By Michele Romoli, MD, PhD, FEBN – Neurology and Stroke Unit, Bufalini Hospital, Cesena, Italy

Follow Michele Romoli on Twitter: @MicheleRomoli

Anticoagulation with direct oral anticoagulants (DOACs) started early after acute ischemic stroke (IS) or transient ischemic attack (TIA) related to nonvalvular atrial fibrillation (NVAF) is critical to reduce the risk of recurrent stroke and systemic embolism.1 The optimal timing to start anticoagulation, however, remains elusive.

A 1-3-6-12 rule has been largely adopted in clinical practice, with early DOAC initiation in TIA and later initiation (12 days or more) in severe stroke.1 Such a timing, proposed on the basis of observational data and consensus/opinions, lacks support from (ongoing) randomized trials. In the meantime, stroke specialists are further shortening the timing for DOAC initiation, with the aim of reducing as much as possible the risk of stroke recurrence and systemic embolism.2 This strategy has to take into account the risk of haemorrhagic transformation, which may have several contributors, such as the ischemic volume.2

In a recent paper in Stroke, Kimura and colleagues pooled data from several observational studies to define safety and efficacy of shortening the interval between index stroke and DOAC initiation.3 In a derivation cohort including mainly Japanese patients, they compared an early (n=785) and late (n=1012) DOAC initiation strategy for ischemic and bleeding outcomes across four stroke groups: TIA, mild stroke with, moderate stroke, and severe stroke. The early initiation strategy consisted in a 1-2-3-4 day DOAC initiation rule according to increasing severity of stroke. In the derivation cohort, the rate of recurrent ischemic stroke dropped from 3.9% with late initiation to 1.9% with early initiation (adjusted hazard ratio 0.50 [95% CI, 0.27–0.89]). Major bleeding occurred in six (0.8%) in the early group and 10 (1.0%) in the late group (aHR 0.81 [0.28–2.19]). In the external validation cohort (n=2063), ischemic stroke occurred in 13 patients (2.4%) of the early group and 33 (2.2%) of the late group (aHR 1.07 [95% CI, 0.54–2.00]. ICH occurred in one (0.2%) in the early and nine (0.6%) in the late initiation group (aHR 0.31 [0.02–1.65]).3

Overall, the results of this large collaborative studies suggest that a shorter delay of anticoagulation initiation (1-2-3-4 rule vs 1-3-6-12 rule according to stroke severity) could be feasible and may not carry an increase in risk of bleeding, with a potential higher efficacy among Japanese people.3

At the moment, the timing of anticoagulation resumption is investigated in four ongoing randomized trials (TIMING, OPTIMAS, ELAN, and START, Clinical trials identifier NCT02961348, NCT03759938, NCT03148457, NCT03021928, respectively), which differ in timing of randomization to DOAC initiation. Indeed, in TIMING and OPTIMAS anticoagulation is initiated no earlier than four days, while a severity-based timing is proposed in ELAN and START. Results from these trials are critically needed, as shorter initiation timing might benefit stroke patients.



  1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18: 1609–1678.
  1. Paciaroni M, Caso V, Agnelli G, et al. Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study. Stroke. Epub ahead of print 11 May 2022. DOI: 10.1161/STROKEAHA.121.038239.
  1. Kimura S, Toyoda K, Yoshimura S, et al. Practical ‘1-2-3-4-Day’ Rule for Starting Direct Oral Anticoagulants after Ischemic Stroke with Atrial Fibrillation: Combined Hospital-Based Cohort Study. Stroke 2022; 53: 1540–1549.