Acute Stroke Treatment in an Anticoagulated Patient: When Is Thrombolysis an Option?

Purpose of Review: Direct oral anticoagulants (DOACs: the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran) are the mainstay of stroke prevention in patients with non-valvular atrial fibrillation (AF). Nevertheless, there is a residual stroke risk of 1–2% per year despite DOAC therapy. Intravenous thrombolysis (IVT) reduces morbidity in patients with ischemic stroke and improves functional outcome. Prior DOAC therapy is a (relative) contraindication for IVT but emerging evidence supports its use in selected patients. // Recent Findings: Recent observational studies highlighted that IVT in patients on prior DOAC therapy seems feasible and did not yield major safety issues. Different selection criteria and approaches have been studied including selection by DOAC plasma levels, non-specific coagulation assays, time since last intake, and prior reversal agent use. The optimal selection process is however not clear and most studies comprised few patients. // Summary: IVT in patients taking DOAC is a clinically challenging scenario. Several approaches have been proposed without major safety issues but current evidence is weak. A patient-oriented approach balancing potential benefits of IVT (i.e., amount of salvageable penumbra) against expected bleeding risk including appropriate monitoring of anticoagulant activity seem justified

Cerebral Small Vessel Disease and Functional Outcome Prediction after Intracerebral Haemorrhage

OBJECTIVE: To determine whether CT-based cerebral small vessel disease (SVD) biomarkers are associated with 6-month functional outcome after intracerebral hemorrhage (ICH), and whether these biomarkers improve the performance of pre-existing ICH score. METHODS: We included 864 patients with acute ICH from a multicentre, hospital-based prospective cohort study. We evaluated CT-based SVD biomarkers (white matter hypodensities [WMH]; lacunes; brain atrophy; and a composite SVD burden score) and their associations with poor 6-month functional outcome (modified Rankin Scale [mRS] score >2). The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test were used to assess discrimination and calibration of the ICH score with and without SVD biomarkers. RESULTS: In multivariable models (adjusted for ICH score components), WMH presence (OR 1.52, 95%CI 1.12-2.06), cortical atrophy presence (OR 1.80, 95%CI 1.19-2.73), deep atrophy presence (OR 1.66, 95%CI 1.17-2.34), and severe atrophy (either deep or cortical) (OR 1.94, 95%CI 1.36-2.74) were independently associated with poor functional outcome. For the ICH score, the AUROC was 0.71 (95%CI 0.68-0.74). Adding SVD markers did not significantly improve ICH score discrimination; for the best model (adding severe atrophy) the AUROC was 0.73 (95%CI 0.69-0.76). These results were confirmed when considering lobar and non-lobar ICH, separately. CONCLUSIONS: The ICH score has acceptable discrimination for predicting 6-month functional outcome after ICH. CT biomarkers of SVD are associated with functional outcome but adding them does not significantly improve ICH score discrimination

MRI and CT imaging biomarkers of cerebral amyloid angiopathy in lobar intracerebral hemorrhage

BACKGROUND: Cerebral amyloid angiopathy (CAA), a common cause of intracerebral hemorrhage (ICH), is diagnosed using the Boston criteria including magnetic resonance imaging (MRI) biomarkers (cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS). The simplified Edinburgh criteria include computed tomography (CT) biomarkers (subarachnoid extension (SAE) and finger-like projections (FLPs)). The underlying mechanisms and diagnostic accuracy of CT compared to MRI biomarkers of CAA are unknown. METHODS: We included 140 survivors of spontaneous lobar supratentorial ICH with both acute CT and MRI. We assessed associations between MRI and CT biomarkers and the diagnostic accuracy of CT- compared to MRI-based criteria. RESULTS: FLPs were more common in patients with strictly lobar CMB (44.7% vs 23.5%; p = 0.014) and SAE was more common in patients with cSS (61.3% vs 31.2%; p = 0.002). The high probability of the CAA category of the simplified Edinburgh criteria showed 87.2% (95% confidence interval (CI): 78.3-93.4) specificity, 29.6% (95% CI: 18.0-43.6) sensitivity, 59.3% (95% CI: 38.8-77.6) positive predictive value, and 66.4% (95%: CI 56.9-75.0) negative predictive value, 2.3 (95% CI: 1.2-4.6) positive likelihood ratio and 0.8 (95% CI 0.7-1.0) negative likelihood ratio for probable CAA (vs non-probable CAA), defined by the modified Boston criteria; the area under the receiver operating characteristic curve (AUROC) was 0.62 (95% CI: 0.54-0.71). CONCLUSION: In lobar ICH survivors, we found associations between putative biomarkers of parenchymal CAA (FLP and strictly lobar CMBs) and putative biomarkers of leptomeningeal CAA (SAE and cSS). In a hospital population, CT biomarkers might help rule-in probable CAA (diagnosed using the Boston criteria), but their absence is probably not as useful to rule it out, suggesting an important continued role for MRI in ICH survivors with suspected CAA

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis

OBJECTIVE: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start. METHODS: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH. RESULTS: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke. CONCLUSIONS: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start

Fatal Intracranial Hemorrhage Occurring after Oral Anticoagulant Treatment Initiation for Secondary Stroke Prevention in Patients with Atrial Fibrillation

BACKGROUND AND PURPOSE: In this pooled analysis of 7 multicenter cohorts we investigated potential differences in the incidence, characteristics and outcomes between intracranial hemorrhages (ICHs) associated with the use of non-vitamin K oral anticoagulants (NOAC-ICH) or vitamin K antagonists (VKA-ICH) in ischemic stroke (IS) patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). METHODS: We included data from 4.912 eligible AF patients who were admitted in a stroke unit with IS or transient ischemic attack (TIA) and who were treated with either VKAs or NOACs within 3 months post-stroke. Fatal ICH was defined as death occurring during the first 30-days after ICH onset. We additionally performed a meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset. RESULTS: During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKA (11 events per 3,385 patient-years) than in those with NOAC (3 events per 2,623 patient-years; HR=0.32,95%CI:0.09-1.14). Three-month functional outcomes were similar (p>0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (RR=0.70,95%CI:0.51-0.95). CONCLUSIONS: NOAC-ICH and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes, except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH

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

Development of a score for prediction of occult malignancy in stroke patients (occult-5 score).

BACKGROUND AND PURPOSE Malignancy associated acute ischemic stroke (AIS) requires specific diagnostic work-up, treatment and prevention to improve outcome. This study aimed to develop a biomarker-based score for prediction of occult malignancy in AIS patients. METHODS Single-center cross-sectional study including consecutive AIS patients treated between July 2017 and November 2018. Patients with active malignancy at presentation, or diagnosed within 1 year thereafter and patients free of malignancy, were included and malignancy associated biomarkers were assessed. LASSO analyses of logistic regression were performed to determine biomarkers predictive of active malignancy. Predictors were derived from a predictive model for active malignancy. A comparison between known and unknown (=occult) malignancies when the index stroke occurred was used to eliminate variables not associated with occult malignancy. A predictive score (OCCULT-5 score) for occult malignancy was developed based on the remaining variables. RESULTS From 1001 AIS patients, 61 (6%) presented an active malignancy. Thirty-nine (64%) were known and 22 (36%) occult. Five variables were included in the final OCCULT-5 score: age ≥ 77 years, embolic stroke of undetermined source, multi-territorial infarcts, D-dimer levels ≥ 820 µ/gL, and female sex. A score of ≥ 3 predicted an underlying occult malignancy with a sensitivity of 64%, specificity of 73%, positive likelihood ratio of 2.35 and a negative likelihood ratio of 0.50. CONCLUSIONS The OCCULT-5 score might be useful to identify patients with occult malignancy. It may thus contribute to a more effective and timely treatment and thus lead to a positive impact on overall outcome

Impact of type of oral anticoagulants in patients with cerebral microbleeds after atrial fibrillation-related ischemic stroke or TIA: Results of the NOACISP-LONGTERM registry.

Background Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC). Methods Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists [VKAs] vs. direct oral anticoagulants [DOACs]) with clinical outcome. Results Of 310 AF-stroke patients treated with OAC [DOACs: n = 234 (75%); VKAs: n = 76 (25%)], CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 [1.614; 8.277]; p = 0.002; DOACs: HR 2.230 [1.233; 4.034]; p = 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups [VKAs 13/20(65%) vs. DOACs 19/66(29%); p < 0.01]. The VKA-group had a 2-fold higher IS [VKAs:4 (20%) vs. DOACs:6 (9%); p = 0.35] and a 10-fold higher ICH rate [VKAs: 3 (15%) vs. DOACs: 1 (1.5%); p = 0.038]. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 [0.17; 0.94]; p = 0.04). Conclusions In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs. Clinical trial registration http://www.clinicaltrials.gov, Unique identifier: NCT03826927

Absence of Susceptibility Vessel Sign in Patients With Malignancy-Related Acute Ischemic Stroke Treated With Mechanical Thrombectomy.

Background and Purpose Clots rich in platelets and fibrin retrieved from patients with acute ischemic stroke (AIS) have been shown to be independently associated with the absence of the susceptibility vessel sign (SVS) on MRI and active malignancy. This study analyzed the association of SVS and the presence of active malignancy in patients with AIS who underwent mechanical thrombectomy (MT). Methods This single-center, retrospective, and cross-sectional study included consecutive patients with AIS with admission MRI treated with MT between January 2010 and December 2018. SVS status was evaluated on susceptibility-weighted imaging. Adjusted odds ratios (aORs) were calculated to determine the association between absent SVS and the presence of active or occult malignancy. The performance of predictive models incorporating and excluding SVS status was compared using areas under the receiver operating characteristics curve (auROC). Results Of 577 patients with AIS with assessable SVS status, 40 (6.9%) had a documented active malignancy and 72 (12.5%) showed no SVS. The absence of SVS was associated with active malignancy (aOR 4.85, 95% CI 1.94-12.11) or occult malignancy (aOR 11.42, 95% CI 2.36-55.20). The auROC of predictive models, including demographics and common malignancy biomarkers, was higher but not significant (0.85 vs. 0.81, p = 0.07) when SVS status was included. Conclusion Absence of SVS on admission MRI of patients with AIS undergoing MT is associated with malignancy, regardless of whether known or occult. Therefore, the SVS might be helpful in detecting paraneoplastic coagulation disorders and occult malignancy in patients with AIS

Potential missed opportunities to prevent ischaemic stroke: prospective multicentre cohort study of atrial fibrillation-associated ischaemic stroke and TIA

OBJECTIVE: We report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation. DESIGN: We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2). SETTING: Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands. PARTICIPANTS: Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation. MAIN OUTCOME MEASURES: Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA_{2}DS_{2}-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF. RESULTS: Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA_{2}DS_{2}-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA_{2}DS_{2} -VASc, other risk factors and demographics were similar. CONCLUSIONS: About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation. TRIAL REGISTRATION NUMBER: NCT02513316