Noncardioembolic Ischemic Stroke Research Articles

Factor XI Inhibitors: perspectives in primary and secondary prevention of ischemic stroke.

Stroke is one of the most common causes of mortality and disability worldwide. Antithrombotic therapy represents the mainstay in primary and secondary prevention, both in cardioembolic and non-cardioembolic stroke. Particularly, direct oral anticoagulants play a crucial role in atrial fibrillation, the most common cause of cardioembolic stroke, whereas single or dual antiplatelet therapy is preferred in non-cardioembolic stroke. However, the limitations related to the residual risk of cardioembolic or cerebrovascular events, and the risk of major bleeding, still represent unmet medical needs. To overcome them, new drugs inhibiting Factor XI (FXI) and Factor XII have been proposed, with a selective inhibition of contact pathway of coagulation, delineating a new anticoagulant approach. This review provides a summary of the currently available evidence and future perspectives on FXI inhibitors, that can represent an additional therapeutic option in the primary and secondary prevention of cardioembolic and non-cardioembolic ischemic stroke, also in challenging therapeutic contexts.

Long-term combined antiplatelet therapy for secondary prevention of noncardioembolic stroke

Introduction. The high risk of recurrent ischemic events after non-cardioembolic ischemic stroke(IS), the prevalence of which is 25% of all strokes in the Russian Federation, determines the need to search for effective and safe secondary prevention strategies.Аim. The study was to evaluate the efficacy and safety of a combination of ADP receptor inhibitors (dipyridamole) with acetylsalicylic acid in patients with ischemic stroke (IS) in the secondary prevention of noncardioembolic stroke.Materials and methods. 229 patients in the early recovery period of noncardioembolic IS (139 women, 90 men), with an average age of 59.0 ± 5.7 years were included in the study. The duration of IS was 54.4 ± 6.1 days. All patients received a multimodal medical rehabilitation (MMR) program. Long-term double antiplatelet therapy with acetylsalicylic acid (ASA) 75 mg per day and dipyridamole at a daily dose of 225 mg divided into 3 doses were prescribed to all the patients. The neurological and neuropsychological status of the patient, quality of life and hemorheological parameters were assessed initially (T0), after MMR (T1, 6 weeks) and 12 months after IS(T2).Results. Motor and coordination indicators of patients as well as the cognitive and emotional parameters were significantly (p < 0,05) improved due to MMR technology. These were confirmed by the dynamics of the corresponding scales. The prescribed double antiplatelet therapy did not cause significant adverse events and worsening of the patients’ well-being both during the MMR process and during the observation period. The combination of ASA with dipyridamole was well tolerated. At the end of the study, recurrent IS, myocardial infarctions, and fatal bleeding were not recorded. In 5.2% patients with severe risks of cardiovascular complications there was occurred TIA. The effectiveness of the dual antiplatelet therapy was confirmed by a decrease in the level of platelet aggregation (p < 0,05).Conclusions. The high effectiveness of secondary prevention of IS with a combination of ASA and dipyridamole with good tolerability and safety in patients after IS has been shown.

Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Author Response: IV Thrombolysis vs Early Dual Antiplatelet Therapy in Patients With Mild Noncardioembolic Ischemic Stroke.

Author Response: IV Thrombolysis vs Early Dual Antiplatelet Therapy in Patients With Mild Noncardioembolic Ischemic Stroke.

Dyslipidaemia In Acute Non-Cardioembolic Ischemic Stroke Patients At A Tertiary Care Center

Objective: To determine the frequency of dyslipidaemia in acute non-cardio embolic ischemic stroke patients at a tertiary care centre in Rawalpindi. Study Design: Cross-sectional study Place and Duration of Study: Neurology Department, Pak Emirates Military Hospital (PEMH), Rawalpindi Pakistan, Jul 2022 to Feb 2023. Methodology: Patients with acute non-cardio embolic ischemic stroke were included. Data was collected from the patient files and hospital records including a thorough history, physical examination information, CT/MRI brain, fasting lipid profiles with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Results: The study included 196 patients, of which dyslipidaemia was seen with a major share of high TG in 44(22.44%), followed by high LDL cholesterol in 38(19.38%), and high TC was found in 28(14.28%). Conclusion: More than 1/3rd of patients with acute non-cardioembolic ischemic stroke have dyslipidaemia.

Abstract TMP64: Time-Trends and Determinants of Dual Antiplatelet Therapy Prescription After Acute Moderate-to-Severe Non-Cardioembolic Ischemic Stroke

Introduction: Short-term dual antiplatelet therapy (DAPT) lowers the risk of early stroke recurrence after mild non-cardioembolic ischemic stroke (NCIS) and high-risk transient ischemic attack. However, DAPT benefit in moderate-to-severe NCIS is unknown. We sought to investigate time-trends and determinants of DAPT prescription after moderate-to-severe NCIS in the Florida Stroke Registry (FSR). Methods: Within 168 FSR-participating hospitals, between January 2010 and September 2022, we analyzed NCIS patients with NIHSS score >3, without other indication(s) for DAPT (e.g., carotid stenting) or systemic anticoagulation, hemorrhagic complications, and whom received at least one antiplatelet agent upon discharge. Using single antiplatelet therapy (SAPT) as comparison, we assessed DAPT determinants through logistic regression models adjusted for demographics, hospital characteristics, clinical presentation, vascular risk factors and stroke subtype. Results: Out of 283,264 ischemic stroke patients during the study period, 53,282 had moderate-to-severe NCIS (mean age 68 +/-14 years, 50% women, median presenting NIHSS score 7 [interquartile range 6]). DAPT was prescribed in 15,107 (28.4%) and SAPT in 38,175 (71.6%). DAPT prescription increased from 24.2% in 2010 to 44.8% in 2022 (Figure 1). Independent determinants of DAPT prescription are shown in Table 1. Conclusion: DAPT prescription after moderate-to-severe NCIS is common now, and has nearly doubled over the past decade. Major DAPT determinants were premorbid SAPT and large-artery atherosclerosis. Further research may determine DAPT efficacy and safety in this population.

Abstract WMP2: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial in Acute Non-Cardioembolic Ischemic Stroke With Adrenomedullin

Background: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke (IS) in several animal models. This phase II clinical trial aimed to test the safety and tolerability of intravenous (IV) AM administration in acute IS (AIS) patients within 24 hours of onset. Methods: The AdrenoMedullin For Ischemic Stroke study is an investigator-initiated, randomized, double-blind, phase II trial. Patients with non-cardioembolic IS within 24 hours after stroke onset and baseline NIH Stroke Scale (NIHSS) score ≥1 were randomly allocated to the intermittent IV AM (I-AM group) (30 μg/kg in total for 7 days, n=20) or placebo group (n=10) in the first cohort and a combination of continuous (the first 3 days) and intermittent (the following 4 days) IV AM (C/I-AM group) (56 μg/kg in total for 7 days, n=20) or placebo group (n=10) in the second cohort. The primary endpoint was serious adverse events related to the protocol treatment and secondary efficacy endpoints were favorable outcomes (mRS 0-2 at 90 days) and good outcomes (mRS 0-3 at 90 days). Results: The population of 60 patients had a median age of 75 years, 21 patients (35%) were female, and the median NIHSS score was 3. The primary endpoint did not occur in all groups. In the secondary efficacy endpoints, the rates of favorable outcome (75.0% vs. 68.9%, adjusted odds ratio [aOR], 1.45; 95% confidential interval [CI], 0.32-6.53) and good outcome (90.0% vs. 73.7%, aOR 3.86; 95% CI, 0.67-22.11) in the I-AM group were not statistically different from those in the placebo group. The rates of good outcomes in the C/I-AM group were comparable with those in the placebo group (85.0% vs. 73.7%, aOR 1.56; 95% CI, 0.72-3.39). Conclusions: Treatment with IV AM within 24 hours of AIS onset is safe. Intermittent IV AM may contribute to improved AIS prognosis. The efficacy and safety of AM will need confirmation in the next phase of clinical trials.

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients > 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p<0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

Abstract TP240: Safety of Dabigatran in Patients With Acute Minor Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack and Cerebral Microbleeds: A Post Hoc Analysis of the DATAS-II Randomized Trial

Introduction: Cerebral microbleeds are reported to predict risk of hemorrhagic transformation (HT) in patients with acute ischemic stroke. We aimed to investigate whether the effect of dabigatran (vs. aspirin) in patients with acute minor non-cardioembolic ischemic stroke/TIA is modified by baseline microbleeds on MRI. Methods: This is a post hoc analysis of the DATAS-II trial that randomized 305 patients with acute minor non-cardioembolic ischemic stroke/TIA to dabigatran (150/110 mg twice daily) or aspirin (81 mg daily) for 30 days. MRIs of patients with T2*-weighted sequences on their baseline scans underwent blinded central adjudication for microbleeds. Results: A total of 251 participants (mean age=66±13 years, 36% women, median [IQR] time from symptom onset to randomization 40 [27-55] hours; mean NIHSS=1.5±1.9) were included in these analyses, of whom 82 (33%) had baseline microbleeds. On 30-day MRI, 6% (n=14) developed HT, and 80% (n=191) achieved mRS 0-1 at 90 days. In multivariable logistic regression analyses, we found no association between microbleeds and HT (adjusted odds ratio [aOR], 0.76; 95% CI, 0.18-3.23) on 30-day MRI or mRS 0-1 at 90 days (aOR, 1.54; 95% CI, 0.70-3.41). The rates of HT and mRS 0-1 in patients with microbleeds were 3% on dabigatran and 4% on aspirin (OR, 0.71; 95% CI, 0.06-8.17), and 74% on dabigatran and 84% on aspirin (OR, 0.54; 95% CI, 0.18-1.64), respectively. The presence, severity, or location of microbleeds did not modify the effect of dabigatran on these outcomes (p-interaction>0.05). Conclusions: Early dabigatran treatment appears safe in patients with acute minor non-cardioembolic ischemic stroke/TIA and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI.

The Model for Clinical, Laboratory, and Genetic Prediction of Recurrent Ischemic Stroke against the Background of Laboratory Aspirin Resistance using Machine Learning

The aim of the study was to determine the incidence of laboratory aspirin resistance; and to study the associations of genetic markers and clinical and laboratory parameters (including parameters of the platelet hemostasis) in patients with non-cardioembolic ischemic stroke using machine learning methods to assess the prognosis of recurrent ischemic strokes. Clinical and laboratory data (including induced platelet aggregation) were analyzed from 296 patients with ischemic stroke who were treated in the stroke center of City Clinical Hospital No. 1 named after. N.I. Pirogov. The frequencies of polymorphic variants of the ITGB3, GPIba, TBXA2R, ITGA2, PLA2G7, HMOX1, PTGS1, PTGS2, ADRA2A, ABCB1, PEAR1 genes and intergenic region 9p21.3) in patients with non-cardioembolic ischemic stroke, which were identified using hydrogel biochip technology, were determined. Using the developed machine learning model, additional clinical and genetic factors influencing the development of laboratory aspirin resistance and recurrent ischemic stroke were studied. In the future, the identified factors can be used for differentiated prevention of recurrent ischemic strokes.

Cerebral microbleeds and asundexian in non-cardioembolic ischemic stroke: Secondary analyses of the PACIFIC-STROKE randomized trial.

Cerebral microbleeds are magnetic imaging resonance (MRI) markers of hemorrhage-prone cerebral small vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exist concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembolic ischemic stroke. This is a secondary analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ⩾ 45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 h of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50 mg daily) versus placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of (1) all pooled asundexian doses and (2) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/transient ischemic attack (TIA) (primary outcome), and ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes). Of 1746 participants (mean age, 67.0 ± 10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n = 122) had ischemic stroke/TIA, 0.5% (n = 8) ICrH, and 2.1% (n = 37) died. New microbleeds developed in 10.3% (n = 155) of participants with adequate follow-up MRIs and HT in 31.4% (n = 345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n = 1507), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR, 0.96; 95% CI, 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction > 0.05). The rates of new microbleeds, HT, and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95% CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95% CI, 3.0-6.3). Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial. ClinicalTrials.gov Identifier: NCT04304508.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. Bristol Myers Squibb and Janssen Research & Development.

Rare Germline Loss-of-Function Variants in HSP47 ( SERPINH1) Are Associated with an Intermediate Osteogenesis Imperfecta Phenotype Characterized By Atopic Inflammation and Increased Risk of Thrombosis

Background: There has been considerable interest in the collagen-specific chaperone HSP47 ( SERPINH1) as a potential drug target for the treatment of cirrhosis, fibrotic disease, and more recently, thrombosis (Thienel et al., Science 380, 178-187, 2023). While homozygous or compound heterozygous loss of function in SERPINH1 is known to cause a rare form of osteogenesis imperfecta (OI) in humans, little is known about the clinical effects of moderately decreased HSP47 activity. In order to assess the potential safety and efficacy of an antithrombotic strategy based on HSP47 blockade, we evaluated the clinical impacts of heterozygous loss-of-function variants in SERPINH1 in a dataset of over 400,000 individuals. Aims: Determine the clinical effects of SERPINH1 loss of function in a large-scale whole exome sequencing dataset. Methods: The UK Biobank (UKBB) contains paired whole exome sequencing and clinical data on 415,921 subjects in addition to plasma proteomics data for a subset of participants (N= 48,892). We identified all rare (MAF&amp;lt;0.1%)variants in SERPINH1 that were predicted in silico to alter protein activity (functional impact score ≥0.7). Using Firth's logistic regression, we controlled for age, sex, ancestry, and other risk factors and assessed the association between the presence of qualifying SERPINH1 variants and four thrombotic disorders: venous thromboembolism (VTE), non-cardioembolic ischemic stroke (NCEIS), myocardial infarction (MI), and peripheral arterial disease (PAD). Replication was performed in a composite dataset from the NIH All of Us program and the Mass General Brigham (MGB) Biobank (N=150,017). We also evaluated differences in the plasma levels of 1,472 proteins (Olink Explore 1536 proteomics panel) between carriers and non-carriers of qualifying SERPINH1 variants. Results: Rare qualifying variants in SERPINH1 were identified in 382 UKBB participants (100% heterozygous). On average, SERPINH1 variant carriers were of significantly shorter stature (P=3.97 x 10-5) and lower weight (P=0.006) than individuals without such variants, and this effect was more pronounced in subjects with higher functional impact scores ( Figure 1). By contrast, bone mineral density did not differ significantly as measured by calcaneal quantitative ultrasound and femur shaft dual x-ray absorptiometry. The presence of SERPINH1 variants was associated with significantly increased risk of VTE (OR=1.87, 95% CI: 1.21-2.76, P=0.006), MI (OR=1.98, 95% CI: 1.27-2.96, P=0.003), PAD (OR=2.37, 95% CI: 1.29-3.98, P=0.007), and NCEIS (OR=2.67, 95% CI: 1.24-4.98, P=0.015). Restricting the analysis to high-confidence loss-of-function variants (i.e., nonsense, frameshift, and essential splice site mutations) markedly boosted effect size estimates for MI, PAD, and NCEIS. The VTE and MI disease associations replicated in the composite dataset (VTE OR=3.29, 95% CI: 1.46-7.39, P=0.004; MI OR=2.31, 95% CI: 1.05-5.08, P=0.038). Additionally, the association with NCEIS demonstrated a strong trend towards significance in the replication dataset (OR=2.08, 95% CI: 0.90-4.83, P=0.088). Plasma proteome analysis showed a significant increase in several proteins related to asthma, atopic inflammation, and/or eosinophil activation among individuals with qualifying SERPINH1 variants, including RNASE3, DPP10, TSPAN1, CCL20, and IL10RA ( Figure 2). In order to further investigate these differences in circulating protein profile, we assessed the risk of obstructive asthma in a meta-analysis of the UKBB, All of Us, and MGB datasets (total N=565,455) and found that SERPINH1 variant carriers were significantly more likely to have disease (OR=1.32, 95% CI: 1.03-1.69, P=0.026). Conclusions: Loss of function in SERPINH1 is associated with a significantly increased risk of both venous and arterial thrombosis, raising concerns that long-term therapeutic inhibition of HSP47 may not be a safe or effective antithrombotic strategy. Our data indicate that SERPINH1 variant carriers experience higher levels of eosinophil-driven inflammation, which has consistently been linked to cardiovascular disease. Further, heterozygous SERPINH1 variant carriers appear to have an intermediate OI phenotype characterized by shorter stature but without significant differences in bone mineral density compared to non-carriers.

Protein Z ( PROZ) Loss of Function Is Associated with Increased Risk of Ischemic Stroke in 416,767 UK Biobank Participants

Background:The vitamin K-dependent coagulation factor protein Z ( PROZ) is canonically considered to have anticoagulant effects through its negative regulation of factor Xa. However, the true role of protein Z in coagulation is controversial, with conflicting data on the impact of plasma protein Z levels across a range of thrombotic phenotypes. In particular, higher circulating protein Z concentrations have consistently been associated with an elevated risk of acute ischemic stroke, but there is little explanation for this apparent paradox. Because studies of plasma protein levels are especially prone to confounding by environmental factors, a large-scale, adjusted analysis examining the thrombosis risk associated with germline loss-of-function variants in PROZ would represent a novel approach with far greater capacity to address causality. Aims:Perform a large-scale genomic association study to examine the risk associated with functional variants in PROZ across four thrombotic phenotypes. Methods:Using paired clinical and whole exome sequencing data for 416,767 participants in the UK Biobank (UKBB), we identified individuals with rare (MAF&amp;lt;0.1%), in silico predicted function-altering (∆F) variants in PROZ. Using Firth's logistic regression and controlling for age, sex, ancestry, and other known risk factors for thrombosis, we assessed the association between ∆F variants in PROZ and venous thromboembolism (VTE), non-cardioembolic ischemic stroke (NCEIS), peripheral arterial disease (PAD), myocardial infarction (MI), and coagulopathic bleeding. Additionally, we evaluated differences in the levels of 1,472 plasma proteins (Olink Explore 1536 proteomics panel) between carriers and non-carriers of qualifying PROZ variants in a subset of 48,892 UKBB participants. Results: Rare ∆F variants in PROZ were identified in 463 UKBB participants (99.14% heterozygous). The presence of ∆F variants was associated with significantly increased risk of NCEIS (OR=2.34, 95% CI: 1.16-4.15, P=0.02). By contrast, no significant association was seen between PROZ ∆F variants and VTE (OR=0.92, 95% CI: 0.54-1.46, P=0.75), MI (OR=1.03, 95% CI: 0.61-1.61, P=0.93), PAD (OR=0.63, 95% CI: 0.21-1.40, P=0.29), or coagulopathic bleeding (OR=0.96, 95% CI: 0.57-1.52, P=0.88) ( Figure 1). Restricting the analysis to high-confidence loss of function variants (i.e., nonsense, frameshift, and essential splice site mutations) increased the effect size estimate for NCEIS (OR=2.53, 95% CI: 0.96-5.26, P=0.058) without meaningfully changing our findings in the other thrombotic or bleeding phenotypes. Plasma proteomic analysis revealed that carriers of a PROZ ∆F variant had significantly elevated levels of two proteins that have previously been found to mediate brain inflammation after acute ischemic stroke, peroxiredoxin 1 (PRDX1, fold-change = 1.83, P=1.3 x 10 -5) and peroxiredoxin 6 (PRDX6, fold-change = 1.78, P=9.6 x 10- 10) ( Figure 2). Conclusions:In this dataset of over 400,000 participants, we found that rare, germline loss-of-function variants in PROZ are associated with significantly increased risk of NCEIS. Plasma proteomics revealed that PROZ variant carriers also have significantly higher circulating levels of two proteins that are known to play a role in acute ischemic stroke. By contrast, we found no association between PROZ mutations and an increased risk for VTE, MI, PAD, or bleeding. Taken together, these findings suggest that protein Z haploinsufficiency likely confers a uniquely higher risk of ischemic stroke without substantially influencing other forms of thrombosis.

Dual antiplatelet therapy is associated with favorable outcome in acute minor stroke with an onset-to-door time beyond 24 h

In patients with noncardioembolic acute minor ischemic stroke (AMIS), dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel within 24h after stroke onset was more effective than aspirin alone. This study investigated the efficacy and safety of DAPT in AMIS patients with an onset-to-door time (OTDT) of more than 24h. This was a retrospective analysis of a prospective stroke registry from 2015 to 2021. Patients with AMIS and an OTDT within seven days were classified into the Early (≤24h) and Late groups (>24h) according to the time of antiplatelet administration after stroke onset. In total, 691 patients were identified. Of these, 446 (64.5%) and 245 (35.5%) patients were classified into the Early and Late groups, respectively. The rates of recurrent infarction and symptomatic intracranial hemorrhage at 90 days were similar between the single antiplatelet therapy (SAPT) and DAPT subgroups in both the Early and Late groups. More patients in the DAPT subgroup had a favorable outcome (modified Rankin scale of 0-1) at 90 days in both Early (84.2% versus 75.0%, p=0.016) and Late (88.2% versus 76.9%, p=0.040) groups. DAPT was independently associated with a favorable outcome in both the Early (odds ratio, 1.95; 95% CI, 1.15-3.32; p=0.013) and Late (odds ratio, 2.72; 95% CI, 1.14-6.48; p=0.024) groups. In patients with AMIS and an OTDT of more than 24h, DAPT was associated with a favorable outcome at 90 days.

Determinants and Temporal Trends of Dual Antiplatelet Therapy After Mild Noncardioembolic Stroke.

Short-term dual antiplatelet therapy (DAPT) reduces early stroke recurrence after mild noncardioembolic ischemic stroke (NCIS). We aim to evaluate temporal trends and determinants of DAPT prescription after mild NCIS in the Florida Stroke Registry, a statewide registry across Get With The Guidelines-Stroke participating hospitals. In this cross-sectional analysis of a cohort study, we included patients with mild NCIS (National Institutes of Health Stroke Scale score ≤3) who were potentially eligible for DAPT across 168 Florida Stroke Registry participating hospitals between January 2010 and September 2022. Using antiplatelet prescription as the dependent variable (DAPT versus single antiplatelet therapy), we fit logistic regression models adjusted for patient-related factors, hospital-related factors, clinical presentation, vascular risk factors, and ischemic stroke subtype, to obtain adjusted odds ratios (aORs) with 95% CIs. From 283 264 Florida Stroke Registry ischemic stroke patients during the study period, 109 655 NCIS were considered eligible. Among these, 37 058 patients with National Institutes of Health Stroke Scale score >3 were excluded, resulting in a sample of 72 597 mild NCIS (mean age 68±14 years; female 47.3%). Overall, 24 693 (34.0%) patients with mild NCIS were discharged on DAPT and 47 904 (66.0%) on single antiplatelet therapy. DAPT prescription increased from 25.7% in 2010 to 52.8% in 2022 (β/year 2.5% [95% CI, 1.5%-3.4%]). Factors associated with DAPT prescription were premorbid antiplatelet therapy (aOR, 4.66 [95% CI, 2.20-9.88]), large-artery atherosclerosis (aOR, 1.68 [95% CI, 1.43-1.97]), diabetes (aOR, 1.29 [95% CI, 1.13-1.47]), and hyperlipidemia (aOR, 1.24 [95% CI, 1.10-1.39]), whereas female sex (aOR, 0.83 [95% CI, 0.75-0.93]), being non-Hispanic Black patients (compared with non-Hispanic White patients; aOR, 0.78 [95% CI, 0.68-0.90]), admission to a Thrombectomy-capable Stroke Center (compared with Comprehensive Stroke Center; aOR, 0.78 [95% CI, 0.66-0.92]), time-to-presentation 1 to 7 days from last seen well (compared with <24 h; aOR, 0.86 [95% CI, 0.76-0.96]), and small-vessel disease stroke (aOR, 0.81 [95% CI, 0.72-0.94]) were associated with not receiving DAPT at discharge. Despite a temporal trend increase in DAPT prescription after mild NCIS, we found substantial underutilization of evidence-based DAPT associated with significant disparities in stroke care.

Ticagrelor plus aspirin vs clopidogrel plus aspirin in mild non-cardioembolic ischemic stroke: A protocol of a randomized, controlled, active comparator arm, outcome assessor blind, feasibility study

Background &amp; Objectives: The risk of recurrence after a transient ischemic attack (TIA) or minor stroke is high especially within three months after first event. The aim of study is assessing the efficacy of ticagrelor plus aspirin in reduction of mild non-cardioembolic ischemic stroke or high risk TIA recurrence during first 3 months. Methods: This is a randomized, controlled, active comparator arm, outcome assessor blind, parallel group, feasibility study design on 90 patients with diagnosis of non-cardioembolic minor ischemic stroke or high risk TIA admitted in Bou-Ali Sina Hospital, Sari, Iran. After meeting all inclusion and exclusion criteria, patients will be randomized to ticagrelor 90 mg BID plus aspirin (ASA) 80 mg daily or clopidogrel 75 mg daily plus ASA 80 mg daily (1:1 ratio) until 21 days and then ASA 80 mg daily. Participants will be visited at month one and three. Any adverse events, serious side effects and outcome events will be recorded. The primary outcome is defined as ischemic stroke recurrence. Conclusion: Ticagrelor plus ASA is expected to be effective for prevention of recurrence in mild non-cardioembolic stroke and high risk TIA. Trial Registration: ClinicalTrials.gov: NCT04738097

Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Asundexian: an oral small moleculefactor XIa inhibitor for the treatment of thrombotic disorders.

Oral anticoagulants, including warfarin and direct oral anticoagulants, are the standard of care for thrombosis prevention and treatment; however, concerns of bleeding often dictate treatment decisions. Inhibition of the intrinsic coagulation system via factor XIa may allow for selective inhibition of the coagulation cascade without significantly impacting hemostasis after injury. Asundexian is an oral small moleculefactor XIa inhibitor that, via this novel mechanism, may prove to be a safe and effective option compared with available anticoagulants. Early clinical data forasundexian was promising as a safer alternative to current therapiesand prompted further analysis incertainpatient populations atincreasedthrombotic risk. Currently, studies areongoing to evaluate thesafety and efficacy in stroke prevention in atrial fibrillation and in patients following an acute noncardioembolic ischemic stroke or high-risk transient ischemic attack.

Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial

ObjectiveTHALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS)...