Assessment and management of TIA 2013. 12. 06 Andre Douen MD, PhD, FRCPC, FAHA Director West GTA Regional Stroke Program, Chief, Division of Neurology,

Assessment and management of TIA2013. 12. 06

Andre Douen MD, PhD, FRCPC, FAHADirector West GTA Regional Stroke Program,Chief, Division of Neurology,Trillium Health Partners MississaugaCMO, Innovate R&Dwww.educatehealth.ca

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

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 SPC

Johnston 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:o Smoking 1ppd x 30 yrso No HTN, No DM, No Cholesterol at her

last visit in Jan 2010

Douen

Case 1 Mrs W.S.• HPI

o Speaking with niece regarding a legal matter when..

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

incoordinated

• EMS o Symptoms resolved with 15 mino Patient declines transfer to ERo Elects to wait overnight and call fam doc

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

CaseExamination in office the next day:

BP = 160/90 ; HR 90 and regular. No neurological deficits, but with right carotid bruit

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

abscess)• Radiculopathies (focal numb/weak)• Neuropathies (focal (CTS, ulnar, radial) or 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

Douen

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-stroke

e) 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-stroke

e) 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.

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

0

5

20

15

10

7-daystroke risk

30-daystroke risk

3-monthstroke risk

Str

oke

pat

ien

ts (

%)

0

5

20

15

10

7-daystroke risk

30-daystroke risk

3-monthstroke risk

TIA

pat

ien

ts (

%)

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

The ABCD2 Score

Indicator Criteria Score

A Age 1 point for age 60 /1B Blood pressure 1 point for BP >140/90 mmHg /1

C Clinical features2 points for focal weakness or1 point for speech disturbance

/2

D Duration of symptoms1 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 /1

C Clinical features2 points for focal weakness or1 point for speech disturbance

/2

D Duration of symptoms1 point for duration 10-59 minutes2 points for duration >60 minutes

/2

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

1

1

2

1

0

5

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.

Risk of recurrent events during the 7 days after a TIA stratified by ABCD2 score

Chandratheva A et al. Stroke 2010;41:851-856Copyright © American Heart Association

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?

Douen

Douen

(Anticoagulation)

Antiplatelet

Pathophysiology: Multiple Mechanisms requiring urgent W/U

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


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)

Stroke Types and Incidence

Ischemic stroke 85-88%

Hemorrhagic stroke 12-15%Other

5%

Cryptogenic30%

Cardiogenicembolism

20%

Small vesseldisease

“lacunes” 25%

Atheroscleroticcerebrovascular

disease20%

Albers GW, et al. Chest 2004; 126 (3 Suppl): 438S–512SMcGrath et al. Stroke 2012; 43: 2048-2054.

Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.The content of this slide may contain information not reviewed by Health Canada.

2. 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

2. 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

Cardioemboli

• AF: High incidence of paroxysmal AF in acute stroke 13.5% detection of new onset AF using a

combination of serial ECG daily x 3 days plus Holter 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

EMBRACE

Prolonged Ambulatory Cardiac Monitoring Improves the Detection and Treatment of Atrial Fibrillation in Patients with Cryptogenic Stroke: Primary Results from the EMBRACE Multicenter Randomized Trial Gladstone DJ, International Stroke Conference, Honolulu, 2013

n=572 (age 73±9yrs;); recent ischemic cryptogenic stroke/TIA, no known AF; 16 stroke centers

Randomized to wear either an event-triggered cardiac monitor up to 30 days or a repeat 24 h Holter

New AF detected among 16% of 30-day monitoring group, vs. 3% in the Holter group (p<0.001)

Presented by: Gladstone DJ, International Stroke Conference, Honolulu, HI

30-day Holter0%

2%

4%

6%

8%

10%

12%

14%

16%

18%16%

3%

New AF

P<0.001

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


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

days

b. 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 weeks

e. All of the above

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

days

b. 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 weeks

e. All of the above

EXPRESSUrgent treatment of TIA and minor stroke

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

Timeliness of Care In Patients with TIA The OXVASC Study

Neurology 2005;65:371-5.

Neurology 2005;65:371-5.c

The Consequences of Delaying Access to CareThe OXVASC Study

Neurology 2005;65:371-5.

Stroke Patients

Neurology 2005;65:371-5.c

30.2

14.817.6

3.3

11.4

4

8.9

-2.9

-10

0

10

20

30

40 70-99% Stenosis

50-69% 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 the wrong decision ? ]

– Should I start Meds ?

– Maybe the ER might be a safe bet ?

Stroke / TIA

Medical

Risk factor management

Interventional

Revascularization

CEA vs Stent

Antiplatelet Anticoagulant

Antithrombotic

4. 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

4. 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

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

a. ASA

b. ASA/ER Dipyridamole

c. Clopidogrel

d. Clopidogrel + ASA

e. Warfarin

f. 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

a. ASA


c. Clopidogrel


e. Warfarin

f. Either b) or c)


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

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

a. ASA


c. Clopidogrel


e. Warfarin

f. Either b) or c)


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

a. ASA


c. Clopidogrel


e. Warfarin

f. Either b) or c)


Clopidogrel + Placebo (n=3,781)

Nu

mb

er (

n/%

) w

ith

eve

nt

MATCH: Bleeding Complications Increased Significantly

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

0.0

0.01

0.02

0.03

0.04

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

Major BleedingC

um

ula

tive

Ha

zard

Rat

es

Years

# at RiskC+A 3335 3172 2403 914OAC 3371 3212 2423 901

2.4 %/year

2.2 %/year

RR = 1.06

P = 0.67

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

a. ASA/ER Dipyridamole

b. Clopidogrel

c. Clopidogrel + ASA

d. Warfarin

e. Either a) or b)

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

a. ASA/ER Dipyridamole

b. Clopidogrel

c. Clopidogrel + ASA

d. Warfarin

e. Either a) or b)

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 ??

Stroke / TIA

Medical


Interventional

Revascularization

CEA vs Stent


Antithrombotic

Cardioemboli

• AF: o High incidence of paroxysmal AF in acute strokeo 13.5% detection of new onset AF using a

combination of serial ECG daily x 3 days plus Holtero 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

EMBRACE

Prolonged Ambulatory Cardiac Monitoring Improves the Detection and Treatment of Atrial Fibrillation in Patients with Cryptogenic Stroke: Primary Results from the EMBRACE Multicenter Randomized Trial Gladstone DJ, International Stroke Conference, Honolulu, 2013

n=572 (age 73±9yrs;); recent ischemic cryptogenic stroke/TIA, no known AF; 16 stroke centers

Randomized to wear either an event-triggered cardiac monitor up to 30 days or a repeat 24 h Holter

New AF detected among 16% of 30-day monitoring group, vs. 3% in the Holter group (p<0.001)

Presented by: Gladstone DJ, International Stroke Conference, Honolulu, HI

30-day Holter0%

2%

4%

6%

8%

10%

12%

14%

16%

18%16%

3%

New AF

P<0.001

AF increases the risk of stroke

• AF is associated with a pro-thrombotic stateo ~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.

Stroke Severity in Patients with AF

Gladstone DJ et al. Stroke. 2009; 40:235-240

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

of

pati

ents

Disabling(discharge mRS ≥ 2)

Fatal

60%

40%

0%

50%

30%

20%

10%

59.7%

20%

mRS=modified Rankin ScaleAF=atrial fibrillation

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

% b

edri

dden p

ati

ents

on a

dm

issi

on (

mR

s* =

5)

(P < 0.0005)

40

30

20

10

0

50

41.2%

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

Increased mortality after ischemic stroke in patients with AF persists for up to 8 years

•Population-based study of 3530 patients with ischaemic stroke•Marini C et al. Stroke 2005;36:1115–9

Patients with AF (n=869)

Patients without AF (n=2661)

Years after stroke

An

nu

al m

ort

alit

y ra

te (

%)

0

10

20

30

40

50

60 Mortality

1 2 3 4 5 6 7 8

AF associated with increased risk of recurrent stroke

Marini C et al. Stroke 2005;36:1115–9

Patients with AF

Patients without AF

Recurrent stroke after ischemic stroke

Months after first stroke

Cu

mu

lati

ve p

rob

abili

ty

of

recu

rren

ce (

%)

10

12

8

6

4

2

00 2 4 6 8 10

P=0.0398

Missed Opportunities for Stroke Prevention in AF:Registry of the Canadian Stroke Network 2003-2007

Gladstone Stroke 2009;40:235

No antithrombotics Dual antiplatelets Single antiplatelet Warfarin: therapeutic Warfarin: sub-therapeutic

Preadmission medications in patients with known AF admitted with acute

ischemic stroke (high-risk cohort, n=597)

Preadmission medications in patients with known AF and a previous ischemic

stroke/TIA admitted with acute ischemic stroke

(very high-risk cohort, n=323)

Need for greater efforts to prescribe and monitor appropriate antithrombotic therapy to prevent stroke in patients with AF

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. OAC (e.g. warfarin) is not beneficial for the elderly

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. OAC (e.g. warfarin) is not beneficial for the elderly

True

False

AF prevalence increases with age

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

AF

pre

va

len

ce

(%)

General population

>60 years >80 years

9

8

7

6

5

4

3

2

1

0

10. Patients with AF who has spontaneous intracranial hemorrhage while using OAC should never be placed back on OAC

True

False

10. Patients with AF who have spontaneous intracranial hemorrhage while using OAC should never be placed back on OAC True False

Cause of bleed needs to be assessed: Elevated INR Concomitant use of antiplatelet agent Overdose of NOAC CrCl Drug abuse H/o trauma/fall HGB, plts etc Risk benefit ratio

CHADS 2

CHADS2 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

year

0 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)

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)

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

a. Warfarin

b. Dabigatran (Pradax)

c. Rivaroxaban (Xaralto)

d. Apixaban (Eliquis)

e. Clopidogrel + ASA

f. ASA/ER Dipyridamole

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

a. Warfarin

b. Dabigatran (Pradax)

c. Rivaroxaban (Xarelto)

d. Apixaban (Eliquis)


f. ASA/ER Dipyridamole

1. Haas S. J Thromb Thrombolysis. 2008;25:52-60.2. Adapted from Ezekowitz MD et al. Mayo Clin Proc. 2004;79:904-913.

Narrow efficacy window + multiple interactions

Challenges of Oral Anticoagulation Therapy (OAC)

hard to use/take1=

ISCHEMIC STROKE INTRACRANIAL BLEED

Od

ds

Rat

io

05.0 6.0 8.0

INR

1.0 2.0 3.0 4.0 7.0

5.0

15.0

10.0

1.0

20.0

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 e

ligib

le p

ati

en

ts

rec

eiv

ing

wa

rfa

rin

Clinical trial1

Clinical practice2

*INR = International normalized ratio

12. Despite the challenges of using warfarin, the lack of antidote for the NOAC makes them less valuable than warfarin in cardioembolic prophylaxis in acute stroke

True

False


True

False

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)

• 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

Prevention of Stroke

Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 mg BID


HR (95% CI)Warfarin betterComparator better

Rivaroxaban 20 mg QD

Apixaban 5 mg BID

Stroke or Systemic Embolism

Ischemic StrokeDabigatran 110 mg BID



Apixaban 5 mg BID

Superiorityp-value

0.29<0.001 0.12 0.01

0.350.03 0.59

0.42

0.90

0.65

1.11

0.76

0.88

0.79

0.94

0.92

Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

Reducing the Bleeding Risk

HR (95% CI)Warfarin betterComparator better

0.50 0.75 1.00 1.250.25




Apixaban 5 mg BID

Intracranial Hemorrhage

ISTH Major BleedingDabigatran 110 mg BID



Apixaban 5 mg BID

Superiorityp-value

<0.001

<0.001

0.02 <0.001

0.0030.31 0.58

<0.001


0.80

0.93

0.30

0.41

0.67

0.42

1.04

0.69


AF Trials: Elements of Primary Endpoint:*Annual Event Rates

0.92

1.210.97 1.05

1.401.52

0.10

0.38

0.240.47

0.260.44

0.15

0.10

0.09

0.100.04

0.19

0

0.5

1

1.5

2

2.5

3Systemic EmbolismHemorrhagic StrokeIschemic/Unspecified Stroke

Dabi 150 mg Warfarin Apixaban Warfarin Rivaroxaban Warfarin

RELY ARISTOTLE ROCKET AF

%/y

ear


In recent trials, the majority of AF strokes were ischemic


†

*Patients experiencing multiple endpoints are included in multiple categories.†Systemic embolism result reported for RELY refers to pulmonary embolism.

CCS 2012 Update to AF Guidelines

When oral anticoagulant therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban, in

preference to warfarin

• Dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention

• Dabigatran and rivaroxaban have no more major bleeding and apixaban has less

• All three new oral anticoagulants have less intracranial hemorrhage and are much simpler to use

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

Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage

Despite Anticoagulant Reversal

Dowlatshahi D, et al. Stroke 2012. DOI: 10.1161/STROKEAHA.112.652065

Hematoma Growth

Significant hematoma growth despite INR correction with PCC.

This patient was treated with 1000 U of PCC and 10 mg vitamin K 98 minutes after baseline CT scan.

Repeat INR was 1.3, 42 minutes after PCC treatment and 1.2 the next day.

INR = international normalized ratio;

PCC = prothrombin complex concentrate

Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

Poor Outcomes

Intracranial hemorrhage type Number In-hospital mortality*

Discharge mRS(Median IQR)†

Intraparenchymal 71 30 (42.3%) 5 (3)‡

Subdural 61 21 (34.4%) 3 (4)§

Epidural 1 0 3

Subarachnoid 8 1 (12.5%) 3 (3)

ICH = intracranial hemorrhage; mRS = modified Rankin Scale; IQR = interquartile range

*P = 0.3; †P=0.012; ‡mRS missing in 9; §mRS missing in 2

Outcome by anticoagulant-associated ICH


30 Day Mortality Associated with Intracranial vs Extracranial Bleeds

• Data from The AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study- a cohort of 13,559 adults with diagnosed nonvalvular atrial fibrillation who received care within Kaiser Permanente of Northern California, a large integrated

• health care delivery system. Risk of death 30 days after hospitalization for warfarin-associated intracranial hemorrhage versus major extracranial hemorrhage; 95% confidence intervals (CIs) (vertical bars). P value refers to the chi-square comparison of mortality rate of intracranial versus extracranial hemorrhage.

Fang et al, The American Journal of Medicine (2007) 120, 700-705

Intracranial Extracranial0

20

40

60

80

100

48.6

5.1

IntracranialExtracranial

Mo

rta

lity

at 3

0 d

ays

(%

)

P<0.001

• Prothrombin complex concentrates (PCC) therapy rapidly corrected INR in the majority of patients with anticoagulant-associated ICH, yet mortality and morbidity rates remained high

• Outcomes after anticoagulant-associated ICH can be devastating even with a reversal strategy

Conclusion



True

False

Stroke / TIA

Medical


Interventional

Revascularization

CEA vs Stent


Antithrombotic

ASA naive patients vs those previously on ASA

a. ASA


c. Clopidogrel

________________________

d. Warfarin


Antiplatelet choices – Summary Non-cardioembolic stroke

Stroke / TIA

Medical


Interventional

Revascularization

CEA vs Stent


Antithrombotic

For patient with cardioembolic (AF) stroke/TIA

a. Warfarinb. Dabigatran (Pradax)c. Rivaroxaban (Xarelto)d. Apixaban (Eliquis)_______________________e. Clopidogrel + ASAf. ASA

Assessment and management of TIA 2013. 12. 06 Andre Douen MD, PhD, FRCPC, FAHA Director West GTA Regional Stroke Program, Chief, Division of Neurology,

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