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Hyperacute management
of TIA and minor stroke.
Shelagh Coutts MD FRCPC
Associate Professor, Clinical Neurosciences
Calgary Stroke Program,
Objectives



To review prognosis of TIA and minor
stroke.
To describe the utility of CT/CTA in
assessment of these patients.
To discuss treatment options for TIA/minor
stroke.
Stroke Risk
Risk of stroke following a TIA is high:
 10% within 90 days
 50% of these within the first 48 hours
 20-40% of strokes are preceded by a TIA or
non disabling stroke.
Golden Opportunity for Stroke Prevention!
What is a TIA in practice

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TIA is a patient that has resolved when
assessed by a physician (usually not a
neurologist).
This is frequently the definition used.
Likely many of the patients in all of the large
epidemiological studies had not resolved
completely.
Really this is a collection of “Minor
cerebrovascular events”.
We have a mountain to climb
Conditions Misdiagnosed as TIA
•
•
•
•
•
•
•
•
•
Migraine aura
Syncope, postural hypotension
Seizure
Vertigo
Transient Global Amnesia
Anxiety/Hyperventilation
Confusion
Unexplained fall
Peripheral nerve palsy
2
ABCD
Score
Derived a 7 point score to stratify the clinical risk
of stroke after TIA:
• A: age > 60 years – 1 point
• B: BP (systolic>140, diastolic>90)- max 1 point
• C: clinical –weakness =2, speech only = 1,
• D: Duration, >60 minutes =2,
• 10-59 =1, <10 =0.
• D: Diabetes mellitus =1
Johnston, SC, Lancet 2007;369:283-292.
In practice ABCD2 not that
useful
ABCD2 >5: Sensitivity of 31.6% for stroke at
7 days and 29.2% at 90 days.
 ABCD2 >2: Sensitivity of 94.7%, specificity
of 12.5% for stroke at 7 days.
 Overall reliability poor –
AUC: 0.56 (0.47–0.65) ED physician; or
0.65 (0.57–0.73) coordinating centre

Perry et al. CMAJ 2011:183(10): 1137–1145.
High risk TIA

Symptom onset within the last 48 hours with
any one of the following:
Motor deficit lasting more than 5 minutes
Speech deficit lasting more than 5 minutes
(Atrial fibrillation with TIA)
EXPRESS
80% reduction in
recurrent stroke
risk by urgent
implementation
of known
treatments
Rothwell et al, Lancet
2007;370:1432
What this means?

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Timing is everything.
High risk TIA: motor or speech symptoms
lasting >5 minutes within last 48hours.
Extremely early assessment makes the
standard TIA/stroke labels difficult to
apply.
All risk is not explained by ABCD2 score.
What role does imaging play in risk
assessment beyond clinical characteristics?
DWI identifies true ischemia
Kidwell C et al. Stroke 1999; 6:1174-1180.
~50% of all TIA’s associated with permanent
damage. Especially if it lasts > 1 hour.
Even brief symptoms
cause areas of
permanent
injury
Event free survival time for new stroke
Coutts SB et al. Annals of Neurology 2005;57:848-854
Proportion Free from Stroke
1.0
0.9
No DWI Lesion & No Occlusion
4.3%
Yes DWI Lesion & No Occlusion
10.8%
Yes DWI Lesion & Yes Occlusion
32.6%
0.8
0.7
0.6
Likelihood ratio test p-value = 0.02
0.5
0
30
60
Days after Presenting Acute TIA or Minor Stroke
90
TIA etiology predicts recurrence

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Large artery disease has the highest early
risk of recurrence.
This appears to be independent of DWI
status.
Not only carotid disease, but also
vertebrobasilar disease and intracranial
atherosclerosis.
What about CT?

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For many sites MRI is unavailable emergently
Intracranial and extracranial
stenosis/occlusion has the highest early risk.
Most patient get CT brain.
Arch to vertex CT Angiography (CTA) can
quickly identify high-risk vascular lesions and
can easily accompany CT brain.
CT And MRI in the Triage of TIA and
minor Cerebrovascular events to identify
High risk patients. (CATCH)


Assess the use of CT/CTA in the prediction
of recurrent events and disability in minor
stroke/TIA.
Prospective enrollment with informed
consent of consecutive high risk TIA and
minor stroke (NIHSS<4) patients
presenting to the ED assessed by a stroke
neurologist within 24 hours of onset.
Methods
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CT/CTA positive metric: Acute ischemic
change on CT or symptomatic intracranial
or extracranial vessel occlusion or stenosis ≥
50%, ipsilateral to the clinically relevant
ischemic brain tissue.1
Primary outcome: recurrent stroke within 90
days.
Secondary outcome: disability at 90
days(mRS >2)
1. Coutts et al. IJS. 2009; 4:448
Results
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510 patients enrolled in 29 months.
Follow up was available in 98% of patients.
Median time from symptom onset to CTA
was 5.5 hours, to MRI 17.5 hours.
CT/CTA positive metric was present in 171
patients (34%).
58% of patients were DWI positive.
Median NIHSS 1.
Coutts et al. Stroke. 2012:43: 1013-7
Primary outcome
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36 recurrent events (7.1% 95%CI: 5.0-9.6).
19 progression, 17 recurrence.
Median time to event 1 day (IQR 7.5).
Variable
Recurrent
stroke % (n/N)
No recurrent
stroke % (n/N)
Hazard Ratio
(CI95)
Age 60 or greater
81 (29/36)
69 (321/463)
1·8 (0·8-4·0 )
Female sex
47 (17/36)
41 189/463
1·3 (0·7-2·5)
Diabetes Mellitus
22 (8/36)
15 (68/463)
1·6 (0·7-3·5)
Hypertension
61 (22/36)
56 (259/463)
1·2 (0·6-2·4)
Current smoker
11 (4/36)
16 (72/463)
0·7 (0·3-2·0)
BP ≥ 140 or ≥ 90 mmHg
78 (28/36)
73 (340/463)
1·2 (0·6-2·7)
Ongoing symptoms in ER
78 (28/36)
60 (279/463)
2·2 (1·02-4·9)
Motor weakness
69 (25/36)
64 (295/463)
1·3 (0·6-2·6)
Speech disturbance
22 (8/36)
31 (145/463)
0·64 (0·3-1·4)
Acute ischemia on CT
14 (5/36)
12 (56/463)
1·2 (0·5-3·0)
Carotid occlusion or stenosis 50%
19 (7/36)
9 (40/463)
2·4 (1·05-5·5)
Intracranial occlusion
39 (14/36)
8 (38/463)
6.1 (3.1-11.8)
CT/CTA positive metric
67 (24/36)
32 (147/463)
4·0 (2·0-8·0)
DWI positive
75 (27/36)
57 (262/463)
2.2 (1.05-4.7)
an
Results

In the multivariable analysis the only
variable that remained predictive of the
primary outcome was apriori designated
CT/CTA positive metric.
CT/CTA positive
MRI positive
Disability
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74 of 499 (15% 95%CI: 12-18%) had a
disabled outcome.
Coutts et al. Stroke. 2012:43:3018-22
Effect of recurrent events
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Of 74 patients with disabled outcome, 55
(74%) had no recurrent stroke and 19 (26%)
had a recurrent event.
Out of the 463 patients who did not have a
recurrent event 55 were disabled (12%).
By contrast 19/36 (53%) patients were
disabled after a new event.
Putting this all together
Canadian Stroke Network Secondary Stroke Prevention guideline update 2012.
Who should get a CTA
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High risk TIA (motor or speech
symptoms >5 minutes) or persistent
focal symptoms within 48 hours of
onset.
Rule out dissection (vertebral or carotid
artery) – focal neurological symptoms
in the setting of neck pain, recent
trauma, neck manipulation etc.
32 year old male. Transient tinnitus right
ear, then 10 minutes of right sided
weakness. Resolved.
Ideal Care. Where are we
headed?
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CTA used to stratify very early risk.
MR as the major screening tool for the brain.
Antiplatelet therapy immediately.
Rapid access to carotid endarterectomy.
Immediate use of anticoagulants for atrial
fibrillation.
Timing of statins? BP management?
Clinical trials for novel treatments –eg
POINT, TEMPO
What’s next for treatment?
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TEMPO-1: Phase II dose escalation safety
study of low dose TNK in minor stroke
patients with intracranial occlusion.
Treatment within 12 hours of symptom
onset.
Multi-centre Canadian trial.
Still looking for other sites.
Imaging is key in the assessment of
TIA and minor stroke
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Confirming the diagnosis can be helpful.
Need to know why it happened to prevent
the next one.
The earlier we make the assessment the
more likely we can intervene.
We need large coordinated trials in these
patients. Target high risk patients.
Questions?
[email protected]
New Oral Anticoagulants in Stroke
Prevention in Atrial Fibrillation
Ashfaq Shuaib, MD
Professor of Neurology and Medicine
Director University of Alberta Stroke
Program
University of Alberta
Competing Interests Declaration
• Competing interests
– chair the steering committee of the SENTIS trial and
FastFlo Trial and am an advisor to CoAxia. I am also
on the steering committee of the DIAS III & DIAS IV
trials, Impact-24 trial and the MASCI trial.
• In the past 5 years, I have received speaker fees
from:
• Sanofi-Aventis/BMS, BI, Pfizer, Merck, Roche, Servier,
AstraZeneca, Bayer
• In the past 5 years, I have served on national
and international advisory boards for:
• AstraZeneca, BI, Lundbeck, Bayer, Sanofi-Aventis/BMS,
Roche, Pfizer
Key questions addressed today
•
•
•
•
Stroke and AF a Case History
Warfarin and stroke prevention in AF
NOACs and stroke prevention in AF
“Flawed” comparison
Case History (three days ago)
• 76 years old male
• AF for 10 years. Initially on warfarin but
switched to Dabigatran 110 twice daily due
to difficulty maintaining INRs therapeutic
• Hypertension, DM, CHF
• Lower GI bleed. Dabi reduced to once/d
• Presents with L face weekness/dysarthria
• Imaging
Course in hospital
• Hold anticoagulation?
• Further imaging?
• Prevention of recurrent stroke (in-hospital)
– ASA ?
– iv anticoagulation ?
• When to start oral anticoagulation
• What is the best medication for long term
prophylaxis
Key questions addressed today
•
•
•
•
Stroke and AF a Case History
Warfarin and stroke prevention in AF
NOACs and stroke prevention in AF
“Flawed” comparison
Atrial Fibrillation is a Major
Preventable Cause of Stroke
• AF accounts for 1 in 6 ischemic strokes
(1 in 4 in the elderly)
– More than 14,000 AF related strokes a year in
Canada
– Many times more ‘silent’ strokes
• Strokes caused by atrial fibrillation are
generally severe; 1-year mortality is 50%
Also remember….
• AF paroxysmal in up to one third of
patients
• The presence of a non-AF identifiable
cause does not rule out cardio-embolic
stroke secondary to AF
• Many “cryptogenic strokes” may be
seconday to AF
Stroke Prevention in AF
• Stroke-risk dependent on presence of
“risk factors”. CHAD2 and CHAD-VASc
scores
• ASA reduces risk but not significant in
patients with previous TIAs or stroke
• ASA+ clopidogrel better than ASA;
however increased bleeding risk
• Warfarin very effective in stroke
prevention: however TTR problematic
RRR = 64%
Hart Ann Int Med 1999;131:492
Key questions addressed today
• Stroke and AF a Case History
• Warfarin and stroke prevention in AF
• New Oral Anticoagulants and stroke
prevention in AF
• “Flawed” comparison
World Stroke Congress
2010
Seoul, South Korea
Advantages of New Oral Anticoagulants
Over Warfarin
Feature
Warfarin
New Orals
Onset
Slow
Rapid
Dosing
Variable
Fixed
Food effect
Yes
No
Interactions
Many
Few
Monitoring
Yes
No
Long
Short
Offset
Disadvantages of New Oral
Anticoagulants Over Warfarin
Features
Warfarin
New Agents
Frequency
Once daily
Once or twice
daily
Monitoring
INR
Uncertain
Clearance
Non-renal
Renal 25-80%
Vit K, FFP, PCC
None
Extensive
Limited
Antidote
Familiarity
Comparative Pharmacology
Characteristic
Rivaroxaban
Apixaban
Dabigatran
Factor Xa
Factor Xa
Thrombin
No
No
Yes
80%
60%
6%
Dosing
o.d. (b.i.d.)
b.i.d.
b.i.d. (o.d.)
Half life
7-11 h
12 h
12-17 h
33% (66%)
25%
80%
Monitoring
No
No
No
Interactions
3A4/P-gp
3A4/P-gp
P-gp
Target
Prodrug
Bioavailability
Renal
Dabigatran and stroke prevention
• RE-LY: probe design (110 and 150 mg
Dabigatran vs Warfarin) 18,118 patients
• Both doses of Dabi non-inferior to Warfarin
• Higher dose superior to Warfarin
• Significantly less bleeding, especially ICH
• Higher dose associated with significantly
fewer ischemic strokes
The Long Term Multi-center
Extension of Dabigatran
Treatment in Patients with Atrial
Fibrillation (RELY-ABLE®) study
Stuart J Connolly, Lars Wallentin, Michael
Ezekowitz, John Eikelboom, Jonas Oldgren,
Janice Pogue, Paul Reilly, Martina
Brueckmann, Salim Yusuf; on behalf of the
RELY-ABLE® Steering Committee and
Investigators
November 2012
•
•
•
Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los
Angeles, CA, 7 Nov 2012
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
Note that there may be discrepancies between the information in this presentation and the final publication
Nov 2012
Stroke and ischaemic events: RELY-ABLE®
D150
D110
(%/yr)
(%/yr)
Stroke or SEE
1.46
All stroke
HR
95% CI
1.60
0.91
0.69–1.20
1.24
1.38
0.89
0.66–1.21
Ischaemic
1.15
1.24
0.92
0.67–1.27
Haemorrhagic
0.13
0.14
0.89
0.34–2.30
Myocardial infarction
0.69
0.72
0.96
0.63–1.45
Pulmonary embolism
0.13
0.11
1.14
0.41–3.15
Event
5851 patients followed for mean of 2.3 years
D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio
SEE = systemic embolic event
•
•
•
Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los
Angeles, CA, 7 Nov 2012
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
Note that there may be discrepancies between the information in this presentation and the final publication
57
Mortality and net benefit: RELY-ABLE®
RELY-ABLE®
Event
D150
(%/yr)
D110
(%/yr)
HR
95% CI
Total mortality
3.02
3.10
0.97
0.80–1.19
Vascular mortality
1.67
1.62
1.03
0.78–1.35
4.53
4.45
1.02
0.86–1.20
7.36
6.89
1.07
0.94–1.22
Disabling stroke, lifethreatening bleed or death
Stroke, systemic embolism,
myocardial infarction,
pulmonary embolism,
major bleed or death
5851 patients followed for mean of 2.25 years
D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio
•
•
•
Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los
Angeles, CA, 7 Nov 2012
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
Note that there may be discrepancies between the information in this presentation and the final publication
58
Conclusions
• During 2.3 years of additional treatment after RE-LY®
(total mean follow-up 4.3 years), rates of stroke and
major bleeding remain low on dabigatran and are
consistent with those seen during RE-LY®
• Dabigatran 150 vs dabigatran 110
– Both doses have very low rates of hemorrhagic stroke
over 4+ years
– With dabigatran 150, there is a lower rate of ischemic
stroke but a higher rate of major bleeding
– Both doses have similar mortality
•
•
•
Connolly, S, The Long Term Multi-centre Extension of Dabigatran Treament in Patients with Atrial Fibrillation (RELY-ABLE ® )study, American Heart Association, Los
Angeles, CA, 7 Nov 2012
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
Note that there may be discrepancies between the information in this presentation and the final publication
59
Study limitations
• Study medication blinded but warfarin
open label
• More MIs in treatment arms (initial
publication)
• GI intolerance
• GI bleeding rates similar to warfarin in
elderly
• Renal disease increased risk of
complications, especially with higher dose
of Dabigatran
Rivaroxaban and stroke
prevention
• ROCKET-AF: 20 mg daily vs Warfarin
14,264 patients, double blind
• CHAD2 scores higher than other trials
• 55 % of patients with previous TIA or
stroke
• Major bleeding, especially ICH lower with
Rivaroxiban
• Rivaroxaban non-inferior to Warfarin
Study limitations
• Non-inferior but NOT superior to Warfarin
on ‘intention to treat” analysis
• Once a day dose of Rivaroxaban
• Higher rates of GI bleeding with study drug
• Study end and switch to Warfarin
– Time to therapeutic INR (13 vs 3 days)
– Higher events in the patients previously on
Rivaroxaban
Apixaban and stroke prevention
• AVERROES (5,599) and ARISTOTLE
(18,201) trials
• AVERROES stopped early because of
significantly fewer events (stroke and ICH)
in apixaban group
• ARISTOTLE: Apixaban superior to
Warfarin
• Significantly fewer hemorrhages (ICH and
systemic)
• Lower mortality
Study limitations
• Patient selection (unable to tolerate
warfarin !!!) in AVERROES
• Short follow up period in AVERROES
– bleeding risk underestimated ?
• Low stroke risk in AVERROES
• Issues with FDA for AF indication
Key questions addressed today
•
•
•
•
•
Stroke and AF a Case History
Warfarin and stroke prevention in AF
NOACs and stroke prevention in AF
Specific stroke prevention sub-groups
“Flawed” comparison
For patients with atrial fibrillation,
anticoagulation effectively reduces the risk of stroke.
Circulation 2012;125:159-164
Stroke risk in patients with
previous TIAs and Stroke
Risk of hemorrhage in patients
with previous TIAs and Stroke
Limitations with NOACs
•
•
•
•
•
•
•
When to start treatment after acute stroke
Reversal of anticoagulation
Treatment of ICH
Thrombolysis in acute stroke
Combination with ASA or dual antiplatelets
Long-term experience lacking
Compliance cannot be monitored
Antithrombotic guidelines for stroke
prevention in AF trial fibrillation
• ACCP 2012
“…we suggest dabigatran 150 mg bid rather
than adjusted-dose VKA therapy…”.
• AHA 2012
“….newer agents superior to VKA therapy…”
• CCS 2012
“…we suggest…that…most patients should
receive dabigatran, rivaroxaban or apixaban
in preference to warfarin...”
You JJ, et al. Chest 2012; 141: e531S-575S
Skanes AC, et al. Can J Cardiol 2012; 28: 125-136
Atrial Fibrillation treatment choices
Characteristic
Choice
Rationale
Mechanical valve or valvular a.fib
Warfarin
New agents not studied
Poor compliance
Warfarin or nothing
Missed doses of greater consequence with shorter-acting new
agents
Stable on Warfarin
Warfarin
Patient preference might mean switching
CrCl < 30 mL/min
Warfarin
Such patients were excluded from trials with new agents
CrCl of 30-50 mL/min
Rivaroxaban or
Apixaban
Oral factor Xa inhibitors are less affected by impaired renal
function than dabigatran
Dyspepsia or upper GI complaints
Rivaroxaban or
Apixaban
Dyspepsia in up to 10% given dabigatran
Recent GI bleed and ongoing risk
Apixaban
More gastrointestinal bleeding with dabigatran (150 mg BID)
or rivaroxaban than with warfarin
Recent Acute Coronary Syndrome
Rivaroxaban or
Apixaban
Small myocardial infarction signal with dabigatran
Poor compliance with BID regimen
or desire for once daily
Rivaroxaban
Only agent that is once a day
Liver dysfunction with elevated INR
Warfarin
New agents require hepatic metabolism
New Oral Anticoagulants
Guidelines and tips
Starting/stopping
Switching/swapping
Measuring/monitoring
Philip Teal MD FRCPC
Sauder Family & Heart and Foundation
Professor of Stroke Neurology
University of British Columbia
Disclosures
• Honorariums (past 5 years)
– Steering Committees, advisory boards, sponsored talks
•
•
•
•
•
•
•
Boehringer Ingelheim
Sanofi Aventis
BMS
Bayer
Roche Canada
Pfizer
Servier
• Clinical trial participation
– Sanofi Aventis
– Boehringer Ingelheim
– Bayer
Objectives
•
•
•
•
•
Risk stratification schemes
2012 Canadian Atrial Fibrillation Guidelines
Starting OAC post stroke
Monitoring the new OACs
Starting/ Stopping
The Stroke Service Perspective on AF
 Patients referred for advise on primary or secondary stroke
prevention in atrial fibrillation (outpatients)
 Unrecognized, undiagnosed atrial fibrillation-first
recognition on presentation with a major stroke
 Recognized atrial fibrillation, untreated or undertreated
presenting with a first or recurrent stroke
 Intracerebral hemorrhage on anticoagulation
 Poor outcomes with acute stroke therapies in atrial
fibrillation – challenges for acute reperfusion therapies
 Cryptogenic strokes that subsequently are attributed to
unrecognized paroxysmal Afib
7
The Stroke Service Perspective on AF
 Shortcomings of traditional antithrombotic therapies ASA,
warfarin, dilemmas with NOACs (new oral anticoagulants)
 Errors in stratification of patients into low, medium, high
stroke risks
 Stroke Severity in atrial fibrillation
 Intracerebral hemorrhage on anticoagulation
 Poor outcomes with acute stroke therapies in atrial
fibrillation
7
VGH Stroke Service – Week of Aug 19th
YY 80 year old man Afib,
untreated
JH 56 year old man with afib
and MAVR. sub therapeutic
7
8
VGH Stroke Service – Week of Aug 19th
YD 62 year old man with AF,
stopped warfarin
HG 86 year old woman with
AF. “falls”
VGH Stroke Service – Week of Aug 19th
JT 71 year old woman with
Afib, untreated
PT 81 year old man with Afib
procedural stop
VGH Stroke Service – Week of Aug 19th
GM 66 year old man post
cardioversion, no Rx
PS 59 year old man post
gastroscopy, procedural stop
Hyperdense MCA Sign
Large territory strokes in Afib
Quantifying the Risk
CCS 2012 Guidelines:
We recommend that all patients with AF or AFL (paroxsymal,
persistent, or permanent), should be stratified for Stroke (e.g.
CHADS2) and for risk of bleeding (e.g. HAS-BLED), and that
most patients should receive either an oral anticoagulant or
ASA (Strong Recommendation, High quality Evidence)
Candian Journal of Cardiology 28 (2012) 125-136
AF Is Classified By Episode Duration And
the Ability To Return To Sinus Rhythm
1st
Detected
Recurrent if ≥2 episodes
Paroxysmal
Persistent
(self-terminating —
usually within 7 days)
(not self-terminating)
Permanent
(Refractory to cardioversion and/or accepted)
ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol 2006;48:854-906.
Prediction of Stroke
in AF: CHADS2
Score
C= CHF
1
H=hypertension
1
A= age ≥ 75
1
D= diabetes
1
S= stroke/TIA
2
% Stroke / yr
Risk Factor
CHADS2 score
Adapted from Cairns JA, et al. Can J Cardiol. 2011; 27:74–90.
CHA2DS2-VASc Score
Patients with a CHADS2 score of 0 or 1 may still be at increased risk of stroke.
The CHA2DS2-VASc score may be useful in these patients to ensure consideration of all stroke
risk factors:
Points
CHA2DS2VASc
Score
Stroke
Rate per
Year
(%/yr)
Recommended
Therapy
Congestive Heart Failure / Left
Ventricular Dysfunction
1
0
0
ASA
1
1.3
OAC or ASA
Hypertension
1
2
2.2
Age ≥ 75 Years
2
3
3.2
Diabetes Mellitus
1
4
4.0
Prior Stroke or TIA or Systemic
Embolism
2
5
6.7
Vascular Disease
1
6
9.8
Age > 65 but < 75
1
7
9.6
Sex Category – Female
1
8
6.7
9
15.2
CHA2DS2-VASc Score
Sum Of:
OAC
Lip Chest 2010;137:263; Camm Eur Heart J 2010;31:2369
Bleeding Risk – HAS-BLED Score
Letter
Clinical Characteristic
Points
H
Hypertension
1
A
Abnormal Liver or Renal Function
1 point each
1 or 2
S
Stroke
1
B
Bleeding
1
L
Labile INRs
1
E
Elderly (age > 65 yr)
1
D
Drugs or Alcohol
1 point each
1 or 2
Maximum 9 points
Pisters R et al. Chest. 2010 Nov;138:1093-100
INR 2.2
Warfarin-associated ICH INR 2.7
74 year old, minor fall. On warfarin INR 2.1
Predictors of CNS Bleeding on OAC
•
•
•
•
•
•
•
•
Advanced age > 75 years
Hypertension (systolic BP > 160)
History of cerebrovascular disease
Intensity of anticoagulation
Agents used - new OACs vs VKA
Concomitant ASA / clopidogrel
Leukoariosis on CT/MRI
Microbleeds of T2*/GRE/SWI MRI sequences
New Oral Anticoagulants vs. Warfarin†
All-Cause Stroke or Systemic Embolism
TRIAL
ARISTOTLE
OAC Agent
Relative Risk (95% CI)
P Value#
Apixaban* 5mg BID
P = 0.01
Dabigatran 110mg BID
P = 0.30
Dabigatran 150mg BID
P < 0.001
RE-LY
ROCKET-AF Rivaroxaban 20mg QD
P = 0.12
0.5
1
Novel Anticoagulant
Better
2
Warfarin
Better
Data obtained from intention-to-treat analysis
†
Not intended as cross-trial comparison
* Not approved in Canada for stroke prevention in AF patients
# P value = superiority
Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361(12):1139-51;
Connolly SJ, et al; for the RE-LY Investigators. N Engl J Med. 2010;363(19):1875-6 (updated);
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365(10):883-91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365(11):981-92.
New Oral Anticoagulants vs. Warfarin†
Intracranial Hemorrhage
TRIAL
Relative Risk (95% CI)
OAC Agent
ARISTOTLE Apixaban* 5mg BID
P Value#
P < 0.001
Dabigatran 110mg BID
P < 0.001
Dabigatran 150mg BID
P < 0.001
RE-LY
ROCKET-AF Rivaroxaban 20mg QD
P = 0.02
0.25
0.50
Novel Anticoagulant
Better
0.75 1
Warfarin
Better
Data obtained from intention-to-treat analysis
†
Not intended as cross-trial
* Not approved in Canada for stroke prevention in AF patients
comparison
# P value = superiority
Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51;
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92.
New Oral Anticoagulants vs. Warfarin†
All-Cause Mortality
TRIAL
Relative Risk (95% CI)
OAC Agent
ARISTOTLE Apixaban* 5mg BID
P Value#
P =0.047
Dabigatran 110mg BID
P = 0.13
Dabigatran 150mg BID
P = 0.051
ROCKET-AF Rivaroxaban
.
20mg QD
P = 0.073
RE-LY
0.5
0.75
1
Novel Anticoagulant
Better
2
Warfarin
Better
Data obtained from intention-to-treat analysis
†
Not intended as cross-trial comparison
* Not approved in Canada for stroke prevention in AF patients
# P value = superiority
Connolly SJ, et al; for the RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-51;
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883-91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981-92.
CCS Atrial Fibrillation Guidelines 2012:
Prevention of Stroke and Systemic
Thromboembolism in
Atrial Fibrillation and Flutter
•
•
•
•
•
•
John A Cairns, MD, FRCPC,
Stuart Connolly, MD, FRCPC,
Gordon Gubitz, MD, FRCPC
Sean McMurtry, MD, PhD, FRCPC,
Mario Talajic, MD, FRCPC
Carl Van Walraven, MD, FRCPC, MSc
Atrial Fibrillation Guidelines
Assessing the Risk of Stroke
Any other risk
factor for stroke?
> Age 65?
Prior stroke?
Anticoagulant
indicated
Diabetes?
Anticoagulant
indicated
Hypertension?
Female with
vascular disease?
AF Guidelines Recommendations
2012 UPDATE
• We recommend that all patients with AF or AFL (paroxysmal,
persistent, or permanent), should be stratified using a
predictive index for stroke (e.g., CHADS2) and for the risk of
bleeding (e.g., HAS-BLED), and that most patients should
receive either an oral anticoagulant or ASA. (Strong
Recommendation, High Quality Evidence)
• We suggest, that when OAC therapy is indicated, most
patients should receive dabigatran or rivaroxaban or
apixaban* in preference to warfarin.
(Conditional Recommendation, High Quality Evidence)
*Once approved by Health Canada.
New Oral Anticoagulants: Drug Interactions
DABIGATRAN
RIVAROXABAN
APIXABAN
P-gp inhibitors*
(e.g., ketoconazole
verapamil, quinidine,
amiodarone)
Potent CYP3A4 and
P-gp inhibitors‡
(e.g., ketoconazole, itraconazole,
voriconazole, posaconazole,
and HIV protease inhibitors [ritonavir])
Potent CYP3A4 and
P-gp inhibitors‡
(e.g., ketoconazole, itraconazole,
voriconazole, posaconazole,
and HIV protease inhibitors)
P-gp inducers†
(e.g., Rifampicin
carbamazepine,
St. John’s Wort)
Potent CYP3A4 and
P-gp inducers‡‡
(e.g., rifampicin, and the anticonvulsants
phenytoin, carbamazapine,
phenobarbitone)
Potent CYP3A4 and
P-gp inducers‡‡
(e.g., rifampicin, and the anticonvulsants
phenytoin, carbamazapine,
phenobarbitone)
*P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban
†P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban
‡Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban
‡‡Combined potemt CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban
Note: Concomitant administration of NSAIDs, aspirin or clopidogrel may increase bleeding time for rivaroxaban, dabigatran and apixaban.
Apixaban not yet approved in Canada for stroke prevention in patients with atrial fibrilliation.
1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd.
2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.
3. Granger C, et al. N Engl J Med 2011;365:981-992.
When to Start OAC Post-Stroke ?
Spontaneous Hemorrhagic
Transformation – 7 days post stroke
Starting OCA post-Stroke
•Pre-treatment CT scan on all symptomatic
patients.
•TIAs – may start immediately after ICH excluded
•Minor/mod strokes – may start within 3-7 days
•Major strokes – the bigger the stroke the longer
you wait (2-4 weeks)
•New OACs – wait at least 2 weeks post-stroke
prior to starting
http://www.esostroke.org/pdf/ESO%20 Guidelines update Jan 2009
Antithrombotic and Thrombolytic Therapy
for Ischemic Stroke
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
• We
recommend initiation of oral
anticoagulation therapy within 2 weeks of a
cardioembolic stroke; however, for patients
with large infarcts or other risk factors for
hemorrhage,
additional
delays
are
appropriate.
CHEST 2012; 141(2)(Suppl):e601S–e636S
Selecting the Optimal Patient
Consider for:
• Those with unexplained poor warfarin control
• Unavoidable drug-drug interactions
• New patients with atrial fibrillation
Avoid in:
• Patients well-controlled on warfarin (TTR ≥ 65%)
• Renal failure (CrCl < 30 mL/min)
• Mechanical heart valve replacement
• Combination of GI disease + elderly
• Poor adherence
• Cost concerns
Schulman & Crowther. Blood 2012;119:3016-23
Important Patient Characteristics
Age
• Be aware of dose adjustment > age 80
Extremes of weight
• Limited data on if / how dose
should be adjusted
Renal Function
• AVOID in patients with CrCl < 30 mL/min
• CAUTION - ? dose adjustment needed
in patients with CrCl 30-50mL /min
:
Switching patients from warfarin to newer
anticoagulants
Assess the patient’s renal function
Estimated creatinine clearance must be ≥30 ml/min to consider using
dabigatran or rivaroxaban
Stop warfarin and monitor INR
Initiate dabigatran or rivaroxaban when INR ≤ 2.0
Dabigatran: Twice daily dosing
Rivaroxaban: In the morning or evening with a meal
Evaluate risk factors for bleeding on dabigatran or rivaroxaban
Low body weight (e.g., <50 kg)
Older age (e.g., ≥75 years)
Concomitant use of ASA, clopidogrel or NSAID
Use dabigatran 150 mg BID regimen unless there is increased
risk for bleeding; in that case use dabigatran 110 mg BID
Use rivaroxaban 20 mg once daily; for patients with increased risk
for bleeding use 15 mg once daily, including in patients with
estimated creatinine clearance between 30-49 mL/min
Clinical Monitoring
The lack of “required” monitoring is convenient, however:
Remember!
• Clinical status
• Reinforce adherence
• Drug interactions
• Patient education for bleeding
Lab Monitoring: When Is It Needed ?
Suspected underdose or overdose
Acute
thromboembolic
event
Bleeding
Pre-procedure safety: elective and urgent,
particularly in the setting of renal dysfunction
Renal Function Monitoring
• Depends on age, pre-existing renal function, comorbidities, other medications and choice of
NOAC
CrCl
Monitoring
> 50
• Yearly
• + with clinical deterioration
30 - 50
• Q6 months
• + with clinical deterioration
< 30
• Contraindicated
Dabigatran
Hemoclot® TT Assay:
linear dose response
aPTT: curvilinear dose response
van Ryn. Thromb Haemost 2010;103:1116-27
Rivaroxaban
PT / INR
• Dose response
(sensitivity) varies
by PT reagent
• INR is not linear at
therapeutic drug
levels
• ISI of the reagent
must be calibrated
for rivaroxaban,
not warfarin*
*Tripodi. J Thromb Haemost 2011;9:226-8
Lab Monitoring Summary
Assessment of “Reversal”
Dabigatran
aPTT
Rivaroxaban & apixaban
PT / INR
Monitoring of Drug Level
Dabigatran
Hemoclot®
Rivaroxaban & apixaban
Anti-Xa
Pre-Procedure Use of Dabigatran
Timing of last dose
pre-procedure
Renal
function
(CrCl,
mL/min)
Half-life
(hr) (range)
Standard risk
High risk
≥ 50
15 (12-34)
1 day
2 days
30 - 49
18 (13-23)
2 days (consider
aPTT pre)
4 days (consider
aPTT pre)
> 27 (22-35)
4 days
(aPTT pre)
6 days
(aPTT pre)
< 30*
* Use of dabigatran contraindicated
Schulman & Crowther. Blood 2012;119:3016-23
Pre-Procedure Use of Rivaroxaban
Timing of last dose
pre-procedure
Renal
function
(CrCl,
mL/min)
Half-life
(hr) (range)
Standard risk
High risk
≥ 30
12 (11-13)
1 day
2 days
< 30*
Unknown
2 days
(INR pre)
4 days
(INR pre)
* Use of rivaroxaban contraindicated
Schulman & Crowther. Blood 2012;119:3016-23
Reversing Anticoagulation
XII
XI
IX
1. The further down
the cascade the
anticoagulant acts,
the harder to reverse
2. Inhibitors are harder
to reverse than
deficiencies
VII
VIII
X
V
II
I
Fibrin clot
Oral Xa inhibitor
• Rivaroxaban
• Apixaban
Oral IIa inhibitor
• Dabigatran
Potential Considerations in
Selection of OAC
•
•
•
•
•
•
•
•
•
Age
Gender
Diabetes
Prior stroke history
Moderate or excellent renal function
CHADS2 score
HASBLED score
Cost
Personal preference
Patients unsuitable for new anticoagulants
(Dabigatran, rivaroxaban)
AF patients not recommended for therapy with new
anticoagulant agents approved for stroke prevention
include:
• Patients with valvular heart disease
• Patients with mechanical valves
• Patients with advanced renal impairment (CrCl<30
mL/min)
• Patients with active bleeding
1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd.
2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.
Summary of 2010 CCS AF Guidelines:
Patients Requiring Surgery
Cairns et al. Can J Card 2011 27:74-90
Perioperative Management of Anticoagulant Therapy
• Alteration of oral anticoagulant regimen may not be
necessary for most patients undergoing low risk
procedures:
– Dental procedures, joint and soft tissue injections and arthrocentesis,
cataract surgery, and upper endoscopy or colonoscopy with or without
biopsy
• For other invasive and surgical procedures, oral
anticoagulation needs to be withheld:
– Decision whether to pursue an aggressive strategy of perioperative
administration of intravenous heparin or subcutaneous low molecularweight heparin should be individualized based on an estimation of the
patient’s risks of thromboembolism and bleeding and the patient’s
preference
Douketis J, et al. Chest 2008;133:299S-339S;
Dunn AS and Turpie AGG. Arch Intern Med 2003;163:901-908
Surgical / Diagnostic Procedures:
Summary of 2010 Canadian Cardiovascular Society (CCS) Guidelines
Patients with Low to Moderate Stroke Risk (CHADS2 ≤2):
• Discontinue antithrombotic therapy before procedure:
–
–
–
–
ASA or clopidogrel for 7-10 days
Warfarin for 5 days if INR within 2-3 range
Dabigatran for 2 days
Rivaroxaban for 2 days
• Reinstate antithrombotic therapy once post-procedure
hemostasis restored ( ~24 hrs)
Cairns et al. Can J Card 2011 27:74-90
Acute Stroke in Setting of Dabigatran
• Obtain aPTT and/or thrombin time
– If normal treat as if not on dabigatran
• If elevated assume therapeutic level of
anticoagulation
– No IV TPA
– Consider intra-arterial treatment based on:
•
•
•
•
Availability/experience
Deficit warrants intervention
Demonstrable arterial occlusion
+/- mismatch
Thank you
Timing of Discontinuation After LAST
Dose of Dabigatran Before Surgery
Creatinine Clearance
> 50 mL/min
> 30 mL/min ≤ 50 mL/min
≤ 30 mL/min
Timing of discontinuation after last
dose of dabigatran before surgery
Standard risk of
bleeding
High risk of
bleeding
24 hours
2 – 4 days
At least 48 hours
4 days
2 – 5 days
> 5 days
Adapted from Van Ryn Thomb Haemost 2010;103:1116