Canadian Pradaxa Acute Stroke Safety Study
Conditions: Ischemic Attack, Transient, Stroke
Sponsor: University of Alberta

 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
PROTOCOL TITLE 
Canadian Pradax Acute Stroke/TIA Safety Study (CPASS) 
 
Protocol No: CSC2012-01 
Version: 2.3 
Date: July 29, 2014 
 
Sponsor: Dr. Ken Butcher 
 
Principal Investigators 
 
A/Prof Ken Butcher (Coordinating Investigator) 
Division of Neurology, University of Alberta 
2E3.27 WMC Health Sciences Centre 
8440 112th St. 
Edmonton, AB 
CANADA 
Phone: +1 780 695 3205 
 
A/Prof Mike Sharma 
Associate Professor of Medicine (Division of Neurology), McMaster 
University, Hamilton General Hospital, Hamilton Health Sciences  
Senior Scientist, Population Health Research Institute 
 
 
 
AMENDMENTS: 
 
1.   
2. 
3. 
4. 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
2 
  
Coordinating Investigator Agreement: 
 
I have read this protocol and agree to abide by all provisions set forth within.  I agree to comply with 
the International Conference on Harmonization Tripartite Guideline on Good Clinical Practice. 
 
 
 
Professor Ken Butcher 
Division of Neurology 
University of Alberta 
Signature:      ____________________________ 
 
Date:  
____________________________ 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
3 
Synopsis	  
 
Study Title: 
Canadian Pradaxa Acute Stroke Safety Study (CPASS) 
 
 
 
Protocol Number: 
CSC2012-01 
 
 
Development Phase: 
Phase IV Registry 
 
 
Indication: 
Minor Stroke (NIHSS Score ≤ 3) and Transient Ischemic 
Attack Patients with a known history of or demonstrated 
atrial fibrillation (paroxysmal or persistent), who can be 
treated with dabigatran following stroke. 
 
 
Study Drugs: 
(Including test, 
comparator, dosage 
form, dosing regimen 
and route) 
Dabigatran Etexilate 
Dose: 150 mg PO BID OR 110 mg PO BID (dose 
determined by patient age and renal function) 
Route: PO 
 
Comparator : None (open label, single arm trial) 
 
 
 
No. Subjects: 
500 
 
 
No. Centres: 
15 centres within Canada 
 
 
Study Duration: 
2 years. Patients will participate in the trial for 1 month. 
 
 
Objectives of the 
Study: 
The primary aim of the CPASS registry is to demonstrate the 
safety of early anticoagulation with dabigatran following 
cardioembolic stroke. Safety will be established by 
demonstrating low rates of hemorrhage in this setting.  
 
 
Study Endpoints: 
(Primary and 
Secondary) 
Primary Outcome 
Symptomatic Hemorrhagic Transformation Rate (PH2) 
associated with clinical deterioration, defined as worsening 
of NIHSS score of 4 or more points within 30 days of 
initiating dabigatran therapy. 
 
Secondary Outcomes 
Any parenchymal haemorrhage (PH1 or PH2) on follow-up 
CT scan at 7±2 days post-enrolment  
Symptomatic hemorrhagic transformation rate (defined as 
above) in patients treated with warfarin prior to the index 
stroke/TIA. 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
4 
Recurrent TIA/Ischemic Stroke within 30 days of enrolment 
Systemic hemorrhagic complication rate within 30 days of 
enrolment 
 
 
Study Design: 
Multicentre, prospective, open-label, single arm phase IV 
study. 
 
 
Eligibility Criteria 
(Inclusion and 
Exclusion) 
Inclusion criteria 
1. All patients will be ≥ 18 years of age. 
2. Minor ischemic stroke, defined as NIHSS score ≤ 3. 
Transient Ischemic Attack (TIA), defined as acute 
focal neurological deficits, with complete resolution 
of symptoms within 24 h of onset. In cases where 
onset time cannot be established, it will be 
considered to be the time when the patient was last 
known to be well. 
3. Atrial Fibrillation (AF, paroxysmal or persistent). AF 
must be confirmed with ECG/Holter monitor, or by 
history All patients prescribed dabigatran according 
to the Canadian product label by the treating 
physician following their stroke/TIA. The decision to 
treat with dabigatran and the timing of the first dose 
will be determined by the attending physician, 
independent of the registry. All patients will have a 
CT scan or MRI, with findings consistent with an 
ischemic etiology of symptoms. 
4. Ability to obtain informed consent obtained from 
patient or legally authorized representative.  
 
Exclusion criteria 
1. Acute or chronic renal failure, defined as eGFR <30 
ml/min (Cockcroft Gault formula). 
2. Known hypersensitivity to dabigatran or any other 
contraindication to dabigatran therapy, as per 
Canadian label information. 
3. Prior treatment with dabigatran or any other novel 
oral 
anticoagulant 
(including 
all 
Factor 
Xa 
antagonists). Treatment with warfarin prior to the 
stroke/TIA is acceptable, but enrolment cannot begin 
until the INR is ≤1.5. 
4. Prior symptomatic ischemic stroke (TIA is not an 
exclusion criterion)  
5. Any significant ongoing systemic bleeding risk, i.e. 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
5 
active GI/GU bleeding or recent major surgery. 
6. Clinically significant recent past history or clinical 
presentation of ICH, subarachnoid haemorrhage 
(SAH), arterio-venous (AV) malformation, 
aneurysm, or cerebral neoplasm. At the discretion of 
each Investigator. 
7. Hereditary or acquired hemorrhagic diathesis.  
8. Anticipated inability to comply with follow up. 
9. Any condition that, in the judgment of the 
investigator could impose hazards to the patient if 
study therapy is initiated or affect the participation of 
the patient in the study.  
 
 
Study Procedures: 
 
This is a phase IV registry study. No additional procedures 
are included in the study. Standard clinical data will be 
collected. This will include a physical examination and 
NIHSS score assessment at baseline. 
In addition, all neuro-imaging will be collected. Standard 
imaging includes a non-contrast CT brain at baseline and  
7±2 days post-treatment. 
Repeat NIHSS score assessment at the time of the 7 day CT 
scan. 
Repeat clinical and NIHSS score assessment 30 days post-
enrolment will also be collected when performed as part of 
standard care. 
 
 
Safety 
Parameters/analysis: 
An independent DSMB will be sent blinded outcome data, 
including all cases with symptomatic or asymptomatic 
parenchymal haemorrhage. The DSMB will review adverse 
events after every 100 patients recruited.  
 
 
Imaging 
Parameters/Analysis 
All imaging data collected as part of standard care will be 
sent to the core imaging lab for analysis. 
Image Analysis. Dicom CT data will be transferred to the 
Stroke Imaging Laboratory at the University of Alberta for 
post-processing and analysis.  All image assessments will be 
performed using the Quantomo software package (Cybertrial 
Inc, Calgary, AB).  
All cases of hemorrhagic transformation seen on day 7 scans 
will be graded using the ECASS (European Cooperative 
Acute Stroke Study) hemorrhage classification scheme:1 
1. PH2 - parenchymal hemorrhage as a blood clot in more 
than 30% of the infarcted area with substantial space-

CPASS                                                                                                              K. Butcher and M. Sharma 
 
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occupying effect. 
2. PH1 - parenchymal hemorrhage as blood clots in 30% or 
less of the infarcted area with some slight space-
occupying effect. 
3. HT2 - hemorrhagic transformation 2 - confluent 
petechiae within the infarcted area but no space-
occupying effect. 
4. HT1 - hemorrhagic transformation 1 – small petechiae 
along the margins of the infarct. 
5. R - remote ICH, i.e. not topographically related to the 
infarct (most often in the contralateral hemisphere). 
A symptomatic ICH will be defined as PH2, associated with 
an NIHSS deterioration of ≥4 points. 
 
 
Laboratory 
Parameters/Analysis: 
Standard bloodwork, including aPTT, INR and TT (when 
ordered) within 20 days will be collected.  No additional 
bloodwork will be collected for the study. 
 
 
 
Sample Size 
Determination: 
 
 
There are currently insufficient data upon which to base a 
sample size. The expected rate of hemorrhagic 
transformation has never been accurately or prospectively 
documented in this population. The sample size of 500 
patients is expected to be sufficient to demonstrate the 
frequency of hemorrhagic transformation within this 
population. 
 
 
Statistical Analyses: 
 
The primary outcome will be occurrence of PH2 at 30 days. 
Secondary outcomes will be ischemic stroke, any 
intracerebral hemorrhage, MI and death. In addition we will 
compare the rate of hemorrhagic transformation in patients 
started on dabigatran within 7 days of stroke/TIA versus 
those started >7 days after symptom onset.  
Descriptive statistics will be used to describe all outcomes 
(see protocol section 7.1).   
 
 
 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
7 
Canadian Pradaxa Acute Stroke/TIA Safety Study (CPASS) 
 
Canadian Stroke Consortium  
 
 
 
 
 
 
Protocol Version 2.3 
 
 
November 14, 2013 
 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
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1. Introduction 
1.1 Medical Background 
A transient ischemic attack (TIA) has traditionally been defined as a focal neurologic deficit lasting less 
than 24 hours, but alternative definitions based on tissue injury have been more recently proposed.2 
This clinical definition has been based on the assumption that TIAs are associated with complete 
resolution of brain ischemia occurring rapidly enough to cause only transient symptoms and no 
permanent brain injury, i.e. stroke. A recently completed MRI research study at the University of 
Alberta indicates that TIA and minor stroke actually represent a continuum of symptoms secondary to 
brain ischemia.3 There is also substantial evidence that the period shortly after a TIA or minor stroke is 
one of elevated recurrent stroke risk; as high as 17% at 3 months.4, 5 We have previously reported that 
MRI markers of new infarction are actually present within 7 days of the index event in 18% of 
patients.3 TIA and minor stroke can therefore be seen as a sentinel warning for impending major stroke, 
which offers a potential window for therapeutic intervention. Given the large number of patients who 
suffer a TIA/minor stroke, it is important to identify and target those patients at highest risk for early 
recurrence. 
Treatment of Minor Stroke/TIA:  In addition to urgent and rapid investigation of stroke mechanism 
after TIA/minor stroke, a logical approach to prevent early recurrence is aggressive hyperacute 
antithrombotic therapy. This treatment strategy is aimed at preventing both recurrent thromboembolism 
and propagation of existing thrombi. In acute coronary syndrome patients, antithrombotic therapy 
consists of both anticoagulants (low molecular weight heparin) and combination antiplatelet agents 
(ASA+high dose clopidogrel, or more recently prasugrel/ticagrelor).  In TIA/stroke, the choice of 
antithrombotic agent varies with the mechanism of cerebral ischemia.  The initial therapy in most 
patients consists of antiplatelet therapy, generally ASA. Combination antiplatelet therapy is sometimes 
used empirically following TIA/minor stroke, although this may not be an ideal approach either. A 
previous trial in 392 patients demonstrated a trend towards reduction of recurrent events by day 90 
when patients were treated with a combination of ASA and clopidogrel for 90 days (Absolute Risk 
Reduction = 3.3% [95% CI -1.9, 9.4]), but this was also complicated by excess hemorrhagic events.6 In 
unselected ischemic stroke patients (treated irrespective of the presence or absence of atrial 
fibrillation), the benefits of traditional anticoagulants, particularly heparin, have been consistently 
offset by an increased incidence of intracranial hemorrhagic complications.7 The risk benefit ratio 
appears to be similar in patients with and without atrial fibrillation, although there are significant 
knowledge and evidence gaps with respect to the timing of anticoagulation in patients with 
cardioembolic stroke. 
Timing of Anticoagulation after Cardioembolic TIA/Stroke: 
It is clearly established that patients with atrial fibrillation who have suffered a stroke/TIA are at high 
risk for recurrence and require long-term anticoagulation. What is unknown is the optimal timing of 
anticoagulation after an ischemic stroke has occurred. Following cardioembolic stroke, atrial 
fibrillation patients are at risk for early recurrent thrombo-embolism.  Estimates of the rate of recurrent 
stroke in this setting vary widely.  Previous studies have indicated new ischemic strokes occur at rates 
anywhere from 3% to 20% within two weeks of the index event.8-11 This is the primary rationale for 
early anticoagulation after cardioembolic stroke. There is some evidence that early anticoagulation is 
associated with improved outcomes after ischemic stroke.12 Indeed, it has been shown that early 
heparin use does reduce recurrent ischemic stroke risk by 2.1%, but this is offset by a 1.7% increase in 
the rate of HT.13 Studies of low molecular weight and unfractionated heparin use in acute stroke have 
generally indicated these agents are associated with moderately increased risk of HT.9-11, 14 There are 
currently no data indicating the frequency of HT associated with early warfarin treatment, without 
heparin bridging. 

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Based on the above evidence, current best practice guidelines recommend against urgent 
anticoagulation in patients with moderate to severe ischemic stroke, however, due to the elevated risk 
of hemorrhagic transformation (HT) immediately after stroke.15 A specific time point at which to begin 
anticoagulation is not recommended in guideline statements.15 This clinical equipoise has resulted in 
significant variation in practice patterns. Currently, most CSC physicians base the timing of 
anticoagulation on clinical severity and infarct size, as seen on CT scan.  Most physicians will defer 
anticoagulation anywhere from 5 to 14 days after ischemic stroke when infarct volume is extensive. In 
patients with small infarct volumes, assessed with CT or MRI, however, anticoagulation is often begun 
within 24-72 hours of stroke onset, and in some cases immediately after clinical assessment and CT 
scan.   
The oral direct thrombin inhibitor dabigatran has recently been approved for the primary and secondary 
prevention of ischemic stroke in patients with atrial fibrillation. Uptake of dabigatran within the 
Canadian stroke community has been rapid. It has several advantages, relative to warfarin. These 
include superior protection from cardioembolic stroke, lower rates of intracranial hemorrhage, fixed 
doses and an absence of coagulation monitoring requirements.16 Recent discussions amongst Canadian 
Stroke Consortium (CSC) members have led to the identification of three major outstanding issues 
related to dabigatran use in patients with cerebrovascular disease: 
1. Timing of dabigatran initiation after ischemic stroke/transient ischemic attack (TIA) 
2. Safety of thrombolytic agents after ischemic stroke in patients taking dabigatran 
3. Optimal management of intracranial hemorrhage in patients taking dabigatran 
From both the population health and stroke physician perspectives, the most important clinical     
problem is the first of these issues. Approximately 20% of acute stroke/TIA is secondary to atrial 
fibrillation, which is diagnosed at the time of the stroke in the majority of cases. In addition, many 
patients with known atrial fibrillation are not treated until after an ischemic stroke.17 The timing of 
dabigatran initiation after ischemic stroke/TIA is therefore an everyday problem that must be addressed 
on stroke units across the country.  
Dabigatran and Ischemic Stroke: 
Due to the uncertain safety of anticoagulation immediately after stroke, patients with recent stroke (< 2 
weeks from symptom onset) have been excluded from clinical trials of newer anticoagulants. 
Dabigatran is unique in that unlike other antithrombotic drugs studied in cerebrovascular disease, it 
appears to be associated with a much lower risk of intracranial hemorrhagic complications, and a 
reduction in ischemic stroke.16 It is probable that dabigatran can be used safely in patients with acute 
and subacute ischemic stroke. We therefore expect that dabigatran will be associated with low rates of 
HT when administered acutely following cardioembolic stroke. Patients will therefore be protected 
from early recurrent stroke, without the concomitant increased risk of hemorrhagic complications 
associated with other anticoagulants.  
Treatment Opportunities: 
The primary benefit of early anticoagulation is a reduction in early recurrent embolic events and 
therefore improved outcomes. Dabigatran offers the possibility of rapid therapeutic anticoagulation in 
this setting, a significant benefit over the days to weeks required to achieve a therapeutic INR with 
warfarin. The complexities associated with initiating warfarin therapy result in a significant treatment 
gap. Data from the Registry of the Canadian Stroke Network indicate that nearly 50% of patients with 
cardioembolic stroke are not anticoagulated one year after their index event.17 Early treatment initiation 
is expected to result in improved rates of anticoagulation following stroke and greater adherence to 
therapy. The acute stroke period, when patients are cared for in stroke units, by specialized physicians 

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represents an opportunity to optimize therapy, including lifelong anticoagulation. If it can be 
demonstrated that dabigatran can be safely administered early after stroke, as warfarin is used 
currently, it may ultimately result in higher rates of long-term anticoagulation and consequently a 
reduction in stroke rates. The current wording in the product monograph stipulating a delay in initiation 
of dabigatran will result in continued use of warfarin in patients for whom Dabigatran would have 
greater safety and efficacy. 
Given the equipoise and variable practice patterns amongst CSC physicians, the safety of dabigatran 
after stroke can be effectively addressed using a prospective single arm study design.  We have 
sufficient variability and ischemic stroke patient volume nation-wide to ensure a broad based sample 
with respect to stroke severity and timing of dabigatran initiation. We have therefore designed a 
registry of dabigatran treatment following ischemic stroke/TIA. A unique feature of the CPASS 
registry is the central collection and reading of all imaging data. This will provide invaluable 
information related to both the nature and predictors of any HT associated with early dabigatran use. 
The CSC has successfully conducted a phase IV registry of this nature, including central image reading 
and analysis, in the past (Canadian Alteplase for Acute Stroke Effectiveness Study).18 
1.2 Drug Profile 
Proprietary name: Dabigatran etexilate (INN). The pro-drug dabigatran etexilate is used in its salt form 
dabigatran etexilate mesilate (BIBR 1048 MS). 
Chirality: Dabigatran etexilate mesilate has no chiral centres and therefore does not form enantiomers. 
Geometric isomers (tautomers) are possible.  
Physical Appearance: Yellow-white to yellow powder. The crystals have a rod-like habit.  
Melting Point: 180 ± 3 °C (DSC: 10 K min-1 heating rate)  
Dissociation Constants: pKa1 = 4.0 ± 0.1, pKa2 = 6.7 ± 0.1  
Apparent Partition Coefficient: The partition coefficient of the neutral form (free base) is log P = 3.8  
Hygroscopicity: Non-hygroscopic  
pH-Solubility Profile: Solubility is strongly pH dependent with increased solubility at acidic pH. The 
solubility in water is 1.8 mg/mL 
 
2. Canadian Pradax Acute Stroke/TIA Safety Study (CPASS) Rationale and Objectives 
2.1 Rationale 
Ideally, anticoagulation should be started as soon as possible following a stroke/TIA in patients with 
new or previously diagnosed atrial fibrillation. This prevents early recurrent events and also ensures 
long-term secondary prevention strategies are implemented at the point of maximum medical contact, 
which is always at the time of the acute event. The rate of hemorrhagic complications associated with 
older anticoagulants has never been well characterized, but is recognized as a genuine risk that must be 
considered and generally delays anticoagulation.  As described above, intracranial hemorrhagic 
complication rates in dabigatran-treated patients are markedly lower than those associated with older 
anticoagulants. Thus, dabigatran is hypothesized to be an ideal drug for early anticoagulation after 
acute stroke/TIA. 
Although aggressive antithrombotic therapy has been shown to reduce the number of new ischemic 
events following stroke/TIA, this has always been offset by an increase in the risk of hemorrhagic 
complications. Dabigatran appears to be much safer with respect to intracranial bleeding and therefore 
offers a unique treatment opportunity in these high-risk patients. A registry will provide critical 
reassurance to stroke clinicians concerned about precipitating hemorrhagic transformation. If it can be 

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demonstrated to be safe, early treatment with dabigatran can be recommended, which may lead to 
lower rates of cardioembolic stroke recurrence. In addition, this will facilitate optimal treatment of 
patients who require long-term anticoagulation after ischemic stroke. 
2.2 Study Objectives 
1. Demonstrate the safety of early dabigatran initiation after minor stroke/TIA in patients with atrial 
fibrillation. 
2. Determine the frequency of asymptomatic hemorrhagic transformation after 7 days of dabigatran 
treatment following stroke/TIA 
3. Determine the effect of asymptomatic hemorrhagic transformation on functional and neurological 
outcome at 30 days. 
2.3 Risk-Benefit Assessment 
The risk of recurrent stroke after TIA/minor stroke in AF patients is estimated to range from 3-20%. It 
is expected that early anticoagulation will reduce the rate of re-emoblization by at least 85%. The risk 
of symptomatic hemorrhagic transformation in patients administered heparin within one week is 1.7%. 
Intracranial hemorrhagic complication rates in RE-LY were 1/3 that of warfarin. We hypothesize that a 
similar pattern of increased safety with respect to intracranial hemorrhagic complications will be seen 
in the acute setting. Thus, symptomatic hemorrhagic transformation rates of 0.6% are expected, which 
is comparable to the rate seen in patients treated with antiplatelet agents alone. The major expected 
benefit of this study is early anticoagulation, resulting in fewer cases of prolonged delays to the 
initiation of appropriate secondary prevention therapy. 
3. Canadian Pradax Acute Stroke/TIA Safety Study (CPASS) Design 
3.1 Study Aim and Design: The primary aim of the CPASS registry is to demonstrate the safety of 
early anticoagulation with dabigatran following cardioembolic stroke. CPASS is a prospective open 
label single arm observational study. Safety will be established by demonstrating low rates of 
hemorrhage in this setting. 
3.1.1 Administrative Structure: CPASS is a Canadian Stroke Consortium led study. The study 
coordinating centre is at the University of Alberta. Case report forms and data monitoring will be 
completed electronically, using an online EDC system. All imaging data will be read centrally at the 
Stroke Imaging Laboratory at the University of Alberta. 
3.2 Study Design Considerations: A randomized controlled design was considered (dabigatran versus 
warfarin). This is considered impractical for a number of reasons. Novel oral anticoagulants are 
recommended as first line agents for stroke prevention in AF patients by the Canadian Cardiovascular 
Society.19 These agents are associated with improved safety with respect to bleeding complications. 
This makes randomization of a patient to warfarin who would otherwise be prescribed dabigatran 
somewhat ethically dubious. In addition, a randomized design would necessitate a very large study, 
which would not be completed in a reasonable period of time. A registry design allows us to address 
the question of safety in a systematic fashion. A safety threshold has been defined for any 
anticoagulant use early after stroke, based on the rates of warfarin-associated intracranial hemorrhage, 
which have been reported to be 0.5 to 2.5 per 100 patient years.20-24 The registry design therefore 
permits determination of whether or not dabigatran is within this threshold. Finally, the systematic 
collection of clinical and imaging data will allow us to determine any risk factors for hemorrhagic 
transformation associated with early anticoagulation.  
3.3 Selection of Population.  A log of all patients included in the study (consent obtained) will be 
maintained at the trial coordinating centre, irrespective of whether they are treated or not. Only patients 
actually treated with dabigatran will be followed in the registry. Basic patient demographics, ethnicity, 
stroke severity (NIHSS), medications, including previous warfarin use, previous stroke/TIA, other co-

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morbidities, particularly hypertension, diabetes, hypercholesterolemia and ischemic heart disease, 
CHADS-Vasc, HAS-BLED, history of gastrointestinal or other hemorrhage will all be recorded 
(Appendix 1).  
3.3.1 Patients. Male and female patients with acute TIA or ischemic stroke will be recruited from the 
Emergency Departments and stroke units at CSC investigator sites. All patients will have documented 
evidence of atrial fibrillation (permanent or paroxysmal). Informed consent will be obtained from 
patients or surrogate decision makers prior to enrolment in all cases.  
3.3.2 Inclusion Criteria. All patients will be 18 years or older. Eligible patients will have ischemic 
stroke (NIHSS score ≤ 3) or TIA (complete resolution of focal neurological deficits within 24 hours) 
and atrial fibrillation (paroxysmal or persistent). The decision to treat with dabigatran and the timing of 
the first dose will be determined by the attending physician, independent of the registry. In cases where 
stroke onset time cannot be established, it will be considered to be the time when the patient was last 
known to be well. All patients will have a CT scan or MRI, with findings consistent with an ischemic 
etiology of symptoms. Patients taking warfarin prior to the stroke/TIA will be eligible, but INR must 
be ≤1.5 prior to initiation of dabigatran.  
3.3.3 Exclusion Criteria. Patients in whom dabigatran is contraindicated according to the Canadian 
product monograph will not be eligible. , i.e. severe renal failure or significant ongoing bleeding risk, 
will not be eligible. These specific contraindications in the Canadian product monograph at the time 
are:  
• 
Severe renal impairment (CrCl < 30mL/min)  
• 
Hemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or 
pharmacological impairment of hemostasis  
• 
Lesions at risk of clinically significant bleeding, e.g. extensive cerebral infarction (hemorrhagic 
or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding  
• 
Concomitant treatment with strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole 
• 
Known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the 
formulation or component of the container 
• 
Concomitant treatment of dabigatran etexilate with any other anticoagulant, including 
unfractionated heparin (UFH), except at doses used to maintain a patent central venous or 
arterial catheter, low molecular heparins (LMWH), such as enoxaparin and dalteparin, heparin 
derivatives, such as fondaparinux, anti-thrombin agents, such as bivalirudin, and oral 
anticoagulants, such as warfarin, rivaroxaban, apixaban, except under circumstances of 
switching therapy to or from dabigatran 
• 
Presence of prosthetic heart valve(s) requiring anticoagulation due to valvular status itself 
 
Patients with a history of symptomatic ischemic stroke prior to the index event will not be eligible. 
All patients taking dabigatran or any other novel oral anticoagulant (including all Factor Xa 
antagonists) prior to the stroke will be ineligible. Individuals on warfarin at the time of the incident 
event are eligible, provided the INR is ≤1.5 prior to initiation of dabigatran. 
4.0 Treatments 
4.1 Prescribed Study Treatments. Patients in whom dabigatran is initiated within 14 days of 
TIA/stroke symptom onset will be included in the registry. The timing of initiation of therapy within 
that 14 day window will be determined by the treating physician. The factors related to physician 
choice of initiation time (relative to symptom onset) will be recorded (appendix 5). 

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13 
4.1.1 Identity of test products and comparators. NA. 
4.1.2 Treatment Group Assignment. NA. 
4.1.3 Selection of Dose. Patients will be treated either at a dose of 110 mg BID or 150 mg BID. The 
dose will be determined by treating physician. The physician rationale for the dose selected will be 
recorded in all cases (appendix 6). 
5. Variables and Assessment. 
5.1.1 Effectiveness. This is a registry of the safety of early anticoagulation (see 5.2). A measure of the 
effect of early anticoagulation will be assessed; the rate of new ischemic stroke/TIA occurrence within 
the 30-day study period will be recorded. It is recognized that the event rate will be low and the study is 
neither designed, nor powered to demonstrate a decrease in early ischemic stroke rates. 
5.1.2 Primary Outcome (Safety). The primary study outcome measure is the symptomatic hemorrhagic 
transformation rate (PH2 associated with clinical deterioration, defined as worsening of NIHSS score 
of 4 or more points, within 30 days of initiating dabigatran therapy). 
5.1.2 Secondary Outcomes.  
The rate of any objective hemorrhagic transformation on the day 7 post-dabigatran initiation non-
contrast CT scan.  
The rate of secondary hemorrhagic transformation in patients taking warfarin prior to the stroke/TIA.  
The rate of hemorrhagic transformation in patients started on dabigatran within 7 days of stroke/TIA 
versus those started >7 days after symptom onset. Recurrent TIA/Ischemic Stroke within 30 days of 
dabigatran initiation. 
Systemic hemorrhagic complication rate within 30 days of dabigatran initiation. 
The rate of hemorrhagic transformation in patients started on dabigatran within 7 days of stroke/TIA 
versus those started >7 days after symptom onset.  
5.2 Assessment of Adverse Events.  
5.2.1 Definitions of Adverse Events.  
Adverse Event. An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship with this 
treatment. 
Serious Adverse Event. A serious adverse event (SAE) is defined as any AE which results in death, is 
immediately life-threatening, results in persistent or significant disability/incapacity, requires or 
prolongs patient hospitalization, is a congenital anomaly/birth defect, or is to be deemed serious for any 
other reason if it is an important medical event when based upon appropriate medical judgment which 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definitions. 
Intensity of Adverse Event. The intensity of the AE should be judged based on the following: 
1. Mild: the adverse event is temporary and easily tolerated by the subject; 
2. Moderate: the adverse event causes the subject discomfort and interrupts the subject’s normal 
activities.  

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3. Severe: the adverse event causes considerable interference with the subject’s normal activities and 
may be incapacitating or life threatening including hospitalization or prolongation of hospitalization. 
 
Causal Relationship of Adverse Event.  Medical judgment should be used to determine the relationship, 
considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant disease and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
 
Yes: There is a reasonable causal relationship between the product administered  and the AE. 
No: There is no reasonable causal relationship between the product administered  and the AE. 
Worsening of the underlying disease or other pre-existing conditions will be recorded as an (S)AE in 
the CRF. 
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an 
(S)AE in CRF, if they are judged clinically relevant by the investigator. 
5.2.2 Adverse Event Reporting. Investigators will report AEs using standardized event, resolution and 
association codes. The SAE reporting period includes the entire study duration (1 month) and an 
additional three days. All  acute coronary syndromes (ACS) will be reported. 
The Principal Investigator shall forward all (1) SAEs and non-serious AEs relevant to the reported SAE 
and (2) non-serious AEs which are assessed as related to the study drug by fax (1-888-723-0333) to the 
BI Safety Contact Point (Dr. Ralph Ferguson). 
For forwarding SAEs, any non-serious AE relevant to the reported SAE, and all related non-serious 
AEs, the Principal Investigator shall use the study specific non-interventional study AE report form. 
All reports concerning SAEs and any non-serious AEs relevant to the reported SAE, and any related 
non-serious AEs shall be forwarded to the BI Safety Contact Point immediately (within twenty four 
hours or next business day whichever is shorter). 
The Principal Investigator shall be responsible to follow up on all information regarding a reported 
Drug Exposure during Pregnancy. Principal Investigator shall ensure that any SAE / related AE during 
and after pregnancy will be reported to the BI Safety Contact Point on the study specific non-
interventional study AE report form and the timeline described above. 
The AE reporting process is further described in the Safety Data Exchange Agreement. 
 
5.2.3 Assessment of safety laboratory parameters.  
Imaging Data Collection. No additional imaging will be required for study participants. Only standard 
clinical data will be collected. Acute baseline CT scans will be collected. Dicom files will be 
transferred to a central imaging database. All patients will have a follow-up non-contrast CT scan 7±2 
days after enrolment, in order to assess for early asymptomatic hemorrhagic transformation. In the 
event of any clinical deterioration, a repeat CT scan will be performed immediately. In addition, any 
supplemental brain imaging completed within the first 30 days after enrolment will be collected. 
Image Analysis. Dicom CT data will be transferred to the Stroke Imaging Laboratory at the University 
of Alberta for post-processing and analysis.  All image assessments will be performed using software 
developed specifically for CT brain image analysis (Quantomo software package, Cybertrial Inc, 
Calgary, AB). The extent of any objective acute and chronic ischemic changes on all CT scans will be 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
15 
assessed using Alberta Stroke Program Early CT Scores (ASPECTS).25 It is expected baseline scans 
will not have evidence of acute ischemic changes, but this will be verified centrally. The extent of 
periventricular leukoariosis will also be measured using planimetric techniques and an intensity 
threshold algorithm included in the Quantomo softare package. 
All cases of hemorrhagic transformation seen on post-dabigatran treatment scans will be graded using 
the ECASS (European Cooperative Acute Stroke Study) hemorrhage classification scheme:1 
6. PH2 - parenchymal hemorrhage as a blood clot in more than 30% of the infarcted area with 
substantial space-occupying effect. 
7. PH1 - parenchymal hemorrhage as blood clots in 30% or less of the infarcted area with some slight 
space-occupying effect. 
8. HT2 - hemorrhagic transformation 2 - confluent petechiae within the infarcted area but no space-
occupying effect. 
9. HT1 - hemorrhagic transformation 1 – small petechiae along the margins of the infarct. 
10. R - remote ICH, i.e. not topographically related to the infarct (most often in the contralateral 
hemisphere). 
A symptomatic ICH will be defined as PH2, associated with an NIHSS deterioration of ≥4 points. 
6. Investigational Plan 
6.1 Visit Schedule / Clinical Data Collection. No additional procedures or assessments will be 
mandated for study participants.  Standard clinical assessments and data will be collected. This will 
include baseline National Institutes of Health Stroke Scale NIHSS, Glasgow Coma Scale (GCS) and 
vital signs, which will be recorded in a case report form. Stroke risk factors, past medical history and 
medications, baseline complete blood count, coagulation profile and renal function tests will also be 
recorded. CHADS2 and CHADSVaSC scores will also be recorded. Clinical endpoints will be 
ischemic stroke or intracranial hemorrhage within 30 days of anticoagulant initiation. All cerebral 
ischemic and intracranial hemorrhagic endpoints will be centrally adjudicated from anonymized 
clinical records, with the intracranial hemorrhages classified as described above. A data collection form 
will be filled out for each subject at 30 days post-enrolment indicating clinical status and occurrence of 
outcome events. 
6.2 Details of Study Procedures 
6.2.1 Screening and run-in procedures. NA. 
6.2.2 Treatment Period.  Patients will be treated long-term with dabigatran if deemed appropriate by 
the attending physician and the patient is in agreement. The study outcome event period is 30 days 
from drug initiation. The SAE reporting period is an additional 7 days. 
The time from symptom onset to dabigatran initiation will be recorded in the CRF. In all cases, 
dabigatran will be prescribed by a stroke neurologist participating in the registry. The location of the 
patient at the time of dabigatran initiation will be recorded (inpatient/outpatient/Emergency 
Department). 
6.2.3. End of Trial and follow-up. The registry data collection period will be complete after 30 days. 
7. Statistical Methods and Sample Size 
7.1 Statistical Analysis and Sample Size Considerations: The registry will include 500 patients. This 
sample size is considered adequate to ensure inclusion of a significant number of patients treated at a 
range of time points within the post-stroke period. The primary analysis will be done on an Intention 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
16 
To Treat basis. We will also complete a sensitivity analysis on individuals who discontinued dabigatran 
treatment and/or switched to other antithrombotic agents. Based on the inclusion/exclusion criteria, 
there will not be any individuals taking dabigatran concomitantly with other antithrombotic drugs. 
 
The primary and secondary outcomes will be defined with descriptive statistics. The rate of PH2 (and 
all other forms of hemorrhagic transformation) will be defined as a ratio (%) of the total number of 
patients enrolled in the study (ITT analysis). 
 
The primary stratification variable is warfarin use prior to the TIA/minor stroke. The secondary strata 
are 1. Dabigatran dose (150 mg BID versus 110 mg BID) and 2. Time to initiation of therapy (0-2 days, 
3-7 days and > 7 days). All results including baseline patient characteristics will be stratified by use of 
warfarin prior to the event and by the dabigatran dose after the event as described in appendices 2-4. 
 
Limitations. There are recognized limitations to this study. The eligibility criteria are consistent with a 
low risk population, and the results of this study will not be generalizable to other, higher risk 
stroke/TIA populations. Even in the population of TIA and minor stroke patients, the time between 
symptom onset and treatment initiation may vary with the severity of the clinical presentation. 
Although it is not our intention, clinicians may be more likely to initiate therapy earlier in patients with 
complete resolution of all neurological deficits. Only dabigatran treated patients will be included in this 
registry. Unintended selection bias may also arise from survival bias over the time from incident 
stroke/TIA to time of dabigatran treatment and start of follow-up. Finally this is a small (500) single 
arm study with a relatively short (30 day) follow-up period. This short time period will permit 
assessment of the most important safety variable (hemorrhagic transformation rates). It will also 
minimize loss to follow-up. Although functional outcome is generally assessed at 90 days, this pilot 
study is too small to adequately assess that endpoint.     
 
7.2 Hypotheses Statements: 
Not applicable.  The study is hypothesis generating only. 
 
7.3 Interim Analyses. No interim analyses are planned. 
 
8. Informed Consent, Data Protection, Study Records 
 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for Good 
Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). Standard medical care 
(prophylactic, diagnostic and therapeutic procedures) remains the responsibility of the treating 
physician of the patient. 
The investigator should inform Boehringer-Ingelheim immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches of the 
protocol/ICH GCP. 
 
The rights of the investigator and of Boehringer-Ingelheim with regard to publication of the results of 
the study are described in the investigator-initiated study contract. As a general rule, no study results 
should be published prior to finalization of the study report. 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
17 
8.1 Source Documents. Source documents provide evidence for the existence of the patient and 
substantiate the integrity of the data collected. Source documents are filed at the investigator site. 
Data reported in the CRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, pending on the trial; also current medical records must be 
available.  
 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
18 
 
9. References 
 
1. 
Trouillas P, von Kummer R. Classification and pathogenesis of cerebral hemorrhages after 
thrombolysis in ischemic stroke. Stroke. 2006;37:556-561 
2. 
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, 
Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, Miller E, Sacco RL. Definition and 
evaluation of transient ischemic attack: A scientific statement for healthcare professionals from 
the american heart association/american stroke association stroke council; council on 
cardiovascular surgery and anesthesia; council on cardiovascular radiology and intervention; 
council on cardiovascular nursing; and the interdisciplinary council on peripheral vascular 
disease. The american academy of neurology affirms the value of this statement as an 
educational tool for neurologists. Stroke. 2009;40:2276-2293 
3. 
Asdaghi N, Hameed B, Saini M, Jeerakathil T, Emery D, Butcher K. Acute perfusion and 
diffusion abnormalities predict early new mri lesions 1 week after minor stroke and transient 
ischemic attack. Stroke; a journal of cerebral circulation. 2011;42:2191-2195 
4. 
Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency 
department diagnosis of tia. Jama. 2000;284:2901-2906 
5. 
Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of transient 
ischemic attacks in ontario. Cmaj. 2004;170:1099-1104 
6. 
Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment 
of stroke and transient ischaemic attack to prevent early recurrence (faster): A randomised 
controlled pilot trial. Lancet Neurol. 2007;6:961-969 
7. 
Sandercock PA, Counsell C, Tseng MC. Low-molecular-weight heparins or heparinoids versus 
standard unfractionated heparin for acute ischaemic stroke. Cochrane Database Syst Rev. 
2008:CD000119 
8. 
Hallevi H, Albright KC, Martin-Schild S, Barreto AD, Savitz SI, Escobar MA, Gonzales NR, 
Noser EA, Illoh K, Grotta JC. Anticoagulation after cardioembolic stroke: To bridge or not to 
bridge? Arch Neurol. 2008;65:1169-1173 
9. 
Immediate anticoagulation of embolic stroke: Brain hemorrhage and management options. 
Cerebral embolism study group. Stroke; a journal of cerebral circulation. 1984;15:779-789 
10. 
Immediate anticoagulation of embolic stroke: A randomized trial. Cerebral embolism study 
group. Stroke; a journal of cerebral circulation. 1983;14:668-676 
11. 
Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin 
in patients with acute ischaemic stroke and atrial fibrillation: A double-blind randomised study. 
Haest study group. Heparin in acute embolic stroke trial. Lancet. 2000;355:1205-1210 
12. 
Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A. Intravenous heparin 
started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar 
hemispheric cerebral infarctions. Stroke; a journal of cerebral circulation. 2005;36:2415-2420 
13. 
The international stroke trial (ist): A randomised trial of aspirin, subcutaneous heparin, both, or 
neither among 19435 patients with acute ischaemic stroke. International stroke trial 
collaborative group. Lancet. 1997;349:1569-1581 
14. 
Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Cerebral embolism study 
group. Archives of internal medicine. 1987;147:636-640 
15. 
Adams HP, Jr., del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida 
RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott 
PA, Wijdicks EF. Guidelines for the early management of adults with ischemic stroke: A 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
19 
guideline from the american heart association/american stroke association stroke council, 
clinical cardiology council, cardiovascular radiology and intervention council, and the 
atherosclerotic peripheral vascular disease and quality of care outcomes in research 
interdisciplinary working groups: The american academy of neurology affirms the value of this 
guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711 
16. 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, 
Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, 
Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial 
fibrillation. The New England journal of medicine. 2009;361:1139-1151 
17. 
Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, Silver FL, Kapral MK. 
Potentially preventable strokes in high-risk patients with atrial fibrillation who are not 
adequately anticoagulated. Stroke; a journal of cerebral circulation. 2009;40:235-240 
18. 
Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: Results of the canadian 
alteplase for stroke effectiveness study. CMAJ. 2005;172:1307-1312 
19. 
Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, 
Nattel S. Focused 2012 update of the canadian cardiovascular society atrial fibrillation 
guidelines: Recommendations for stroke prevention and rate/rhythm control. The Canadian 
journal of cardiology. 2012;28:125-136 
20. 
Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, Singer DE. Death and 
disability from warfarin-associated intracranial and extracranial hemorrhages. The American 
journal of medicine. 2007;120:700-705 
21. 
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability 
of warfarin in the first year of therapy among elderly patients with atrial fibrillation. 
Circulation. 2007;115:2689-2696 
22. 
Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, Jensvold NG, Selby JV, 
Singer DE. Anticoagulation therapy for stroke prevention in atrial fibrillation: How well do 
randomized trials translate into clinical practice? JAMA : the journal of the American Medical 
Association. 2003;290:2685-2692 
23. 
Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunso J, Gadsboll N, Gislason GH, 
Folke F, Andersen SS, Schramm TK, Abildstrom SZ, Poulsen HE, Kober L, Torp-Pedersen C. 
Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in 
patients with atrial fibrillation. Archives of internal medicine. 2010;170:1433-1441 
24. 
Suzuki S, Yamashita T, Kato T, Fujino T, Sagara K, Sawada H, Aizawa T, Fu LT. Incidence of 
major bleeding complication of warfarin therapy in japanese patients with atrial fibrillation. 
Circulation journal : official journal of the Japanese Circulation Society. 2007;71:761-765 
25. 
Pexman JHW, Barber PA, Hill MD, Sevick RJ, Demchuk AM, Hudon ME, Hu WY, Buchan 
AM. Use of the alberta stroke program early ct score (aspects) for assessing ct scans in patients 
with acute stroke. AJNR Am J Neuroradiol. 2001;22:1534-1542 
 
 
 

CPASS                                                                                                              K. Butcher and M. Sharma 
 
20 
Appendix 1: Baseline patient characterists to be collected in case report form. 
 
Variable	  
Stratification	  (if	  applicable	  
Sex	  
M	  
F	  
Age	  
>80	  
<80	  
Prior	  TIA	  
Y	  
N	  
Prior	  Stroke	  
Y	  
N	  
Carotid	  Stenosis	  
Y	  
N	  
Carotid	  Endarterectomy	  
Y	  
N	  
Carotid	  Stent	  
Y	  
N	  
Prior	  STEMI	  
Y	  
N	  
Prior	  NSTEMI	  
Y	  
N	  
CABG	  
Y	  
N	  
Coronary	  Stent	  
Y	  
N	  
Chronic	  Renail	  Failure	  
eGFR	  <60	  >50	  ml/min	  
eGFR	  >30	  <50	  ml/min	  
Diabetes	  
Y	  
N	  
HbA1c	  
>7%	  
<7%	  
Hypertension	  
Y	  
N	  
Systolic	  BP	  at	  recruitment	  
>140	  mmHg	  
<140	  mmHg	  
Diastolic	  BP	  at	  recruitment	  
>90	  mmHg	  
<90	  mmHg	  
CHF	  history	  
Y	  
N	  
Dementia	  history	  
Y	  
N	  
Medications	  
List	  
Current	  Smoker	  
	  
	  
Ex-­‐smoker	  
	  
	  
CHADS2	  (0-­‐6)	  
	  
CHADS-­‐VASc	  (0-­‐6)	  
HAS-­‐BLED	  (0-­‐6)	  
Alcohol/drug	  abuse	  
Y	  
N	  
History	  of	  PE/DVT	  
Y	  
N	  
Impaired	  liver	  function	  
Y	  
N	  
Prior	  intracranial	  hemorrhage	  
Y	  
N	  
Prior	  GI/GU	  hemorrhage	  
Y	  
N	  
Prior	  other	  hemorrhage	  
Y	  
N	  
Prior	  cerebral	  aneurysm	  
Y	  
N	  
peripheral	  artery	  disease	  
(PAD),	  aortic	  plaque	  
Y	  
N	  
time	  since	  first	  AF	  diagnosis	  
Y	  
N	  
Previous	  cardioversion	  
Y	  
N	  
Ethnicity	  
	  
Heart	  rate	  
	  
	  
Weight/height/BMI	  
	  

 
 
21 
 
 
Appendix 2: Patient characteristics stratified by prior stroke treatment and dabigatran dose post 
TIA/stroke. 
 
	  
Treatment	  	  prior	  to	  TIA/stroke	  
	  
	  
VKA	  naive	  
VKA	  
	  
	  
Dabigatran	  dose	  post	  TIA/stroke	  
	  
Baseline	  
110	  mg	  
150	  mg	  
110	  mg	  
150	  mg	  
P	  value	  (VKA	  
niaive	  vs.	  
VKA)	  
Age,	  Sex	  
	  
	  
	  
	  
	  
Prior	  TIA	  
	  
	  
	  
	  
	  
Indext	  event	  
	  
	  
	  
	  
	  
TIA/stroke	  
	  
	  
	  
	  
	  
Treatment	  
	  
	  
	  
	  
	  
Lysis,	  surgery	  
	  
	  
	  
	  
	  
Dabigatran	  
treatment	  
initiation	  
after	  
TIA/stroke	  
	  
	  
	  
	  
	  
0-­‐2	  days	  
	  
	  
	  
	  
	  
0	  
	  
	  
	  
	  
	  
1	  
	  
	  
	  
	  
	  
2	  
	  
	  
	  
	  
	  
3-­‐7	  days	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

 
 
22 
	  
Appendix	  3:	  Patient	  characteristics	  stratified	  by	  time	  of	  treatment	  intitiation	  after	  TIA/stroke.	  
	  
Dabigatran	  treatment	  initiation	  after	  TIA/stroke	  
	  
0-­‐2	  	  days	  
3-­‐7	  days	  
>7	  days	  
Prior	  untreated	  
	  
	  
	  
110	  mg	  dabi	  (post	  
TIA/stroke)	  
	  
	  
	  
150	  mg	  Dabi	  (post	  
TIA/stroke)	  
	  
	  
	  
Prior	  VKA	  
	  
	  
	  
110	  mg	  dabi	  (post	  
TIA/stroke)	  
	  
	  
	  
150	  mg	  Dabi	  (post	  
TIA/stroke)	  
	  
	  
	  
Baseline	  charateristic	  
	  
	  
	  
Age,	  sex,	  …	  prior	  
TIA/stroke	  
	  
	  
	  
Index	  event	  
	  
	  
	  
TIA/stroke	  
	  
	  
	  
Treatment	  
	  
	  
	  
Lysis,	  surgery	  
	  
	  
	  
	  
Appendix	  4:	  Outcome	  events	  stratified	  by	  prior	  TIA/stroke	  treatment	  and	  dabigatran	  dose	  post	  TIA/stroke.	  
	  
Treatment	  	  prior	  TIA/stroke	  
	  
	  
VKA	  niaive	  
VKA	  
	  
	  
Dabigatran	  dose	  post	  TIA/stroke	  
	  
	  
110	  mg	  
150	  mg	  
110	  mg	  
150	  mg	  
	  
Symptomatic	  HT	  
	  
	  
	  
	  
	  
0-­‐2	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
3-­‐7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
>7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
Asymptomatic	  HT	  	  
	  
	  
	  
	  
	  
0-­‐2	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
3-­‐7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
>7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
Recurrent	  
Stroke/TIA	  	  
	  
	  
	  
	  
	  
0-­‐2	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
3-­‐7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
>7	  days	  after	  DE	  Initiation	  
	  
	  
	  
	  
	  
	  

 
 
23 
	  
Appendix	  5:	  Factors	  in	  physicians’s	  decision	  when	  to	  initiate	  post	  TIA/stroke	  treatment.	  
	  
Most	  important	  
Important	  
Less	  important	  
Not	  important	  
Baseline	  
characteristic	  	  
	  
	  
	  
	  
Age,	  sex,	  prior	  
TIA/stroke,	  CrCl	  
	  
	  
	  
	  
Index	  event	  
	  
	  
	  
	  
TIA	  
	  
	  
	  
	  
stroke	  
	  
	  
	  
	  
Stroke	  Severity	  
(NIHSS)	  
	  
	  
	  
	  
Infarct	  Size	  
(CT/MRI)	  
	  
	  
	  
	  
Thrombolysis	  
	  
	  
	  
	  
Previous	  
Surgery	  	  
	  
	  
	  
	  
Other	  
medications	  
(list	  drug(s)	  
factored	  in	  
decision)	  
	  
	  
	  
	  
Co-­‐morbidiities	  
(list	  those	  
factored	  in	  
decision)	  
	  
	  
	  
	  
Others	  
	  
	  
	  
	  
	  
Appendix	  6:	  Factors	  in	  physicians’	  choice	  of	  dabigatran	  dose.	  
	  
Most	  important	  	  
Important	  	  
Less	  important	  	  
Not	  important	  
Baseline	  
characteristics	  	  
	  
	  
	  
	  
Age,	  sex,	  prior	  
TIA/stroke.	  
CrCl/eGFR	  
	  
	  
	  
	  
Index	  event	  
	  
	  
	  
	  
TIA	  
	  
	  
	  
	  
stroke	  
	  
	  
	  
	  
Treatment	  
	  
	  
	  
	  
Lysis,	  surgery	  
	  
	  
	  
	  
Others