Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

RATIONALE

An estimated 15% of all strokes are associated with untreated atrial fibrillation. Long-term secondary stroke prevention in atrial fibrillation is anticoagulation, increasingly with non-vitamin K oral anticoagulants. The optimal time to initiate anticoagulation following an atrial fibrillation-related stroke that balances hemorrhagic conversion with recurrent stroke is not yet known.

AIMS

To determine if there is an optimal delay time to initiate anticoagulation after atrial fibrillation-related stroke that optimizes the composite outcome of hemorrhagic conversion and recurrent ischemic stroke.

SAMPLE SIZE ESTIMATES

The study will enroll 1500 total subjects split between a mild to moderate stroke cohort (1000) and a severe stroke cohort (500).

METHODS AND DESIGN

This study is a multi-center, prospective, randomized, pragmatic, adaptive trial that randomizes subjects to four arms of time to start of anticoagulation. The four arms for mild to moderate stroke are: Day 3, Day 6, Day 10, and Day 14. The time intervals for severe stroke are: Day 6, Day 10, Day 14, and Day 21. Allocation involves a response adaptive randomization via interim analyses to favor the arms that have a better risk-benefit profile.

STUDY OUTCOMES

The primary outcome event is the composite occurrence of an ischemic or hemorrhagic event within 30 days of the index stroke. Secondary outcomes are also collected at 30 and 90 days.

DISCUSSION

The optimal timing of direct oral anticoagulants post-ischemic stroke requires prospective randomized testing. A pragmatically designed trial with adaptive allocation and randomization to multiple time intervals such as the START trial is best suited to answer this question in order to directly inform current practice on this question.