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

Thrombolysis for ischaemic stroke despite direct oral anticoagulation.

Intravenous thrombolysis is not recommended in anticoagulated patients receiving direct oral anticoagulants (DOACs) and a recent intake within the last 48 hours in US and European guidelines. However, three observational studies now suggest safety of thrombolysis in patients with recent intake of DOACs, and thus support previous experimental data. In this perspective, the current evidence and practical consequences are discussed

Characteristics of acute ischemic stroke and unusual aura in patients with migraine with aura.

BACKGROUND Sometimes migraine aura changes from attack to attack, raising the question of whether the change is heralding an ischemic stroke or an unusual aura. Differentiating unusual migraine aura from the onset of an acute ischemic stroke in patients with migraine with aura (MwA) can be challenging. OBJECTIVE The aim of this cohort study was to assess clinical characteristics that help distinguish between MwA and minor stroke in patients with a previous history of MwA who presented with suspicion of stroke. METHODS We interviewed patients with MwA and ischemic stroke (MwA + IS) and patients with MwA and unusual aura, but without ischemic stroke (MwA - IS) from a tertiary hospital using a structured questionnaire. We assessed how symptoms of ischemic stroke or unusual aura differed from usual, that is, the typical aura in each patient. Stroke or exclusion of stroke was verified by multimodal magnetic resonance imaging. RESULTS Seventeen patients with MwA + IS and twelve patients with MwA - IS were included. New focal neurological symptoms (13/17 [76%] vs. 3/12 [25%]), change of the first symptom (10/17 [59%] vs. 1/12 [8%]), and absence of headache (6/15 [40%] vs. 2/10 [20%]) were more often reported during ischemic stroke. The physical examination was normal in 8/17 (47%) MwA + IS and in 6/12 (50%) MwA - IS patients. In 5/17 (29%) patients with MwA + IS, there were unequivocal physical signs suggestive of stroke such as persistent visual loss, ataxia, or paresis. CONCLUSION There are clues from the history that might help identify stroke in patients with MwA with changed aura symptoms. These might be particularly useful in patients presenting without physical findings suggestive of stroke

Migraine aura-like symptoms at onset of stroke and stroke-like symptoms in migraine with aura.

Background and objectives In general, suddenly occurring neurological deficits, i.e., negative neurological symptoms, are considered symptoms of focal cerebral ischemia, while positive irritative symptoms with gradual onset are viewed as the characteristics of migraine aura. Nevertheless, cortical spreading depolarization, the pathophysiological basis of migraine aura, has also been observed in acute ischemic stroke. The aim of our study was to determine the frequency of migraine aura-like symptoms at ischemic stroke onset and stroke-like symptoms in migraine with aura. Methods We interviewed 350 consecutive patients with ischemic stroke and 343 with migraine with aura using a structured questionnaire. Stroke diagnosis was confirmed by imaging, and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Patients with wake-up strokes or severe cognitive deficits that precluded a useful interview were excluded from the study. Results Seventy-eight patients with stroke (22.3%) reported visual symptoms, 145 (41.4%) sensory symptoms, 197 (56.3%) a paresis, and 201 patients (57.4%) more than one symptom, compared to 326 migraine patients with aura (95%) with visual symptoms (P < 0.001), 175 (51%) with sensory symptoms (p = 0.011), 50 (14.6%) with paresis (P < 0.001), and 211 (61.5%) with more than one symptom (p = 0.27). Among patients with stroke, migraine-like symptoms were frequent: 36 patients (46.2%) with visual disturbance and 78 (53.8%) with sensory symptoms experienced irritative sensations. Paresis-onset in stroke lasted longer than 5 min in 43 patients (21.8%). Spreading of sensory and motor symptoms occurred in 37 (25.5%) and 37 (18.8%) patients, respectively. Stroke-like negative symptoms in migraine with aura occurred in 39 patients (12%) with visual symptoms, in 55 (31.4%) with sensory symptoms, and paresis appeared suddenly in 14 patients (28%). More than one symptom in succession occurred in 117 patients with stroke (58.2%) and in 201 migraine with aura patients (95.3%; P < 0.001). Conclusion Many patients with stroke experience migraine-like symptoms at stroke onset, and many migraine with aura patients have stroke-like symptoms. Though overall the symptom frequencies of the two groups are significantly different, clarifying the differential diagnosis in an individual patient requires additional history elements, physical findings, or results of ancillary investigations

Cardiovascular MRI Compared to Echocardiography to Identify Cardioaortic Sources of Ischemic Stroke: A Systematic Review and Meta-Analysis

Background: To compare the diagnostic yield of echocardiography and cardiovascular MRI (CMR) to detect structural sources of embolism, in patients with ischemic stroke with a secondary analysis of non-stroke populations. Methods and Results: We searched MEDLINE/Embase (from 01.01.2000 to 24.04.2021) for studies including CMR to assess prespecified sources of embolism. Comparison included transthoracic and/or transesophageal echocardiography. Two authors independently screened studies, extracted data and assessed bias using the QUADAS-2 tool. Estimates of diagnostic yield were reported and pooled. Twenty-seven studies with 2,525 patients were included in a study-level analysis. Most studies had moderate to high risk of bias. Persistent foramen ovale, complex aortic plaques, left ventricular and left atrial thrombus were the most common pathologies. There was no difference in the yield of left ventricular thrombus detection between both modalities for stroke populations (4 studies), but an increased yield of CMR in non-stroke populations (28.1 vs. 16.0%, P < 0.001, 10 studies). The diagnostic yield in stroke patients for detection of persistent foramen ovale was lower in CMR compared to transoesophageal echocardiography (29.3 vs. 53.7%, P < 0.001, 5 studies). For both echocardiography and CMR the clinical impact of the management consequences derived from many of the diagnostic findings remained undetermined in the identified studies. Conclusions: Echocardiography and CMR seem to have similar diagnostic yield for most cardioaortic sources of embolism except persistent foramen ovale and left ventricular thrombus. Randomized controlled diagnostic trials are necessary to understand the impact on the management and potential clinical benefits of the assessment of structural cardioaortic stroke sources. Registration: PROSPERO: CRD42020158787

Heterogeneity of the Relative Benefits of TICI 2c/3 over TICI 2b50/2b67 : Are there Patients who are less Likely to Benefit?

PURPOSE Incomplete reperfusion after mechanical thrombectomy (MT) is associated with a poor outcome. Rescue therapy would potentially benefit some patients with an expanded treatment in cerebral ischemia score (eTICI) 2b50/2b67 reperfusion but also harbors increased risks. The relative benefits of eTICI 2c/3 over eTICI 2b50/67 in clinically important subpopulations were analyzed. METHODS Retrospective analysis of our institutional database for all patients with occlusion of the intracranial internal carotid artery (ICA) or the M1/M2 segment undergoing MT and final reperfusion of ≥eTICI 2b50 (903 patients). The heterogeneity in subgroups of different time metrics, age, National Institutes of Health Stroke Scale (NIHSS), number of retrieval attempts, Alberta Stroke Programme Early CT Score (ASPECTS) and site of occlusion using interaction terms (pi) was analyzed. RESULTS The presence of eTICI 2c/3 was associated with better outcomes in most subgroups. Time metrics showed no interaction of eTICI 2c/3 over eTICI 2b50/2b67 and clinical outcomes (onset to reperfusion pi = 0.77, puncture to reperfusion pi = 0.65, onset to puncture pi = 0.63). An eTICI 2c/3 had less consistent association with mRS ≤2 in older patients (>82 years, pi = 0.038) and patients with either lower NIHSS (≤9) or very high NIHSS (>19, pi = 0.01). Regarding occlusion sites, the beneficial effect of eTICI 2c/3 was absent for occlusions in the M2 segments (aOR 0.73, 95% confidence interval [CI] 0.33-1.59, pi = 0.018). CONCLUSION Beneficial effect of eTICI 2c/3 over eTICI 2b50/2b67 only decreased in older patients, M2-occlusions and patients with either low or very high NIHSS. Improving eTICI 2b50/2b67 to eTICI 2c/3 in those subgroups may be more often futile

Transient ischemic attacks in patients with active and occult cancer.

BACKGROUND AND AIM Paraneoplastic coagulopathy can present as stroke and is associated with specific biomarker changes. Identifying paraneoplastic coagulopathy can help guide secondary prevention in stroke patients, and early cancer detection might improve outcomes. However, unlike ischemic stroke, it remains unclear whether paraneoplastic coagulopathy is associated with transient ischemic attacks (TIA). This study assessed the presence of cancer-related biomarkers in TIA patients and evaluated long-term mortality rates in patients with and without active cancer. METHODS Active cancer was retrospectively identified in consecutive TIA patients treated at a comprehensive stroke center between 2015 and 2019. An association between the presence of cancer and cancer-related biomarkers was assessed using multivariable logistic regression. Long-term mortality after TIA was analyzed using multivariable Cox regression. RESULTS Among 1436 TIA patients, 72 had active cancer (5%), of which 17 were occult (1.2%). Cancer-related TIA was associated with male gender (adjusted odds ratio [aOR] 2.29, 95% CI 1.12-4.68), history of smoking (aOR 2.77, 95% CI 1.34-5.7), elevated D-dimer (aOR 1.77, 95% CI 1.26-2.49), lactate dehydrogenase (aOR 1.003, 95% CI 1.00-1.005), lower leukocyte count (aOR 1.20, 95% CI 1.04-1.38), and lower hemoglobin (aOR 1.02, 95% CI 1.00-1.04). Long-term mortality was associated with both active cancer (adjusted hazard ratios [aHR] 2.47, 95% CI 1.58-3.88) and occult cancer (aHR 3.08, 95% CI 1.30-7.32). CONCLUSION Cancer-related TIA is not uncommon. Biomarkers known to be associated with cancer-related stroke also seem to be present in TIA patients. Early identification would enable targeted treatment strategies and could improve outcomes in this patient population

Association of the 24‐Hour National Institutes of Health Stroke Scale After Mechanical Thrombectomy With Early and Long‐Term Survival

Background The National Institutes of Health Stroke Scale (NIHSS) obtained 24 hours after ischemic stroke is a good indicator for functional outcome and early mortality, but the correlation with long‐term survival is less clear. We analyzed the correlation of the NIHSS after 24 hours (24h NIHSS) and early clinical neurological development after mechanical thrombectomy with early and long‐term survival as well as its predictive power on survival. Methods We reviewed a prospective observational registry for all patients undergoing mechanical thrombectomy between January 2010 and December 2018. Vital status was extracted from the Swiss Population Registry. Adjusted hazard ratio (aHR) and crude hazard ratios were calculated using Cox regression. To assess predictive power of the 24h NIHSS, different Random Survival Forest models were evaluated. Results We included 957 patients (median follow‐up 1376 days). Patients with lower 24h NIHSS and major early neurological improvement had substantially better survival rates. We observed significantly higher aHR for death in patients with 24h NIHSS 12 to 15 (aHR, 1.78; 95% CI, 1.1–2.89), with 24h NIHSS 16 to 21 (aHR, 2.54, 95% CI, 1.59–4.06), and with 24h NIHSS >21 (aHR, 5.74; 95% CI, 3.47–9.5). The 24h NIHSS showed the best performance predicting mortality (receiver operating characteristic area under the curve at 3 months [0.85±0.034], at 1 year [0.82±0.029], at 2 years [0.82±0.031], and at 5 years [0.83±0.035]), followed by NIHSS change. Conclusions Patients with acute ischemic stroke achieving a low 24h NIHSS or major early neurological improvement after mechanical thrombectomy had markedly lower long‐term mortality. Furthermore, 24h NIHSS had the best predictive power for early and long‐term survival in our machine learning–based prediction

Geographical Requirements for the Applicability of the Results of the RACECAT Study to Other Stroke Networks.

Background The RACECAT (Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory) trial was the first randomized trial addressing the prehospital triage of acute stroke patients based on the distribution of thrombolysis centers and intervention centers in Catalonia, Spain. The study compared the drip-and-ship with the mothership paradigm in regions where a local thrombolysis center can be reached faster than the nearest intervention center (equipoise region). The present study aims to determine the population-based applicability of the results of the RACECAT study to 4 stroke networks with a different degree of clustering of the intervention centers (clustered, dispersed). Methods and Results Stroke networks were compared with regard to transport time saved for thrombolysis (under the drip-and-ship approach) and transport time saved for endovascular therapy (under the mothership approach). Population-based transport times were modeled with a local instance of an openrouteservice server using open data from OpenStreetMap.The fraction of the population in the equipoise region differed substantially between clustered networks (Catalonia, 63.4%; France North, 87.7%) and dispersed networks (Southwest Bavaria, 40.1%; Switzerland, 40.0%). Transport time savings for thrombolysis under the drip-and-ship approach were more marked in clustered networks (Catalonia, 29 minutes; France North, 27 minutes) than in dispersed networks (Southwest Bavaria and Switzerland, both 18 minutes). Conclusions Infrastructure differences between stroke networks may hamper the applicability of the results of the RACECAT study to other stroke networks with a different distribution of intervention centers. Stroke networks should assess the population densities and hospital type/distribution in the temporal domain before applying prehospital triage algorithms to their specific setting