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

Abstract

ObjectiveTo investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).MethodsWe 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.ResultsAmong 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.ConclusionsStroke 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 numberISRCTN48292829.

Recurrent Ischemic Stroke and Cardiovascular Outcomes in Patients With Atrial Fibrillation With Ischemic Stroke Despite Direct Oral Anticoagulants

“…Our data also supported that the switch from original DOACs to another DOACs may not lead to a significant benefit in reducing the risk of recurrent IS. [1][2][3][4] However, a benefit may be exhibited if we broaden the outcomes to MACEs since a higher incidence of cardiovascular events may be noted in stroke patients with atrial fibrillation. Further investigation may be warranted to develop an exact algorithm for DOAC failure.…”

Occurrence of Ischemic Stroke in Patients With Atrial Fibrillation Receiving Non-Vitamin K Oral Anticoagulants: Causes and Prevention Strategies

“…This is the most common and challenging entity in the selection of optimal pharmacological and non-pharmacological strategies to prevent recurrent ischemic stroke. Polymeris et al 34 analyzed 2,946 patients from a multinational prospective registry and showed that stroke despite anticoagulation has heterogeneous etiologies with cardioembolism despite sufficient anticoagulation being the most common (44%), followed by insufficient anticoagulation (32%) and competing mechanisms (24%). Although appropriate anticoagulation at the time of stroke onset was associated with better functional outcome and smaller infarct volume, [35][36][37] the higher risk of ischemic stroke recurrence in patients with AF on NOAC failure may result in severe neurological disability (Figure 2).…”

“…8 In the RENO-EXTEND study, the rates of ischemic and bleeding events were not different in patients irrespective of changing the original NOAC treatment (OR 1.2, 95% CI 0.8-1.7). 14 Polymeris et al 34 showed that while NOACs were associated with better outcomes than VKAs, adding antiplatelets to the treatment regimen was linked to worse outcomes. Switching between different NOAC types was not associated with better outcomes.…”

“…Inappropriate low dose of NOACs Cardioembolism despite sufficient anticoagulation Proportion 24% Among prior NOAC user 34 16.4% Had atherosclerotic stenosis >50%. 8 25.8% Had non-cardioembolic stroke.…”

“…14 30.8% Recurred as non-cardioembolic stroke. 15 32% Among prior NOAC user 34 13.3% Recurred with off-label reduced dose of a NOAC. 15 44% Of prior NOAC users 34 Examples Atherosclerotic or lacunar stroke (Figure 1 higher risk than in patients with AF and no prior anticoagulation therapy).…”