scholarly journals Screening of Multiple Biomarkers Associated With Ischemic Stroke in Atrial Fibrillation

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Ziad Hijazi ◽  
Lars Wallentin ◽  
Johan Lindbäck ◽  
John H. Alexander ◽  
Stuart J. Connolly ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Matrix Metalloproteinase ◽  
Random Sample ◽  
Cox Regression ◽  
Trefoil Factor ◽  
Systemic Embolism ◽  
Trefoil Factor 3 ◽  
Metalloproteinase 9 ◽  
Random Survival Forest

Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case‐cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow‐up was used for identification. Validation was provided by a similar case‐cohort sample of patients with AF from the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase‐9, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor‐3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00–1.38), 1.55 (1.28–1.88), 1.28 (1.07–1.53), 1.19 (1.02–1.39), 1.23 (1.05–1.45), and 1.19 (0.97–1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase‐9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT‐proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor‐3). Registration URL: https://www.clinicaltrials.gov . Unique Identifiers: NCT00412984 and NCT00262600.

scholarly journals Edoxaban versus warfarin on stroke risk in patients with atrial fibrillation: a territory-wide cohort study

2021 ◽  
Author(s):  
Dicken Kong ◽  
Jiandong Zhou ◽  
Sharen Lee ◽  
Keith Sai Kit Leung ◽  
Tong Liu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cohort Study ◽  
Ischemic Stroke ◽  
Propensity Score ◽  
Ischaemic Stroke ◽  
Propensity Score Matching ◽  
Lower Risk ◽  
Cox Regression ◽  
Significant Risk ◽  
Risk Predictors

AbstractBackgroundIn this territory-wide, observational, propensity score-matched cohort study, we evaluate the development of transient ischaemic attack and ischaemic stroke (TIA/Ischaemic stroke) in patients with AF treated with edoxaban or warfarin.MethodsThis was an observational, territory-wide cohort study of patients between January 1st, 2016 and December 31st, 2019, in Hong Kong. The inclusion were patients with i) atrial fibrillation, and ii) edoxaban or warfarin prescription. 1:2 propensity score matching was performed between edoxaban and warfarin users. Univariate Cox regression identifies significant risk predictors of the primary, secondary and safety outcomes. Hazard ratios (HRs) with corresponding 95% confidence interval [CI] and p values were reported.ResultsThis cohort included 3464 patients (54.18% males, median baseline age: 72 years old, IQR: 63-80, max: 100 years old), 664 (19.17%) with edoxaban use and 2800 (80.83%) with warfarin use. After a median follow-up of 606 days (IQR: 306-1044, max: 1520 days), 91(incidence rate: 2.62%) developed TIA/ischaemic stroke: 1.51% (10/664) in the edoxaban group and 2.89% (81/2800) in the warfarin group. Edoxaban was associated with a lower risk of TIA or ischemic stroke when compared to warfarin.ConclusionsEdoxaban use was associated with a lower risk of TIA or ischemic stroke after propensity score matching for demographics, comorbidities and medication use.

Abstract P146: Comparative Effectiveness Of Direct Oral Anticoagulants Versus Warfarin Among Medicare Beneficiaries With Atrial Fibrillation

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Shirin Ardeshirrouhanifard ◽  
Huijun An ◽  
Ravi Goyal ◽  
Mukaila Raji ◽  
Caleb Alexander ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Cancer Patients ◽  
Risk Model ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Competing Risk ◽  
Secondary Outcome ◽  
Systemic Embolism ◽  
Competing Risk Model

Objective: Post-hoc analysis of three pivotal clinical trials suggests no difference in risk of ischemic stroke or systemic embolism among cancer patients with atrial fibrillation treated with direct oral anticoagulants (DOACs) vs. warfarin. However, these studies were underpowered and also do not reflect the context of real-world use. We compared the effectiveness of DOACs versus warfarin for the risk of stroke or systemic embolism and all-cause death in patients with NVAF. Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2009 to 2016 and included patients aged ≥66 years diagnosed with cancer (breast, bladder, colorectal, esophagus, lung, ovary, kidney, pancreas, prostate, stomach or uterus) and NVAF. We limited the cohort to patients who newly initiated warfarin or DOACs (from 2010 to 2016) with no history of ischemic stroke or systemic embolism. The primary outcome was hospitalization due to ischemic stroke or systemic embolism and the secondary outcome was all-cause death. We used Fine and Gray’s competing risk model, while treating death as a competing risk, to determine the association of oral anticoagulants with the incidence of stroke or systemic embolism. We also adjusted the analysis using inverse probability of treatment weighted (IPTW). Additionally, an IPTW-adjusted Cox proportional hazards regression model was constructed for all-cause death. Results: Of 1,028,784 patients with cancer, 158,744 (15.4%) were diagnosed with atrial fibrillation. After applying all inclusion criteria, the final study cohort included 7,334 cancer patients diagnosed with incident NVAF who newly initiated warfarin or DOACs, of which 3,194 (43.6%) used warfarin and 4,140 (56.4%) used DOACs. The unadjusted rate of stroke or systemic embolism was similar among warfarin and DOACs users (1.20 vs. 1.32 cases per 100 person-years, p=0.27). In the IPTW weighted competing risk model, the use of DOACs was not associated with an increased risk of stroke or systemic embolism compared with warfarin users (Hazard Ratio [HR] 1.41, 95% confidence intervals [CI] 0.90-2.20). However, DOACs users had a significantly lower risk of all-cause death compared with warfarin users (HR 0.82, CI 0.74-0.91). Conclusion: Among cancer patients diagnosed with NVAF, DOACs had a similar risk for stroke or systemic embolism compared to warfarin, although DOAC use was associated with reduced risk of all-cause mortality.

Abstract 160: Impact of Medication Adherence on Risk of Stroke, Major Bleeding and Other Outcomes in Atrial Fibrillation Patients Using Novel Oral Anticoagulants (Dabigatran and Rivaroxaban)

2017 ◽  
Vol 10 (suppl_3) ◽  
Author(s):  
Chinmay G Deshpande ◽  
Cynthia Willey Temkin ◽  
Robert Laforge ◽  
Stephen Kogut
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Drug Use ◽  
Propensity Score ◽  
Major Bleeding ◽  
Cox Regression ◽  
Oral Anticoagulants ◽  
Cox Models ◽  
Adherence Assessment ◽  
The Impact

Introduction: Dabigatran and Rivaroxaban have shown better or similar efficacy to lower stroke risk compared to warfarin in clinical trials. Evidence suggests adherence to cardiac drugs tend to reduce outcomes and cost. Our study is the first to examine the impact of atleast 6 to 12 month adherence to NOACs on ischemic stroke, major bleeding, Deep Vein Thrombosis and Pulmonary Embolism (DVTPE) risk in a propensity score based matched sample. Methods: A retrospective cohort study utilized de-identified data from Optum® Clinformatics™ Data Mart database (OptumInsight, Eden Prairie, MN) (Jan 1, 2010 and Dec 31, 2012). Adult patients with ≥ 1 diagnosis of atrial fibrillation or flutter (ICD9 427.31/32), >1 prescription of NOACs, 6 months pre-index continuous enrollment and CHA2DS2VASC score >1 were included. Adherence was calculated using Proportion of Days Covered (PDC ≥80%) for atleast 6 and 12 months of NOAC use and cohorts (adherent vs. non adherent) were matched on propensity score using Inverse Probability Treatment Weighting (IPTW) controlling for demographic and clinical characteristics at baseline. The risk of ischemic stroke, major bleeding (primary outcomes) and DVTPE (exploratory outcome) was evaluated for the matched cohorts post adherence assessment using Cox regression. Results: Out of 25,150 NOAC patients, a total of 3,629 and 1,946 patients with atleast 6 and 12 months of NOAC use were included. Across 2 cohorts, the mean age of the sample was 65 years, 65% were males and >60% had a moderate-high risk of stroke (CHA2DS2VASC>2). Adherence (PDC ≥80%) was 77% and 76% for patients with 6 and 12 month drug use. Post 12 months of drug use, the overall incidence of bleeding, stroke, and DVTPE in the follow-up period was 4.42%, 1.80%, and 0.82% respectively. Each outcome was analyzed separately to avoid calculation of competing risks. Using Cox models with IPTW balanced cohorts, non-adherence was significantly (p ≤0.05) associated with an increase in stroke (≥ 1.5 fold) and DVTPE (≥ 2 fold) risk in both 6 and 12 month users. The risk of bleeding was not significantly different across adherent vs. non adherent users (Table). Conclusion: In our sample, adherence to NOACs was associated with a reduction in stroke and DVTPE risk but did not substantially increase bleeding risk. Further studies with newer NOACs are warranted.

Abstract TMP22: Intravenous Glyburide Treatment is Associated with Reduced Matrix Metalloproteinase-9 in Human Acute Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Ly Pham ◽  
Sydney O’Connor ◽  
Karen Yarbrough ◽  
Sven Jacobson ◽  
Barney J Stern ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Matrix Metalloproteinase ◽  
Active Form ◽  
Pilot Trial ◽  
Specific Inhibitor ◽  
Matrix Metalloproteinase 9 ◽  
Stroke Patients ◽  
Hemispheric Stroke ◽  
Intravenous Tissue Plasminogen Activator ◽  
Metalloproteinase 9

Background: Elevated matrix metalloproteinase-9 (MMP-9) following acute ischemic stroke is associated with blood-brain barrier breakdown and hemorrhagic conversion. Prior retrospective evidence suggests that sulfonylurea use may be associated with reduced risk of hemorrhagic conversion. We hypothesized that sulfonylureas may reduce MMP-9 level in stroke patients. Methods: Using serial plasma samples from six subjects in the Glyburide Advantage in Malignant Edema and Stroke Pilot trial (GAMES-Pilot), we evaluated the level of MMP-9 in human subjects presenting with large hemispheric stroke who were treated with intravenous glyburide (RP-1127). MMP-9 was measured in a control cohort with large ischemic stroke who were not treated with glyburide. Commercially available ELISA kits and gel zymography were used to measure MMP-9 at baseline and at approximately 48 hours after stroke. GAMES subjects had additional time points analyzed until approximately 84 hours after stroke. Results: Average MMP-9 level in glyburide-treated stroke patients was 47.2 ± 8.0 ng/mL compared to 143.4 ± 60.35 ng/mL in untreated control subjects (p=0.004). Zymography analysis demonstrated a significant decrease in the pro-enzyme but no change in the active form of MMP-9. There was no difference in the level of the MMP-9 specific inhibitor, TIMP-1. No subjects exhibited parenchymal hemorrhagic conversion on 24 hour head CT scan. Conclusions: Glyburide treatment in human stroke patients with large hemispheric stroke is associated reduced level of MMP-9. Elucidating the underlying mechanism of glyburide’s effect on MMP-9 and the risk of hemorrhagic conversion may highlight future directions of therapy, including in combination with intravenous tissue plasminogen activator (IV t-PA).

scholarly journals Association of Matrix Metalloproteinase 9 and Cellular Fibronectin and Outcome in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 11 ◽  
Author(s):  
Lu Wang ◽  
Linghui Deng ◽  
Ruozhen Yuan ◽  
Junfeng Liu ◽  
Yuxiao Li ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Matrix Metalloproteinase ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Brain Edema ◽  
Meta Analysis ◽  
Hemorrhagic Transformation ◽  
Poor Outcome ◽  
Metalloproteinase 9 ◽  
Cellular Fibronectin

Introduction: The role of matrix metalloproteinase 9 (MMP-9) and cellular fibronectin (c-Fn) in acute ischemic stroke is controversial. We systematically reviewed the literature to investigate the association of circulating MMP-9 and c-Fn levels and MMP-9 rs3918242 polymorphism with the risk of three outcome measures after stroke.Methods: We searched English and Chinese databases to identify eligible studies. Outcomes included severe brain edema, hemorrhagic transformation, and poor outcome (modified Rankin scale score ≥3). We estimated standardized mean differences (SMDs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs).Results: Totally, 28 studies involving 7,239 patients were included in the analysis of circulating MMP-9 and c-Fn levels. Meta-analysis indicated higher levels of MMP-9 in patients with severe brain edema (SMD, 0.76; 95% CI, 0.18–1.35; four studies, 419 patients) and hemorrhagic transformation (SMD, 1.00; 95% CI, 0.41–1.59; 11 studies, 1,709 patients) but not poor outcome (SMD, 0.30; 95% CI, −0.12 to 0.72; four studies, 759 patients). Circulating c-Fn levels were also significantly higher in patients with severe brain edema (SMD, 1.55; 95% CI, 1.18–1.93; four studies, 419 patients), hemorrhagic transformation (SMD, 1.75; 95% CI, 0.72–2.78; four studies, 458 patients), and poor outcome (SMD, 0.46; 95% CI, 0.16–0.76; two studies, 210 patients). Meta-analysis of three studies indicated that the MMP-9 rs3918242 polymorphism may be associated with hemorrhagic transformation susceptibility under the dominant model (TT + CT vs. CC: OR, 0.621; 95% CI, 0.424–0.908; P = 0.014). No studies reported the association between MMP-9 rs3918242 polymorphism and brain edema or functional outcome after acute stroke.Conclusion: Our meta-analysis showed that higher MMP-9 levels were seen in stroke patients with severe brain edema and hemorrhagic transformation but not poor outcome. Circulating c-Fn levels appear to be associated with all three outcomes including severe brain edema, hemorrhagic transformation, and poor functional outcome. The C-to-T transition at the MMP-9 rs3918242 gene appears to reduce the risk of hemorrhagic transformation.

scholarly journals The Controversy Continues Again: which Direct Anticoagulant is More Effective and Safe when Administered to Patients with Atrial Fibrillation?

2020 ◽  
Vol 16 (4) ◽  
pp. 635-637
Author(s):  
S. Yu. Martsevich
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Observational Study ◽  
Statistical Methods ◽  
Clinical Characteristics ◽  
Large Database ◽  
Systemic Embolism ◽  
Made In

The data from the observational study of M. Fralick et al. were analyzed in the article. The authors analyzed a large database of patients with atrial fibrillation and concluded that rivaroxaban is inferior to apixaban in its ability to prevent ischemic stroke and systemic embolism and is more likely to cause bleeding. Serious methodological defects of the analysis take place. No statistical methods are capable of correcting the absence of such important information in the database as the doctor's motives for prescribing a particular drug, as well as the patient's adherence to taking it. It is also noted that the patients included in the study, according to clinical characteristics, did not correspond to the typical population of patients with atrial fibrillation. The author considers the conclusions made in the mentioned work to be unauthorized.

scholarly journals Association of Preceding Antithrombotic Therapy in Atrial Fibrillation Patients With Ischemic Stroke, Intracranial Hemorrhage, or Gastrointestinal Bleed and Mortality

2019 ◽  
Author(s):  
Joris J Komen ◽  
Tomas Forslund ◽  
Aukje K Mantel-Teeuwisse ◽  
Olaf H Klungel ◽  
Mia von Euler ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Propensity Score ◽  
Intracranial Hemorrhage ◽  
Cox Regression ◽  
Mortality Rates ◽  
Antithrombotic Treatment ◽  
Healthcare Database ◽  
Gastrointestinal Bleed ◽  
History Of

Abstract Aims To analyze 90-day mortality in AF patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event. Methods and Results From the Stockholm Healthcare database, we selected 6 017 patients with a known history of AF who were diagnosed with ischemic stroke, 3 006 with intracranial hemorrhage, and 4 291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischemic stroke, 31.6% after intracranial hemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial hemorrhage, there was a significantly higher mortality rate in warfarin compared to NOAC treated patients (adjusted hazard ratio (aHR): 1.36 CI: 1.04 – 1.78). After an ischemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84 CI: 0.63 – 1.12 after ischemic stroke, aHR 0.91 CI: 0.66 – 1.25 after severe GIB). Propensity score matched analysis yielded similar results. Conclusion Mortality rates were high in AF patients suffering from an ischemic stroke, an intracranial hemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90 day mortality after intracranial hemorrhage than warfarin.

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