Translational Cancer Research Unit

John M Worthington,1,2,3, 4

South Western Sydney Clinical School, Faculty of Medicine, UNSW

1Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia. 2Associate Professor (Conjoint) South Western Sydney Clinical School, The University of New South Wales.

3 Senior Staff Specialist Department of Neurology, Liverpool Health Service, Sydney, Australia. 4 Medical Co-chair Stroke Services New South Wales, Agency of Clinical Innovation.

What matters in stroke and transient ischaemic attack?

ANNA, Sydney 2013.

Examples of ischaemic stroke 30 day mortality in NSW

Site and date Type N Crude

30 day

Mortality%

Standardised

(Adjusted) %

CI 95%

Hospital A Principal

referral

ATC

353 17.1 20.7

15.3-27.2

Hospital B Principal

referral

ATC

289 8.0 8.2 5.0-12.6

Hospital C Non-

principal,

Metro.

138 11.6 9.2 5.2-15.1

Hospital D Rural 197 20.8 19.1 13.6-26.15

Hospital E Rural ATC 213 8.9 9.6 5.6-15.3

Hospital F Rural 83 22.9 30.6 7.6-63.0

Our care varies and there is a wide clinical variation in ischaemic and

haemorrhagic stroke outcomes.

What matters in stroke and TIA?

• Urgent treatment of TIA.

• Poor long-term outcomes after TIA.

• TIA, the ABCD2 score and stroke risk prediction.

• Stroke Units – essential features and outcomes.

• Bed-side practice.

• Stroke thrombolysis

• Primary prevention in non-valvular atrial fibrillation

In Australia, in 2012, there were 50,000 strokes and 420,000 stroke survivors. The cost

of stroke in that year was 5 billion dollars and the burden of disease cost is estimated at

49.3 billion. Deloitte/NSF

Transient ischaemic attack (TIA) 2013

• Urgent comprehensive treatment of TIA.

• Outcomes of TIA in SW Sydney and NSW.

• The ABCD2 score – ‘rolling-the-dice’

• ‘TIA’ should be managed urgently.

• The importance of TIA ‘mimic’ disorders.

Prism: Programme of Research Informing Stroke Management

SWS-TIA: South-West Sydney TIA Study

Transient ischaemic attack (TIA) is an arbitrary clinical syndrome of stroke-like

neurological symptoms or signs lasting less than 24 hours, including amaurosis

fugax. It is treated as a warning of stroke, although many patients have had a

completed stroke or have a non-neurovascular cause, known as a TIA ‘mimic’

Cumulative risk of stroke after TIA in 90 days

Coull et al BMJ 2004 and Johnston et al JAMA 2000

Almost 50% of post-TIA strokes occur in 48 hours

TIA is an

Emergency

Benefits of urgent care in TIA

Lower stroke risks are reported with rapid TIA assessment and

management, and the lowest are reported with hospitalisation in SWS!

• EXPRESS trial: 90 day stroke occurrence fell from 10.2% in usual outpatient

clinic review to 2.1% (p=.0001) in TIA clinic.1

• SOS-TIA trial: 90 day stroke (5.96% predicted) and 1.24% with rapid (24/7)

assessment service. Only 26% of TIAs needed to be admitted to the stroke

unit.2

• SW Sydney: 28 day stroke occurrence of 2.09% in ED discharged TIA cases compared with 0.66% for hospital admitted TIA cases (p<0.01) in 6 South

Western Sydney hospitals.3

• SWS-TIA Study: 30 day risk of 3.10% in ED discharged TIA cases compared

with 0% with admission to a stroke service at Liverpool and Bankstown

hospitals. Ninety day stroke risk 3.98% Vs 1.07%.4

1. Rothwell et al (EXPRESS) Lancet 2007; 2. Lavallée, et al (SOS-TIA) Lancet Neurol. 2007; 3. Kehdi E et al MJA 2008; Ghia et al, in press IMJ 2011.

Admitting TIA patients to hospital can be cost-effective if only for the potential

benefits of in-patient thrombolysis for early stroke occurrence Nguyen-Huynh MN, Johnston SC.Neurology. 2005 Dec 13;65(11):1799-801.

TIA stroke rates SW Sydney N=2,535

Blue bars: TIA and stroke after admission Green bars: TIA and stroke after ED discharge

28 day stroke rates: 0.66% in admitted and 2.09% in those discharged from ED

Discharge from emergency is

associated with a higher early

risk of stroke and TIA

Hospital admission of

TIA significantly lowers risk of stroke and TIA

1.Kehdi E, Cordato DJ, Thomas PT, Worthington JM et al. Outcomes of patients with transient ischaemic attack after hospital admission or discharge from the emergency department. MJA 2008; 189: 9–12

HOIST data review

across 6 South

West Sydney

hospitals

TIA stroke rates after ED presentation SWS-TIA Study

N=789

Ghia et al Internal Medicine Journal, 2011 (in press and available on line)

%

SWS-TIA

ED diagnoses of

TIA with medical

record review at

Liverpool and

Bankstown

Over 70% of TIAs are admitted in NSW; up to 85% in stroke unit hospitals

Stroke rates after TIA vary by urgency of care and

population

Population/study 2

days

7

days

28-30

days

90 days

Historic UK/USA population (ABCD2)1 3.9 7.5 9.2

Express Study (UK) 20072* 2.1

SOS-TIA (France) 20073* 1.24

Monash MT3 (Australia) 20114* 2.42

SWS Discharged from ED 2008 and 20115,6 2.09-3.1 4.0

SWS Hospitalised 2008 and 2011+5,6 0-0.7 1.1

NSW Hospitalised PRISM Study 0.2 0.7 1.3

+SWS hospitalised TIAs were older and had more risk factors

and co-morbidities than patients discharged from ED (and did better).

1. Johnston et al Lancet 2007 2. Rothwell et al (EXPRESS) Lancet 2007; 3. Lavallée, et al (SOS-TIA) Lancet Neurol. 2007; 4. Sanders et al MJA 2011; 5. Kehdi E et al MJA 2008; 6. Ghia et al, in press IMJ 2011

The stroke rates seen in the historic cohorts used to develop the ABCD2 score are much higher than

modern studies

* Urgent ambulant management with 25% admitted to hospital

0

5

10

15

20

25

7 days 30 days 90 days 365 days

%

Days post-admission

Triple end-point of stroke, heart attack and death

TIA

*Adjusted for age, sex, year, comorbidity and hospital

Triple-end point (Stroke/AMI/death) after

hospitalisation for TIA* in NSW (N=22,088)

PRISM Study: Worthington, Goumas and Gattellari

It is not just about stroke risk!

Unadjusted TIA, AMI, and stroke readmission,

death and triple-end point after TIA N=6,808

0

2

4

6

8

10

12

14

16

18

7 days 30 days 90 days 365 days

Pe

rce

nta

ge %

Days after TIA

TIA

AMI

Stroke

Death

Triple

Prism

Observed, expected and relative survival# in NSW 2000-2007 after an admitted* TIA diagnosis. N=22,882

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

(%)

Years since diagnosis

Observed with TIA

Expected

Relative survival

#Relative survival is the ratio of survival in a particular group of interest to that in the general population.

Post-hospital mortality following a TIA

Is similar to post-hospital mortality of

acute coronary syndrome

Years 1 2 3 4 5

Survival % 91.5 84.8 78.7 73 67.2

*Gattellari et al, Cerebrovasc Dis 2011;32:370–382

•Excess mortality of 3.8% and 11.7% at one and 9 years,

•33% dying within 5 years.*

*More than 70% of TIAs are admitted in NSW

At five years the relative survival for males and females

was 87.1 and 86.5% respectively

All stroke readmissions (ischaemic, NOS, haemorrhagic)

by departure status for NSW TIA 2005-07 N=12,850

All Stroke 7

days

30

days

90

days

Admitted 0.8% 1.7% 2.6%

Discharged 2.2% 3.1% 3.6%

Ischaemic

stroke

Admitted 0.6% 1.1% 1.7%

Discharged 1.3% 1.8% 2.0%

NSW stroke readmission rates are much

lower than those published in some UK

studies

Prism

Triple end point (death/AMI/stroke) by departure status for

NSW TIA 2005-07 N=12,850

Triple end point: time to first event of AMI, stroke or death, exceeds 16% at one year

7 days 30 days 90 days

Admitted 1.7% 4.1% 8.3%

Discharged 3.1% 5.3% 8.4%

Admitted patients have lower stroke rates, an

initially lower triple end-point and higher mortality rates

Prism

Diagnosis and investigation of TIA

Relative exclusions of TIA:

•Evidence of cerebral infarction or an apparent non-vascular cause (mimic)

•Hypotension and symptoms of syncope and pre-syncope require different approach

Essential and urgent investigations: Urgent CT scan to exclude bleeding 12 lead ECG Urgent carotid imaging (ultrasound or CT) Echocardiography if murmur or ECG changes

Urgent and comprehensive investigation with expert opinion and management

reduces the high early risk of stroke

Preferred investigations: Blood tests eg UEC, BSL, CRP, ESR, Fasting lipid MRI Brain (38% of TIA patient have changes) Holter or bed-side monitoring for arrhythmias Echocardiography (TTE or TOE)

Selected investigations: MRI or CT venography or angiography Young stroke work-up<age 50 Screening for hypercoagulable states Inflammatory/rheumatological markers

Carotid duplex ultrasound study

Can investigations be delayed in some patients?

0

10

20

30

40

50

60

70 Co-morbidities

TIA

+ Current co-morbidities and a 5 year ‘look-++ Smoking and lifestyle factors

TIA co-morbidities by diagnosis in NSW 2005-2007 (N=7,091)+

Can a patient’s age

and co-morbidities

predict the early stroke

risk?

The ABCD2 stroke risk score

The (Unified) ABCD2 stroke risk score was developed and tested, using UK and US databases*, as a prognostic score to predict early stroke risk following TIA

(Johnston et al, Lancet 2007; 369:28397). Now a proposed ABCD3 and ABCD3i.

Five clinical factors make up the ABCD2 score:

• A - Age ≥ 60 yrs (1 point)

• B - BP>140/90 at presentation (1 point)

• C - Clinical features: unilateral weakness (2 points) and speech impairment without focal weakness (1 point)

• D - Duration: greater than 60 minutes (2 points) or 10-59 minutes (1 point)

• D - Diabetes-(1 point)

*The ABCD2 stroke risk score was created using TIA cohorts up to 20 years old

and without the effect of modern urgent care

In older UK and USA databases without modern care the ABCD2 score was highly

predictive of early stroke:

• High risk: 6-7 points predicted 8.1% 2 day stroke risk

• Moderate risk: 4-5 points predicted 4.1% 2 day stroke risk

• Low risk: 0-3 points 1.0% predicted 2 day stroke risk

Previous Australian (NSF) ‘Acute Stroke Management Guidelines’

• Score greater than 3 (Moderate-high): receive rapid assessment and treatment

• Score of 0-3 (Low) : managed in the community or specialist clinic in 7-10 days.

The ABCD2 stroke risk score

Two peer reviewed studies from Monash (Saunders et al, MJA 2012) and SWS-TIA have

found that ABCD2 is no better than chance at predicting stroke risk after TIA in Australia

*NSF Position paper : Internal Medicine Journal 42 (2012)

Low Vs moderate-high ABCD2 scores and stroke

Where urgent comprehensive

care is available for the majority

of patients the use of the ABCD2

score, to stratify treatment, may

lead to avoidable stroke

Test performance of a moderate-high ABCD2 score at one month for prediction of stroke

Sensitivity Specificity Positive predictive Value

66.6% 32.3 1.87%

Ghia et al IMJ, in press.

SWS-TIA

Reclassification of TIA after admission to hospital

Admitted TIA patientsICD-10 diagnoses SWS

TIA

Stroke

TIA mimic

Stroke29%

TIA46%

Admitted TIA patientsExpert diagnosis SWS

TIA

Stroke

TIA mimic

Mimic

Stroke26%

TIA51%

Ghia et al Neuroepidemiology 2010 44% of TIA admissions retain a TIA diagnosis

SWS-TIA

Mimic

NEUROLOGICAL MIMIC DISORDERS (N=77)

Expert Diagnosis

NO.OF

PATIENTS

Migraine or other headache syndromes

Dizziness or other specific vestibular disorders including peripheral vestibulopathy

(n=7), benign positional vertigo (n=5), and labyrinthitis (n=1)

Cranial nerve disorders including Bell’s palsy (n=5), visual loss or blurring (n=3), third

cranial nerve palsy (n=1), fourth cranial nerve palsy (n=1) and Horner’s syndrome (n=1)

Disorientation including transient global amnesia (n=7), vascular dementia (n=1)

Epilepsy and convulsions

Neoplasia to the brain and meninges

Paraesthesia or peripheral nerve disorders

Miscellaneous including Parkinson’s disease (n=3), multiple sclerosis (n=1),

carbamazepine toxicity (n=1), intracranial thrombophlebitis (n=1)

17

13

12

9

9

3

3

11

NON-NEUROLOGICAL MIMIC DISORDERS(N=51)

Expert diagnosis

NO.OF

PATIENTS

Syncope or orthostatic hypotension

Other cardiac related disorders including arrhythmia (n=4), acute myocardial infarction

(n=2) , valvular heart disease (n=1) and cardiac failure (n=1)

Infection including urinary tract infection (n=2), pneumonia (n=2), septicaemia (n=1),

sinusitis (n=1) and otitis media (n=1)

Psychiatric disorders including panic disorder or anxiety (n=4)

Diabetes mellitus with hypoglycaemia

Peripheral joint disorders including cervical radiculopathy (n=2), tenosynovitis (n=1)

Miscellaneous including alcohol related (n=1), respiratory failure (n=1), pulmonary

embolism (n=1) and oesophageal dysfunction (n=1)

19

9

8

4

4

3

4

Mortality (%) after TIA by ED departure status and final ICD-10 discharge diagnosis 2005-07. Follow up is from ED arrival. N=12,850

Mimic disorders have a higher mortality rate than final ICD-10 diagnoses of TIA

Patients discharged

from ED were younger

and had fewer co-

morbidities

Triple end point (death/AMI/stroke) by departure status and in-patient ICD 10 final diagnosis. N=12,850

The triple end point in final diagnoses of TIA and mimic disorder are similar

Prism

Prism

What matters in TIA?

• Half the 30-90 day stroke risk is realised in the first 48 hours.

• Mortality after TIA is comparable to acute coronary syndromes.

• The triple-end point is 15% at one year and 33% of TIAs are dead in 5 years.

• Only 44% or TIAs diagnosed in ED retain a TIA diagnosis after admission and the remainder have stroke or a non-neurovascular ‘mimic’

• Mimic disorders have poor outcomes and need different treatment to TIA.

• Urgent and comprehensive investigation with expert opinion and management reduces the high early risk of stroke.

• Hospitalisation for TIA has the lowest reported stroke rates and allows more accurate diagnosis.

• In Australian studies the ABCD2 Study is no better than chance at predicting who should or should not be investigated urgently.

STROKE UNITS

Stroke units improve outcomes as much

as thrombolysis

You have to survive the complications of stroke to recover

The Stroke Unit Trialists’ Collaborative (SUTC) BMJ 1997, SUTC Cochrane Library, 2007:

Issue 1. AHA Guidelines for the early management of adults with ischemic stroke Stroke.

2007; 38:1635. NSF Acute Stroke guidelines.

Causes of death after stroke

The Silver et al Stroke 1984

A hectic two weeks

Surviving to recover

The ‘simple’ things matter

• Patients improve for months and years

• Acutely our patients depend on excellent care if they are to survive

long enough to recover

• ‘Simple’ things save brain

• In the past 20% or more of ischaemic stroke patients died in the first

thirty days and we can now almost halve that figure!

• Organised care in stroke units brings 30% improvement in stroke

outcomes in research trials (Cochrane) .

With co-localised stroke beds the stroke experienced multidisciplinary nursing and allied health team better recognise complications and avoid the avoidable

Stroke units

Collaborative systematic review

“Stroke Units Do Save Lives”

♦ 17% reduction in death

♦ 31% reduction in death or dependency

♦ 25% reduction in death or institutional

care

♦ 8% reduction in length of stay

The Stroke Unit Triallists’ Collaborative (SUTC) Published BMJ 1997

What matters on stroke units

Stroke unit patients receive:

♦ Earlier imaging

♦ More monitoring (particularly SaO2)

♦ More detection of aspiration

♦ More NGT/PEG

♦ More oxygen for hypoxia and increased use of warfarin for AF

Stroke unit patients had a reduced incidence of:

♦ Pneumonia (there may be no reduction in initial aspiration pneumonia – Gattellari et al, 2008)

♦ Dehydration

♦ Stroke progression

The incidence of complications correlates with mortality

Evans et al. Lancet 2001

968975

56

Pre-programme Post-programme

Stroke units improve the quality of stroke care

• Clinical care plan is defined as evidence of a written plan by health professionals to avoid complications.

• **Clinical pathway is defined as a structured tool detailing the activities of care during hospital admission.

High standards for patient

care led to improvements in

clinical care processes

• Within 24 hrs of admission

– 7% more patients

received brain imaging

– 19% more patients

were swallow-tested

• Clinical care plans were

written for an additional

27% of patients

• Clinical pathways were

recorded for an additional

49% of patients

Patient undergoes clinical processes within 24 hours of admission13

% of patients

72

45

65

16

Post-programme Pre-programme

Clinical care plan and clinical pathway developed during admission13

% of patients Clinical care plan*

Clinical pathway**

Swallow-tested

Brain imaging

(CT & MRI)

13. Cadilhac DA et al. Qual Saf Health Care. 2008.

Stroke units increase patient access to specialised care

Enhancing existing SCUs

and establishing new SCUs

increased patient access to

specialised stroke care

• 75% more patients were

admitted to a stroke unit

• Within 48 hrs of admission:

– 21% more patients

received physiotherapy

– 14% more patients

received speech

therapy

– 25% more patients

received occupational

therapy

* Pre-programme period was 12 months prior to the commencement of the stroke programme i.e. 2001-2002. Includes both SCU and non-SCU cases.

** Post-programme period was at least 6-12 months after commencement of the stroke programme i.e. Sept 2003- Dec 2006. Includes only SCU cases.

13

88 +75

Post-programme** Pre-programme*

Percent of patients admitted to stroke unit13

% of patients

Post-programme

50

64

Pre-programme

25

69

55

43

Patients receiving allied health

assessment within 48 hours of admission13

% of patients

Occupational therapy

Speech therapy

Physiotherapy

13. Cadilhac DA et al. Qual Saf Health Care. 2008.

Adjusted mortality %: Hospital type before and after

the 2003 stroke unit roll-out in NSW

Non-principal referral hospitals NPR Principal referral hospitals PRH

Melina Gattellari, John M Worthington, Bin Jalaludin, Mohammed Mohsin Stroke 2008

DISCHARGE DESTINATION

Home Nursing home Death Other*

Before 38.7% 6.3% 13.8% 41.2%

After 44.5% 4.9% 10.5% 40.2%

p<0.001 (significant main effect and interaction type*time)

Controlling for: age, co-morbidity (modified Charlson Index), sex, marital status, country of birth, hours on mechanical ventilation, insurance status, and clustering of outcomes by hospital in GEE multivariate model.

*transfer to other hospitals/change in type

Outcomes for ischaemic stroke: 10 Non-Principal

Referral NSW hospitals with stroke units

Gattellari et al Stroke, 2008.

DISCHARGE DESTINATION Home Nursing home Death Other*

NON-PRINCIPAL REFERRAL HOSPITALS (METRO)

Before 20.3% 12.9% 26.8% 40.0%

After 28.7% 10.3% 19.7% 41.4%

PRINCIPAL REFERRAL HOSPITALS

After 25.7% 11.2% 20.2% 43.0%

*transfer to other hospitals/change in type

Outcomes for ischaemic stroke before and after

stroke unit in 10 Non-Principal Referral NSW

hospitals ≥ 85 years

Gattellari et al Stroke, 2008.

Roll-out of GMCT stroke units in 2003 appear to have a favourable impact on patient outcomes in Non-Principal Referral hospitals which now closely approach the principal teaching hospitals (Gattellari et al, Stroke 2008).

• Death reduced from 13.8% to 10.6%.

• Discharges to home increased from 38.8% to 44.5% (p<0.001).

• Discharge to nursing home decreased from 6.5 to 4.9%.

• Over 85s benefit significantly

Principal Referral Hospitals maintained good mortality rates and discharges to home in the face of increasing activity and increasing complexity

Benefits of stroke units in Australia

Melina Gattellari, John M Worthington, Bin Jalaludin, Mohammed Mohsin Stroke 2008

Equity in patient outcomes was achieved

-5.3

+0.8

38.8

+3.1

5.5

Discharged to

home

6.3

Died

13.8 10.7

44.1

10.5 10.6 0

45.1

-0.6

-0.1

4.9

44.5

4.9

Discharge destination

of patients

before SCU

implementation8

% of patients

Principal referral hospital

Non-principal referral hospital

• Non-principal referral hospitals significantly reduced in-hospital mortality and increased discharges to homes

• Principal referral hospitals maintained their good outcomes across time – This suggests the threshold effect for SCU has been reached

8. Gattellari M et al. Stroke. 2009.

Before SCU implementation, patient outcomes were dependent on the type of hospital a patient was admitted to

Discharge destination of

patients

after SCU

implementation8

% of patients

After SCU implementation, patient outcomes were independent of the type of hospital a patient was admitted to

Principal referral hospital

Non-principal referral hospital

Discharged to

nursing home

Discharged to

home Discharged to

nursing home

Died

Stroke thrombolysis

The brain needs blood and oxygen

• Reduced brain activity occurs

quickly when blood supply is

reduced for more than ten

seconds

• When an artery is blocked

without excellent collaterals

brain cells will be lost over the

following hours.

Brain wave activity after blockage of blood flow

The concept of an ischaemic penumbra -astronomy meets stroke

Ischaemic core

Penumbra

Penumbra of an eclipse

Ischaemic Penumbra in Acute Stroke

Perfusion deficit

(MTT) at 12 hours

Neuronal injury (DWI)

at 12 hours

Neuronal injury

(DWI) at 4 days

Difference between perfusion deficit (MTT) and neuronal injury

(DWI) image represents the ischaemic penumbra

Courtesy Andy Evans

What is an ischaemic core and an ischaemic penumbra?

Ischaemic core • Severe lack of blood

• Failure of glucose and oxygen delivery leads to progressive cell injury and death

• Infarcting/dying brain tissue

Ischaemic penumbra • Area around the ischaemic core with

some blood flow.

• Cells in the ischaemic penumbra may remain alive for hours

• Salvageable with reperfusion?

Analogy • Analogy of dead, dying and wounded

neurones on a battle field

• Neurones can be saved

Small ischaemic

core

Penumbra

around the core

If circulation is not restored

the ischaemic core

expands over hours into a

large completed stroke

Two stories: Good and bad, with and without tPA

Opening of artery with

improvement after tPA

Completion of stroke with

continued middle cerebral

artery blockage 30-37% have significant reduction in

disability with thrombolysis

CT-Perfusion the penumbra and thrombolysis

• CT ‘perfusion’ is more readily available

than MRI

• ‘Multi-modal CT’

• A combination of CT. CT-A and CT-P

allows identification of a treatable

ischaemic penumbra

• CT-P may be used to guide treatment

in stroke on waking (SOW) patients

and in the 3-6 hour window

MRI

A-CT

B-CTA

C-CTS1*

D-CBF

E-CBV

F-TTP

Blocked LICA and LMCA

*Early enhanced scan (source

image) gives information about

infarct core

Schramm et al Stroke 2004;35:1652-1658

Recent report of successful CT-P guided thrombolysis with Tenecteplase up to 6 hours. Parsons et al Cerebrovascular Diseases 2011;

Vol.31(2)

The original NINDS thrombolysis trial of rt-PA

• Carotid and vertebral strokes < 3 hours

• 302 treated within 90 minutes

• 0.9 mg per kg and no ancillary aspirin or heparin (maximum

dose 90 mg of Alteplase)

• No change in mortality

• A lower than expected haemorrhage rate of 6.4% for rt-PA vs

0.6 % for placebo

The original NINDS thrombolysis trial of rt-PA

• Haemorrhage rate was higher than for rt-PA use in AMI

• Increased haemorrhage rate if the diastolic blood pressure is

above 100 mmHg

• 30% more patients made a complete recovery (a 15%

“absolute” benefit)

• Extensive strokes did less well

Conditions for r-tPA use in the NINDS trial/ADEC

• Assessment by a stroke physician experienced in review of the CT

scan

• Patient treatable within 3 hours of onset

• ICU/HDU or acute stroke unit management

• Careful management of BP<180

• Facilities to handle cerebral haemorrhage in NINDS (but no longer

considered essential)

You need two bottles of Alteplase in the fridge/maximum dose is 90mg. Dose is 0.9

mg/kg with 10% given as a bolus (1 minute) and the remainder over 60 minutes

Conditions for r-tPA use in the NINDS trial/ADEC

• Carotid and vertebral strokes

• 30% or less of MCA territory abnormal on CT. No haemorrhage

• 0.9mg/kg-maximum dose 90mg of Alteplase

• 10% bolus and 90% infusion over 60 minutes

• No ancillary aspirin or heparin for 24 hours

Conditions for rt-PA use in the NINDS trial/ADEC

Restrictions

• Avoid use of IDC, vascular access and nasogastric tubes

Exclusions in the NINDS research trial

• If BP >185/110, large clinical stroke, early CT evidence of

infarction, seizure at onset or abnormal prothrombin time

• A long list of exclusions on a thrombolysis check-list!

In studies of thrombolysis the protocol violations have dire effects!

Time and thrombolysis

At 90 minutes NNT=3

An NSF survey suggests 80% of strokes arrive at DUBBO in less than 3 hours

NNT at 90 minutes=3

NNT at 3 hours=7 CASES Study Canada

The first (urgent) non-contrast CT brain

• The first scan is often normal or shows

subtle signs. It may show a thickened

MCA sign.

• 50% of CT reports by general radiology

will over or under diagnose changes on

brain CT.

• First scan: look for ‘malignant’ stroke, old

strokes, ICH, SAH, SDH and metastases

Intracerebral

haemorrhage

with oedema

Subtle right

MCA changes

with loss of

Sylvian fissure

and sulcal

effacement

Imaging with non-contrast CT is rapidly and widely available, an major advantage

although the area of infarction and the clot are not usually visible

Left thickened

MCA sign

Stroke and thrombolysis pathways

Stroke and thrombolysis pathways

• Everyone needs a checklist!

• Avoid a plane crash! • When thrombolysis check-lists are

not used the haemorrhage and death rates are unacceptable (Cleveland)

Cleveland’s lesson: Follow the check-list!

♦ 70 patients in 29 hospitals over 1 year

♦ 1.8% of all strokes

♦ 50% protocol deviations

♦ 15.7% mortality vs 7.9% predicted

Cleveland NINDS

Symptomatic bleed 16% 6%

Fatal bleed 6% 3%

Courtesy of Andy Evans

Katzan I, Furlan A, Lloyd L, et al. Use of tissue-type plasminogen activator for acute ischemic stroke. The Cleveland area experience.

JAMA. 2000;238:1151-1158. Katzen IMM , Hammer MDM, Furlan AJM, et al. Quality improvement and tissue-type plasminogen

activator for acute stroke. A Cleveland update. Stroke; 34: 799-800.

The poor outcomes in

Cleveland were

overcome with clinician

education and protocol

adherence

17.3

38.4

44.3

18.4

51.4

30.2

0

20

40

60

80

100

Thrombolysis Control

Alive and

independent

Alive but

dependent

Dead

3 research trial n=869 Wardlaw, Cochrane 1999

Outcomes of tPA thrombolysis < 3 hours

• Odds ratio death and disability: 0.67 (0.56-0.80)

• Increased mortality in first 7 days. Favourable beyond 2 weeks.

• The NNT at 90 minutes is 3 and at 3 hours it is 7

ECASS 3 Study: 3-4.5 hours

• N= 821

• Excluding major infarct or haemorrhage on CT

• Mean onset-to-needle time 3 hours 59 minutes.

• Primary endpoint was disability at 90 days.

• Outcome dichotomised by mRS (0-6).

• Favourable outcome 0-1; unfavourable 2-6.

• More patients had a favourable outcome with Alteplase

than with placebo 52.4% Vs. 45.2%; odds ratio 1.34; 95% confidence interval 1.02 -1.76. p = 0.04.

• Symptomatic haemorrhage 2.4 Vs 0.2% and no significant difference in mortality 7.7 Vs 8.4 %

More modest benefit at 4.5 hours than under 3 hours ‘onset-to-needle’

CASES

Canadian Alteplase for Stroke Effectiveness Study

A real world thrombolysis study with routine CT follow-up

• Over 1100 patients and 61 community and academic hospitals

• Most hospitals did one thrombolysis a month

• Only 20% of CT brain scans were normal

• Excellent outcomes 37%

• Benefit of thrombolysis 31-36% (depending on measures)

• Haemorrhage rate not significantly different between mild and severe

stroke

Initial CT brain scan changes did not correlate with haemorrhage incidence!

CASES

• Less than 20% got treated under two hours and most were

treated with little time to spare (average 153 minutes)

• Numbers needed to treat: 3 patients at 90 minutes and 7 at 3

hours

• Eighty year olds benefited but not as much as younger patients

• CT scan changes did not correlate with haemorrhage rates

• CT scan changes did correlate with outcomes; worse scan worse

outcome

CASES and brain haemorrhage

• 4.6% had symptomatic haemorrhage

• 28.9% of the thrombolysed patients had a

cerebral haemorrhage

• 79% with symptomatic cerebral bleeds

died (fatal ICH occurred in 3.6%)

• Symptomatic haemorrhage rates stayed

on a straight line up to 3 hours then rose

sharply (3.9%<3hrs and 7.8%>3hrs)

Hill, M. D. et al. CMAJ 2005;172:1307-1312

Copyright ©2005 CMA Media Inc. or its l icensors

Hill, M. D. et al. CMAJ 2005;172:1307-1312

Observed versus expected outcomes among CASES patients

Outcomes of intravenous rt-PA thrombolysis Onset-to-needle<3 hours

• Alteplase (rt-PA) reduces stroke disability and mortality by 44%.

• The number needed to treat (NNT) at 90 minutes is 3 and at 3 hours the NNT is 7.

• The odds-ratio for death and disability Vs placebo at 3 hours is 0.67.

• Large ‘real-world’ observational studies mirror the randomised control results.

• A 37% benefit is seen in both low volume community hospitals and high volume teaching hospital settings.

The 3-4.5 hour window

• More modest but valuable benefits.

• Odds-ratio for a favourable treatment Vs placebo is 1.34 (ECASS 3).

• Supported by analysis of pooled studies and observational data from ‘real world’ practice.

• Caution should be used in those over age 80 years, beyond 3 hours.

Wardlaw, J., del Zoppo, G., Yamaguchi, T., & Berge, E. (2003). Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews

(3), CD000213. 2003. Hill MD, Buchan AM. Thrombolysis for acute ischaemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study (CASES). CMAJ May 10; 2005; 172 (10). Wahlgren N, Ahmed N, Davalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe

Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007 Jan 27; 369(9558):275-82. Hacke W,

Kaste M, Bluhmki E, et al. Thrombolysis with Alteplase 3-4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008:359: 1317-29. Hacke, W, Donnan

G, Fieschi C, et al Association of outcomes with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768-74. Ahmed N, Wahlgren, Grond M, et al. Implementation and outcome of thrombolysis with alteplase 3—4·5 h after an acute stroke: an

updated analysis from SITS-ISTR. The Lancet Neurology, Sept 2010. 9; 866 – 874.

Outcomes of intravenous rt-PA thrombolysis

Haemorrhage and mortality

• Haemorrhage with deterioration occurs in 4-7% and 75% of these patients will die.

• In systematic review haemorrhage accounts for an early excess mortality of 3%.6

• With protocol based treatment overall mortality is at least the same in thrombolysis and control arm, when measured beyond two weeks.

• Overall ischaemic stroke mortality is high at 10-20% in the weeks after an acute stroke rising to 23-39% at one year, in non-AF and AF-related strokes, respectively.

• Stroke mortality generally relates to stroke severity, co-morbidities and age.

• Reduction in stroke severity with ‘clot-busting’ translates into lower late mortality, offsetting early treatment-related mortality.

Wardlaw, JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ishaemic stroke (Review). Cochrane Database of Sytematic

Review 2009, Issue 4. CD000213. Gattellari M, Goumas, C, Aitken, R, et al. Outcomes for Patients with Ischaemic Stroke and Atrial

Fibrillation: The PRISM Study. Cerebrovasc Dis 2011; 32:370-382.

Intravenous thrombolysis

• Alteplase (rt-PA) intravenous thrombolysis is proven, licensed and important treatment*

• Intravenous rt-PA is now a ‘usual treatment’ and perhaps we can be exposed medico-legally for not providing it!

• Alteplase rt-PA thrombolysis still under-utilised treatment (with rates around 2-3%).

• Rates can approach 20% where there is pre-hospital and hospital redesign similar to the new state-wide Early Access to Thrombolysis programme)

* Recent license (TGA) approval for rt-PA use out to 4.5 hours

Recent report of successful CT-P guided thrombolysis with Tenecteplase up to 6 hours. Parsons et al Cerebrovascular Diseases 2011; Vol.31(2)

Quain DA, Parsons MW, Loudfoot AR, et al. Improving access to stroke therapies: a controlled trial of organised pre-hospital and

emergency care. MJA 2008;189: 429-433. O’Brien W, Crimmmins D, Donaldson W, et al. FASTER: experience of Central Coast

Stroke Services implementation of a pre-hospital notification system for expedient management of acute stroke. J Clin Neurosci.

2012 Feb: 19(2):241-5.

Things to remember about IV thrombolysis

• The check list is critical-every line must be completed and every

criteria met (remember Cleveland!)

• Time of onset is critical (if big CT changes go and check onset time)

• Time of onset is the time last well (do not count onset from time of

waking with the stroke)

• A stroke specialist should be assessing the patient.

• INR less than or equal to 1.3

Things to remember about IV thrombolysis

• BP in most trials is a major haemorrhage determinant .

• BP must be less than 180/110 at treatment and afterwards

• Ninety milligram maximum dose (50mg per vial and you need two in

the ED refrigerator). Dose by weight.

• Patient and family estimates of weight are often most accurate

• Anaphylaxis rate 1.3%

Time to stroke service and thrombolysis

In Australia patients present quicker to regional centres and one of Australia’s fastest thrombolysis door-to-needle times, about 20 minutes, is held by Chris Bladin at Box Hill Hospital

• Direct home to stroke service is quicker (99 minutes) than stopping

over at a non-stroke unit/ non-thrombolysing hospital (127 minutes).

• Doing a brain scan at the peripheral hospital before transfer causes

further delay (out to 210 minutes). Nedeltchev et al 2003.

• Stopping-over at another site uses too much time.

• Delays to medical assessment, thrombolysis time and a stroke unit bed

increase death and disability.

Direct to stroke unit hospital

Time to stroke service and thrombolysis

• The record door-to-needle time in Australia is about 20 minutes

(unofficially held by Bladin Box Hill and Donnan Austin Hospital).

• This is about the average time when using the latest ‘Helsinki

protocol’*

• Many now do a finger prick BSL and use a POC device for INR, ‘running’

the other bloods to pathology but not waiting for the results to

proceed.

Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Meretoja et al Neurology 2012;79:306–313

The stroke pathway Some obsession (and adherence) is a good thing

Initial treatment of stroke and ‘TIA’ in Emergency:

• ABC

• Begin neurological observations (Glascow Coma Scale/ Scandinavian

Stroke Scale/ NIHSS) 2nd hourly in ED.

• Nurse 30-450 head-up.

• NBM* until swallowing assessment.

• IV canula and IV fluids. Even mild dehydration causes deterioration.

• Oxygen 2 litres by nasal prongs.

• Apply ted stockings (knee high) or sc heparin/clexane.

• Arrange CT scan urgently all hours.

• Usually no acute treatment of high BP is required in ischaemic stroke. It

usually settles and acute BP management can be dangerous (see later).

• In-dwelling catheter considered in patients with haemodynamic problems or

retention. Otherwise use a specific contiinence management plan.

The pathway should cover the preventable issues and act as a guide to experienced and inexperienced alike

Investigations

TOE*

Carotid duplex ultrasound

LA

Aorta

Atrial fibrillation

Evolving subtotal

MCA stroke

Subtle right

MCA changes

with loss of

Sylvian fissure

and sulcal

effacement

*TOE – Transoesophageal echo-cardiography

Initial and daily investigations

Immediate investigation after suspected stroke and TIA:

• Urgent cerebral CT scan (initially without contrast) and consider CTA.

• Initial CT is often normal and a 2nd ‘delayed’ scan is often important.

• CXR (order PA and Lateral, if possible).

• 12 Lead ECG looking for atrial fibrillation, other arrhythmia, LVH and signs of ischaemic heart disease, including Q waves and T wave inversion

• Immediate FBC, APTT and INR, ESR, CRP, random BSL, acute cholesterol

and triglycerides.

• Biochemistry including calcium, magnesium and liver function tests

• Arterial blood gas if drowsy or post-ictal (20% will have seizures after stroke)

• Daily bloods in larger stroke - FBC, CRP, UEC, LFTs.

• Repeat any abnormalities on initial results.

• Patients on heparin infusion should have 4th hourly APTTs until stable at 1.5-2 times normal with FBC every second or third day.

• Using therapeutic Clexane - needs a Factor Xa blood test after two doses.

Initial and daily investigations

Investigations to be booked on admission

• Patients on warfarin always require a daily INR in hospital

• Carotid duplex studies should be arranged or a neck CT angiogram (if renal function intact)

• Transoesophageal echocardiogram (TOE). Transthoracic only gathers half the information and will not usually detect key indications of paroxysmal AF

• At least 48 hours of cardiac monitoring is recommended, longer if poor rate control or other arrhythmia problems.

• Monitoring is some assistance in detecting paroxysmal atrial fibrillation but in one study it took 1.7 months of continuous monitoring to capture the majority with paroxysmal AF. Hence the importance of features on TOE

Most ischaemic stroke in Australian is embolic from extracranial arteries or the heart (cardioembolic), with some intracranial vertebro-basilar thrombosis. The incidence of thrombotic (and haemorrhagic) stroke seems much higher in some Asian ethic groups

Patients under fifty years of age with no major risk factors for stroke need a ‘young stroke work-up’ ordered (see Young Stroke Work-sheet)

Hypertension and acute ischaemic stroke (IS)

• Initially, in acute ischaemic stroke 80% have hypertension at presentation.

• It starts to fall within hours and often decreases substantially within 7 days.

• It is not clear if early elevation is a protective physiological reaction to assist perfusion or harmful reaction.

• American and European guidelines suggest treating at 220/120 mm Hg although evidence for this is not clear.

• Acute reasons to treat would include signs of hypertensive encephalopathy or acute heart failure or above 180 mm Hg in a thrombolysis candidate.

• There is evidence that even modest BP treatment in the first hours and week after IS harms functional outcomes and should be avoided after acute ischaemic stroke.

Sandset et al. Stroke. 2012 Aug;43(8):2108-14 . Hubert et al. International Journal of Hypertension 2013, Article ID 349782.

Supplemental oxygen in stroke and TIA

• Pneumonia

• Unstable airway

• Sleep disordered breathing

• Cheyne-Stokes respirations

• Existing respiratory and cardiac disease

• O2 may protect the ischaemic brain from further damage

• There is no evidence in this setting of oxygen being toxic

• Saturation monitors are poor at detecting intermittent hypoxia

Hypoxia occurs during Cheyne-Stokes

breathing in your stroke patients

Despite what we were taught Cheyne-

Stokes is not an ‘agonal’ or end-stage

breathing pattern and is common after

hemispheric stroke

Supplemental oxygen in stroke and TIA

A saturation of 90% can

be equivalent to an

oxygen level of 50

mmHg!

• Connect yourself to an oximeter and hold your breath. When you are gasping your

saturation will may be about 70% but it will often look normal on the oximeter! Do not

be reassured by the oximeters - give the oxygen.

• Over 60% of your patients have obstructive or central apnea causing significant

intermittent hypoxia. Not to mention heart failure, chronic lung disease and aspiration.

Why is supplemental

oxygen on the

pathway?

23% of 100 stroke patients (thought not to need oxygen) had a mean awake SaO2 of 94.5%

but spent more than 30minutes with SaO2 below 90% at night (Roffe et al Stroke 2004)

Supplemental oxygen in stroke and TIA

• Sitting up is best for hypoxaemia and orthostatic hypotension is a very uncommon issue (<10%) (Panayiotou et al, 1999)

• 25% hypoxic in the CT scanner (Rowat et al, WSC 2004)

• Hypoxaemia is worse in bad strokes (Rowat et al, 2006)

• Hypoxia (<90% SaO2 >10% of the time) occurs in 15% of stroke patients in ED.

• Mean SaO2 is often low during transfers (23%) (Rowat et al 2006)

• Hypoxia may harm the ischaemic penumbra.

- 24% O2 by mask increases saturation 1%

- 2L via prongs and 35% by mask gives 2%

-3L via nasal prongs gives saturation increase of 3%

Most patients prefer nasal prongs

Ali, Sills and Roffe 2005

• Half or most stroke and TIA patients have sleep disordered breathing

• Obstructive and central apneas and hypopneas

• Oxygen is ‘poor man’s’ CPAP.

• CPAP itself is poorly tolerated in acute stroke. (C-Y Hsu et al JNNP 2006;77:1143-1149)

• Oxygen reduces central apnea CSA

• Supplemental O2 reduces desaturation in CSA, OSA, hypopnea and Cheyne-Stokes breathing

S Kapen 1991 Ischaemic stroke n=47

RDI level*

>10 in 72%

V. Mohsenin 1995

Hemispheric stroke >10 in 52%

ME Dyken Recent stroke

n=24

>10 in 7%

C Bassetti 1996

Stroke (n=13)

TIA (n=13)

>10 in 70%

>10 in 69%

C-Y Hsu et al Ischaemic stroke = 66

>10 in 85%

>30 in 50%

After H.Teschler

Supplemental oxygen in stroke and TIA

*RDI : Apneas and hypopneas per hour.

An RDI > 30 is severe

Martin et al 1982, McNicholas et al 1982, Gold et al 1985, Motta et al 1978, Hanley et al 1993 and Krieger et al 1983

A role for hyperoxia in stroke?

• Human pilot study

• Serial MRI of a RMCA embolic stroke given eight hours of eubaric hyperoxia (NBO)

• Humidified O2 45l/min by face mask

• Increases brain tissue oxygen tension in penumbral tissue

• Transient improvement in signs and MRI abnormalities

• Lowers lactate and increases N-acetyl-aspartate (NAA)

Singhal et al Stroke 2005;36:797 and Stroke. 2007; 38: 2851-2854

Aspiration

• A swallow assessment tool is an urgent part of acute assessment.

• Patients with significant face and arm weakness will often have dysphagia

and can aspirate despite a reassuring speech pathology clearance.

• We treat for aspiration at temperatures of 37.5 or with elevated CRP or

WCC in an at risk patient. We also check for gout. *

• Patients only have fever a few hours a day

• Aspiration is far-and-away the most likely infection in the first fortnight.

• Aspiration may not be associated with consolidation but it can still deadly

• CXR is normal in 60% (although a CT will show it)

• Recommended written instructions for culture/ UA/ MSU/ CXR/ and review

of feeding orders (usually suspend and start IV), antibiotics and fever

control

• Static/basal atelectasis is anther source of lung infection.

*CRP will often rise sharply days before symptoms of gout or pseudogout. Treatment with stat sc Depot synacthen (synthetic ACTH) is highly recommended. May need repeat dosing.

Aspiration management

• Suggest a single daily IV dose of 2 grams of Ceftriaxone without needing

Flagyl, although it may be added later.

• Always measure and record the position of the naso-gastric tube.

• We do not recommence feeds until a fall in fever, WCC or CRP. The WCC

usually falls first.

• Little evidence for benefits of early feeding in stroke patients (FOOD Trial).

• Most patients with dysphagia improve significantly by the second week.

• Large MCA and brainstem strokes can have recurrent aspiration for weeks

before airway protection improves. (Surviving to improve.)

• NG tubes and PEG tubes are as much about meeting fluid and calorie needs

as aspiration.

• Patients often need significant PEG water flush volumes for hydration.

Most patients on thickened fluids will become dehydrated within days and deteriorate and need IV fluid ‘top-ups’. Even mild dehydration without urea rise has Level 1 evidence for poor outcomes

Stroke prevention in NVAF

Non-valvular atrial fibrillation (NVAF) and stroke

Estimated rate of stroke:

-Valvular atrial fibrillation 15-20% per annum

-Non-valvular atrial fibrillation 2-18%

NPS News 62 2009

25% of patients hospitalised for ischaemic stroke have AF

AF related strokes are more severe than non-AF

Mortality is higher

• ~20% of patients with AF die in-hospital (twice the average rate)

• Almost half of in-hospital deaths (42%) occur in patients with AF

• 12-months mortality is 39% in Australia

Risk of disability is higher

• 60% leave hospital disabled

• In Canadian stroke units only 20% of the NVAF strokes escape death or disability.

Background

Andersen & Olsen 2007; Béjot et al 2009, Gladstone et al, Stroke 2009, 40: 235-240; Gattellari, Worthington, Jalaludin, Mohsin. Stroke; 2009,40; 10-17; Frost,

Andersen, Vestergaard, 2007, American J of Med 2007; 120: 47-53

NSW Crude-mortality rates after NVAF related

stroke (N=27,007)

30-day 90-day 365-day

With AF 20.0% 27.9% 38.5%

Without AF 11.7% 15.9% 22.6%

Total 13.8% 18.9% 26.6%

HR=1.4 (95% CI: 1.3-15) Adjusted for: Sex, age, Charlson Comorbidity Score and year of separation

PRISM Study: Gattellari, Worthington, Aitken and Jalaludin 2009

NSW Linked data

Prism

The prevalence of atrial fibrillation increases with age and appears higher in men compared with women

Australian sample of 321 GPs and 14,750 patients over 30 years

<50 50-59 60-69 70-79 80+

Men ~<1% ~<2% ~6% ~14% ~16%

Women ~<1% ~<1% ~3% ~9% ~13%

BEACH study

The prevalence of atrial fibrillation is increasing in Australia

1998-99 NVAF managed at a rate of 0.6 per 100 encounters

2007-08 NVAF managed at a rate of 1.0 per 100 encounters

How common is atrial fibrillation?

Sturm, Davis, O’Sullivan, Vedadhaghi, Donnan. MJA 2002; 176: 312-316; Britt et al 2008 General practice series no. 23. Cat. no. GEP 23. AIHW

AF has a more powerful effect in younger stroke

patients

• Older AF patients have worse stroke outcomes.

• However……the relative effect of AF on outcomes appears

stronger in younger stroke patients (Pinteraction<0.0001).

• At 30-days, the relative risk of mortality due to AF (adjusting

for all other factors) was 3.16 amongst those younger than 50.

Age RR of mortality (95% CI)

18-49 3.16 (1.92-5.25)

50-64 1.71 (1.32-2.22)

65-74 1.39 (1.16-1.66)

75-84 1.29 (1.17-1.43)

85+ 1.23 (1.13-1.33)

The affect of AF on LOS and use of

rehabilitation is also greatest in younger

AF stroke patients (Vs non-AF patients

stroke patients)

Gattellari, Goumas, Aitken and Worthington accepted for publication Cerebrovascular diseases

Older AF patient with multiple co-

morbidities have worse stroke risk and

outcomes but AF has the greatest direct

effect on outcomes in younger patients

Stroke risk factors and risk of stroke

Wolf, Abbot, Kannel. Stroke 1991; 22: 983-988

Two year stroke incidence in by risk factor

Atrial fibrillation brings the highest stroke risk

Consensus derived risk factors

• History of stroke or TIA

• Older age

– 65 years or older/75 years or older (depending on risk scheme)

• Hypertension

– A history of hypertension or systolic blood pressure

greater than 160 mm Hg

• Diabetes Mellitus

• Congestive heart failure – History or presence

• Findings on echocardiography

– Abnormal left ventricular function

The risk of stroke in NVAF

Stroke Risk in Atrial Fibrillation Working Group, Stroke 2008; 39: 1901-1910.

CHADS2 score % Stroke Risk

1 year

Case 1: 70 year old AF patient 0 1.9

Case 2: 75 year old AF patient

+ Hypertension+CHF 3 5.9

Case 3: 75 year old AF patient +

hypertension+TIA 4 8.5

Case 4: 70 year old AF patient +

diabetes 1 2.8

Case 5: 85 year old AF patient +

hypertension+diabetes 3 5.9

CHADS2 score and risk of stroke

54% 60% 78% 33% 70% 68% 64%

Stroke Rate (% per person years)

Warfarin for NVAF Stroke Reduction in Randomised Trials

26% relative risk reduction

all-cause mortality

Hart, Pearce & Aguilar. 2007; Ann Internal Medicine; 146: 857-867

Relative Risk Reduction

45% 10% 10% 67% 23% 20% 100% 43% - 38%

Relative Risk Reduction

Warfarin vs aspirin for NVAF Stroke Reduction in Randomised Trials

9% relative risk reduction

all-cause mortality Stroke Rate

(% per person years)

Hart, Pearce & Aguilar. 2007; Ann Internal Medicine; 146: 857-867

Results: BAFTA study

Mant et al Lancet 2007; 370: 493-503

Major bleeding: BAFTA study

Warfarin Aspirin

Major bleeding risk (per year)

Intracranial or intracerebral haemorrhage 0.7% 0.5%

Major extracranial haemorrhage 1.4% 1.6%

Other hospital admission for haemorrhage 1.8% 1.5%

All major haemorrhages 1.9% 2.0%

Warfarin is as safe as aspirin in patients > 75 years

Mant et al Lancet 2007; 370: 493-503

An evidence-practice gap

There is a wide evidence practice gap in antithrombotic use for NVAF

despite 20 years of evidence from 29 high quality trials, a high

prevalence and serious outcomes

The National Institute of Clinical Studies (NHMRC) identified atrial fibrillation as a clinical

area where there are significant gaps between current management and “best practice”

evidence guidelines: “Every year, for every 1000 patients with atrial fibrillation who are

given anticoagulants, we can assume that about 25 fewer people will experience a stroke

and 12 fewer people will die from a stroke than would be the case if they were not given

them.”

Gladstone et al, Stroke 2009

• Only 40% of high risk NVAF patients presenting to Canadian stroke units

are taking warfarin for primary prevention

• Over 90% of NVAF related stroke patients were not appropriately anti-

coagulated on presentation

• Even in those at highest risk, determined by previous stroke or TIA, 43%

were not taking warfarin and 15% were on no antithrombotic

The effect of a sin of commission

– Drs are less likely to prescribe warfarin to any of their NVAF patients

after one of their NVAF patients on warfarin is admitted to hospital with

a major bleed

The effect of a sin of omission

– Following a stroke, in an NVAF patient not on warfarin, doctors are no

more likely to prescribe warfarin to other patients with AF

Choudhry et al BMJ, 2006; 332: 141-145.

Sins of commission and omission

Warfarin selection in four case scenarios

A survey of Australian GPs

Gattellari et al. Stroke 2008;39:227-230.

% o

f G

Ps s

ele

cting

wa

rfa

rin

as ‘m

ost

ap

pro

pri

ate

’

20

40

60

80

Case 1: Low-risk, 65 yrs

Case 2: High-risk, 65 yrs

Case 3: High-risk, 75 years

Case 4: High-risk, 75 yrs

Case scenarios

100

61.7

88.8

73.3 71.0

Percentage of Australian GPs selecting warfarin as most

appropriate

Case 4:High risk of stroke. 75 year old with a history of hypertension and

heart failure and a previous TIA with transient hemiparesis. CHADS 5 with

annual stroke risk of 12.5%. Should have warfarin

Four perceived risks modifying case 4

Case 4:High risk of stroke. 75 year old with a history of

hypertension and heart failure and a previous TIA

with marked right hemiparesis. Should have warfarin

Clinical features were added to assess the effect of perceived bleeding risks on warfarin selection

– Case 5: Two falls in the previous 12 months on rough ground without injury

– Case 6: Prior upper GI ulcerative bleed, now treated

– Case 7: Nosebleeds at least once every two months

– Case 8: Hypertensive ICH three years ago

Would they still prescribe warfarin 71% of the time?

Four perceived risks modifying Case 4

% o

f G

Ps s

ele

cting

wa

rfa

rin

a

s ‘m

ost a

ppro

pria

te’

20

40

60

80

Case 4: High-risk, 75 yrs

Case 5: Minor falls risk

Case 6: Prior GI ulcerative bleed,

now treated

Case 7: Recurrent nose

bleeds

Case scenarios

100

71.0

45.6

28.9

9.6

Case 8: Hypertensive ICH 3 years

ago

17.1

Percentage of Australian GPs Selecting warfarin as most

appropriate

Case 4:High risk of stroke. 75 year old with a history of hypertension and

heart failure and a previous TIA with transient hemiparesis. CHADS 5 with

annual stroke risk of 12.5%. Should have warfarin

Falls risk: not so risky

• The history two minor explicable falls, without injury, reduced warfarin

prescribing from 71% to 46%

• 1.8 falls per year is average for a patient with a history of falls

• High falls risk is not an important factor in the decision to anticoagulate.

• Patients with a ‘high falls’ risk are frailer, older and have a higher ischaemic

stroke risk with NVAF. There is higher haemorrhage risk but risk-benefit still

substantially favours warfarin use.

• You have to fall over more 295 times in one year to obviate the benefits of

warfarin in NVAF.

Gage et al, American Journal of Medicine, 2005: 118: 612-7; Man-Son-Hing et al; Archives of Internal Medicine;1999; 159: 677-865.

• A history of treated peptic ulcer bleeding reduced prescribing intention from 71% to 17%

• Upper GIT bleeding risk is manageable for continued use of aspirin and warfarin

• Following an upper GIT bleed on aspirin a process of brief aspirin cessation, endoscopy, proton pump inhibitor use and helicobacter eradication reduces re-bleeding to one in fifty

• Untreatable lower GIT bleeding can be a significant contraindication for all antithrombotics

Upper GIT bleeding is a modifiable bleeding risk

Chan et al. NEJM, 2005; 352: 238-44; Lai et al. Clinical Gastroenterology & Hepatology. 2006; 4: 860-5; McQuaid & Laine. American Journal of Medicine; 2006; 119: 624-38;

Caprie Steering Committee; Lancet 1996; 348: 1329-39.

Recurrent nose bleeds is a modifiable bleeding risk

• A perceived risk reducing indicated prescribing from

71% to 29%

• Nose bleeding is a preventable bleeding source with the

help of a ENT surgeon

Barriers to anticoagulation

• In an ‘ideal’ patient there is a high (88%) intention to use

anticoagulants

• Intention to prescribe falls significantly with a non-evidence based age

bias

• The impacts of sins of commission (ICH) Vs sins of commission do

not favour anticoagulation use

• Low rates of prescription can often be explained by commonly

perceived risks-which are not evidence based

Choudhry et al BMJ, 2006; 332: 141-145 and Gattellari et al. Stroke 2008;39:227-230.

Please view the

New Anticoagulants talk

What matters in stroke and TIA?

• Urgent treatment of TIA.

• Poor long-term outcomes after TIA.

• TIA, the ABCD2 score and stroke risk prediction.

• Stroke Units – essential features and outcomes.

• Bed-side practice.

• Stroke thrombolysis

• Primary prevention in non-valvular atrial fibrillation

In Australia, in 2012, there were 50,000 strokes and 420,000 stroke survivors. The cost

of stroke in that year was 5 billion dollars and the burden of disease cost is estimated at

49.3 billion. Deloitte/NSF

Authors and acknowledgements

Melina Gattellari, Chris Goumas, Robert Aitken, Frances Garden, B Jalaludin, Dominic Leung, N Zwar, Darshan Ghia, E Kehdi, Denis Cordato, Peter J Thomas, Daniel Epstein, M Mohsin (UK), Mark Longworth (ACI), Jeremy

Grimshaw (Canada), Andy Evans (UK) and the late Dr Ian Black.

Funding sources

NHMRC, BUPA Foundation (MBF), NSW Office of Health and Medical Research, UNSW and the Clinical Excellence Commission.

No conflicts of interests

No payments accepted from pharma post 2004.

Honorariums donated to charity at arms length.

In memoriam

Dr Tiziana Savio and Dr Ian Black

PRISM DESPATCH

STOP-STROKE OASIS

Thank you!