Intravenous Thrombolytic Therapy in Acute Ischemic Stroke Patients on DOAC (DOAC-IVT)

Intravenous Thrombolytic Therapy in Acute Ischemic Stroke Patients on Direct Oral Anticoagulants - A Prospective Multicenter Study

Direct oral anticoagulants (DOAC) have emerged as safe and efficacious ischemic stroke prophylaxis for non-valvular atrial fibrillation (NVAF). All four DOACs - apixaban, dabigatran, edoxaban, rivaroxaban - were associated with lower risks of major bleeding compared to warfarin. Listed as core essential medicines by the World Health Organization, DOAC prescriptions have been surging worldwide. In Hong Kong, approximately 80,000 patients received DOACs from January 2009 through December 2022 according to the Hospital Authority registry.

The widespread DOAC usage had created DOAC-specific clinical dilemmas that lack evidence-based treatment despite twenty years of prescribing experience. Ischemic stroke despite DOAC (IS-DOAC), in particular, may occur in up to 6% of DOAC users annually. Due to the in vivo anticoagulation effect, there had been concerns of intracerebral bleeding (ICH) with intravenous thrombolytic therapy (IVT) for acute IS-DOAC. Under the current guideline recommendations, most acute IS-DOAC are contraindicated to IVT (see Intravenous thrombolytic therapy), which resulted in only a small proportion of acute ISDOAC patients being able to receive IVT even if presented early. Nonetheless, our group found that majority of patients had a DOAC level of <50ng/mL only 24 hours after DOAC cessation (see work done by us), a level deemed clinically negligible and safe for thrombolytic therapy. Together with evolving clinical evidence discussed below, IS-DOAC patients maybe unnecessarily barred from IVT, thus compromised functional recovery.

With robust pharmacokinetic and retrospective clinical evidence to support, it is hypothesized that IVT are safe in IS-DOAC patient. The investigators hereby propose a prospective multicenter study to determine the efficacy and safety of IVT in acute IS-DOAC.

Study Overview

• Status: Not yet recruiting
• Conditions: CVA (Cerebrovascular Accident)
• Intervention / Treatment: Drug: alteplase or tenecteplase

Detailed Description

In this prospective cohort study, the investigators aim to recruit consecutive DOAC users with IS-DOAC who meet the inclusion criteria. The investigators aim to determine the safety and efficacy of IVT among DOAC patients with acute ischemic stroke. It is hypothesized that compared to a matched cohort of patients with acute IS-DOAC excluded from IVT, IVT in IS-DOAC patients with a last-DOAC-ingestion of 12-48 hours improves neurological outcomes with an acceptable safety profile.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yiu Ming Bonaventure Ip; Phone Number: +85226352152; Email: bonaventureip@cuhk.edu.hk
• Study Contact Backup: Name: Trista Hung; Phone Number: +85226352152; Email: tristahung@cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Chinese University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Acute ischemic stroke patients with a last-known-well to presentation time within 4.5 hours
2. Patients who took any doses of apixaban (2.5mg or 5mg twice daily), dabigatran (110mg or 150mg twice daily), edoxaban (30mg or 60mg daily) or rivaroxaban (15mg or 20mg daily) 12-48 hours before presentation
3. National Institute of Health Stroke Scale (NIHSS) ≥ 3
4. Alberta Stroke Programme Early CT (ASPECT) score ≥ 6
5. Pre-morbid modified Rankin Scale (mRS) ≤ 3
6. Patients aged ≥ 18 years old

Exclusion Criteria:

1. Initial CT brain showing intracranial haemorrhage
2. Contraindications to IVT according to current guideline recommendations [5], except for the use of DOAC within 12-48 hours
3. Patients with an estimated glomerular filtration rate of ≤ 30ml/min/1.73m2
4. Patients with bleeding propensities apart from the use of DOAC, e.g. platelet count of < 100x109/L
5. Patients with significant head injury immediately prior to presentation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IVT group; For patients enrolled into the IVT group from participating centers that allow IVT in patients with last DOAC intake 12-48 hours before presentation (PWH, QEH, QMH, UCH, TMH): Either alteplase (0.6 or 0.9mg/kg, maximum dosage 90mg, intravenous infusion) or tenecteplase (0.25mg/kg, maximum dosage 25mg, intravenous infusion) will be given at discretion of the treating physician.	Drug: alteplase or tenecteplase; Either alteplase (0.6 or 0.9mg/kg, maximum dosage 90mg) or tenecteplase (0.25mg/kg, maximum dosage 25mg) will be given; Other Names: tPA or TNK
No Intervention: Control; For patients enrolled into the control group from participating centers that exclude eligible patients from IVT (PMH, PYNEH): no IVT will be given unless specific antidote can be administered before IVT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	To measure the degree of disability as a primary efficacy outcome, on the scale of 0-6: 0= no symptoms at all, 6=dead	3 months after CVA
Presence of symptomatic intracerebral hemorrhage (ICH)	As primary safety outcome. By the Heidelberg Bleeding Classification, the investigators shall categorize intracranial hemorrhages into HI1, HI2, PH1, PH2, and define symptomatic ICH as blood at any site in the brain with clinical deterioration (e.g. drowsiness and increased hemiparesis) or an increase in National Institute of Health Stroke Scale (NIHSS) score of ≥ 4 points (scores ranging from 0-42, higher scores indicating greater severity.)	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of asymptomatic ICH	As seen from computer tomography (CT) and magnetic resonance imaging (MRI)	up to 1 year
Presence of hemorrhagic transformation	As seen from computer tomography (CT) and magnetic resonance imaging (MRI)	up to 1 year
Presence of malignant cerebral edema	As seen from computer tomography (CT) and magnetic resonance imaging (MRI)	up to 1 year

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: Queen Mary Hospital, Hong Kong; Princess Margaret Hospital, Canada; Tuen Mun Hospital; Pamela Youde Nethersole Eastern Hospital; The Queen Elizabeth Hospital; United Christian Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 5, 2024
• Primary Completion (Estimated): December 12, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: January 17, 2024
• First Submitted That Met QC Criteria: January 26, 2024
• First Posted (Actual): February 5, 2024

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

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; Stroke; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Tenecteplase
• Other Study ID Numbers: CIRB-2023-167-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No