Andre Douen MD , PhD, FRCPC, FAHA Director West GTA Regional Stroke Program,

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Andre Douen MD, PhD, FRCPC, FAHADirector West GTA Regional Stroke Program,Chief, Division of Neurology,Trillium Health Centre, Mississauga

2012. 12. 07

Disclosures: Ad Board: BI, Sanofi-Aventis, BMS, BayerSpeaker: BI, BMS

The Big Deal About Mini-Strokes: Treating TIA

So…what is the big deal ? Or

Should there be a big deal ?

www.educatehealth.ca


Transient ischemic attack• A forthcoming stroke is often announced by a

transient ischemic attack (TIA)• Like ischemic strokes, TIAs are caused by

vessel occlusion or reduction of blood flow• The symptoms are the same as stroke

symptoms, and may include: Impaired vision, speech disruption, weakness and numbness

• TIAs are brief due to early revascularization/reperfusion

Johnston et al. National Stroke Association. Ann Neurol 2006; 60: 301–13.


The work-up and management is similar to a stroke

• Etiology not different from definite stroke• Clinically < 24-hour duration, but....• New MRI lesions seen in up to 80% of patients

with clinical course of TIA• Frequently followed by more severe stroke• TIA and stroke have a similar risk for early

recurrent stroke, ~ up to 14% within the first 2 weeks

• Opportunities for prevention – Rapid W/U in SPCJohnston et al. JAMA 2000; 284: 2901–2906.

Warach, Kidwell. Neurology 2004; 62: 359–360.Mohr. Neurology 2004; 62 (8 Suppl 6): S3–S6.

Case 1 Mrs W.S., LLM

• 62 y/o obese lawyer with GERD • PMH:

– Smoking 1ppd x 30 yrs– No HTN, No DM, No Cholesterol at her last

visit in Jan 2010

Douen www.educatehealth.ca

Case 1 Mrs W.S.• HPI

Speaking with niece regarding a legal matter when..

Slurred speech Loss of speech Right facial droop, Right arm weak and

incoordinated

• EMS – Symptoms resolved with 15 min– Patient declines transfer to ER– Elects to way overnight and call fam doc in

AM for a quick visit and head to office after to prepare for prosecuting a medico-legal case


CaseExamination in office the next day:

BP = 160/90 ; HR 90 and regular. No neurological deficits, but with right carotid Bruits.Current Meds: Losec, Tylenol prn for back pain

Next steps:– DDX ? [Is this a TIA, if not what could it be ?]– If TIA, what’s her risk of recurrent stroke ? – Is there a tool that can help assess this ? – What investigations is needed now ?– What should I do...panic ? [Will I get sued if I make

the wrong decision ? ]– Should I start Meds ?– Maybe the ER might be a safe bet ?


Stroke Mimics• Migraine (aura)• Vertigo • Syncope (vaso-vagal, cardiogenic, metabolic)• Seizure (simple, CPSz, grand mal with “Todd’s”)• Structural brain lesions (tumors, AVM, subdurals,

abscess)• Carpal tunnel (focal numbness)• Radiculopathies (focal numb/weak)• Neuropathies (more diffuse numb +/- weak)• Dementia (confusion)• Neuroses• Stress/Anxiety• Malingering


Case 1 Mrs W.S.• Needs to get back to office ASAP• Thinks this “TIA” thing is non-sense, as she

feels she was a bit stressed over the case and that caused her symptoms

• Not keen on extensive investigations for such a minor episode

• She might comply if she can schedule these in between her practice over the next 2 months

• If it was a “TIA” (she is skeptical) then she wants to estimate her risk of recurrence



1. What do you think her stroke risk might be within the next month:a. ~ 2%b. ~ 8%c. ~ 20%d. She’ll almost certainly re-strokee. Her risk can only be measured over 3 months


1. What do you think her stroke risk might be with in the next month:a. ~ 2%b. ~ 8%c. ~ 20%d. She’ll almost certainly re-strokee. Her risk can only be measured over 3 months


Stroke Recurrence • Antecedent stroke/TIA is the most

significant indicator of a possible recurrent stroke

• High incidence of early recurrent stroke following either TIA or minor stroke

• Early recognition and treatment significantly reduces the risk of stroke recurrence

Johnston et al. JAMA 2000; 284: 2901–2906.Warach, Kidwell. Neurology 2004; 62: 359–360.

Mohr. Neurology 2004; 62 (8 Suppl 6): S3–S6.


0

5

20

15

10

7-daystroke risk

30-daystroke risk

3-monthstroke risk

Stro

ke p

atie

nts

(%)

0

5

20

15

10

7-daystroke risk

30-daystroke risk

3-monthstroke risk

TIA

patie

nts

(%)

Stroke patients: risk of recurrent event TIA patients: risk of recurrent event

Coull et al. BMJ 2004; 328: 326.

11.5

15.0

18.5

8.0

11.5

17.3

Nearly 1 in 5 stroke/TIA patients is at risk of a recurrent event within 3 months

The ABCD2 Score

Indicator Criteria Score

A Age 1 point for age 60 /1B Blood pressure 1 point for BP >140/90 mmHg /1C Clinical features 2 points for focal weakness or

1 point for speech disturbance /2

D Duration of symptoms 1 point for duration 10-59 minutes2 points for duration >60 minutes

/2

D Diabetes 1 point for presence of diabetes /1 Total Score /7


The ABCD2 Score

Indicator Criteria Score

A Age 1 point for age 60 /1B Blood pressure 1 point for BP >140/90 mmHg /1C Clinical features 2 points for focal weakness or

1 point for speech disturbance /2

D Duration of symptoms 1 point for duration 10-59 minutes2 points for duration >60 minutes

/2

D Diabetes 1 point for presence of diabetes /1 Total Score /7

112

1

05


Risk Factors for Stroke Within 90 Days of a TIAThe ABCD2 Score

0

5

10

15

20

25

0 1 2 3 4 5 6 7

2 Days7 Days30 Days90 Days

StrokeRisk(%)

ABCD2 Score

LowRisk

HighRisk

IntermediateRisk

Lancet 2007;369:283-92.


Case 1 Mrs W.S.• After reviewing ABCD2 and showing her

these charts, she is now more agreeable to comply with investigations

• She wants to know, how do stroke and TIA occur, and also what investigations she would need

• She also wants to know about how soon she can have the studies completed

• She will reluctantly cancel appointments to attend these investigations

• What can she take to prevent this from recurring?



(Anticoagulation)

Antiplatelet

Pathophysiology: Multiple Mechanisms requiring urgent W/U

Douen

Case

Next steps:– DDX ? [Is this a TIA, if not what could it be ?]– If TIA, what’s her risk of recurrent stroke ? – Is there a tool that can help assess this ? – What investigations are needed now ? How soon ?– What should I do...panic ? [Will I get sued if I make the

wrong decision ? ]– Should I start Meds ?– Maybe the ER might be a safe bet ?


What investigations would you consider for this patient (why, when)?

ECHO (TEE,TTE) Routine labs Carotid doppler CT scan ECG, Echo (TTE/TEE) Holter Angiogram (CTA / MRA)


4. What priority would you give these investigations?


a) ECG > ECHO> Telemetry/Holter>Carotid Doppler>CT

b) CT>Telemetry/Holter>ECHO>Carotid Doppler> ECG

c) ECHO > Holter > CT>Carotid Doppler > ECG

d) CT> Carotid Doppler = ECG > Holter > ECHO e) CT = ECG = Carotid Doppler > Holter > ECHO

CaseNext steps:

– DDX ? [Is this a TIA, if not what could it be ?]– If TIA, what’s her risk of recurrent stroke ? – Is there a tool that can help assess this ? – What investigations are needed now ? How soon ?– What should I do...panic ? [Will I get sued if I make




3. Which of the following statements about the management of patients with TIA or minor stroke are correct:a. If possible work-up should be completed within 2-3

daysb. Early treatment and intervention could reduce stroke

recurrence by 80%c. Early management through a stroke clinic is likely

superior to routine out patient management.d. For those with ipsilateral severe stenosis

revascularization is recommended within 2 weekse. All of the above


Outcome Phase 1 Phase 2 Time to clinic visit - 3 days ( 2 -5) 1 day (0-3) Time to prescription- *20 days (8 -53) 1 day (0-3) 90 day risk of stroke- ~10.3% 2.1%**

*No prescriptions given. Patients advised to see family MD

**80% reduction in risk of recurrent stroke

EXPRESSUrgent treatment of TIA and minor stroke


Timeliness of Care In Patients with TIA The OXVASC Study

Neurology 2005;65:371-5.


The Consequences of Delaying Access to CareThe OXVASC Study

Neurology 2005;65:371-5.

Stroke Patients

30.2

14.817.6

3.3

11.4

48.9

-2.9

-10

0

10

20

30

40 70-99% Stenosis50-69% Stenosis

0-2 4-122-4 >12

Time From Event to Randomization (weeks)

5 Year ARRIn Stroke

(%)

Timing of Surgical InterventionThe NASCET and ECST Studies

Lancet 2004;363:915-24.


CaseNext steps :

– DDX ? [Is this a TIA, if not what could it be ?]– If TIA, what’s her risk of recurrent stroke ? – Is there a tool that can help assess this ? – What investigations are needed now ? How soon ?– What should I do...panic ? [Will I get sued if I make




2. Following and ischemic stroke it is best to wait 3 - 4 days before initiating antiplatelet therapy because of increased risk of bleeding.

a. True b. False

Stroke / TIA

Medical

Risk factor management

Interventional

RevascularizationCEA vs Stent

Antiplatelet Anticoagulant

Antithrombotic


5. In an ASA naive patient which of the following Antitrhombotic agents is recommended for secondary prevention of Non- Cardioembolic stroke

a. ASAb. ASA/ER Dipyridamolec. Clopidogreld. Clopidogrel + ASAe. Warfarinf. Either b) or c) g. Any of a) , b) or c)


5. In an ASA naive patient which of the following Antitrhombotic agents is recommended for secondary prevention of Non-Cardioembolic stroke




ASA vs. Placebo: Efficacy by Dose*

ASA Dose Relative Risk of Vascular Events**

1,000 – 1,300 mg/d

300 mg/d

50 – 75 mg/d

Overall

0.8†

ASA better Placebo better

* A meta-analysis of 10 controlled trials comparing acetylsalicylic acid (ASA) with placebo. ** Vascular events comprise stroke, MI, or vascular death.† Signifies a 20% relative risk reduction

Prevention of Vascular Events in Stroke/TIA Patients with ASA Following First Stroke

Adapted from Albers GW et al. Neurology. 1999; 53(suppl 4): S25-S38.

6. For patients already on ASA which of the following Antitrhombotic agents is recommended for secondary prevention of Non-Cardioembolic stroke



6. For patients already on ASA which of the following Antitrhombotic agents is recommended for secondary prevention of non- cardioembolic stroke




Clopidogrel + Placebo (n=3,781)

Num

ber (

n/%

) with

eve

nt

Life-threateningbleeding

0

20

40

60

80

100

Majorbleeding

Minorbleeding

Clopidogrel + ASA (n=3,759)

96 (3%)

49 (1%)

73 (2%)

22 (1%)

120 (3%)

39 (1%)

120

Diener et al. Lancet 2004; 364: 331–337.

p<0·0001

p<0·0001

p<0·0001

MATCH: Bleeding Complications Increased Significantly


0.0

0.01

0.02

0.03

0.04

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

Major BleedingC

umul

ativ

e H

azar

d R

ates

Years

# at Risk

C+A 3335 3172 2403 914OAC 3371 3212 2423 901

2.4 %/year

2.2 %/year

RR = 1.06P = 0.67

7. For patients already on Plavix which of the following Antitrhombotic agents is recommended for secondary prevention of Non-Cardioembolic stroke

a. ASA/ER Dipyridamoleb. Clopidogrelc. Clopidogrel + ASAd. Warfarine. Either a) or b)


8. In terms of the efficacy for non-cardioembolic prophylaxis which of the following are true:

a) ASA/ER Dipyridamole > ASA > warfarinb) Clopidogrel >ASA > warfarinc) Warfarin > Clopidogrel = ASA/ER Dipyridamoled) Warfarin = ASAe) Clopidogrel = ASA/ER Dipyridamolef) D) and e) correct


8. In terms of the efficacy for non-cardioembolic prophylaxis which of the following are true:

a) ASA/ER Dipyridamole > ASA > warfarinb) Clopidogrel >ASA > warfarinc) Warfarin > Clopidogrel = ASA/ER Dipyridamoled) Warfarin = ASAe) Clopidogrel = ASA/ER Dipyridamolef) d) and e) correct


Secondary prevention- Which Antiplatelet ?

• Physician’s choice• Compliance• Cost


Case

CT brain: Nil acute.

ECG: AF with HR of 95

Is a Doppler still required ??

Meds: …. ???

what is incidence of AF in acute stroke ??


Case

CT brain: Nil acute.

ECG: AF with HR of 95

Is a Doppler still required ?? YES

Meds: …. ???

what is incidence of AF in acute stroke ??


Cardioemboli

• AF: – High incidence of paroxysmal AF in acute stroke– 13.5% detection of new onset AF– Overall ~20 % of acute stroke patient with AF.

(Douen et al, Stroke 2008)

• Up to 3 million people worldwide suffer strokes related to AF each year1-3

1. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf

2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 2. 1991:22(8);983-8

3. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996;27:1760-4


http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf


AF increases the risk of stroke• AF is associated with a pro-thrombotic state

– ~5- 17 fold increase in stroke risk

• Risk of stroke is the same in patients with chronic of PAF2,3

• There is a high 30-day mortality (~25%) following cardioembolic stroke4

• AF-related stroke has a 1-year mortality of ~50%5

1. Wolf PA, et al. Stroke 1991;22:983-988; 2. Rosamond W et al. Circulation. 2008;117:e25–146; 3.Hart RG, et al. J Am Coll Cardiol 2000;35:183-187; 4. Lin H-J, et al. Stroke 1996; 27:1760-1764; 5. Marini C, et al. Stroke 2005;36:1115-1119.


Effect of first ischemic stroke in patients with AF (n=597)%

of p

atie

nts

Disabling(discharge mRS ≥ 2)

Fatal

60%

40%

0%

50%

30%

20%

10%

59.7%

20%

Stroke Severity in Patients with AF

mRS=modified Rankin ScaleAF=atrial fibrillationGladstone DJ et al. Stroke. 2009; 40:235-240


% b

edrid

den

patie

nts

on a

dmiss

ion

(mRs

* = 5

)

(P < 0.0005)

40

30

20

10

0

5041.2%

23.7%

With AF Without AF

Dulli DA, et al. Neuroepidemiology. 2003;22:118-123.

Odds ratio for bedridden state following stroke due to AF was 2.23 (95% CI, 1.87-2.59; P < 0.0005)

*mRS=modified Rankin ScaleAF=atrial fibrillation

Ischemic Stroke Associated With AF is Typically More Severe Than Stroke due to Other Etiologies


CHADS 2CHADS2 Score* Stroke rate

0 1.9 (1.2 -3.0)

1 2.8 (2.0-3.8)

2 4.0 (3.1-5.1)

3 5.9 (4.6-7.3)

4 8.5 (6.3 -11.1)

5 12.5 (8.2-17.5)

6 18.2 (10.5-17.4)

*Score 0: Patients can be administered aspirin*Score 1: Patients can be on aspirin and anticoagulant therapy*Score ≥2: Patients should be on anticoagulant therapy

• 1 point for Congestive Heart Failure

• 1 point for Hypertension

• 1 point for Age ≥ 75 years• 1 point for Diabetes Mellitus • 2 points for Prior Stroke or

TIA

CHA2DS2-VASc Score• 1 point for Congestive Heart

Failure/LV Dysfunction

• 1 point for Hypertension

• 2 points for Age ≥ 75 years

• 1 point for Diabetes Mellitus

• 2 points for Prior Stroke or TIA1 or TE2

• 1 point for Vascular Disease3

• 1 point for Age 65-74 years

• 1 point for Sex category (female gender)

CHA2DS2-VASc Score*

One year event rate (95% CI) of hospital admission and death due to thromboembolism† per 100 person

year0 0.78 (0.78 – 1.04)1 2.01 (1.70 – 2.36)2 3.71 (3.36 – 4.09)3 5.92 (5.53 – 6.34)4 9.27 (8.71 – 9.86)5 15.26 (14.35 – 16.24)6 19.74 (18.21 – 21.41)7 21.5 (18.75 – 24.64)8 22.38 (16.29 – 30.76)

9 23.64 (10.62 – 52.61)*Score 0: Patients can be administered aspirin*Score 1: Patients can be administered aspirin or anticoagulant therapy*Score ≥2: Patients should be administered anticoagulant therapy†Includes peripheral artery embolism, ischemic stroke, and pulmonary embolism

1TIA = Transient ischemic attack; 2TE = Thromboembolism3Prior myocardial infarction, peripheral artery disease, aortic plaque1. Lip GY et al. Chest 2010;137:263-272

2. Olesen JB, et al. BMJ 2011;342:d1243. Task Force or the Management of Atrial Fibrillation of the ESC.

Eur Heart J 2010;31:236902429

CHA2DS2-Vasc score Mrs W.S. = 4 (hypertension, age 65-74 yr, female)

CHA2DS2-VAScScore

One year event rate (95% Cl) of hospital admission and death due to thromboembolism† per 100 person

year

CCS 2012 Update to AF Guidelines

CHADS2 = 0

*Aspirin is a reasonable alternative in some as indicated by risk/benefit

CHADS2 = 1 CHADS2 ≥ 2

No anti-thrombotic

Assess Thromboembolic Risk (CHADS2)

No additional

risk factors for stroke

Increasing stroke risk

ASA OAC* OAC* OAC*

Either female sex or vascular

disease

Age ≥ 65 yrs or combination

of female sex and vascular

disease

*OAC = Oral anticoagulant ASA = Aspirin

Consider stroke risk vs. bleeding risk

Only when the stroke risk is low and bleeding risk is high does the risk/benefit ratio favor no antithrombotic therapy

1. Skanes AC, et al. Can J Cardiol 2012;28:125-136.


Case - Paul

Mrs W.S. Risk: 62-year-old - < 75 : 0HTN : 1No h/o CHF : 0No DM : 0TIA symptoms : 2

CHADS Risk = 3

CHADS-VASC Risk = 4 (HTN, F, Stroke symptoms)


Stroke / TIA

Medical


Interventional



Antithrombotic


9. The patients who benefit the most from warfarin therapy are those with AF in the age group 65-75 and with no other medical issues.– True– False


9. The patients who benefit the most from warfarin therapy are those with AF in the age group 65-75 and with no other medical issues– True– False


10. Recent studies have shown that ASA+Plavix is equally efficacious to warfarin for cardio-embolic stroke prophylaxis in patients with AF– True– False


11. Patients with AF who has spontaneous intracranial hemorrhage while using OAC should never be placed back on OAC– Ture– False


11. Patients with AF who has spontaneous intracranial

hemorrhage while using OAC should never be placed back on OAC– Ture– False


12. For patient with cardioembolic (AF) stroke/TIA which of the following Antitrhombotic Agents is recommended for secondary prevention

a. Warfarinb. Dabigatran (Pradax)c. Rivaroxaban (Xaralto)e. Apixaban (Eliqus)f. Clopidogrel + ASAg. ASA/ER Dipyridamole


13. Because older patients (> 80 yrs old) with AF are generally at high risk of falls and spontaneous bleeding and so should not in general be treated with OAC– True – False


AF prevalence increases with age

1. Go AS, et al. JAMA 2001;285:2370-2375.

Age

AF

prev

alen

ce (%

)

General population

>60 years >80 years

9

8

7

6

5

4

3

2

1

0

INR control: clinical trials v. clinical practice

INR* control in clinical trial versus clinical practice (TTR**)

1. Kalra L, et al. BMJ 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials; 2. Matchar DB, et al. Am J Med 2002; 113:42-51.

** TTR = Time in Therapeutic Range (INR2.0-3.0)

66%

44%

9%

18%

38%

25%

<2.0 2.0 – 3.0 >3.0 INR

% o

f elig

ible

pat

ient

s re

ceiv

ing

war

farin

Clinical trial1

Clinical practice2

*INR = International normalized ratio

New OAC• Dabigatran Etexilate (Direct Thrombin Inhibitor) in Atrial Fibrillation (RE-LY)

• Rivaroxaban (Factor Xa inhibitor)in Atrial Fibrillation (ROCKET-AF)

• Apixaban (Factor Xa inhibitor)in Atrial Fibrillation (AVERROES; ARISTOTLE)

Pros : No MonitoringRapid onset of actionSimilar or better bleeding profile to warfarin

Con : No antidote, no clear way of measuring effect


Recent Oral Anticoagulation Trials:Stroke or Systemic Embolism

The new oral anticoagulant agents are consistently associated with a numerically lower risk for stroke or systemic embolism compared to warfarin†

Data obtained from intention-to-treat analysis†Not intended as cross-trial comparison

1. Connoly SJ, et al. N Engl J Med 2009;361:1139-1151.2. Patel MR, et al. N Engl J Med 2011;365:883-891.3. Granger C, et al. N Engl J Med 2011;365:981-992


Recent Oral Anticoagulation Trials:Hemorrhagic Stroke

The new oral anticoagulants are consistently associated with a numerically lower risk of hemorrhagic stroke compared with warfarin†




Recent Oral Anticoagulation Trials:Major Bleeding

HR (95% CI)New Agent Better Warfarin Better




Stroke / TIA

Medical


Interventional



Antithrombotic


ASA naive patients vs those previously on ASA

a. ASAb. ASA/ER Dipyridamolec. Clopidogrel________________________d. Warfarin e. Clopidogrel + ASA

Antiplatelet choices – Summary Non-cardioembolic stroke


Stroke / TIA

Medical


Interventional



Antithrombotic


For patient with cardioembolic (AF) stroke/TIA

a. Dabigatran (Pradax)b. Apixaban (Eliqus)c. Rivaroxaban (Xaralto)d. Warfarin_______________________e. Clopidogrel + ASAf. ASA



Recommendations - Antithrombotic We recommend that patients at very low risk of stroke

(CHADS2 = 0) should receive aspirin (75-325 mg/day). (Strong recommendation, High Quality Evidence). We suggest that some young persons with no standard risk factors for stroke may not require ay antithrombotic therapy. (Conditional recommendation, Moderate Quality Evidence).


Recommendations - Antithrombotic We recommend that patients at low risk of stroke

(CHADS2 = 1) should receive OAC therapy (either warfarin [INR 2 – 3] or dabigatran). (Strong recommendation, High Quality Evidence). We suggest, based on individual risk/benefit considerations, that aspirin is a reasonable alternative for some. (Conditional recommendation, Moderate Quality Evidence).

We recommend that patients at moderate risk of stroke (CHADS2 ≥ 2) should receive OAC therapy (either warfarin [INR 2 – 3] or dabigatran). (Strong recommendation, High Quality Evidence)


Recommendations - Antithrombotic We suggest, that when OAC therapy is indicated, most

patients should receive dabigatran in preference to warfarin. In general, the dose of dabigatran 150 mg po bid is preferable to a dose of 110 mg po (exceptions discussed in text). (Conditional recommendation. High Quality Evidence).

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Andre Douen MD , PhD, FRCPC, FAHA Director West GTA Regional Stroke Program,

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