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Optimal Timing for Starting DOACs After Ischemic Stroke With Atrial Fibrillation
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This prospective, registry-based analysis evaluated the optimal timing for the initiation of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation and acute ischemic stroke or transient ischemic attack (TIA). Early DOAC initiation within 1, 2, 3, and 4 days of TIA was associated with a significant reduction in the incidence of recurrent ischemic stroke (1.7% vs 3.2%; HR, 0.54) and systemic embolism (1.9% vs 3.9%; HR, 0.50) as compared with later initiation at 1, 3, 6, and 12 days. No increase in the risk of major bleeding or intracranial hemorrhage was observed with respect to the early-initiation strategy.
- These data suggest that early DOAC initiation in this population may be safe and effective for the prevention of recurrent ischemic stroke and systemic embolism.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity.
METHODS
The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation.
RESULTS
In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data.
CONCLUSIONS
In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.
Additional Info
Disclosure statements are available on the authors' profiles:
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 Feb 02;[EPub Ahead of Print], S Kimura, K Toyoda, S Yoshimura, K Minematsu, M Yasaka, M Paciaroni, DJ Werring, H Yamagami, T Nagao, S Yoshimura, A Polymeris, A Zietz, ST Engelter, B Kallmünzer, M Cappellari, T Chiba, T Yoshimoto, M Shiozawa, T Kitazono, M KogaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
When should we start anticoagulation after a TIA or a stroke?
Intuitively, we would think earlier anticoagulation would give the best results post TIA or stroke. However, there is always this fear that we could cause more bleeding. The thought is that, in severe strokes, the damaged brain tissue could bleed if anticoagulation is started early and we could make things much worse, which is why the “1-3-6-12-day” rule was established for starting direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation who suffered an ischemic stroke or transient ischemic attack. Patients were divided into four categories: TIA, mild, moderate, and severe stroke. For TIA in which there was no damage to the brain tissues, DOACs could be started on day 1; but, for the most severe strokes, where there was a lot of damaged brain tissue, anticoagulation was started on day 12.
Now 12 days is a long time to wait before we could protect these patients with a DOAC. So, the question is could we safely start the DOACs earlier than 12 days?
This first paper answered this question by looking at patients from two stroke registries in Japan, which had data on a total of 1797 patients.1 The researchers used the median days of initiation of anticoagulant treatment and divided the patients into two groups: early and late initiation. The early group had therapies started on day 1, 2, 3, 4 for the four categories of patients, and that group did better than the late group. Stroke or systemic emboli was reduced by 50% (HR, 0.50; 95% CI, 0.27–0.89), and ischemic stroke was reduced by 46% (HR, 0.54; 95% CI, 0.27–0.999). Major bleeding was not increased, occurring at 0.8% and 1.0% in the two groups.
This study tells us that we can get the benefits of anticoagulation earlier without triggering an increase in bleeding by following the rule of 1-2-3-4 days. Patients suffering the most severe strokes can now get therapy on day 4 instead of waiting until day 12.
The second study bolsters this idea that earlier treatment is better.2 We know that earlier reperfusion would help save more brain tissue post stroke. In this study, the researchers looked at mobile stroke units (MSU), which are specialized ambulances equipped with a CT scanner that could bring intravenous thrombolysis directly to patients. This would reduce the time to reperfusion and hopefully save more brain tissue.
These authors looked at 14 studies comparing MSU with usual care, and they concluded that there was a 65% increase in the odds of having an excellent outcome and reduced disability at 90 days with the MSU. This was mainly associated with thrombolysis administered more quickly by 30 minutes. A half hour made all the difference, and there was no increase in intracranial hemorrhage.
With both of these studies, it is clear that earlier treatment is better. Let’s make sure that all patients know that “time = brain.” The quicker they get assessed and treated the more brain is protected.
References
In this article recently published in Stroke, Kimura and colleagues propose a novel approach for initiating early anticoagulation after an ischemic stroke (IS) in patients who have concomitant non-valvular atrial fibrillation (AF). Traditionally, the “1-3-6-12 day rule” has been used to guide the timing of anticoagulation initiation after a transient ischemic attack (TIA) or an IS in patients with AF. However, this traditional approach comes with the possible risk of delaying the initiation of anticoagulation to prevent recurrent stroke in favor of erring on the side of caution out of concern for the hemorrhagic conversion of the initial ischemic insult. Kimura and colleagues thus propose a new “1-2-3-4 day rule” for direct oral anticoagulant (DOAC) initiation.
The authors evaluated two combined prospective, multicenter, observational studies (SAMURAI-NVAF and RELAXED registries), which included 1797 Japanese patients with either TIA or IS who also had a diagnosis of AF. The study used a derivation cohort (Japanese population, predominantly on rivaroxaban at lower than usual doses uses in the United States) and a European validation cohort (homogenous DOAC distribution). The authors compared an early versus late anticoagulation approach in patients with AF after a TIA or IS. The subject population was divided into four study subgroups based on neurologic severity: TIA (<24h symptom resolution), mild stroke (National Institutes of Health Stroke Scale [NIHSS] 0-7), moderate stroke (NIHSS 8-15), and severe stroke (NIHSS ≥16). The subgroups were then allocated to an early or late treatment group, depending on the median time to DOAC initiation. The early group initiated anticoagulation in the “1-2-3-4 day rule” format: day 1 for TIA, day 2 for mild stroke, day 3 for moderate stroke, and day 4 for severe stroke. The study showed a trend towards better efficacy and similar safety of stroke in the derivation cohort (Early vs late group ischemic stroke: 1.7% vs 3.2%, respectively. Adjusted HR 0.54 [0.27-0.999, 95% CI], P=0.0497, with similar intracranial hemorrhage [ICH] rates: 0.3% vs 0.4%, respectively. Adjusted HR 0.66, [0.09-3.39]).
As the authors noted, the study had design limitations and biases. First and foremost, this was not a randomized trial. Additionally, factors such as infarct size, which is correlated with the risk of hemorrhagic transformation, as well as evidence of cardiac thrombus, need for neurosurgical intervention at any time, neurologic instability, or hypertensive urgency/emergency are not incorporated into decisions regarding the timing of DOAC initiation. By design, the study only evaluated DOAC as a form of anticoagulation, though this is justified as DOACs have, overall, shown to be generally superior to vitamin K antagonists in four main randomized clinical control trials (RE-LY Trial, ROCKET-AF Trial, ARISTOTLE Trial, and ENGAGE AF-TIMI 48 Trial) (1-4).
Of note, the “1-2-3-4 day rule” and the “1-3-6-12 day rule” are not endorsed by the current American Heart Association (AHA)/American Stroke Association (ASA) 2021 guidelines for the prevention of stroke in patients with TIA/IS (5). The AHA/ASA 2021 guidelines suggest that it is reasonable to delay DOAC initiation beyond 14 days in patients with severe stroke with AF (NIHSS >15 or >1 cerebral artery territories) (COR 2a, LOE C-EO). For mild stroke, they suggest that it is reasonable to initiate anticoagulation 2-14 days after stroke with AF (COR 2b, LOE B-R). Conversely, for TIA in the setting of AF, it is reasonable to immediately initiate anticoagulation after an index event to reduce the risk of stroke (COR 2a, LOE C-EO), contrary to waiting for 1 day as suggested by the 1-2-3-4 and 1-3-6-12 day rule approaches.
The authors are to be applauded for this study for proposing an earlier treatment system. Validation of such an earlier approach awaits validation by four ongoing randomized trials. Until then, these study results need to be integrated with other factors that can influence the timing of anticoagulation initiation, current expert consensus and organizational guidelines, and, of course, good clinical judgment.
References