Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial.

RATIONALE: Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery. AIM AND HYPOTHESIS: To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo. DESIGN: ESTREL (Enhancement of Stroke REhabilitation with Levodopa) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial. PARTICIPANTS: 610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living. INTERVENTION: Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset. COMPARISON: Matching placebo plus standardized rehabilitation. OUTCOMES: The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events. CONCLUSION: The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.

Lipoprotein(a) as a blood marker for large artery atherosclerosis stroke etiology: validation in a prospective cohort from a swiss stroke center.

BACKGROUND: Lipoprotein (a) [Lp(a)] serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort. METHODS: This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients [NCT00878813]), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers. RESULTS: Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 [95% CI 1.03and#x2013;2.09], p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes. CONCLUSIONS: In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov. REGISTRATION NUMBER: NCT00878813.

Absent leptomeningeal collateralization is associated with greatest benefit from mechanical thrombectomy in the 6-24 hour time window.

INTRODUCTION: The impact of leptomeningeal collateralization on the efficacy of mechanical thrombectomy (MT) in patients with anterior circulation large vessel occlusion (aLVO) presenting in the 6-24 h time window remains poorly elucidated. PATIENTS AND METHODS: Retrospective multicenter study of aLVO patients presenting between 6 and 24 h after stroke onset who received MT plus Best Medical Treatment (BMT) or BMT alone. Leptomeningeal collateralization was assessed using single-phase computed tomography angiography (grade 0: no filling; grade 1: filling ⩽50%; grade 2: filling >50% but <100%; grade 3: filling 100% of the occluded territory). Inverse probability of treatment weighted ordinal regression was performed to assess the association between treatment and shift of the modified Rankin Scale (mRS) score toward lower categories at 3 months. We used interaction analysis to explore differential treatment effects on functional outcomes (probabilities for each mRS subcategory at 3 months) at different collateral grades. RESULTS: Among 363 included patients, 62% received MT + BMT. Better collateralization was associated with better functional outcomes at 3 months in the BMT alone group (collateral grade 1 vs 0: acOR 5.06, 95% CI 2.33-10.99). MT + BMT was associated with higher odds of favorable functional outcome at 3 months (acOR 1.70, 95% CI 1.11-2.62) which was consistent after adjustment for collateral status (acOR 1.54, 95% CI 1.01-2.35). Regarding treatment effect modification, patients with absent collateralization had higher probabilities for a mRS of 0-4 and a lower mortality at 3 months for the MT + BMT group. DISCUSSION AND CONCLUSION: In the 6-to-24-h time window, aLVO patients with absent leptomeningeal collateralization benefit most from MT + BMT, indicating potential advantages for this group despite their poorer baseline prognosis.

Toward Individual Treatment in Cervical Artery Dissection: Subgroup Analysis of the TREAT-CAD Randomized Trial.

OBJECTIVE: Uncertainty remains regarding antithrombotic treatment in cervical artery dissection. This analysis aimed to explore whether certain patient profiles influence the effects of different types of antithrombotic treatment. METHODS: This was a post hoc exploratory analysis based on the per-protocol dataset from TREAT-CAD (NCT02046460), a randomized controlled trial comparing aspirin to anticoagulation in patients with cervical artery dissection. We explored the potential effects of distinct patient profiles on outcomes in participants treated with either aspirin or anticoagulation. Profiles included (1) presenting with ischemia (no/yes), (2) occlusion of the dissected artery (no/yes), (3) early versus delayed treatment start (median), and (4) intracranial extension of the dissection (no/yes). Outcomes included clinical (stroke, major hemorrhage, death) and magnetic resonance imaging outcomes (new ischemic or hemorrhagic brain lesions) and were assessed for each subgroup in separate logistic models without adjustment for multiple testing. RESULTS: All 173 (100%) per-protocol participants were eligible for the analyses. Participants without occlusion had decreased odds of events when treated with anticoagulation (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.07-0.86). This effect was more pronounced in participants presenting with cerebral ischemia (n = 118; OR = 0.16, 95% CI = 0.04-0.55). In the latter, those with early treatment (OR = 0.26, 95% CI = 0.07-0.85) or without intracranial extension of the dissection (OR = 0.34, 95% CI = 0.11-0.97) had decreased odds of events when treated with anticoagulation. INTERPRETATION: Anticoagulation might be preferable in patients with cervical artery dissection presenting with ischemia and no occlusion or no intracranial extension of the dissection. These findings need confirmation. ANN NEUROL 2024;95:886-897.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Targeting inflammation to reduce recurrent stroke.

BACKGROUND: Approximately one in four stroke patients suffer from recurrent vascular events, underlying the necessity to improve secondary stroke prevention strategies. Immune mechanisms are causally associated with coronary atherosclerosis. However, stroke is a heterogeneous disease and the relative contribution of inflammation across stroke mechanisms is not well understood. The optimal design of future randomized control trials (RCTs) of anti-inflammatory therapies to prevent recurrence after stroke must be informed by a clear understanding of the prognostic role of inflammation according to stroke subtype and individual patient factors. AIM: In this narrative review, we discuss (1) inflammatory pathways in the etiology of ischemic stroke subtypes; (2) the evidence on inflammatory markers and vascular recurrence after stroke; and (3) review RCT evidence of anti-inflammatory agents for vascular prevention. SUMMARY OF REVIEW: Experimental work, genetic epidemiological data, and plaque-imaging studies all implicate inflammation in atherosclerotic stroke. However, emerging evidence also suggests that inflammatory mechanisms are also important in other stroke mechanisms. Advanced neuroimaging techniques support the role of neuroinflammation in blood-brain barrier dysfunction in cerebral small vessel disease (cSVD). Systemic inflammatory processes also promote atrial cardiopathy, incident and recurrent atrial fibrillation (AF). Although several inflammatory markers have been associated with recurrence after stroke, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) are presently the most promising markers to identify patients at increased vascular risk. Several RCTs have shown that anti-inflammatory therapies reduce vascular risk, including stroke, in coronary artery disease (CAD). Some, but not all of these trials, selected patients on the basis of elevated hsCRP. Although unproven after stroke, targeting inflammation to reduce recurrence is a compelling strategy and several RCTs are ongoing. CONCLUSION: Evidence points toward the importance of inflammation across multiple stroke etiologies and potential benefit of anti-inflammatory targets in secondary stroke prevention. Taking the heterogeneous stroke etiologies into account, the use of serum biomarkers could be useful to identify patients with residual inflammatory risk and perform biomarker-led patient selection for future RCTs.

Clinical Course and Recurrence in Transient Global Amnesia: A Study From the TEMPiS Telestroke Network.

BACKGROUND AND PURPOSE: While the clinical hallmarks of transient global amnesia (TGA) are well defined, its pathophysiological causes are poorly understood. Specifically, risk factors for recurrences are yet to be determined. METHODS: This retrospective study analyzed TGA cases diagnosed and treated within the TEMPiS telestroke network and a university stroke center in Germany. Demographic and clinical data were assessed and characteristics of TGA episodes were recorded, such as season of occurrence, trigger factors, duration, and concomitant symptoms. Follow-up of the potential recurrence of TGA was performed using a standardized questionnaire. RESULTS: Overall 109 patients were included (age 64±8 years [mean±SD], 59.6% female). The most common vascular risk factor was arterial hypertension (60.6%), and other concomitant conditions included migraine (11.9%), hypothyroidism (22.9%), and atrial fibrillation (4.6%). The most frequent concomitant clinical feature accompanying the TGA episode at admission was elevated blood pressure (48.6%). Nineteen patients experienced at least one recurrent TGA episode. Migraine and hypothyroidism were only observed in subjects with a single TGA episode without recurrence (migraine: 14.4% without recurrence vs. none in the recurrence group, p=0.02; hypothyroidism: 27.8% without recurrence vs. none in the recurrence group, p=0.009). In contrast, atrial fibrillation was more common in subjects with TGA recurrence (p<0.001). CONCLUSIONS: Arterial hypertension is prevalent in TGA patients, with elevated blood pressure being the most-frequent concomitant condition. In our cohort, recurrence of TGA occurred in approximately one-fifth of patients. Concomitant conditions such as migraine, hypothyroidism, and atrial fibrillation occurred at different frequencies in the two groups.

Anticoagulation in acute ischemic stroke patients with mechanical heart valves: To bridge or not with heparin. The ESTREM study.

INTRODUCTION: The best therapeutic strategy for patients with mechanical heart valves (MHVs) having acute ischemic stroke during treatment with vitamin K antagonists (VKAs) remain unclear. Being so, we compared the outcomes for: (i) full dose heparin along with VKA (bridging therapy group) and (ii) restarting VKA without heparin (nonbridging group). PATIENTS AND METHODS: For this multicenter observational cohort study, data on consecutive acute ischemic stroke patients with MHV was retrospectively collected from prospective registries. Propensity score matching (PSM) was adopted to adjust for any treatment allocation confounders. The primary outcome was the composite of stroke, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding at 90 days. RESULTS: Overall, 255 out of 603 patients (41.3%) received bridging therapy: 36 (14.1%) had combined outcome, compared with 28 (8.0%) in the nonbridging group (adjusted OR 1.83; 95% CI 1.05-3.18; p = 0.03). Within the bridging group, 13 patients (5.1%) compared to 12 (3.4%) in the nonbridging group had an ischemic outcome (adjusted OR 1.71; 95% CI 0.84-3.47; p = 0.2); major bleedings were recorded in 23 (9.0%) in the bridging group and 16 (4.6%) in the nonbridging group (adjusted OR 1.88; 95% CI 0.95-3.73; p = 0.07). After PSM, 36 (14.2%) of the 254 bridging patients had combined outcome, compared with 23 (9.1%) of 254 patients in the nonbridging group (OR 1.66; 95% CI 0.95-2.85; p = 0.07). CONCLUSION: Acute ischemic stroke patients with MHV undergoing bridging therapy had a marginally higher risk of ischemic or hemorrhagic events, compared to nonbridging patients.

The impact of competing stroke etiologies in patients with atrial fibrillation.

BACKGROUND: Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce. METHODS: We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed. RESULTS: Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause. CONCLUSION: In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients. CLINICAL TRIAL REGISTRATION: NCT03826927.

Apical pulmonary lesions suspected of malignancy visible on neck CT angiography performed for acute stroke: Prevalence, treatment, and clinical implications - the PLEURA study.

BACKGROUND: Computed tomography angiography (CTA) of the supraaortic arteries is commonly used for acute stroke workup and may reveal apical pulmonary lesions (APL). AIM: To determine the prevalence, follow-up algorithms, and in-hospital outcomes of stroke patients with APL on CTA. METHODS: We retrospectively included consecutive adult patients with ischemic stroke, transient ischemic attack, or intracerebral hemorrhage and available CTA at a tertiary hospital between January 2014 and May 2021. We reviewed all CTA reports for the presence of APL. APL were classified as malignancy suspicious or benign appearing based on radiological-morphological criteria. We performed regression analyses to investigate the impact of malignancy suspicious APL on different in-hospital outcome parameters. RESULTS: Among 2715 patients, APL on CTA were found in 161 patients (5.9% [95%CI: 5.1-6.9]; 161/2715). Suspicion of malignancy was present in one third of patients with APL (36.0% [95%CI: 29.0-43.7]; 58/161), 42 of whom (72.4% [95%CI: 60.0-82.2]; 42/58) had no history of lung cancer or metastases. When performed, further investigations confirmed primary or secondary pulmonary malignancy in three-quarters (75.0% [95%CI: 50.5-89.8]; 12/16), with two patients (16.7% [95%CI: 4.7-44.8]; 2/12) receiving de novo oncologic therapy. In multivariable regression, the presence of radiologically malignancy suspicious APL was associated with higher NIHSS scores at 24 h (beta = 0.67, 95%CI: 0.28-1.06, p = 0.001) and all-cause in-hospital mortality (aOR = 3.83, 95%CI: 1.29-9.94, p = 0.01). CONCLUSIONS: One in seventeen patients shows APL on CTA, of which one-third is malignancy suspicious. Further work-up confirmed pulmonary malignancy in a substantial number of patients triggering potentially life-saving oncologic therapy.

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

Mechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort Study.

BACKGROUND: We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria. METHODS: Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days. RESULTS: Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 [1.02-2.10]; P=0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 [0.37-0.93]; P=0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%, P=0.63). CONCLUSIONS: Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.

Global Cortical Atrophy Is Associated with an Unfavorable Outcome in Stroke Patients on Oral Anticoagulation.

INTRODUCTION: Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA). METHODS: Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death. RESULTS: In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34-11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23-12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17-14.84, p = 0.028). CONCLUSION: GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation.

Mechanical thrombectomy for large vessel occlusion between 6 and 24 h: outcome comparison of DEFUSE-3/DAWN eligible versus non-eligible patients.

BACKGROUND: The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h. AIMS: We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice. METHODS: We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage [sICH] and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score [mRS] shift toward lower categories and mRS of 0-2 at 3 months). RESULTS: Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p = 1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64-6.84, p = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37-1.79, p = 0.60; mRS 0-2: aOR 0.91, 95% CI 0.31-2.57, p = 0.85). CONCLUSION: Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.

Genetic proxies for PCSK9 inhibition associate with lipoprotein(a): Effects on coronary artery disease and ischemic stroke.

BACKGROUND AND AIMS: Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS). METHODS: To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels. RESULTS: Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: -0.038, 95%CI: -0.053 to -0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989-0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992-0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively. CONCLUSIONS: Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS.

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.

Cerebral Amyloid Angiopathy and the Risk of Hematoma Expansion.

OBJECTIVE: We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH). METHODS: Among participants with ICH enrolled in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non-CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms. RESULTS: A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age = 71 years, interquartile range = 60-80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA-ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non-CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction  < 0.001) and baseline ICH volume (constant risk regardless of volume, pinteraction  < 0.001) but no association between type of ICH and risk of HE or favorable outcome. Tranexamic acid significantly reduced the risk of HE (adjusted odds ratio = 0.7, 95% confidence interval = 0.6-1.0, p = 0.020) without statistically significant interaction with type of ICH (pinteraction  = 0.058). Tranexamic acid was not associated with favorable outcome. INTERPRETATION: Risk of HE in patients with lobar CAA-ICH was not independently increased but seems to have different dynamics compared to other types of ICH. The time window for treatment of CAA-ICH to prevent HE may be longer. ANN NEUROL 2022;92:921-930.

Once versus twice daily direct oral anticoagulants in patients with recent stroke and atrial fibrillation.

Background: Data on the safety and effectiveness of once-daily (QD) versus twice-daily (BID) direct oral anticoagulants (DOAC) in comparison to vitamin K antagonists (VKA) and to one another in patients with atrial fibrillation (AF) and recent stroke are scarce. Patients and methods: Based on prospectively obtained data from the observational registry Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients(NOACISP)-LONGTERM (NCT03826927) from Basel, Switzerland, we compared the occurrence of the primary outcome - the composite of recurrent ischemic stroke, major bleeding, and all-cause death - among consecutive AF patients treated with either VKA, QD DOAC, or BID DOAC following a recent stroke using Cox proportional hazards regression including adjustment for potential confounders. Results: We analyzed 956 patients (median age 80 years, 46% female), of whom 128 received VKA (13.4%), 264 QD DOAC (27.6%), and 564 BID DOAC (59%). Over a total follow-up of 1596 patient-years, both QD DOAC and BID DOAC showed a lower hazard for the composite outcome compared to VKA (adjusted HR [95% CI] 0.69 [0.48, 1.01] and 0.66 [0.47, 0.91], respectively). Upon direct comparison, the hazard for the composite outcome did not differ between patients treated with QD versus BID DOAC (adjusted HR [95% CI] 0.94 [0.70, 1.26]). Secondary analyses focusing on the individual components of the composite outcome revealed no clear differences in the risk-benefit profile of QD versus BID DOAC. Discussion and conclusion: The overall benefit of DOAC over VKA seems to apply to both QD and BID DOAC in AF patients with a recent stroke, without clear evidence that one DOAC dosing regimen is more advantageous than the other.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.