Canadian Pradaxa Acute Stroke Safety Study (CPASS)

Study Design:

This is a multicentre, prospective, open-label, single arm, 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.

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Ischemic Attack, Transient
• Intervention / Treatment: Drug: Dabigatran

Detailed Description

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.

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.

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.

Prescribed Study Treatments:

Patients in whom dabigatran is initiated within 14 days of TIA/stroke symptom onset will be included in the registry. Patients will be treated either at a dose of 110 mg BID or 150 mg BID. The dose and 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.

Visit Schedule / Clinical Data Collection:

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.

• Study Type: Observational
• Enrollment (Actual): 101

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Minor Stroke (NIHSS Score ≤ 3) and Transient Ischemic Attack Patients ≥ 18 years of age, with a known history of or demonstrated atrial fibrillation (paroxysmal or persistent), who can be treated with dabigatran following stroke.

Description

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. 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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic Hemorrhagic Transformation Rate (PH2)	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.	30 days post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any Parenchymal Haemorrhage (PH1 or PH2)	Any parenchymal haemorrhage (PH1 or PH2) on follow-up CT scan at 7±2 days post-enrolment.	7 days post-enrollment
Symptomatic Hemorrhagic Transformation Rate	Symptomatic hemorrhagic transformation rate (defined as above) in patients treated with warfarin prior to the index stroke/TIA.	30 days post enrolment
Recurrent TIA/Ischemic Stroke	Monitoring and documentation of recurrent TIAs or Ischemic Stroke occuring in participants of both arms	30 days post enrolment
Systemic Hemorrhagic Complication Rate	Monitoring and documentation of the number of the rate of hemorrhagic complications for participants in either arm of the study.	30 days post enrolment

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Boehringer Ingelheim

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): March 31, 2018
• Study Completion (Actual): May 18, 2018

Study Registration Dates

• First Submitted: April 9, 2015
• First Submitted That Met QC Criteria: April 9, 2015
• First Posted (Estimate): April 14, 2015

Study Record Updates

• Last Update Posted (Actual): June 19, 2020
• Last Update Submitted That Met QC Criteria: June 8, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Stroke; Ischemic Attack, Transient; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran
• Other Study ID Numbers: CSC2012-01