Eliquis Acute Stroke Safety Evaluation
Conditions: Ischemic Stroke, Transient Ischemic Attack, Atrial Fibrillation
Sponsor: University of Alberta

 
 
 
 
 
 
Eliquis Acute Stroke Safety Evaluation  
EASSE 
 
Version 2.0 
September 30, 2016 
 
 
 
 
 
 
 
 
Principal Investigator: 
Dr. Kenneth Butcher 
 
 
 
 
7-132D Clinical Sciences Buidling 
 
 
 
 
11350-83 Avenue 
 
 
 
 
Edmonton, Alberta T6G 2B7 
 
 
 
 
Phone: 780-248-1927 
 
 
 
 
Email: ken.butcher@ualberta.ca 
 
 

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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conduct according to all stipulations of the 
protocol, including all statements regarding confidentiality and according to local legal and 
ethical requirements and applicable Canadian regulations and ICH guidelines. 
 
Qualified Investigator/Principal Investigator 
 
 
Name:  ________________________________ 
 
 
Signed: ________________________________   Date:  ___________________(dd/mmm/yyyy) 
 
 
 
Site Name: 
_____________________________________ 
 
 
Address: 
_____________________________________ 
 
_____________________________________ 
 
_____________________________________ 
 
_____________________________________ 
 
 
 
 

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Table of Contents 
 
1.0 
Background and Rationale 
 
 
 
 
 
 
 
5 
1.1 Timing of Anticoagulation after Cardioembolic TIA/Stroke 
 
 
5 
2.0 
Study Objectives 
 
 
 
 
 
 
 
 
6 
2.1 Overall Aim and Hypothesis 
 
 
 
 
 
 
6 
2.2 Outcome Variables 
 
 
 
 
 
 
 
6 
2.2.1 Primary Outcome 
 
 
 
 
 
 
6 
2.2.2 Secondary Outcome   
 
 
 
 
 
6 
3.0 
Study Design 
 
 
 
 
 
 
 
 
 
6 
4.0 
Enrolment Criteria 
 
 
 
 
 
 
 
 
7 
4.1 Inclusion Criteria  
 
 
 
 
 
 
 
7 
4.2 Exclusion Criteria 
 
 
 
 
 
 
 
7 
5.0 
Treatment 
 
 
 
 
 
 
 
 
 
7 
6.0 
Study Procedures and Evaluations 
 
 
 
 
 
 
8 
6.1 Screening/Baseline 
 
 
 
 
 
 
 
8 
6.2 Imaging Procedures 
 
 
 
 
 
 
 
8 
6.3 Clinical Follow-up Assessments  
 
 
 
 
 
8 
7.0 
Statistics 
 
 
 
 
 
 
 
 
 
9 
8.0 
Assessment of Adverse Events  
 
 
 
 
 
 
9 
8.1 Definition of Adverse Events 
 
 
 
 
 
 
9 
8.2 Adverse Event Reporting 
 
 
 
 
 
 
9 
9.0 
Central Imaging Adjudication and Analysis 
 
 
 
 
 
10 
10.0 Funding Source  
 
 
 
 
 
 
 
 
10 
11.0 References 
 
 
 
 
 
 
 
 
 
12 
 
 

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PROTOCOL SUMMARY 
 
Title: EASSE – Eliquis Acute Stroke Safety Evaluation 
 
The Eliquis Acute Stroke Safety Evaluation (EASSE) is an investigator initiated, prospective, 
open label, single arm phase IV study. 
 
Overall Study Aims:  
1. Demonstrate the safety of early anticoagulation with apixaban following cardioembolic 
stroke and TIA. 
2. Document the rate of recurrent cerebrovascular ischemic events. 
 
Primary Outcome:  The primary endpoint is the rate of symptomatic hemorrhagic 
transformation (PH2) associated with clinical deterioration, defined as worsening of NIHSS 
score of 4 or more points within 30 days of initiating anticoagulant therapy. 
 
Secondary Outcome:  The major secondary endpoint is the rate of any parenchymal 
haemorrhage (PH1 or PH2) seen on on follow-up MRI scans at 7±2 days post-enrolment. Other 
secondary endpoints include recurrent TIA/Ischemic Stroke within 90 days of enrolment, and 
systemic hemorrhagic complication rate within 90 days of enrolment 
 
Population:  50 participants will be enrolled.  Participants are males and females, >18 years of 
age, with TIA or ischemic stroke and a known history of or demonstrated atrial fibrillation 
(paroxysmal or persistent), who can be treated with apixaban following stroke.  
 
Phase:  IV 
 
Protocol Therapy:  Patients will be treated with apixaban within 14 days of symptom onset. 
Patients fulfilling at least two (2) of the following characteristics, will have received a reduced 
dose of ELIQUIS 2.5 mg twice daily: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 
133 μmol/L (1.5 mg/dL). All other patients will have received 5 mg dose taken orally twice 
daily. 
 
Study Duration:   It is estimated that recruitment will take place over 2 years in the three 
participating centres.  Enrolment is anticipated to commence by the beginning of 2017.   
 
Subject Participation Duration:  All patients will be assessed clinically at Day 7 and Day 90. 
 
 

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1.0 Background and Rationale  
 
1.1 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. Data from 
the Ontario Stroke Registry demonstrated that half of the ischemic stroke cases occurred within 
the first 2 days after the initial event. 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. 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. 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. There are 
currently no data indicating the frequency of HT associated with early warfarin treatment, 
without heparin bridging. 
 
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. A specific time point at which 
to begin anticoagulation is not recommended in guideline statements. 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.   
 
Currently, the Alliance has no data related to early use of apixaban after TIA or ischemic stroke. 
In ARISTOTLE, patients were not eligible for enrolment/randomization within 7 days of 
ischemic stroke or TIA. The contraindications section of the product monograph states apixaban 
should not be used in patients with ‘Lesions or conditions at increased risk of clinically 
significant bleeding, e.g., recent cerebral infarction (ischemic or hemorrhagic)’. This is therefore 
an area of clinical equipoise. As with warfarin (with/without heparin bridging), stroke specialists 
will make individual treatment decisions, based primarily on the extent of infarction visible on 
CT brain scan. 
 
Although a randomized study of delayed versus early anticoagulation with apixaban will ideally 
answer this question, at the moment, there is no feasibility or safety data. There is also 
insufficient data in the present literature to indicate what the true event rates for both 
symptomatic hemorrhagic transformation and recurrent cerebral ischemia are. These data can be 
obtained by prospectively collecting clinical and imaging data from patients who are treated, as 
per standard clinical practice in most Canadian stroke centres, within this 7-day period of clinical 

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uncertainty. The results of this registry will be used to assess the safety and feasibility of a larger 
randomized controlled trial of early versus delayed apixaban use after stroke/TIA. 
 
 
2.0 Study Objectives 
 
2.1 Overall Aim and Hypothesis 
 
The primary aim of the Eliquis Acute Stroke Safety Evaluation registry is to demonstrate the 
safety of early anticoagulation with apixaban following cardioembolic stroke and TIA. Safety 
will be established by demonstrating low rates of hemorrhage in this setting. The secondary 
study objective is to document the rate of recurrent cerebrovascular ischemic events. It is fully 
recognized that this uncontrolled registry study is not properly designed and underpowered to 
demonstrate a reduction in cerebrovascular ischemic events.  
 
We hypothesize that early initiation of apixaban within the first 14 days of stroke or TIA is not 
associated with increased symptomatic intracranial haemorrhage. 
 
2.2 Outcome Variables 
 
2.2.1 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 anticoagulant therapy. 
 
2.2.2 Secondary Outcomes: 
 
1. Any parenchymal haemorrhage (PH1 or PH2) on follow-up MRI scan at 7±2 days 
post-enrolment. 
2. Recurrent TIA/Ischemic Stroke within 90 days of enrolment. 
3. Systemic hemorrhagic complication rate within 90 days of enrolment. 
 
 
3.0 Study Design 
 
The Eliquis Acute Stroke Safety Evaluation (EASSE) is an investigator initiated, prospective, 
open label, single arm phase IV study.  
 
Consecutive patients with atrial fibrillation (new onset or previous history) with acute ischemic 
stroke or TIA will be screened from Emergency Department or stroke unit. A total of 50 male 
and female patients will be recruited within 24 hours of initiation of apixaban after TIA or 
stroke. Informed consent will be obtained from the patient or substitute decision maker, in all 
cases prior to enrolment. Patients will be approached by the Stroke team or stroke unit attending 
physicians participating in the trial.  
 

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4.0 Enrolment Criteria 
 
4.1 Inclusion Criteria 
1. Male or female patients 
2. Must be ≥ 18 years of age.  
3. Diagnosis of minor ischemic stroke, or 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 
patient was last known to be well.  
4. CT scan or MRI, with findings consistent with an ischemic etiology of symptoms. 
5. Atrial Fibrillation (AF, paroxysmal or persistent), confirmed with ECG/Holter monitor, 
or by history (clinical documentation of previous AF must be provided).  
6. Patients prescribed apixaban by their treating physician following their stroke/TIA. 
7. Ability to obtain consent from patient or legally authorized representative. 
 
Note: The decision to treat with apixaban and the timing of the first dose will be determined by 
the attending physician, independent of the registry. Consent to participate in the registry will be 
obtained only after the treating physician has made the decision to initiate apixaban therapy 
within 14 days of stroke/TIA. 
 
4.2 Exclusion Criteria 
1. Acute or chronic renal failure, defined as eGFR <30 ml/min (Cockcroft Gault formula). 
2. Known hypersensitivity to apixaban.  
3. Prior treatment with apixaban 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 ≤2.0. 
4. Any significant ongoing systemic bleeding risk, i.e. active GI/GU bleeding or recent 
major surgery. 
5. 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.  
6. 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 haemorrhagic diathesis. 
8. Stroke mimics (such as seizures, migraine etc.) 
9. Contraindications to MRI, including metallic implants. 
 
 
5.0 Treatment 
 
Patients in whom apixaban 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. Patients fulfilling at least two of the following 
characteristics, will have received a reduced dose of ELIQUIS 2.5 mg twice daily: age ≥ 80 
years, body weight ≤ 60 kg, or serum creatinine ≥ 133 μmol/L (1.5 mg/dL). All other patients 
will have received a 5 mg dose to be taken orally twice daily. 

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6.0 Study Procedures and Evaluations 
 
6.1 Screening/Baseline 
 
The screening/baseline visit will be conducted within 24 hours of the initiation of apixaban in the 
patient as decided by their treating physician. All stroke patients will initially be screened with a 
non-contrast CT scan of the brain (standard of care). 
 
Standard clinical assessments and data will be collected. This will include baseline National 
Institutes of Health Stroke Scale (NIHSS), Premorbid Modified Rankin Scale (mRS), Montreal 
Cognitive Score (MoCA) and vital signs, which will be recorded in a case report form. Past 
medical history and medications, baseline complete blood count, coagulation profile and renal 
function tests will also be recorded. 
 
6.2 Imaging Procedures  
 
6.2.1 MRI Study 1: Performed within 24 hours of recruitment 
 
All MRI sequences will be completed in approximately 20 minutes. The MRI protocol 
will consist of a T1-weighted sagittal localizer, time of flight MRA and diffusion-
weighted (DWI) and perfusion-weighted images (PWI; in patients without any 
contraindications to gadolinium contrast). Single shot Echoplanar (EPI) DWI images 
obtained using diffusion gradient strengths (b values) between 0 s/mm2, equivalent to a 
T2-weighted image, and 1000 s/mm2, applied in 3 orthogonal planes, will be obtained. 
The DWI acquisition parameters will be: repetition time (TR) of 3 s, spin echo time (TE) 
of 86 ms, 8 averages, 128x128 matrix base resolution zero filled to 256x256, 22 cm field-
of-view, and 1396 Hz/pixel acquisition bandwidth. The entire brain will be imaged using 
19 contiguous axial slices each 5 mm in thickness, with a 1.5 mm inter-slice gap. 
 
6.2.2 MRI Study 2: Imaging studies repeated at day7 (±2 days) 
 
All imaging sequences including susceptibility weighted imaging will be repeated at day 
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. We 
hypothesize micro-hemorrhages may predict symptomatic bleeding. In addition, any 
supplemental brain imaging completed within the first 30 days after enrolment will be collected. 
 
6.3 Clinical Follow-up Assessments 
 
All patients will be followed for 90 days. This is the standard post-stroke assessment period (the 
majority of neurological and functional recovery occurs within this time frame). Patients will be 
assessed clinically at follow-up visits performed on Day 7(±2 days), and Day 90 (± 30 days) by a 
study team member (i.e. co-investigator, study coordinator). At each visit, vital signs will be 
noted, a comprehensive neurologic examination will be performed and mRS, NIHSS and MoCA 

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assessments will be conducted with the patient. Patients will be interviewed in detail to identify 
and ascertain any recurrent vascular event suggestive of a stroke or TIA. Work-up to determine 
the underlying etiology of stroke will be reviewed and any change in management plan will be 
recorded. 
 
 
7.0 Statistics 
 
The primary outcome will be tested with a single sample t-test. The null hypothesis is that the 
frequency of symptomatic hemorrhagic transformation is <2%. A convenience sample of 50 
patients is planned initially. This will provide initial safety and feasibility data that can be used to 
plan future definitive studies as required. The primary efficacy analysis will be on an intention-
to-treat basis. 
 
 
8.0 Assessment of Adverse Events 
 
8.1 Definition 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.  
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. 
 
8.2 Adverse Event Reporting 
 
Investigators will report serious adverse events (SAE), using standardized event, resolution and 
association codes. The SAE reporting period includes the entire study duration (3 months) and an 
additional week. All SAEs will be reported. Non-serious Adverse Events (AEs) unrelated to 
Apixaban treatment will not be reported. 
 

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9.0 Central Imaging Adjudication and Analysis 
 
Dicom CT and MRI 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 assessed using Alberta Stroke Program Early CT Scores (ASPECTS). The 
extent of subacute ischemic changes will also be assessed using the day 1 MRI (Diffusion-
Weighted Imaging sequences). Infarct volumes will be measured objectively using planimetric 
techniques. The extent of periventricular leukoariosis will also be measured using planimetric 
techniques and an intensity threshold algorithm included in the Quantomo software 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. PH2 - parenchymal hemorrhage as a blood clot in more than 30% of the infarcted area 
with substantial space-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 (primary endpoint) will be defined as PH2, associated with an NIHSS 
deterioration of ≥4 points. The primary endpoint will be assessed using the day 7 MRI scan and 
any additional scans performed within 30 days of apixaban initiation. 
 
 
10.0 Funding Source 
 
This investigator-initiated study is funded by the Alliance. The funding will be used for MR 
imaging. 
 
 
 
 

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Figure 1: Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute Ischemic Stroke or TIA 
Atrial Fibrillation 
Yes 
No 
Excluded 
Apixaban independently initiated within 14 
days of symptom onset by attending physician  
Informed Consent obtained  
Day 1 MRI and clinical data obtained 
Day 7 MRI and clinical data obtained 
Day 90 clinical data obtained 
Yes 
No 
Excluded 

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12.0 References 
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department diagnosis of tia. JAMA : the journal of the American Medical Association. 
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Tendera M, Syzdol M, Parma Z. Aristotle re-lys on the rocket. What's new in stroke 
prevention in patients with atrial fibrillation? Cardiology journal. 2012;19:4-10 
3. 
Gladstone DJ1, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of 
transient ischemic attacks in Ontario. CMAJ. 2004 Mar 30;170(7):1099-104. 
4. 
Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A. Intravenous 
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4. 
The international stroke trial (ist): A randomised trial of aspirin, subcutaneous heparin, 
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5. 
Adams HP, Jr., del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines 
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heart association/american stroke association stroke council, clinical cardiology council, 
cardiovascular radiology and intervention council, and the atherosclerotic peripheral 
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educational tool for neurologists. Stroke; a journal of cerebral circulation. 2007;38:1655-
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6. 
Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein AL, et 
al. Validation and refinement of scores to predict very early stroke risk after transient 
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8. 
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Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly 
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Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements 
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van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver 
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Sims JR, Gharai LR, Schaefer PW, Vangel M, Rosenthal ES, Lev MH, et al. Abc/2 for 
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13. 
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Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous 
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