Transcript HSFO clinical update workshop

Assessment and management of TIA
2013. 12. 06
Andre Douen MD, PhD, FRCPC, FAHA
Director West GTA Regional Stroke Program,
Chief, Division of Neurology,
Trillium Health Partners Mississauga
CMO, Innovate R&D
www.educatehealth.ca
Disclosures:
Ad Board: BI, Sanofi-Aventis,
Pfizer, BMS, Bayer
Speaker: 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 yrs
o 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 speech
o Right facial droop, Right arm weak and
incoordinated
• EMS
o
o
o
Symptoms resolved with 15 min
Patient declines transfer to ER
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
Case
Examination 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)
b)
c)
d)
e)
~ 2%
~ 8%
~ 20%
She’ll almost certainly re-stroke
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)
b)
c)
d)
e)
~ 2%
~ 8%
~ 20%
She’ll almost certainly re-stroke
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.
Stroke patients: risk of recurrent event
18.5
20
17.3
15.0
15
11.5
10
5
0
7-day
30-day
3-month
stroke risk stroke risk stroke risk
TIA patients (%)
Stroke patients (%)
20
TIA patients: risk of recurrent event
15
11.5
10
8.0
5
0
7-day
stroke risk
30-day
stroke risk
3-month
stroke risk
Coull et al. BMJ 2004; 328: 326.
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
B Blood pressure
1 point for BP >140/90 mmHg
C Clinical features
2 points for focal weakness or
1 point for speech disturbance
/2
D Duration of symptoms
1 point for duration 10-59 minutes
2 points for duration >60 minutes
/2
D Diabetes
1 point for presence of diabetes
Total Score
/1
/1
/1
/7
The ABCD2 Score
Indicator
Criteria
Score
A Age
1 point for age 60
1 /1
B Blood pressure
1 point for BP >140/90 mmHg
1 /1
C Clinical features
2 points for focal weakness or
1 point for speech disturbance
2 /2
D Duration of symptoms
1 point for duration 10-59 minutes
2 points for duration >60 minutes
1 /2
D Diabetes
1 point for presence of diabetes
0 /1
Total Score
5 /7
Risk Factors for Stroke Within 90 Days of a TIA
The ABCD2 Score
High
Risk
25
20
2 Days
7 Days
30 Days
90 Days
Intermediate
Risk
Stroke 15
Risk
(%)
10
Low
Risk
5
0
0
1
2
3
4
5
ABCD2 Score
6
7
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;41:851-856
Copyright © 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
Pathophysiology:
Multiple Mechanisms
requiring urgent W/U
Antiplatelet
(Anticoagulation)
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)
Stroke Types and Incidence
Hemorrhagic stroke
12-15%
Other
5%
Cryptogenic
30%
Cardiogenic
embolism
20%
Atherosclerotic
cerebrovascular
disease
20%
Small vessel
disease
“lacunes”
25%
Ischemic stroke
85-88%
Albers GW, et al. Chest 2004; 126 (3 Suppl): 438S–512S
McGrath 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
EMBRACE
18%
16%
16%
P<0.001
14%
12%
10%
Gladstone DJ, International Stroke Conference, Honolulu, 2013
8%
6%
4%
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
3%
2%
0%
30-day
Holter
New AF
 n=572 (age 73±9yrs;); recent ischemic
cryptogenic stroke/TIA, no known AF; 16
stroke centers
 Randomized to wear either an eventtriggered 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
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 ?
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
EXPRESS
Urgent 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%
*No prescriptions given. Patients advised to see family MD
** 80% reduction in risk of recurrent stroke
2.1%**
Timeliness of Care In Patients with TIA
The OXVASC Study
Neurology 2005;65:371-5.c
Neurology 2005;65:371-5.
The Consequences of Delaying Access to Care
The OXVASC Study
Stroke
Patients
Neurology 2005;65:371-5.c
Neurology 2005;65:371-5.
Timing of Surgical Intervention
The NASCET and ECST Studies
5 Year ARR
In Stroke
(%)
40
30
70-99% Stenosis
50-69% Stenosis
30.2
20
17.6
14.8
11.4
10
4
3.3
0
0-2
2-4
8.9
4-12
>12 -2.9
-10
Time From Event to Randomization (weeks)
Lancet 2004;363:915-24.
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 ?
Stroke / TIA
Interventional
Medical
Revascularization
CEA vs Stent
Risk factor
management
Antithrombotic
Antiplatelet
Anticoagulant
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.
b.
c.
d.
e.
f.
g.
ASA
ASA/ER Dipyridamole
Clopidogrel
Clopidogrel + ASA
Warfarin
Either b) or c)
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.
b.
c.
d.
e.
f.
g.
ASA
ASA/ER Dipyridamole
Clopidogrel
Clopidogrel + ASA
Warfarin
Either b) or c)
Any of a) , b) or c)
Prevention of Vascular Events in Stroke/TIA Patients
with ASA Following First Stroke
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
ASA vs. Placebo: Efficacy by Dose*
* 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.
b.
c.
d.
e.
f.
g.
ASA
ASA/ER Dipyridamole
Clopidogrel
Clopidogrel + ASA
Warfarin
Either b) or c)
Any of a) , 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.
b.
c.
d.
e.
f.
g.
ASA
ASA/ER Dipyridamole
Clopidogrel
Clopidogrel + ASA
Warfarin
Either b) or c)
Any of a) , b) or c)
MATCH: Bleeding Complications Increased Significantly
Clopidogrel + ASA (n=3,759)
p<0·0001
Clopidogrel + Placebo (n=3,781)
Number (n/%) with event
120
100
120 (3%)
p<0·0001
96 (3%)
p<0·0001
73 (2%)
80
60
49 (1%)
39 (1%)
40
22 (1%)
20
0
Life-threatening
bleeding
Major
bleeding
Minor
bleeding
Diener et al. Lancet 2004; 364: 331–337.
0.04
2.4 %/year
RR = 1.06
0.03
P = 0.67
0.02
2.2 %/year
0.01
OAC
Clopidogrel+ASA
0.0
Cumulative Hazard Rates
Major Bleeding
# at Risk
C+A
OAC
0.0
0.5
1.0
3335
3371
3172
3212
2403
2423
Years
1.5
914
901
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
Interventional
Medical
Revascularization
CEA vs Stent
Risk factor
management
Antithrombotic
Antiplatelet
Anticoagulant
Cardioemboli
• AF:
High incidence of paroxysmal AF in acute stroke
o 13.5% detection of new onset AF using a
combination of serial ECG daily x 3 days plus Holter
o Overall ~20 % of acute stroke patient with AF
o
(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
EMBRACE
18%
16%
16%
P<0.001
14%
12%
10%
Gladstone DJ, International Stroke Conference, Honolulu, 2013
8%
6%
4%
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
3%
2%
0%
30-day
Holter
New AF
 n=572 (age 73±9yrs;); recent ischemic
cryptogenic stroke/TIA, no known AF; 16
stroke centers
 Randomized to wear either an eventtriggered 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
AF increases the risk of stroke
• AF is associated with a pro-thrombotic state
o
~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
Effect of first ischemic stroke in patients with AF (n=597)
60%
59.7%
% of patients
50%
40%
30%
20%
20%
10%
0%
mRS=modified Rankin Scale
AF=atrial fibrillation
Gladstone DJ et al. Stroke. 2009; 40:235-240
Disabling
(discharge mRS ≥ 2)
Fatal
Ischemic Stroke Associated With AF is Typically
More Severe Than Stroke due to Other Etiologies
% bedridden patients
on admission (mRs* = 5)
50
41.2%
40
30
23.7% (P < 0.0005)
20
10
0
With AF
Without AF
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 Scale
AF=atrial fibrillation
Dulli DA, et al. Neuroepidemiology. 2003;22:118-123.
Increased mortality after ischemic stroke in
patients with AF persists for up to 8 years
Mortality
Annual mortality rate (%)
60
Patients with AF (n=869)
Patients without AF (n=2661)
50
40
30
20
10
0
1
2
3
4
5
Years after stroke
6
•Population-based
•Marini
7
8
study of 3530 patients with ischaemic stroke
C et al. Stroke 2005;36:1115–9
AF associated with increased
risk of recurrent stroke
Recurrent stroke after ischemic stroke
10
Cumulative probability
of recurrence (%)
8
Patients with AF
6
Patients
without AF
4
P=0.0398
2
0
0
2
4
6
8
10
12
Months after first stroke
Marini C et al. Stroke 2005;36:1115–9
Missed Opportunities for Stroke Prevention in AF:
Registry of the Canadian Stroke Network 2003-2007
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
Gladstone Stroke 2009;40:235
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
9
AF prevalence (%)
8
7
6
5
4
3
2
1
0
General
population
1. Go AS, et al. JAMA 2001;285:2370-2375.
>60 years
Age
>80 years
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
• 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
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
CHA2DS2-VASc Score
• 1 point for Congestive Heart
Failure/LV Dysfunction
CHA2DS2-VASc
Score*
One year event rate (95% CI) of
hospital admission and death due to
thromboembolism† per 100 person
year
• 2 points for Age ≥ 75 years
0
0.78 (0.78 – 1.04)
• 1 point for Diabetes Mellitus
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)
• 1 point for Vascular Disease3
5
15.26 (14.35 – 16.24)
• 1 point for Age 65-74 years
6
19.74 (18.21 – 21.41)
• 1 point for Sex category
(female gender)
7
21.5 (18.75 – 24.64)
8
22.38 (16.29 – 30.76)
9
23.64 (10.62 – 52.61)
• 1 point for Hypertension
• 2 points for Prior Stroke or
or TE2
TIA1
CHA2DS2-Vasc score Mrs W.S. = 4
(hypertension, age 65-74 yr, female)
1TIA
= Transient ischemic attack; 2TE = Thromboembolism
myocardial infarction, peripheral artery disease, aortic plaque
1. Lip GY et al. Chest 2010;137:263-272
3Prior
*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
2. Olesen JB, et al. BMJ 2011;342:d124
3. Task Force or the Management of Atrial Fibrillation of the ESC.
Eur Heart J 2010;31:236902429
CCS 2012 Update to AF
Guidelines
Assess Thromboembolic Risk (CHADS2)
CHADS2 = 0
CHADS2 = 1
CHADS2 ≥ 2
Increasing stroke risk
No antithrombotic
No
additional
risk factors
for stroke
ASA
Either
female
sex or
vascular
disease
OAC*
Age ≥ 65 yrs
or combination
of female sex
and vascular
disease
*OAC = Oral anticoagulant
ASA = Aspirin
1. Skanes AC, et al. Can J Cardiol 2012;28:125-136.
OAC*
*Aspirin is a reasonable
alternative in some as
indicated by risk/benefit
OAC*
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
Case - Paul
Mrs W.S. Risk:
62-year-old - < 75
HTN
No h/o CHF
No DM
TIA symptoms
:0
:1
:0
:0
: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)
e. Clopidogrel + ASA
f.
ASA/ER Dipyridamole
Challenges of Oral
Anticoagulation Therapy (OAC)
Narrow efficacy window
+ multiple interactions = hard to use/take1
20.0
Odds Ratio
15.0
INTRACRANIAL BLEED
ISCHEMIC STROKE
10.0
5.0
1.0
0
1.0
2.0
3.0
4.0
5.0
INR
1. Haas S. J Thromb Thrombolysis. 2008;25:52-60.
2. Adapted from Ezekowitz MD et al. Mayo Clin Proc. 2004;79:904-913.
6.0
7.0
8.0
INR control: clinical trials v. clinical practice
INR* control in clinical trial versus clinical practice (TTR**)
% of eligible patients
receiving warfarin
66%
Clinical trial1
Clinical practice2
44%
38%
25%
18%
9%
<2.0
*INR = International normalized ratio
2.0 – 3.0
>3.0 INR
** TTR = Time in Therapeutic Range (INR2.0-3.0)
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.
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
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
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 Monitoring
Rapid onset of action
Similar or better bleeding profile to warfarin
Con: No antidote, no clear way of measuring effect
Prevention of Stroke
Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.
Stroke or Systemic Embolism
Dabigatran 110 mg BID
Superiority
p-value
0.90
0.29
<0.001
0.12
0.01
0.65
Dabigatran 150 mg BID
0.88
Rivaroxaban 20 mg QD
0.79
Apixaban 5 mg BID
Ischemic Stroke
1.11
Dabigatran 110 mg BID
0.35
0.03
0.59
0.42
0.76
Dabigatran 150 mg BID
0.94
Rivaroxaban 20 mg QD
0.92
Apixaban 5 mg BID
0.50
0.75
1.00
1.25
1.50
HR (95% CI)
Comparator better
Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med
2011;365:883; Granger N Engl J Med 2011;365:981
Warfarin better
Reducing the Bleeding Risk
Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.
Intracranial Hemorrhage
Superiority
p-value
0.30
Dabigatran 110 mg BID
<0.001
<0.001
0.02
<0.001
0.41
Dabigatran 150 mg BID
0.67
Rivaroxaban 20 mg QD
0.42
Apixaban 5 mg BID
ISTH Major Bleeding
0.80
Dabigatran 110 mg BID
0.003
0.31
0.58
<0.001
0.93
Dabigatran 150 mg BID
1.04
Rivaroxaban 20 mg QD
0.69
Apixaban 5 mg BID
0.25
0.50
0.75
1.00
1.25
HR (95% CI)
Comparator better
Warfarin better
Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981
AF Trials: Elements of Primary Endpoint:*
Annual Event Rates
Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.
3
Systemic Embolism
Hemorrhagic Stroke
Ischemic/Unspecified Stroke
%/year
2.5
2
0.10
1.5
1
0.15
0.10
0.92
0.10†
0.38
0.09
1.21
0.24
0.19
0.04
0.26
0.47
0.97
1.05
Apixaban
Warfarin
1.40
0.44
1.52
0.5
0
Dabi 150 mg Warfarin
RELY
ARISTOTLE
Rivaroxaban Warfarin
ROCKET AF
*Patients experiencing multiple endpoints are included in multiple categories.
†Systemic embolism result reported for RELY refers to pulmonary embolism.
In recent trials, the majority of AF strokes were ischemic
Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981
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
Outcome by anticoagulant-associated
ICH
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)
Intracranial hemorrhage type
ICH = intracranial hemorrhage; mRS = modified Rankin Scale; IQR = interquartile range
*P = 0.3; †P=0.012; ‡mRS missing in 9; §mRS missing in 2
Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065
30 Day Mortality Associated with
Intracranial vs Extracranial Bleeds
Mortality at 30 days (%)
100
80
48.6
P<0.001
60
Intracranial
Extracranial
40
5.1
20
0
Intracranial
Extracranial
•
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
Conclusion
• 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
Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065
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
Stroke / TIA
Interventional
Medical
Revascularization
CEA vs Stent
Risk factor
management
Antithrombotic
Antiplatelet
Anticoagulant
Antiplatelet choices – Summary
Non-cardioembolic stroke
ASA naive patients vs those previously on ASA
a. ASA
b. ASA/ER Dipyridamole
c. Clopidogrel
________________________
d. Warfarin
e. Clopidogrel + ASA
Stroke / TIA
Interventional
Medical
Revascularization
CEA vs Stent
Risk factor
management
Antithrombotic
Antiplatelet
Anticoagulant
For patient with cardioembolic (AF)
stroke/TIA
a. Warfarin
b. Dabigatran (Pradax)
c. Rivaroxaban (Xarelto)
d. Apixaban (Eliquis)
_______________________
e. Clopidogrel + ASA
f. ASA