Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation "START"

Recruiting

Phase 3 Results N/A

Trial Description

Title:
Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation (START): a pragmatic, adaptive randomized clinical trial.
Primary Objective:
• To determine the optimal time to initiate anticoagulation with a Non-Vitamin K Oral Anticoagulant (NOAC) after ischemic stroke in patients with non-valvular atrial fibrillation.
Secondary Objectives:
- To compare the rates of primary adverse outcomes in a per protocol analysis
- To compare 30 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
- To compare 90 day clinical outcomes by the modified Rankin scale among the time-to-treatment groups
- To explore the optimal timing in subgroups of age, sex, outcome category, and NOAC choice

Detailed Description

Long-term oral anticoagulation is standard for secondary stroke prevention in patients with atrial fibrillation (AFib). However, there is limited data and no consensus on the timing of when to initiate anticoagulation therapy, and concern that starting too soon risks symptomatic hemorrhagic transformation. These data are derived almost exclusively from heparins and Vitamin K antagonists (e.g.,warfarin). Now that NOACs have become the mainstay of stroke prophylaxis in AFib and have more rapid and consistent anticoagulation and fewer strokes (hemorrhagic especially), the question of optimal timing of NOAC initiation is of increasing importance.
The primary aim is to determine the time-to-treatment interval with the lowest associated risk for adverse events in the context of anticoagulation therapy with NOACs for acute stroke patients with non-valvular AFib. The question will be investigated with a prospective, adaptive, randomized, controlled "dose-exploration" trial with the time to treatment with NOAC therapy treated as the incremental "dose".
An adaptive, pragmatic trial will be performed that will not deviate from the treating physicians' usual practice except for randomizing the time to start the NOAC. Data collection will be limited to those fields necessary for the planned primary and secondary analyses.
The composite primary outcome event will be any of the following within 30 days of the index stroke: Ischemic Events (symptomatic ischemic stroke or systemic embolism), Hemorrhagic Events (symptomatic hemorrhagic transformation of index ischemic stroke, other symptomatic intracranial hemorrhage, or major extracranial hemorrhage), or all-cause mortality.
Four time-to-treatment intervals, i.e. study arms, between 2 and 14 days will be investigated: 60 hours, 132 hours, 228 hours, and 324 hours. An innovative adaptive design will be used which includes response adaptive randomization and modeling of ischemic and hemorrhagic outcome events. The ischemic and hemorrhagic events within the composite primary endpoint are modeled separately using their known monotonic property that the risk of an event increases (ischemic) or decreases (hemorrhage) as the time-to-treatment interval lengthens. Interim analyses will occur after every 50 subjects are randomized, where the primary outcome will be analyzed and new randomization probabilities will be calculated to favor the arms that have a better risk-profile.

Conditions

Interventions

  • Time-To-Treatment Randomization Other
    Intervention Desc: The time after symptom onset to initiate treatment will be randomized to one of four possible treatment arms: 60 hours, 132 hours, 228 hours, or 324 hours (+/- 12 hours each).
    ARM 1: Kind: Experimental
    Label: 60 hours
    Description: Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 60 hours correlates to starting treatment on Day 3, 132 hours starts on Day 5, 228 hours starts on Day 9, and 324 hours starts Day 13.
    ARM 2: Kind: Experimental
    Label: 132 hours
    Description: Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 60 hours correlates to starting treatment on Day 3, 132 hours starts on Day 5, 228 hours starts on Day 9, and 324 hours starts Day 13.
    ARM 3: Kind: Experimental
    Label: 228 hours
    Description: Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 60 hours correlates to starting treatment on Day 3, 132 hours starts on Day 5, 228 hours starts on Day 9, and 324 hours starts Day 13.
    ARM 4: Kind: Experimental
    Label: 324 hours
    Description: Time to delay the initiation of anticoagulation is determined at randomization. The Time-To-Treatment Randomization of 60 hours correlates to starting treatment on Day 3, 132 hours starts on Day 5, 228 hours starts on Day 9, and 324 hours starts Day 13.

Outcomes

Type Measure Time Frame Safety Issue
Primary Recurrent IschemicEvent 30 days
Primary Hemorrhagic Event 30 days
Primary All-Cause Mortality 30 days
Secondary Modified Rankin Scale 30 days

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