.
Comment: In this SVD score one point is allocated for each of the presence of lacunes, presence
of microbleeds, >10 basal ganglia perivascular spaces, and severe periventricular or moderate
to severe deep white matter hyperintensity. The total score seems predictive of recurrent stroke
events. The authors acknowledge differences between the Caucasian and Chinese populations
and the relatively small number of clinical outcomes. However, the results are obtained from a
large number of subjects (and from different scanners) and appear to be practically useful. It also
seems a score that neuro-radiologists could get interested in.
Reference: Neurology 2017 Jun 13;88(24):2260-2267
Abstract
Antiplatelet pretreatment and outcomes in intravenous
thrombolysis for stroke: A systematic review and meta-analysis
Authors: Tsivgoulis G, et al
Summary: The meta-analysis included seven randomised-controlled clinical trials with 4,376
patients; 33.7% with antiplatelet pretreatment. The team concluded after adjusting for confounders
(age and admission stroke severity) antiplatelet pretreatment was not associated with a higher risk
of symptomatic ICH (OR adjusted = 1.67, 95% CI 0.75-3.72), 3-month functional independence
(OR adjusted = 0.88, 95% CI 0.54-1.42), or death (OR adjusted = 1.01, 95% CI 0.55-1.86) in acute
ischaemic stroke patients treated with intravenous alteplase.
Comment: There seems to be scepticism about the safety of intravenous thrombolysis in patients
on antiplatelet therapy. This study provides comfort that thrombolysis should not be withheld in
those acute stroke patients already on antiplatelet therapy. There is double the risk of intracerebral
haemorrhage (absolute increase of 4.5%), which did not translate to outcome with similar 3 month
outcomes in those with or without prior antiplatelet use. The authors did not carefully separate
the three readily available antiplatelet therapies to my mind it would have been helpful to be
specific about clopidogrel, and the use of dual antiplatelet therapy.
Reference: J Neurol 2017 Jun;264(6):1227-1235
Abstract
www.researchreview.com.au
Stroke and other cardiovascular events in
patients with obstructive sleep apnea and
the effect of continuous positive airway
pressure
Authors: Schipper MH, et al
Summary: The investigators analysed the incidence of
cardiovascular events in patients with obstructive sleep apnoea
(OSA) and the impact of continuous positive airway pressure
(CPAP) therapy. Of the 554 patients included in the study,
50 cardiovascular events occurred in 44 patients during follow-up
(mean follow-up time 5.9 years). They showed events were
significantly higher in patients with increasing classification of
OSA-severity (p = 0.016). It was also noted untreated CPAP
patients had significantly more cardiovascular events compared
to treated patients; hazard ratio of 2.66 partially adjusted for age,
apnoea-hypopnea index and smoking.
Comment: Although OSA is a known risk-factor for
cardiovascular disease, the relationship between OSA and
cardiovascular risk is not well understood. The result for
this study applies to those who were already known to have
moderate to severe OSA and provide evidence that we should
be strongly counselling patients with significant OSA to use
the available therapies! However, one limitation in applying
this specifically to stroke is that the number of stroke or
TIA events was small. Another way of saying this is that,
compared to stroke/TIA, it is easier to show events when
they are cardiovascular!
Reference: J Neurol 2017 Jun;264(6):1247-1253
Abstract
Association of a primary stroke center
protocol for suspected stroke by
large-vessel occlusion with efficiency
of care and patient outcomes
Authors: McTaggart RA, et al
Summary: In this retrospective cohort study, 14 regional
primary stroke centres (PSCs) were instructed on the use of
the following protocol for patients with suspected emergent
large-vessel occlusion (1) notify the comprehensive stroke centre
(CSC) on arrival, (2) perform computed tomographic angiography
concurrently with noncontract computed tomography of the brain
and within 30 minutes of arrival, and (3) share imaging data with
the CSC using a cloud-based platform. A total of 101 patients were
transferred, however, only 70 patients met the inclusion criteria.
The protocol was partially executed for 48 patients (68.6%) and
fully executed for 22 patients (31.4%). The authors found when
fully executed, the protocol was associated with a reduction in
the median time for PSC arrival to CSC groin puncture (from
151 minutes [95% CI, 141-166 minutes] to 111 minutes [95% CI,
88-130 minutes]; P<.001) and patients were twice as likely to
have a favourable outcome (50% vs 25%, P<.04).
Comment: Its now all about large-artery occlusion and
determining protocols to enable the delivery of care to patients
who are remote to the hospital that can deliver intra-arterial
therapy. There are a few limitations to this retrospective cohort
study and the results need to be applicable to different
geographical areas. The authors acknowledge that their
protocol isnt the only answer.
Reference: JAMA Neurol 2017 Jul 1;74(7):793-800
Abstract
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Monitored anesthesia care vs intubation for
vertebrobasilar stroke endovascular therapy
Authors: Jadhav AP, et al
Summary: This retrospective, matched, case-control study compared
outcomes between monitored anaesthesia care (MAC) and general
anaesthesia (GA) in patients presenting with vertebrobasilar occlusion
strokes treated with endovascular therapy at two academic institutions.
Of the 215 patients who underwent therapy during the study period 39
were excluded due to emergent pre-endovascular therapy intubation.
Sixty-three patients had MAC (36%) and 113 patients had GA (64%).
The conversion rate from MAC to GA was 13% (n=8). After matching,
61 pairs of patients (n=122) were included in the primary analysis
and the 2 groups balanced for baseline characteristics. The group
concluded, when compared with the elective GA group, patients
who underwent MAC had similar rates of successful reperfusion,
good clinical outcomes, haemorrhagic complications, and mortality.
Comment: This is a nice practical study. Previous studies have
suggested that conscious sedation/MAC is safe and feasible
for intra-arterial therapy and that patients treated with MAC
may actually have better outcomes than those treated with GA.
This study now applies this to posterior circulation strokes.
The study highlights that GA carries a factor of increased time
to treatment. The limitations are that it is retrospective and
small numbers. Its also more complex and very much hospital
and anaesthetist dependent. However, it seems clear there will
be a trend towards declining use of GA for posterior circulation
thrombectomy.
Computed tomographic perfusion to predict response to
recanalization in ischemic stroke
Authors: Lansberg MG, et al
Summary: These researchers assessed computed tomographic (CT) perfusion for selection
of patients for endovascular therapy up to 18 hours after symptom onset. The study cohort of
190 patients were classified as target mismatch if they had a small ischaemic core and a
large penumbra on their baseline CT perfusion. Rate of reperfusion was 89%. The researchers
concluded in patients with target mismatch (n=131), reperfusion was associated with higher odds of
favourable clinical response, defined as an improvement of 8 points on the NIHSS (83% vs 44%).
They also reported the association did not differ between patients treated within 6 hours and those
treated>6 hours after symptom onset.
Comment: This is a multicentre cohort study. The authors highlight that practically most acute
stroke centres have CT not MRI access. Based on this result - is the trend for acute stroke
decisions going to be increasingly based on perfusion imaging rather than time? Limitations
of the study include the absence of a control group and the results were obtained from expert
centres (ie. most patients achieved successful reperfusion). There was also a relatively small
number in the greater than 12 hour group. The study used rapid software. A main frontline
issue is to have rapid CT perfusion results to guide decision-making.
Reference: Ann Neurol 2017 Jun;81(6):849-856
Abstract
Neurology
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Abstract

T HE C O NF ID ENC E O F EVID ENC E T H E R EAS S UR ANC E O F R E V E R S A L

STREAMLINED AUTHORITY CODE 4269 for stroke prevention in non-valvular atrial fibrillation
PBS Information: PRADAXA: Authority required (STREAMLINED) for the prevention of stroke or systemic embolism in patients
with non-valvular atrial fibrillation and one or more risk factors for developing stroke or systemic embolism. Authority required
(STREAMLINED) for prevention of venous thromboembolism in a patient undergoing total hip replacement or total knee replacement.
This product is not listed on the PBS for treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), or for the prevention of
recurrent DVT and PE in adults. Refer to PBS Schedule for full authority information. PRAXBIND: This product is not listed on the PBS.
Before prescribing please review the Product Information. Please click here for access to the full Product Information
Further information is available on request from Boehringer Ingelheim. Pradaxa and Praxbind are registered trademarks of Boehringer Ingelheim Pty Limited,
ABN 52 000 452 308, 78 Waterloo Road, North Ryde NSW 2113. AUS/PRA-171033 S&H BOIPX0093-AFRR-HP-P. January 2017.

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