High Soluble Thrombomodulin Is Associated with an Increased Risk of Major Bleeding during Treatment with Oral Anticoagulants: A Case–Cohort Study

2020 ◽  
Author(s):  
Myrthe M. A. Toorop ◽  
Nienke van Rein ◽  
Suzanne C. Cannegieter ◽  
Felix J. M. van der Meer ◽  
Pieter H. Reitsma ◽  
...  
Keyword(s):  
Cohort Study ◽  
Vitamin K ◽  
Major Bleeding ◽  
Cox Regression ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
Soluble Thrombomodulin ◽  
Major Bleed ◽  
Increased Risk

Abstract Background Major bleeding occurs in 1 to 3% of patients treated with oral anticoagulants per year. Biomarkers may help to identify high-risk patients. A proposed marker for major bleeding while using anticoagulants is soluble thrombomodulin (sTM). Methods Plasma was available from 16,570 patients of the BLEEDS cohort that consisted of patients who started treatment with vitamin K antagonists between 2012 and 2014. A case–cohort study was performed including all patients with a major bleed (n = 326) during follow-up and a random sample of individuals selected at baseline (n = 652). Plasma sTM levels were measured and stratified by percentiles. Patients were also categorized by international normalized ratio (INR). Adjusted hazard ratios (for age, sex, hypertension, and diabetes) with 95% confidence intervals (CIs) were estimated by means of Cox regression. Results Plasma sTM levels were available for 263 patients with a major bleed and 538 control subjects. sTM levels were dose-dependently associated with risk of major bleeding, with a 1.9-fold increased risk (95% CI: 1.1–3.1) for levels above the 85th percentile versus the <25th percentile. A high INR (≥4) in the presence of high (≥70th percentile) sTM levels was associated with a 7.1-fold (95% CI: 4.1–12.3) increased risk of major bleeding, corresponding with a bleeding rate of 14.1 per 100 patient-years. Conclusion High sTM levels at the start of treatment are associated with major bleeding during vitamin K antagonist treatment, particularly in the presence of a high INR.

scholarly journals Bleeding and thromboembolism due to drug-drug interactions with non-vitamin K antagonist oral anticoagulants—a Swedish, register-based cohort study in atrial fibrillation outpatients

2020 ◽  
Author(s):  
Johan Holm ◽  
Buster Mannheimer ◽  
Rickard E Malmström ◽  
Erik Eliasson ◽  
Jonatan D Lindh
Keyword(s):  
Atrial Fibrillation ◽  
Cohort Study ◽  
Ischemic Stroke ◽  
Vitamin K ◽  
Cox Regression ◽  
Oral Anticoagulants ◽  
Outcome Data ◽  
Vitamin K Antagonist ◽  
Drug Register ◽  
Increased Risk

Abstract Purpose To study the association between interacting drugs and bleeding or thromboembolism in atrial fibrillation outpatients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods Population-based cohort study of outpatients treated with NOACs in Sweden from 2008 to 2017. Patients with atrial fibrillation and newly initiated NOAC treatment were identified in the Prescribed Drug Register. Comorbidities and outcome data were retrieved from the Patient Register and the Cause of Death Register. Cox-regression analyses were performed to evaluate the primary endpoints any severe bleed and ischemic stroke/transient ischemic attack/stroke unspecified during the first six months of treatment. Secondary endpoints were gastrointestinal bleeding, intracranial bleeding, ischemic stroke, and venous thromboembolism. Results Increased risk of any severe bleed was found when NOAC treatment, and drugs with pharmacodynamic effect on bleeding were combined, compared to NOAC only. An increased risk with these combinations was evident for apixaban (hazard ratio (HR) 1.47; 95% CI 1.33–1.63), rivaroxaban (HR 1.7; 95% CI 1.49–1.92), and dabigatran (HR 1.26; 95% CI 1.05–1.52). For apixaban, there was an increased risk of any severe bleed when combined with CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (HR 1.23; 95% CI 1.01–1.5). The use of inducers of CYP3A4 and/or P-gp was low in this cohort, and effects on ischemic stroke/TIA/stroke unspecified could not be established. Conclusion Increased risk of bleeding was seen for pharmacodynamic and pharmacokinetic interactions with NOACs. Prescribers need to be vigilant of the effect of interacting drugs on the risk profile of patients treated with NOACs.

scholarly journals Direct oral anticoagulants in patients with antiphospholipid syndrome: a cohort study

Lupus ◽  
2019 ◽  
Vol 29 (1) ◽  
pp. 37-44 ◽  
Author(s):  
K Malec ◽  
E Broniatowska ◽  
A Undas
Keyword(s):  
Cohort Study ◽  
Antiphospholipid Syndrome ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Real Life ◽  
Double Positive ◽  
Increased Risk ◽  
Long Term Follow Up

Objectives Despite controversies, direct oral anticoagulants (DOACs) are increasingly used in antiphospholipid syndrome (APS). We investigated the safety and efficacy of DOACs versus vitamin K antagonists (VKAs) in real-life consecutive APS patients. Patients and methods In a cohort study of 176 APS patients, which included 82 subjects who preferred DOACs or had unstable anticoagulation with VKAs, we recorded venous thromboembolism (VTE), cerebrovascular ischemic events or myocardial infarction, along with major bleeding or clinically relevant non-major bleeding (CRNMB). Results APS patients were followed for a median time of 51 (interquartile range 43–63) months. Patients on DOACs and those on VKAs were similar with regard to baseline characteristics. APS patients treated with DOACs had increased risk of recurrent thromboembolic events and recurrent VTE alone compared with those on VKAs (hazard ratio (HR) = 3.98, 95% confidence interval (CI): 1.54–10.28, p = 0.004 and HR = 3.69, 95% CI: 1.27–10.68, p = 0.016, respectively) with no differences between rivaroxaban and apixaban or single- or double-positive and triple-positive APS. Thromboembolism on DOACs was associated with older age (median 52 versus 42 years, p = 0.008) and higher global APS score (median 13 versus 8.5, p = 0.013). Patients on DOACs had increased risk of major bleeding or CRNMB (HR = 3.63, 95% CI: 1.53–8.63, p = 0.003), but rates of gastrointestinal bleeds (HR = 3.36, 95% CI: 0.70–16.16, p = 0.13) and major bleeds or CRNMB other than heavy menstrual bleeding (HR = 2.45, 95% CI: 0.62–9.69, p = 0.2) were similar in both treatment groups. Conclusion During long-term follow-up of real-life APS patients, DOACs are less effective and less safe as VKAs in the prevention of thromboembolism.

scholarly journals Selective serotonin reuptake inhibitor use is associated with major bleeding during treatment with vitamin K antagonists: results of a cohort study

2021 ◽  
Author(s):  
Sanne Bakker ◽  
Louise Burggraaf ◽  
MJHA Kruip ◽  
Felix van der Meer ◽  
WM Lijfering ◽  
...  
Keyword(s):  
Vitamin K ◽  
Major Bleeding ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Cox Regression ◽  
Conditional Logistic Regression ◽  
Vitamin K Antagonists ◽  
Selective Serotonin ◽  
Bleeding Complications ◽  
Increased Risk

Aims: To determine whether Selective serotonin reuptake inhibitors (SSRIs) cause major bleeding during vitamin K antagonist (VKA) treatment and investigate the possible mechanisms behind this interaction. Methods: Information on SSRI use and bleeding complications was obtained from patient records at the Anticoagulation Clinics of Leiden and Rotterdam of VKA initiators between 2006 and 2018. Conditional logistic regression and time-dependent Cox regression were used to estimate the effect of SSRIs on a high INR (≥ 5) within 2 months after SSRI initiation and on major bleeding during the entire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9 inhibitors. Results: 58,918 patients were included, of whom 1504 were SSRI users. SSRI initiation versus non-use was associated with a 2.41-fold (95% confidence interval [CI] 2.01-2.89) increased risk for a high INR, which was 3.14-fold (95%CI 1.33-7.43) among CYP2C9 inhibiting SSRIs. SSRI use versus non-use was associated with a 1.22-fold (95%CI 0.99-1.50) increased risk for major bleeding in all SSRI users, which was 1.31-fold (95%CI 0.62-2.72) in CYP2C9 inhibiting SSRIs compared to non-users. Conclusion: SSRIs are associated with an increased risk of high INR and major bleeding. These risks were slightly more elevated for CYP2C9 inhibiting SSRI users, suggesting that this was due to a pharmacokinetic interaction (by CYP2C9 inhibition) as well as a pharmacodynamic effect of SSRIs on platelet activation.

The relevance of depressive symptoms for the outcome of patients receiving vitamin K antagonists: results from the thrombEVAL cohort study

2020 ◽  
Author(s):  
Matthias Michal ◽  
Lisa Eggebrecht ◽  
Sebastian Göbel ◽  
Marina Panova-Noeva ◽  
Markus Nagler ◽  
...  
Keyword(s):  
Cohort Study ◽  
Depressive Symptoms ◽  
Vitamin K ◽  
Cox Regression ◽  
Vitamin K Antagonists ◽  
Independent Study ◽  
Prognostic Information ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
Patient Health

Abstract Aims Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown. Methods and results We analysed data from the multicentre cohort study thrombEVAL (NCT01809015) investigating the efficacy of OAC with vitamin K antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n = 1558 participants, information about depressive symptoms, as measured by the two-item screener of the patient health questionnaire (PHQ-2), was available in n = 1405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically relevant bleeding [hazard ratio (HR) 1.13, 95% confidence interval 1.03–1.24; P = 0.011] and all-cause mortality (HR 1.18, 1.08–1.28; P = 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of serotonin reuptake inhibitors, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 ≥ 3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08–2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09–2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 ≥ 3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86–1.35; P = 0.52). Conclusion Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy.

Subtherapeutic Anticoagulation Control under Treatment with Vitamin K-Antagonists—Data from a Specialized Coagulation Service

2019 ◽  
Vol 119 (08) ◽  
pp. 1347-1357 ◽  
Author(s):  
Jürgen H. Prochaska ◽  
Christoph Hausner ◽  
Markus Nagler ◽  
Sebastian Göbel ◽  
Lisa Eggebrecht ◽  
...  
Keyword(s):  
Risk Factors ◽  
Vitamin K ◽  
Cox Regression ◽  
Statistical Significance ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Living Alone ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
Anticoagulation Control

AbstractIn contrast to overanticoagulation, evidence on risk factors and outcome of subtherapeutic oral anticoagulation (OAC) with vitamin K-antagonists (VKAs) under optimum care is limited. We investigated the clinical phenotype, anticoagulation control, and clinical outcome of 760 VKA patients who received OAC therapy by a specialized coagulation service in the thrombEVAL study (NCT01809015). During 281,934 treatment days, 278 patients experience ≥ 1 episode of subtherapeutic anticoagulation control and had lower quality of OAC therapy compared to 482 patients without subtherapeutic international normalized ratio: 67.6%, interquartile range (IQR) 54.9%/76.8% versus 81.0%, IQR 68.5%/90.4%; p < 0.001. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, and treatment characteristics, female sex (hazard ratio [HR], 1.4, 95% confidence interval [CI], 1.0/1.9; p = 0.03), diabetes (HR, 1.4, 95% CI, 1.0/2.0; p = 0.03), and living alone (HR, 1.5, 95% CI, 1.1/2.1; p = 0.009) were independent risk factors of subtherapeutic anticoagulation control, whereas atrial fibrillation (HR, 0.6, 95% CI, 0.4/0.9; p = 0.02) and self-management of OAC therapy (HR, 0.2, 95% CI, 0.1/0.6; p = 0.001) were protective. In addition, active smoking (HR, 1.7, 95% CI, 0.9/3.0; p = 0.086) and living in a nursing home (HR, 1.6, 95% CI, 0.8/3.2; p = 0.15) indicated an elevated risk at the borderline of statistical significance. For the prediction of recurrent subtherapeutic anticoagulation, living alone was the only independent risk factor (HR, 1.7, 95% CI, 1.1/2.5; p = 0.013). The present study suggests that women, diabetics, and patients living alone experience an increased risk of low-quality VKA therapy and might potentially benefit from treatment with direct-acting anticoagulants.

scholarly journals Vitamin K antagonists versus direct oral anticoagulants after cardiac surgery: a 31-country cohort study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Whitlock ◽  
E.P Belley-Cote ◽  
J Healey ◽  
P.J Devereaux ◽  
J Eikelboom ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cohort Study ◽  
Vitamin K ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Funding Source ◽  
Arterial Embolism ◽  
History Of

Abstract Background About 10% of patients undergoing cardiac surgery have a history of atrial fibrillation (AF). Among these patients, uncertainty exists regarding the safest and most effective oral anticoagulant (OAC) during the postoperative period. Purpose To evaluate practice patterns regarding OAC early after cardiac surgery in patients with a preoperative history of AF and to compare the safety and effectiveness of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). Methods We conducted a nested cohort study within the Left Atrial Appendage Occlusion Study (LAAOS) III (NCT01561651). LAAOS III included patients with AF undergoing cardiac surgery with a CHA2DS2-VASC ≥2. In this substudy, we examined patients without end-stage renal dysfunction (eGFR &gt;30 mL/min/1.73m2) who were discharged on OAC. We evaluated bleeding and thromboembolism within 90 days postoperatively using logistic regression adjusting for CHA2DS2-VASC score. Results Recruitment started in 2012 and completed in 2018 in 113 centres in 31 countries. Of the 4811 patients enrolled in LAAOS III, 3725 (77%) were included in this substudy. Preoperatively, 58% of patients received OAC: 56% DOACs and 44% VKAs. At hospital discharge 23% received DOACs and 77% VKAs; 55% of patients on a DOAC at baseline were switched to a VKA while 5% of patients on a VKA were switched to a DOAC. Patients discharged on a DOAC were older, had a higher CHA2DS2-VASC, and were more likely to be male. Patients having undergone an isolated coronary bypass procedure were more likely prescribed DOACs than VKAs (41% vs 23%, p&lt;0.001) whereas isolated non-mechanical valve patients were more likely to be prescribed VKAs (43% vs 28%, p&lt;0.001). Switching from a DOAC to a VKA postoperatively occurred in 42% of patients In Australia/New Zealand, 49% in Europe, and 63% in North America. Major bleeding between 48 hours postoperatively and 30 days occurred in 1.5% in the DOAC group and 1.3% in the VKA group (aOR 1.14, 95% CI 0.60–2.15, p=0.69) while between 48 hours and 90 days, it occurred in 1.8% of patients in both groups (aOR 0.97, 95% CI, 0.54–1.17, p=0.91). Cardiac tamponade, the composite of stroke and systemic arterial embolism, and the composite of stroke, systemic arterial embolism and death did not differ significantly at 30 and 90 days between the DOAC and VKA groups. Conclusions VKAs was the dominant OAC used early after cardiac surgery, but postoperative OAC practices varied by region. After adjustment for CHA2DS2-VASC score, the early postoperative incidence of major bleeding and of the composite of stroke and systemic arterial embolism did not differ significantly when DOACs were compared with VKAs. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): CIHR, Heart and Stroke Foundation

scholarly journals Bleeding and related mortality with NOACs and VKAs in newly diagnosed atrial fibrillation: results from the GARFIELD-AF registry

2021 ◽  
Vol 5 (4) ◽  
pp. 1081-1091
Author(s):  
Jean-Pierre Bassand ◽  
Saverio Virdone ◽  
Marc Badoz ◽  
Freek W. A. Verheugt ◽  
A. John Camm ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K ◽  
Major Bleeding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Bleeding Risk ◽  
Minor Bleeding ◽  
Newly Diagnosed ◽  
Risk Of Death ◽  
Major Bleed

Abstract In atrial fibrillation (AF), lower risks of death and bleeding with non-vitamin-K oral anticoagulants (NOACs) were reported in meta-analyses of controlled trials, but whether these findings hold true in real-world practice remains uncertain. Risks of bleeding and death were assessed in 52 032 patients with newly diagnosed AF enrolled in GARFIELD-AF (Global Anticoagulant Registry in the FIELD–Atrial Fibrillation), a worldwide prospective registry. Baseline treatment was vitamin K antagonists (VKAs) with or without antiplatelet (AP) agents (VKA ± AP) (20 151; 39.3%), NOACs ± AP agents (14 103; 27.5%), AP agents only (10 748; 21.0%), or no antithrombotics (6219; 12.1%). One-year follow-up event rates (95% confidence interval [CI]) of minor, clinically relevant nonmajor (CRNM), and major bleedings were 2.29 (2.16-2.43), 1.10 (1.01-1.20), and 1.31 (1.21-1.41) per 100 patient-years, respectively. Bleeding risk was lower with NOACs than VKAs for any bleeding (hazard ratio (HR) [95% CI]), 0.85 [0.73-0.98]) or major bleeding (0.79 [0.60-1.04]). Compared with no bleeding, the risk of death was higher with minor bleeding (adjusted HR [aHR], 1.53 [1.07-2.19]), CRNM bleeding (aHR, 2.59 [1.80-3.73]), and major bleeding (aHR, 8.24 [6.76-10.04]). The all-cause mortality rate was lower with NOACs than with VKAs (aHR, 0.73 [0.62-0.85]). Forty-five percent (114) of all deaths occurred within 30 days, and 40% of these were from intracranial/intraspinal hemorrhage (ICH). The rates of any bleeding and all-cause death were lower with NOACs than with VKAs. Major bleeding was associated with the highest risk of death. CRNM bleeding and minor bleeding were associated with a higher risk of death compared to no bleeding. Death within 30 days after a major bleed was most frequently related to ICH. This trial was registered at www.clinicaltrials.gov as #NCT01090362.

scholarly journals New Oral Anticoagulants vs. Vitamin K Antagonists Among Patients With Cardiac Amyloidosis: Prognostic Impact

2021 ◽  
Vol 8 ◽  
Author(s):  
Eve Cariou ◽  
Kevin Sanchis ◽  
Khailène Rguez ◽  
Virginie Blanchard ◽  
Stephanie Cazalbou ◽  
...  
Keyword(s):  
Vitamin K ◽  
Cardiac Amyloidosis ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Bleeding Complications ◽  
Prognostic Impact ◽  
Transthyretin Amyloidosis ◽  
Increased Risk ◽  
All Cause Mortality ◽  
History Of

Background: Atrial arrhythmia (AA) is common among patients with cardiac amyloidosis (CA), who have an increased risk of intracardiac thrombus. The aim of this study was to explore the prognostic impact of vitamin K-antagonists (VKA) and direct oral anticoagulants (DOAC) in patients with CA.Methods and Results: 273 patients with CA and history of AA with long term anticoagulation−69 (25%) light chain amyloidosis (AL), 179 (66%) wild-type transthyretin amyloidosis (ATTRwt) and 25 (9%) variant transthyretin amyloidosis (ATTRv)–were retrospectively included between January 2012 and July 2020. 147 (54%) and 126 (46%) patients received VKA and DOAC, respectively. Patient receiving VKA were more likely to have AL with renal dysfunction, higher NT-proBNP and troponin levels. Patients with ATTRwt were more likely to receive DOAC therapy. There were more bleeding complications among patients with VKA (20 versus 10%; P = 0.013) but no difference for stroke events (4 vs. 2%; P = 0.223), as compared to patients with DOAC. A total of 124 (45%) patients met the primary endpoint of all-cause mortality: 96 (65%) and 28 (22%) among patients with VKAs and DOACs, respectively (P &lt; 0.001). After multivariate analysis including age and renal function, VKA was no longer associated with all-cause mortality.Conclusion: Among patients with CA and history of AA receiving oral anticoagulant, DOACs appear to be at least as effective and safe as VKAs.

scholarly journals Objectives and Design of BLEEDS: A Cohort Study to Identify New Risk Factors and Predictors for Major Bleeding during Treatment with Vitamin K Antagonists

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0164485 ◽  
Author(s):  
Nienke van Rein ◽  
Willem M. Lijfering ◽  
Mettine H. A. Bos ◽  
Martien H. Herruer ◽  
Helga W. Vermaas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Vitamin K ◽  
Major Bleeding ◽  
Vitamin K Antagonists
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