Direct oral anticoagulants in the early phase of non valvular atrial fibrillation-related acute ischemic stroke: focus on real life studies

Masotti, Luca; Grifoni, Elisa; Dei, Alessandro; Vannucchi, Vieri; Moroni, Federico; Panigada, Grazia; Spolveri, Stefano; Landini, Giancarlo

doi:10.1007/s11239-018-1775-2

Cited by 7 publications

(10 citation statements)

References 29 publications

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“…[9][10][11][12] Several more recent observational studies, published in parallel with or after the conduct of the TIMING study, have demonstrated substantially lower rates of symptomatic intracranial hemorrhages in patients treated early with NOACs after ischemic stroke in atrial fibrillation. 16,32,33 The primary outcome results in TIMING were consistent across prespecified subgroups, including age, sex, previously known atrial fibrillation, and antithrombotic treatment before hospitalization. Signs of potential harm with early initiation of NOAC were implied only in the small groups of patients who underwent thrombectomy or had admission NIHSS scores >15, that is, patients with more severe ischemic strokes.…”

Section: Discussionmentioning

confidence: 64%

Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study

et al. 2022

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Background: There are no evidence-based recommendations on the optimal time point to initiate non–vitamin K antagonist oral anticoagulants (NOACs) after acute ischemic stroke in patients with atrial fibrillation. We aimed to investigate the efficacy and safety of early versus delayed initiation of NOAC in these patients. Methods: TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) was a registry-based, randomized, noninferiority, open-label, blinded end-point study at 34 stroke units using the Swedish Stroke Register for enrollment and follow-up. Within 72 hours from stroke onset, patients were randomized to early (≤4 days) or delayed (5–10 days) NOAC initiation, with choice of NOAC at the investigators’ discretion. The primary outcome was the composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days. The prespecified noninferiority margin was 3%. Secondary outcomes included the individual components of the primary outcome. Results: Between April 2, 2017, and December 30, 2020, 888 patients were randomized to either early (n=450) or delayed (n=438) initiation of NOAC. No patient was lost to 90-day follow-up. Mean age was 78.3 years (SD, 9.9 years); 46.2% were women; 49.1% had previously known atrial fibrillation; and 17.5% prior stroke. The primary outcome occurred in 31 patients (6.89%) assigned to early initiation and in 38 patients (8.68%) assigned to delayed NOAC initiation (absolute risk difference, −1.79% [95% CI, −5.31% to 1.74%]; P noninferiority =0.004). Ischemic stroke rates were 3.11% and 4.57% (risk difference, −1.46% [95% CI, −3.98% to 1.07%]) and all-cause mortality rates were 4.67% and 5.71% (risk difference, −1.04% [95% CI, −3.96% to 1.88%]) in the early and delayed groups, respectively. No patient in either group experienced symptomatic intracerebral hemorrhage. Conclusions: Early initiation was noninferior to delayed start of NOAC after acute ischemic stroke in patients with atrial fibrillation. Numerically lower rates of ischemic stroke and death and the absence of symptomatic intracerebral hemorrhages implied that the early start of NOAC was safe and should be considered for acute secondary stroke prevention in patients eligible for NOAC treatment. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT02961348.

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Section: Discussionmentioning

confidence: 64%

Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study

et al. 2022

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“…nticoagulation with direct oral anticoagulants (DOACs) started early after acute ischemic stroke (IS) or transient ischemic attack (TIA) related to nonvalvular atrial fibrillation (NVAF) has been found to be associated with a decreased risk of poor clinical outcomes compared with warfarin in practical clinical settings, mainly attributed to lower risks of intracranial hemorrhage (ICH). [1][2][3] However, the optimal timing for initiating DOACs after IS has remained unclear. Ongoing randomized trials on early versus late DOAC initiation have not published their final results.…”

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confidence: 99%

Practical “1-2-3-4-Day” Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study

Kimura

Toyoda

Yoshimura

et al. 2022

Stroke

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Background: 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.

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“…In the latest years a lot of literature evidence about the introduction of DOACs in the early phase of NVAF-related AIS was available. Much recently, Masotti et al provided a summary of the literature evidence reporting on DOACs in this context [12]. The authors selected fifteen studies, overall enrolling 2920 patients.…”

Section: Discussionmentioning

confidence: 99%

“…The authors selected fifteen studies, overall enrolling 2920 patients. Median time of starting DOACs ranged from 2 to 8 days, and in twelve of the fifteen selected studies, median or mean starting time was ≤ 7 days [12]. The authors found a 90-day TIA/stroke recurrence, HT/intracranial bleeding, and all-cause mortality incidence of 2.25%, 0.90%, and 1.5% of patients, respectively [12].…”

Section: Discussionmentioning

confidence: 99%

“…Median time of starting DOACs ranged from 2 to 8 days, and in twelve of the fifteen selected studies, median or mean starting time was ≤ 7 days [12]. The authors found a 90-day TIA/stroke recurrence, HT/intracranial bleeding, and all-cause mortality incidence of 2.25%, 0.90%, and 1.5% of patients, respectively [12]. Ten of the fifteen selected studies, overall including 2552 patients, reported on percentage of patients undergoing systemic thrombolysis and/or mechanical thrombectomy (32.4%), but only three studies separately reported on efficacy and safety of DOACs in patients receiving systemic thrombolysis or mechanical thrombectomy [12].…”

Section: Discussionmentioning

confidence: 99%

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Direct Oral Anticoagulants in Patients Undergoing Urgent Reperfusion for Nonvalvular Atrial Fibrillation-Related Ischemic Stroke: A Brief Report on Literature Evidence

Masotti

Grifoni

Dei

et al. 2019

Neurology Research International

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Introduction. The optimal timing for starting anticoagulation in the early phase of nonvalvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) remains a challenge, especially in patients undergoing urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. The aim of our study was to review the literature evidence reporting on safety of direct oral anticoagulants (DOACs) starting in the early phase of NVAF-related AIS undergoing systemic thrombolysis and/or mechanical thrombectomy. Materials and Methods. We reviewed the PubMed databases searching articles reporting on efficacy and safety of DOACs starting time within two weeks from AIS onset in patients undergoing systemic thrombolysis and/or mechanical thrombectomy. Results. Three studies were selected, overall including one hundred and six patients (62 females, 58.4%). Median National Institute of Health Stroke Scale (NIHSS) score at hospital admission ranged from 9 to 13 points. Median DOACs starting time ranged from 2 to 6 days. Median CHA2DS2-VASC score ranged from 4 to 6 points. Follow-up was limited to 14 days in one study, 30 days in another, and 90 days in a third one. Overall, stroke recurrence and/or intracranial bleeding occurred in two patients (1.9%) and no patient died at follow-up. Conclusion. Small sample size real life studies seem to demonstrate that the introduction of DOACs in the early phase of NVAF-related AIS undergoing urgent reperfusion is efficacious and safe. Prospective RCTs are necessary to confirm these findings.

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Direct oral anticoagulants in the early phase of non valvular atrial fibrillation-related acute ischemic stroke: focus on real life studies

Cited by 7 publications

References 29 publications

Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study

Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study

Practical “1-2-3-4-Day” Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study

Direct Oral Anticoagulants in Patients Undergoing Urgent Reperfusion for Nonvalvular Atrial Fibrillation-Related Ischemic Stroke: A Brief Report on Literature Evidence

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