Piyush Ojha, MBBS, MD, DM

Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, Itabashi R, Takagi M, Todo K, Shiozawa M, Yagita Y, Yoshimoto T, et al. Early Initiation of Direct Oral Anticoagulants After Onset of Stroke and Short- and Long-Term Outcomes of Patients With Nonvalvular Atrial Fibrillation. Stroke. 2020;51:883–891.

Ischemic strokes due to embolism arising from non-valvular atrial fibrillation (NVAF) account for approximately one-fourth of cases, which further increases with age. Lack of or inadequate anticoagulation may lead to an increased risk of recurrence of stroke during the post stroke period. However, the decision about when to start or resume anticoagulation in such patients is not straightforward and depends on multiple variables. Early anticoagulation may also increase the chances of intracranial hemorrhage/hemorrhagic transformation of the infarct. Recent guidelines allow DOAC administration soon after stroke according to stroke severity based on the 1-3-6-12 day rule, which is based only on expert consensus.

Among the conventional anticoagulants, heparin has shown to cause a nonsignificant reduction in recurrent ischemic stroke within 4 to 14 days, while warfarin was reported to paradoxically increase the risk of stroke during the first 30 days after initiation.

The use of direct oral anticoagulants (DOACs) has shown to cause a decreased risk of intracranial hemorrhage with a similar efficacy in preventing stroke as compared with conventional anticoagulants. However, the timing of initiation of DOACs after acute stroke is still debatable.

The SAMURAI (Stroke Acute Management with Urgent Risk-factor Assessment and Improvement)-NVAF registry was a prospective, multicenter, observational study which included acute ischemic stroke and TIA patients with NVAF. All participants were registered within 7 days after the onset of index event from multiple stroke centers in Japan between September 2011 and March 2014 and followed up for 2 years. The authors found a significantly lower risk for intracerebral hemorrhage within 2 years in patients with NVAF who received DOACs compared to those with Warfarin, without any difference in the incidence of ischemic events and systemic embolism. Similar results were reproduced by an individual patient data analysis of 7 prospective cohort studies comprising 4912 patients with NVAF derived from the SAMURAI-NVAF registry and 6 European studies.1

Mizoguchi et al in this sub-study aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of DOACs after the index event in patients from the SAMURAI-NVAF registry.

Patient who received DOACs during acute hospitalization were analyzed and divided into 2 groups (early and late) according to a median day of DOAC initiation (4 days) after onset. Primary outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years, while major bleeding event was the primary safety outcome. The eligibility and choice of oral anticoagulants, as well as the timing to start anticoagulation, were determined by each investigator in charge, based on patient’s preference, stroke severity, and sequelae such as dysphagia, and relevant comorbidities such as renal dysfunction.

A total of 499 patients who received DOACs during acute hospitalization were included for analysis. Median age was 75 years, and approximately one-third were females. 223 patients were assigned to the early group (≤3 days) and 276 patients to the late (≥4 days) group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up, and had similar incidences between the two groups. The early group had higher proportions of premorbid AF diagnosis, and AF of sustained type, lower CHA2DS2-VASc score, lower baseline NIHSS score, and smaller infarcts.

The cumulative incidence of stroke or systemic embolism at 2 years was 8.9% (20/223) in the early group compared with 10.5% (29/276) in the late group. Statistical analysis (adjusted and unadjusted) showed that there was no difference in primary outcome (stroke or systemic embolism) events between the two groups at the end of 3 moths or 2 years along with similar safety outcomes.

The authors hence concluded that there were no significant differences in the incidences of stroke or systemic embolism or that of major bleeding, as well as that of other secondary outcomes such as ischemic events, ischemic stroke or TIA, intracranial hemorrhage and death between the patients initiating DOACs within 3 days and those initiating DOACs at 4 days or later after the onset of NVAF associated ischemic stroke or TIAs.

This sub-study had several limitations such as nonrandomized study leading to selection bias, and that the timing to start DOACs was determined by each investigator in charge based on patient’s preference, stroke severity, and sequelae. Background differences in the two study groups such as baseline NIHSS scores, infarct size, and CHA2DS2-VASc also reflect that the early group had a relatively lower potential risk of recurrent stroke as compared with the late group. Although the early group had a higher prevalence of sustained AF associated with a higher risk of stroke than paroxysmal AF, the results should be interpreted with caution. Both groups contained different contents and dosage of DOACs, leading to inadequate sample size for individual analysis. The period of registration of the SAMURAI-NVAF study was between 2011-2014, when anticoagulants were given to milder stroke in Japan and the median initial NIHSS score was relatively low in both patient groups as compared with general cohorts of stroke in the main registry; hence, the results cannot be generalized to any severity.

There are 4 ongoing randomized trials to determine the appropriate timing of DOAC initiation after stroke: ELAN [Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients  With Atrial Fibrillation], TIMING [Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation], OPTIMAS [Optimal Timing of Anticoagulation After Acute Ischaemic Stroke], and START [Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation]. All of these trials are using 4 days after the index event as a cut off of patient groups with different timing for DOAC initiation similar to the present study. Once the results of these trials are available, we will have further data regarding the optimal timing for DOAC initiation after the index event.


1.  Seiffge DJ, Paciaroni M, Wilson D, Koga M, Macha K, Cappellari M, et al; CROMIS-2, RAF, RAF-DOAC, SAMURAI, NOACISP LONGTERM, Erlangen and Verona Registry Collaborators. Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation. Ann Neurol.  2019;85:823–834.