Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation (START): a pragmatic, adaptive randomized clinical trial
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). As NOACs are becoming a 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.
Our 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. We will investigate the question with a prospective, adaptive, randomized, controlled “dose-exploration” trial with the time to treatment with NOAC therapy treated as the incremental “dose”.
How will the results of the study change or improve clinical practice or patient outcomes?
This study was designed with the objective that the results would not only answer the research question, but would do so in a manner that would be directly applicable to clinical practice. Several features of the trial support this objective. The drugs used are not investigational and their indication and value for secondary stroke prevention in AFib is already a settled question. We are testing one aspect of the variability in an established practice that may have an impact on patient outcomes.
The results of this study will either conclude that no one delay interval between 2 and 14 days is advantageous over another, and physicians will make the decision of when to start for reasons other than risk-benefit, or the results will indicate that one or more time delays does have a more favorable risk profile than another, and physicians will conform their practice to that evidence.
A pragmatic trial design was chosen in order that results can be directly generalized to clinical practice. We will not ask physicians to change their criteria of whom to anticoagulate or their choice of anticoagulant. We ask them only to randomize the time to start the anticoagulant if they will be prescribing a NOAC. Patient inclusion/exclusion criteria will be kept to a minimum to achieve a sample typically treated in practice. We will exclude only the mildest, about whom less uncertainty exists, and the most severe, in whom expected neurological worsening may confound the effect of the anticoagulant. Determination of adverse outcome events will be made by the treating physician.
We expect that this project will provide novel insights on timing of anticoagulation for acute stroke patients with AFib. This will address the current gap in knowledge and lack of guidelines for time-to-treatment interval of anticoagulation therapy with a NOAC following ischemic stroke in patients with AFib. The long term impact of this project could lead to changes in stroke management, particularly secondary stroke prevention in patients with AFib, as well as guide study design for future clinical trials of novel anticoagulation therapies in this context.