Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation.

OBJECTIVE: To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). METHODS: We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. RESULTS: Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. CONCLUSIONS: Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. TRIAL REGISTRATION NUMBER: ISRCTN48292829.

Etiology of Ischemic Strokes of Patients with Atrial Fibrillation and Therapy with Anticoagulants.

BACKGROUND: Reducing the number of ischemic strokes in patients with atrial fibrillation despite oral anticoagulation remains an important, yet largely unsolved challenge. Therefore, we assessed the etiology of ischemic strokes despite anticoagulation with vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs). METHODS: Patients with known atrial fibrillation (AF), treatment with VKA or NOAC, and acute ischemic stroke admitted between 2015 and 2018 (1st half) were identified from the hospital database. Brain imaging data were independently reviewed. An integrated etiologic classification according to the ASCOD system was made. Medication errors (admission INR <2.0 in the VKA- or NOAC-specific concentration <10 ng/mL) or dosage/dosing errors were also analyzed. RESULTS: Of 3610 patients screened, n = 341 were included (VKA, n = 127; NOAC, n = 214). An overall increasing rate of OAC-associated stroke per year was observed. In 95.3% of patients with adequate diagnostic work-up (n = 321/337), at least one additional potential, uncertain, or unlikely non-cardiac cause of stroke was identified. More patients in the VKA than in the NOAC group had a medication error (81/127, 63.8% vs. 102/205, 49.8%; p = 0.013). CONCLUSIONS: Stroke risk factors despite atrial fibrillation were highly prevalent. Although less common with NOACs than VKAs, medication errors are still frequent.