Changes Of Coagulation Activation Parameters After Discontinuation Of VTE Treatment With Vitamin-K Antagonists, Apixaban, Rivaroxaban Or Dabigatran and Impact On Clinical Outcome After 12 Months

Abstract Background At the end of VTE treatment, increasing D-Dimer levels after discontinuation of Vitamin-K antagonists (VKA) have been shown to indicate coagulation activation and increased risk of VTE recurrence. However, it is unknown if changes of coagulation activation parameters will be similar after discontinuation of direct oral anticoagulants (DOAC) such as apixaban, rivaroxaban and dabigatran. Furthermore, the clinical impact of these changes is still unclear. Objectives To quantify changes of coagulation activation parameters at the end of VTE treatment with VKA or DOAC and to evaluate their positive predictive value for VTE recurrence at 12 months. Patients and Methods Blood samples for coagulation tests were collected from consenting patients with proximal VTE who discontinued anticoagulation treatment at the end of apixaban, dabigatran or rivaroxaban phase-III VTE treatment trials. Furthermore, similar samples were obtained from VKA patients at the end of treatment. From all patients, samples for D-dimer (DD), prothrombin fragments (F1+2) and thrombin-antithrombin complexes (TAT) measurements were collected at the end of treatment and 4 weeks later. Samples were analysed by blinded lab personnel and statistically evaluated for differences between VKA and DOAC regarding changes between both samples as well as absolute values at 4 weeks. Finally, all patients underwent 12 months follow-up by phone calls to establish rates of recurrent VTE or death from any cause. Results Blood samples were obtained from patients discontinuing apixaban (A; n=37), dabigatran (D; n=17), rivaroxaban (R; n=9) and VKA (n=184), respectively. Absolute values and relative changes of DD, F1+2 and TAT at baseline and 4 weeks were not significantly different between VKA or the DOAC cohorts. Irrespective of the anticoagulant treatment, DD and F1+2 but not TAT demonstrated a significant increase between baseline and week 4 (figure 1). At 12 months, 18 patients (7.3%) had recurrent VTE and 2 patients (0.8%) were dead. Regarding clinical outcomes at 12 months, the negative predictive values (NPV) of DD, F1+2 and TAT were highest for patients after VKA treatment (at least 0.93) and systematically lower for DOAC patients (ranging between 0.86 and 0.91). In contrast, positive predictive values (PPV) of DD, F1+2 and TAT were systematically higher in DOAC patients (0.19 to 0.43) compared to VKA patients (0.03-0.16) with highest values for TAT-complexes > 200% baseline (PPV VKA 0.14; PPV DOAC 0.43), which was also seen in logistic regression analysis with a significant risk increase for VTE/death (Odds ratio for TAT > 200% baseline 5.0; p=0.006). None of the other parameters showed a correlation to the risk of recurrent VTE or death. Conclusion Changes of DD, F1+2 and TAT values post treatment are not different between patients discontinuing VTE treatment with VKA, apixaban, dabigatran or rivaroxaban. NPV of DD, F1+2 and TAT for recurrent VTE/death are higher in VKA than DOAC patients, while PPV are higher in DOAC patients. At 4 weeks, a TAT increase over 200% of baseline value was found to be associated with a 5-fold increase of recurrent VTE or death with a PPV of 0.14 for VKA patients and of 0.43 for DOAC patients. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

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Prothrombin Complex Concentrate (Octaplex®) In Patients Requiring Immediate Reversal of Vitamin K Antagonist Anticoagulation.

Blood ◽

10.1182/blood.v116.21.1115.1115 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1115-1115

Author(s):

Madeline Song ◽

Connor Warne ◽

Mark A. Crowther

Keyword(s):

Vitamin K ◽

Research Funding ◽

Prothrombin Complex Concentrate ◽

Therapeutic Option ◽

Vitamin K Antagonists ◽

Tertiary Care ◽

Urgent Surgery ◽

Cilioretinal Artery Occlusion ◽

Rapid Reversal ◽

The Mean

Abstract Abstract 1115 Rapid reversal of vitamin K antagonists (VKAs) is required when patients experience acute bleeding or are in need of urgent surgery. Traditionally, in Canada, the only therapeutic option for warfarin reversal was fresh frozen plasma (FFP); recently a four factor prothrombin complex concentrate (PCC) has become available. In this retrospective chart review, we examined the use of Octaplex®, a four factor (FII, FVII, FIX, FX), solvent/detergent (S/D) treated and nanofiltered PCC, in a tertiary care centre over 18 months (November 2008 to May 2010), to determine its efficiency and safety in VKA reversal. The PCC was used 85 times in 82 patients. All patients had received warfarin prior to PCC administration. Patients received a mean dose of 1792 (1000 – 3500) IU of PCC for treatment of bleeding (36), urgent surgery (40) and excessively elevated international normalized ratio (INR) (8). One patient received PCC for an unknown indication and is excluded from the results presented here; a further 6 patients did not have INR tests done immediately before and immediately after PCC administration and are excluded from the laboratory results presented here. The mean INR before administration of the PCC was 5.10 (range 1.2 – 25). The mean INR after administration of the PCC was 1.43 (range 0.9 – 3.3). Forty-seven of seventy-nine [59.5%, 95% CI 47.9 to 70.4%] administrations resulted in an INR of 1.3 or less and 60/79 [75.9%, 65.0 to 84.9%] resulted in an INR of 1.5 or less. Of the 40 patient encounters where PCC was administered due to need for urgent surgery, 39 were able to undergo the procedure. Three patients experienced a thromboembolic event; one had a venous thromboembolism due to a clot extension of a previously diagnosed left leg DVT 8 days after PCC administration, another had a non-occlusive renal vein clot 8 days after PCC administration and the last had a cilioretinal artery occlusion 238 days after receiving PCC. No other adverse events potentially related to PCC were observed. We conclude that the prothrombin complex concentrate Octaplex® provides efficacious, safe and rapid reversal of VKA therapy. Disclosures: Crowther: Pfizer: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Leo Laboratories: Consultancy, Research Funding; Artisan: Consultancy. Off Label Use: The product described in this abstract is not available in the US. The described use is “on label” in Canada.

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Pattern and Management of Intracranial Haemorrhage with Rivaroxaban or Dabigatran Compared to Vitamin K Antagonists - Results of the Prospective Dresden Noac Registry

Blood ◽

10.1182/blood.v126.23.1127.1127 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1127-1127

Author(s):

Sandra Marten ◽

Luise Tittl ◽

Katharina Daschkow ◽

Jan Beyer-Westendorf

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Research Funding ◽

Intracranial Haemorrhage ◽

Vitamin K Antagonists ◽

Bleeding Risk ◽

Interventional Therapy ◽

Phase Iii ◽

Bayer Healthcare ◽

Phase Iii Trials

Abstract Background: In recent phase-III trials, the rate of intracranial haemorrhage (ICH) - the most feared complication of anticoagulant therapy - was around 0.8% per year for patients treated with vitamin K antagonists (VKA) and consistently lower (around 0.3-0.5%) for patients treated with the non-VKA oral anticoagulants (NOACs) rivaroxaban and dabigatran However, patients in clinical trials present a selected population treated under a strict protocol in dedicated academic facilities. Consequently, the risk, management and outcome of ICH need to be evaluated in cohorts of patients treated with NOACs or VKA in daily care. Aim: To evaluate the rate of ICH in patients treated with NOAC compared to VKA patients. Patients and methods: The prospective NOAC registry was initiated in November 2011. A network of more than 230 physicians in the district of Saxony, Germany, enrol up to 3000 patients in the registry, which are prospectively followed by the central registry office for up to 60 months with central outcome event adjudication. For this analysis, every intracranial haemorrhage was identified in the database and ICH management and outcome were evaluated. Results: Until January 31th 2015, 2682 patients were registered and treated with dabigatran (348, mostly treated for atrial fibrillation), Rivaroxaban (1907; 1204 treated for atrial fibrillation and 703 for venous thromboembolism) or vitamin K antagonists (427; treated for atrial fibrillation). VKA patients had lower HAS-BLED scores compared to NOAC patients and were excellently managed with a time-in-therapeutic-range of 75%. During follow-up (mean follow-up duration 25.6 months) ICH occurred in 7/427(1.6%) of VKA treated patients and in 14/2255 (0.6%) of patients treated with NOAC, which translated into an annualized rate of 1.3 events/100 pt. years (95%-CI 0.5-2.7) for VKA and 0.4 events/100 pt. years (95%-CI 0.2-0.6) for NOAC (p=0.0039). Treatment of ICH consisted of PCC in 10 cases, plasma in 3 cases and surgical or interventional therapy in 7 cases (table 1, multiple treatments possible). As indicated, use of factor concentrates, plasma or other hemostatic agents or surgery was much more frequent in VKA patients compared to NOAC patients. Table 1. Cause and treatment of ICH ICH/total Spontaneous vs. traumatic ICH (n) treatment with PCC treatment with fresh frozen plasma treatment with other hemostatic agents no hemostatic treatment surgical or interventional therapy dabigatran 2/348 (0.6%) 2 vs. 0 0 0 0 2/2 (100%) 1/2 (50%) rivaroxaban 12/1907 (0.6%) 4 vs. 8 5/12 (41.7%) 2/12 (16.7%) 2/12 (16.7%) 7/12 (58.3%) 3/12 (25%) VKA 7/427 (1.6%) 2 vs. 5 5/7 (71.4%) 1/7 (14.3%) 4/7 (57.1%) 2/7 (28.6%) 3/7 (42.9%) At Day 90 after ICH, 7/21 patients were dead (2/7 or 28.6% of VKA patients and 5/14 or 35.7% of NOAC patients). The surviving 14 patients received the following antithrombotic agents: 5 (35.7%) rivaroxaban, 3 (21.4%) heparin, 1 (7.1%) apixaban, 1 (7.1%) VKA, 3 (21.4%) aspirin, 1 (7.1%) none.Following ICH, oral anticoagulation therapy was either interrupted (n=7; 6 NOAC vs. 1 VKA) or permanently discontinued (n=10; 6 NOAC vs. 4 VKA). Conclusion: Despite low bleeding risk and excellent INR control in our VKA cohort, the rate of ICH was higher than that of VKA patients treated in recent phase-III trials. Furthermore, ICH rates in our VKA cohort were significantly higher than those seen in our NOAC cohorts, which represented more patients with relevant comorbidities and higher bleeding risk. Consequently, the risk of ICH remains high even in "stable" VKA patients with good INR control and a preventive switch from VKA to NOAC may help to reduce ICH risk and should be discussed with the patient. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding.

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Abstract 164: Specific Point-of-Care Testing of Coagulation in Patients Treated With Non-Vitamin K Antagonist Oral Anticoagulants Part I (SPOCT-NOAC I)

Stroke ◽

10.1161/str.47.suppl_1.164 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Florian Härtig ◽

Andreas Peter ◽

Charlotte Spencer ◽

Matthias Ebner ◽

Christine S Zürn ◽

...

Keyword(s):

Vitamin K ◽

Point Of Care ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Rapid Assessment ◽

Plasma Concentrations ◽

Vitamin K Antagonist ◽

Point Of Care Testing ◽

Blood Samples ◽

First Time

Introduction: Non-vitamin K antagonist oral anticoagulants (NOAC) are increasingly replacing vitamin K antagonists for prevention of thromboembolism in atrial fibrillation (AF) and venous thrombosis. Ischemic stroke rate in NOAC-treated AF-patients is 1-2% per year. Subsequently, stroke physicians face a growing number of NOAC-treated patients with acute stroke. Rapid assessment of coagulation in NOAC-treated patients is vital prior to thrombolysis, but existing point-of-care testing (POCT) is suboptimal. For the first time we evaluate NOAC-specific POCT. Hypothesis: Ecarin clotting time (ECT)- and anti-Xa activity-POCT accurately predict plasma concentrations of dabigatran and apixaban/edoxaban/rivaroxaban. Methods: 80 patients receiving first NOAC-dose and 80 already on NOAC-treatment will be enrolled (N=40 for each NOAC). Subjects receiving other anticoagulants will be excluded. 6 blood samples will be collected from each patient: before drug intake, 30min, 1, 2, and 8h after intake, and before next dose. NOAC-concentrations will be measured by mass spectrometry. Results (preliminary): Until now 138 blood samples of 23 dabigatran-treated patients were analyzed. Dabigatran-concentrations ranged from 0-371ng/mL. ECT-POCT ranged from 20-219s. Pearson’s correlation coefficient showed strong correlation for ECT-POCT and dabigatran-concentrations (r=0.94, p<0.001). Dabigatran-concentrations >50ng/mL (threshold for thrombolysis according to expert recommendation) were detected by ECT-POCT (>50s) with 100% sensitivity and 82% specificity. Baseline-samples not containing any dabigatran yielded normal ECT-POCT. Conclusions: This is the first study evaluating NOAC-specific POCT. Preliminary results show excellent correlation for ECT-POCT and dabigatran; relevant dabigatran-concentrations were detected in 100%. More pioneering results on NOAC-specific POCT will be presented.

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Point-of-care monitoring of vitamin K-antagonists: validation of CoaguChek XS test strips with International Standard thromboplastin

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-200934 ◽

2012 ◽

Vol 65 (11) ◽

pp. 1031-1035 ◽

Cited By ~ 10

Author(s):

Anton M H P van den Besselaar ◽

Nathalie C V Péquériaux ◽

Marij Ebben ◽

Joke van der Feest ◽

Kerst de Jong ◽

...

Keyword(s):

The Netherlands ◽

Vitamin K ◽

Point Of Care ◽

Vitamin K Antagonists ◽

Capillary Blood ◽

Blood Samples ◽

Test Strips ◽

International Standard ◽

The Mean ◽

Coaguchek Xs

AimsMany patients treated with vitamin K-antagonists (VKA) use point-of-care (POC) whole blood coagulometers for self-testing. The majority of patients in the Netherlands use one type of POC coagulometer, that is, the CoaguChek XS. Each new lot of test strips for the CoaguChek XS is validated by a group of collaborating thrombosis centres. We assessed the International Normalised Ratio (INR) differences between each of 51 new lots of test strips and the International Standard for thromboplastin rTF/95 or its successor rTF/09.MethodsEach year, a particular lot of CoaguChek XS test strips was used as reference lot. The reference lot was validated by comparison to the International Standard, yielding a relationship between the reference lot INR and International Standard INR. Successive lots of test strips were compared to the reference lot by three centres using 19–29 capillary blood samples obtained from VKA-treated patients. Each patient provided two blood drops from the same finger prick, one for the reference lot strip and one for the new lot.ResultsThe mean INR differences between each lot and the International Standard varied between −8% and +4%. The mean absolute values of the relative differences varied between 2.4% and 8.1%. There were small but clinically unimportant differences in INR between the first and second drop of blood.ConclusionsAccuracy of CoaguChek XS INR determinations can be assessed by a group of collaborating centres using a limited number of capillary blood samples. As the mean INR differences with the International Standard were smaller than 10%, the lots were approved for use by the Netherlands Thrombosis Services.

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The Utility of Thromboelastography (TEG) In the Management of Patients with Isolated Antiphospholipid Antibodies (aPL) or Primary Antiphospholipid Syndrome (PAPS)

Blood ◽

10.1182/blood.v116.21.3179.3179 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3179-3179 ◽

Cited By ~ 4

Author(s):

Karen A Breen ◽

Beverley J Hunt

Keyword(s):

Antiphospholipid Syndrome ◽

Vitamin K ◽

Whole Blood ◽

Antiphospholipid Antibodies ◽

Vitamin K Antagonists ◽

Control Group ◽

Healthy Individuals ◽

Oral Vitamin ◽

Blood Samples ◽

Obstetric Aps

Abstract Abstract 3179 Introduction: Antiphospholipid syndrome (APS) is an immune disorder characterised by recurrent thrombosis and/or complications during pregnancy associated with the presence of persistent antiphospholipid antibodies (aPL). Several mechanisms have been proposed to underlie the pathogenic mechanisms of aPL but studies of markers of coagulation activity and thrombin generation suggest healthy individuals with aPL do not usually have a hypercoagulable state. Thromboelastography (TEG) is a global measure of haemostasis and has been shown to demonstrate hypercoagulable states. Also, studies have shown women with recurrent first trimester loss have hyercoagulable TEG parameters. There have been no studies to date assessing the use of TEG in patients with aPL/PAPS. Objective: The aim of this study was to assess the potential role of TEG to assess hypercoagulability of individuals with antiphospholipid antibodies or PAPS. Methods: Local ethical committee approval was obtained. Samples were obtained from patients attending clinics at our institution who had PAPS according to International Consensus statement criteria, or had persistent aPL without associated complications. The control group were recruited from hospital staff who were not known to have aPL, were non smokers and not taking the oral contraceptive pill. Control blood samples were obtained from 17 healthy non-pregnant women (median age 37.5 (range 20–58) years). Patient blood samples were obtained from 39 women with apL and previous thrombosis, 5 of whom had previous pregnancy morbidity, 3 of whom were smokers and all of whom were on oral vitamin K antagonists (median 47 (23-61)), 14 women with obstetric APS and no history of thrombosis, 2 of whom were smokers (median 41 (32-54)), and 17 women with isolated aPL, 2 of whom were smokers (median 43.5 (19-73)). Fresh whole blood was drawn by flawless venepuncture into tubes containing citrate 0.105M and stored at room temperature for 30 minutes prior to analysis. 500μl of whole blood was activated with 12.5μl of Kaolin and thromboelastography was performed by the same technician on 340μl of activated blood using a TEG® analyzer according to the manufacturer's protocol. Statistical analysis of all TEG parameters was performed using the unpaired t-test. A P-value of <0.05 was considered statistically significant. Results: Results of TEG parameters including R time, K, α angle, Maximal amplitude (MA), Coagulation Index (CI), and % lysis after 30 minutes (LY30) are shown below in table described as means and standard deviations. A significantly prolonged R time was found in the thrombotic APS group compared to aPL group (p<0.01) and control group (p<0.01), reflecting the use of oral vitamin K antagonists in this group. There was no significant difference in any other parameters except for LY30. LY30 was significantly greater in patients with thrombotic APS compared to the aPL group (p=0.03) and in patients with) obstetric APS (p=0.02) and isolated aPL (p<0.01) compared to controls. Conclusion: Healthy individuals with aPL or PAPS do not appear to have a hypercoagulable state by TEG criteria. Indeed, there is evidence of significantly increased fibrinolytic activity compared to controls. This is currently unexplained and worthy of further study. Disclosures: Breen: NovoNordisk: Research Funding.

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Performance Of The Simplified Pesi Score In Patients With Pulmonary Embolism Treated With Rivaroxaban Or Standard Therapy

Blood ◽

10.1182/blood.v122.21.1139.1139 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1139-1139

Author(s):

Petra MG Erkens ◽

Gregory J Fermann ◽

Martin H Prins ◽

Philip S Wells ◽

Akos F Pap ◽

...

Keyword(s):

Pulmonary Embolism ◽

Board Of Directors ◽

Vitamin K ◽

Standard Therapy ◽

Research Funding ◽

Vitamin K Antagonists ◽

Adverse Outcomes ◽

Phase Iii ◽

Advisory Committees ◽

Symptomatic Pulmonary Embolism

Abstract Background The Pulmonary Embolism Severity Index (PESI) has been validated in the setting of standard treatment of pulmonary embolism with initial low molecular weight heparin followed by vitamin K antagonists. We evaluated the proposed simplified PESI in a large, phase III randomized trial involving patients with symptomatic pulmonary embolism with or without deep vein thrombosis, who were treated with rivaroxaban or standard therapy. Methods The EINSTEIN PE study was an open-label, randomized, phase III study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin overlapping with and followed by a vitamin K antagonist (warfarin or acenocoumarol, target international normalized ratio 2.0–3.0) for 3, 6, or 12 months in patients with acute, symptomatic pulmonary embolism. At baseline, the simplified PESI score was assessed, with 1 point each assigned for age >80 years, history of cancer, chronic cardiopulmonary disease, heart beat ≥110 beats per minute, systolic blood pressure <100 mm Hg, and arterial oxyhemoglobin saturation <90%. Recurrent venous thromboembolism, fatal pulmonary embolism, all-cause mortality, and major bleeding at 7 days, 14 days, 30 days, 90 days, and at the end of the full intended treatment period were related to the simplified PESI score. Results It was possible to calculate the simplified PESI score in 4831 of the 4832 included patients, of whom 2589 (53.6%) had a PESI score of 0; 1775 (36.7%) had a score of 1; and 467 (9.7%) had a score of 2 or 3. No patient had a simplified PESI score greater than 3. Incidences of outcomes in relation to time period, simplified PESI score and treatment are presented in the following table. Conclusions Among patients with a simplified PESI score of 0 or 1, major clinical outcome events were rare during the first 30 days of treatment and were similar in patients treated with rivaroxaban or standard therapy. Patients with a simplified PESI score of 2 or more in both treatment groups had more frequent adverse outcomes both initially and in the long term. Disclosures: Fermann: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Radiometer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cubist: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cardiorentis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Prins:Bayer HealthCare: Consultancy; Sanofi-aventis: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Consultancy; Leo Pharma: Consultancy; Thrombogenics: Consultancy; Pfizer: Consultancy. Wells:BMS/Pfizer: Research Funding; Pfizer: Honoraria; Bayer Schering Pharma: Honoraria; Boehringer Ingelheim: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria; Biomerieux: Honoraria. Pap:Bayer Pharma AG: Employment. Lensing:Bayer Pharma AG: Employment.

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Vergleich von hämostaseologischen Parametern im arteriellen und venösen Blut bei Patienten mit peripherer arterieller Verschlußkrankheit

VASA ◽

10.1024/0301-1526.28.1.10 ◽

1999 ◽

Vol 28 (1) ◽

pp. 10-14 ◽

Cited By ~ 4

Author(s):

Woller ◽

Lawall ◽

Amann ◽

Angelkort

Keyword(s):

Venous Blood ◽

Arterial System ◽

Coagulation Activation ◽

Blood Samples ◽

Coagulation Parameters ◽

Arterial Blood ◽

Artery Disease ◽

Peripheral Arterial ◽

D Dimer

Background: Several studies proved the co-existence of peripheral arterial occlusive disease (PAOD) and hypercoagulability. However, in practice coagulation parameters are mainly determined from venous blood samples. In this study several coagulation parameters in arterial and venous blood were examined for differences and the validity of coagulation parameters determined in venous blood was investigated. Patients and methods: In 22 patients with peripheral artery disease venous and arterial blood samples from vessels of the diseased leg were examined for the concentration of thrombine-antithrombine III-complex (TAT), prothrombin fragments (F1 and F2) and D-dimers, and results were compared. Results: Mean concentrations of TATs and prothrombin fragments F1 and F2 were significantly higher in arterial than in venous blood. TAT-complex was the most sensitive parameter for quantification of thrombin generation. D-dimer levels did not differ in arterial and venous blood. TAT and F1 and F2 concentrations in arterial and venous blood did not correlate in individual patients whereas D-dimer concentration did. Conclusion: The determination of TAT and F1+F2 in venous blood does not adequately reflect the degree of the local coagulation activation in the arterial system. As indicators for hypercoagulability, D-Dimer values are less sensitive than F1+2, but venous D-dimer concentrations mirror arterial levels.

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Uninterrupted Dabigatran Administration Provides Greater Inhibition against Intracardiac Activation of Hemostasis as Compared to Vitamin K Antagonists during Cryoballoon Catheter Ablation of Atrial Fibrillation

Journal of Clinical Medicine ◽

10.3390/jcm9093050 ◽

2020 ◽

Vol 9 (9) ◽

pp. 3050

Author(s):

Zsuzsa Bagoly ◽

Orsolya Hajas ◽

Réka Urbancsek ◽

Alexandra Kiss ◽

Edit Fiak ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Endothelial Damage ◽

Cryoballoon Ablation ◽

Fviii Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

D Dimer

Background. Cerebral thromboembolism is a rare but feared complication of transcatheter ablation in patients with atrial fibrillation (AF). Here, we aimed to test which pre-procedural anticoagulation strategy results in less intracardiac activation of hemostasis during ablation. Patients and methods. In this observational study, 54 paroxysmal/persistent AF patients undergoing cryoballoon ablation were grouped according to their periprocedural anticoagulation strategy: no anticoagulation (oral anticoagulation (OAC) free; n = 24), uninterrupted vitamin K antagonists (VKA) (n = 11), uninterrupted dabigatran (n = 17). Blood was drawn from the left atrium before and immediately after the ablation procedure. Cryoablations were performed according to standard protocols, during which heparin was administered. Heparin-insensitive markers of hemostasis and endothelial damage were tested from intracardiac samples: D-dimer, quantitative fibrin monomer (FM), plasmin-antiplasmin complex (PAP), von Willebrand factor (VWF) antigen, chromogenic factor VIII (FVIII) activity. Results. D-dimer increased significantly in all groups post-ablation, with lowest levels in the dabigatran group (median [interquartile range]: 0.27 [0.36] vs. 1.09 [1.30] and 0.74 [0.26] mg/L in OAC free and uninterrupted VKA groups, respectively, p < 0.001). PAP levels were parallel to this observation. Post-ablation FM levels were elevated in OAC free (26.34 [30.04] mg/L) and VKA groups (10.12 [16.01] mg/L), but remained below cut-off in all patients on dabigatran (3.98 [2.0] mg/L; p < 0.001). VWF antigen and FVIII activity increased similarly post-ablation in all groups, suggesting comparable procedure-related endothelial damage. Conclusion. Dabigatran provides greater inhibition against intracardiac activation of hemostasis as compared to VKAs during cryoballoon catheter ablation.

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Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial

European Heart Journal ◽

10.1093/eurheartj/ehz190 ◽

2019 ◽

Vol 40 (36) ◽

pp. 3013-3021 ◽

Cited By ~ 37

Author(s):

Stefan H Hohnloser ◽

John Camm ◽

Riccardo Cappato ◽

Hans-Christoph Diener ◽

Hein Heidbüchel ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Primary Endpoint ◽

Vitamin K Antagonists ◽

Brain Magnetic Resonance Imaging ◽

Study Drug ◽

Haemorrhagic Stroke ◽

Open Label ◽

Af Ablation ◽

End Of Treatment

Abstract Aims Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. Methods and results The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02–1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62). Conclusion Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.

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Treatment of Acute VTE with Rivaroxaban - Results of the Prospective Dresden Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v128.22.2618.2618 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2618-2618

Author(s):

Loretta Keller ◽

Sandra Marten ◽

Judith Hecker ◽

Sebastian Werth ◽

Luise Tittl ◽

...

Keyword(s):

Major Bleeding ◽

Research Funding ◽

Phase Iii ◽

Bleeding Complications ◽

Daily Care ◽

Age Related ◽

Fatal Bleeding ◽

End Of Treatment ◽

Recurrent Vte ◽

Mean Time

Abstract Background: The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be evaluated in unselected patients treated under daily care conditions. Patients and methods: The Dresden NOAC registry is a prospective regional registry in which patients with oral anticoagulation undergo prospective follow- up (FU). So far, more than 3200 patients have been enrolled, including 772 VTE patients with rivaroxaban treatment. For this analysis, only patients with acute VTE who started rivaroxaban within 14 days after diagnosis of VTE and who were enrolled within these 14 days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. All reported outcome events were centrally adjudicated based on source documentation and standard definitions. Results: Between December 1st 2011 and March 31st 2016, 407 patients received rivaroxaban for acute VTE treatment (51.6% female, 80.8% DVT; 19.2% PE±DVT, mean age 61.4 years). Mean time between VTE diagnosis and initiation of rivaroxaban was 1.7±3.3 days (median 0d; 25th/75th percentile 0; 1d). At baseline, rivaroxaban doses consisted of 15 mg BID in 93.1%, 20 mg OD in 3.4%, 15 mg OD in 3.2% and 10 mg OD in 0.2% of patients. Reasons for not using 2x15 mg rivaroxaban BID were pre-treatment with therapeutic parenteral anticoagulants for ≥7 d in 14 cases, comorbidities (e.g. bleeding history, renal impairment) in 4 cases and unknown in 10 cases. During FU (mean 762.4±462.7d), the mean rivaroxaban exposure was 357.7±385.9 days. During treatment with rivaroxaban, 4/407 patients (1.0%) experienced a recurrent VTE, which translated into a recurrence rate of 1.0/ 100 pt. years. During treatment, 172/407 (42.3%) patients reported bleeding complications, which in 13 cases (3.2%; 3.3/100 pt. years) were major bleeding according to ISTH definition, including one fatal intracranial bleeding. Patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) had similar rates of recurrent VTE during rivaroxaban treatment (1.01 and 1.01/100 pt. years) but PE patients had numerically higher rates of major bleeding (3.99/100 pt. years compared to 3.09/100 pt.years in the DVT group). Effectiveness and safety profiles were consistent across relevant subgroups (table 1). 18 patients died during FU (2.12/100 pt.years), of which 8 deaths occurred during or within 3 days after last intake of rivaroxaban. Most common causes of death were fatal cardiovascular event (n=7) and terminal malignant disease (n=4), followed by sepsis/infection (n=3), age related death (n=1), fatal bleeding (n=1) and other reasons (n=2). At 6 months (FU completed in 365 pts.), 61.4% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (28.8%) or were switched to other anticoagulants (7.1%). Therefore, the rate of unplanned complete discontinuation at 6 months was 2.7%. At 12 months (FU completed in 289 pts.), 41.5% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (45.0%) or were switched to other anticoagulants (8.3%). Therefore, the rate of unplanned complete discontinuation at 12 months was 5.2%. After rivaroxaban interruption for more than 3 days or permanent discontinuation, 21 patients experienced a recurrent VTE (9 PE±DVT, 12 DVT) with a mean time between last intake of rivaroxaban and VTE recurrence of 351.2±282.6 days (range 7-926d). PE was a common manifestation of VTE recurrence and, despite numerically lower bleeding rates after discontinuation, 2 cases of intracranial haemorrhage occurred (table 2). Conclusions: In unselected patients in daily care, rivaroxaban treatment for acute VTE has high effectiveness and acceptable rates major bleeding. Initial dosing was according to label in over 90% of patients and, at 6 and 12 months, persistence to rivaroxaban therapy was excellent with low rates of unplanned complete discontinuation. Fatal VTE and fatal bleeding are rare events during rivaroxaban therapy and all-cause mortality is mostly related to underlying diseases, age or acute co-morbidities. Treatment discontinuation resulted in a relevant increase in VTE recurrence, of which more than 40% manifested as PE. In contrast, major bleeding rates declined after discontinuation but with 1%/year remained at a clinically relevant level, probably due to co-morbidities. Disclosures Marten: Bayer: Honoraria; Daichii Sankyo: Honoraria. Werth:Pfizer: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; OmniaMed: Honoraria; LEO-Pharma: Honoraria. Beyer-Westendorf:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding.

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