Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries.

BACKGROUND: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation. METHODS: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months. RESULTS: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)). CONCLUSIONS: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Time for "code ICH"? - Workflow metrics of hyperacute treatments and outcome in patients with intracerebral haemorrhage.

INTRODUCTION: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department are scarce. METHODS: Single centre retrospective study of consecutive patients with ICH between 01/2018-08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital or other). RESULTS: We enrolled 332 patients (age 73years, IQR 63-81 and GCS 14 points, IQR 11-15, onset-to-admission-time 284 minutes, IQR 111-708minutes) of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%) and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150mmHG received IV antihypertensive and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 hours of admission. Median treatment times from admission to first IV-antihypertensive treatment was 38 minutes (IQR 18-72minutes) and 59 minutes (IQR 37-111 minutes) for PCC, with significant differences according to mode of referral (p<0.001) but not early arrival (≤6hours of onset, p=0.92). The median time in the emergency department was 139 minutes (IQR 85-220 minutes) and among patients with elevated blood pressure, only 44% achieved a successful control (<140mmHG) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hopsital mortality (aOR 0.30, 95%CI 0.12-0.73, p=0.008) and a non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54 95%CI 0.26-1.12, p=0.097). CONCLUSION: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short but not all patients achieve treatment targets during ED stay. Code ICH concordant treatment may improve clinical outcomes. Further improvements seem achievable advocating for a "code ICH" to streamline acute treatments.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Long-Term Effect of Mechanical Thrombectomy in Stroke Patients According to Advanced Imaging Characteristics.

PURPOSE: Data on long-term effect of mechanical thrombectomy (MT) in patients with large ischemic cores (≥ 70 ml) are scarce. Our study aimed to assess the long-term outcomes in MT-patients according to baseline advanced imaging parameters. METHODS: We performed a single-centre retrospective cohort study of stroke patients receiving MT between January 1, 2010 and December 31, 2018. We assessed baseline imaging to determine core and mismatch volumes and hypoperfusion intensity ratio (with low ratio reflecting good collateral status) using RAPID automated post-processing software. Main outcomes were cross-sectional long-term mortality, functional outcome and quality of life by May 2020. Analysis were stratified by the final reperfusion status. RESULTS: In total 519 patients were included of whom 288 (55.5%) have deceased at follow-up (median follow-up time 28 months, interquartile range 1-55). Successful reperfusion was associated with lower long-term mortality in patients with ischemic core volumes ≥ 70 ml (adjusted hazard ratio (aHR) 0.20; 95% confidence interval (95% CI) 0.10-0.44) and ≥ 100 ml (aHR 0.26; 95% CI 0.08-0.87). The effect of successful reperfusion on long-term mortality was significant only in the presence of relevant mismatch (aHR 0.17; 95% CI 0.01-0.44). Increasing reperfusion grade was associated with a higher rate of favorable outcomes (mRS 0-3) also in patients with ischemic core volume ≥ 70 ml (aOR 3.58, 95% CI 1.64-7.83). CONCLUSION: Our study demonstrated a sustainable benefit of better reperfusion status in patients with large ischemic core volumes. Our results suggest that patient deselection based on large ischemic cores alone is not advisable.

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.

Small vessel disease burden and risk of recurrent cerebrovascular events in patients with lacunar stroke and intracerebral haemorrhage attributable to deep perforator arteriolopathy.

INTRODUCTION: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. PATIENTS AND METHODS: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months. RESULTS: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aORshift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. DISCUSSION/CONCLUSION: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

Absence of susceptibility vessel sign and hyperdense vessel sign in patients with cancer-related stroke.

Background and aim: Identification of paraneoplastic hypercoagulability in stroke patients helps to guide investigations and prevent stroke recurrence. A previous study demonstrated an association between the absence of the susceptibility vessel sign (SVS) on brain MRI and active cancer in patients treated with mechanical thrombectomy. The present study aimed to confirm this finding and assess an association between the absence of the hyperdense vessel sign (HVS) on head CT and active cancer in all stroke patients. Methods: SVS and HVS status on baseline imaging were retrospectively assessed in all consecutive stroke patients treated at a comprehensive stroke center between 2015 and 2020. Active cancer, known at the time of stroke or diagnosed within 1 year after stroke (occult cancer), was identified. Adjusted odds ratios (aOR) and their 95% confidence interval (CI) for the association between the thrombus imaging characteristics and cancer were calculated using multivariable logistic regression. Results: Of the 2,256 patients with thrombus imaging characteristics available at baseline, 161 had an active cancer (7.1%), of which 36 were occult at the time of index stroke (1.6% of the total). The absence of SVS was associated with active cancer (aOR 3.14, 95% CI 1.45-6.80). No significance was reached for the subgroup of occult cancer (aOR 3.20, 95% CI 0.73-13.94). No association was found between the absence of HVS and active cancer (aOR 1.07, 95% CI 0.54-2.11). Conclusion: The absence of SVS but not HVS could help to identify paraneoplastic hypercoagulability in stroke patients with active cancer and guide patient care.

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. METHODS: We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). RESULTS: We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). CONCLUSIONS: Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

Yield of Echocardiography in Ischemic Stroke and Patients With Transient Ischemic Attack With Established Indications for Long-Term Direct Oral Anticoagulant Therapy: A Cross-Sectional Diagnostic Cohort Study.

Background We aimed to determine the diagnostic yield of transthoracic (TTE) and transesophageal echocardiography (TEE) in patients with ischemic stroke and transient ischemic attack with established indications for direct oral anticoagulants before the index event. Methods and Results This was a retrospective cohort study of consecutive patients with preceding established indications for long-term therapeutic direct oral anticoagulants presenting to a single comprehensive stroke center with ischemic stroke or transient ischemic attack. Choice of echocardiography modality was based on expert recommendations. The primary outcome was a composite of prespecified management-relevant high-risk findings adjudicated by an expert panel, based on TTE and TEE reports according to evidence-based recommendations. Explorative analyses were performed to identify biomarkers associated with the primary outcome. Of 424 patients included (median [interquartile range] age, 78 [70-84] years; 175 [41%] women; National Institutes of Health Stroke Scale, 4 [1-12]; 67% atrial fibrillation), 292 (69%) underwent echocardiography, while 132 (31%) did not. Modality was TTE in 191 (45%) and TEE in 101 (24%). Median time from index event to echocardiography was 2 (1-3) days. TTE identified 26 of 191 (14%) patients with 35 management-relevant pathologies. TEE identified 16 of 101(16%) patients with 20 management-relevant pathologies. Most management-relevant findings represented indicated coronary artery disease and valvular pathologies. In a further 3 of 191 (2%) patients with TTE and 4 of 101 (4%) patients with TEE, other relevant findings were identified. Variables associated with management-relevant high-risk pathologies included more severe stroke, diabetes, and laboratory biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide], C-reactive protein, d-dimer, and troponin levels). Conclusions In patients with established indications for long-term direct oral anticoagulant therapy and stroke who received echocardiography, both TTE and TEE identified a relevant and similar proportion of management-relevant high-risk pathologies and predictive biomarkers could help to guide diagnostic workup in such patients.

Intracerebral haemorrhage volume, haematoma expansion and 3-month outcomes in patients on antiplatelets. A systematic review and meta-analysis.

Aims: We assessed the association of prior antiplatelet therapy (APT) at onset of intracerebral haemorrhage (ICH) with haematoma characteristics and outcome. Methods: We performed a systematic review and meta-analysis of studies comparing ICH outcomes of patients on APT (APT-ICH) with patients not taking APT (non-APT-ICH). Primary outcomes were haematoma volume (mean difference and 95% CI), haematoma expansion (HE), in-hospital 3-month mortality rates and good functional outcome (modified Rankin Scale score 0-2). We provide odds ratios (ORs) from random effects models and subgroup analyses for haematoma expansion and short-term mortality rates. Results: We included 23 of 1551 studies on 30,949 patients with APT-ICH and 62,018 with non-APT-ICH. Patients on APT were older (Δmean 6.27 years, 95% CI 5.44-7.10), had larger haematoma volume (Δmean 5.74 mL, 95% CI 1.93-9.54), higher short-term mortality rates (OR 1.44, 95% CI 1.14-1.82), 3-month mortality rates (OR 1.58, 95% CI 1.14-2.19) and lower probability of good functional outcome (OR 0.61, 95% CI 0.49-0.77). While there was no difference in HE in the overall analysis (OR 1.32, 95% CI 0.85-2.06), HE occurred more frequently when assessed within 24 h (OR 2.58, 95% CI 1.18-5.67). We found insufficient data for comparison of single versus dual APT-ICH. Heterogeneity was substantial amongst studies. Discussion: APT is associated with larger baseline haematoma volume, early (<24 h) haematoma expansion, mortality rates and morbidity in patients with ICH. Data on differences in single and dual APT-ICH are scarce and warrant further investigation. New treatment options for APT-ICH are urgently needed.