Effects Of Dabigatran Research Articles

Abstract WP73: No Influence of Dabigatran or its Specific Reversal Agent, Idarucizumab, on rTPA-induced Thrombolysis of Clots in Human Plasma: an in vitro Study

Oral anticoagulation reduces the elevated incidence of stroke in patients with atrial fibrillation. Though stroke risk is reduced, it is not entirely prevented. When patients present with ischemic stroke and are also being treated with newer oral anticoagulants, such as dabigatran, this can complicate therapy. Currently a specific reversal agent to dabigatran, idarucizumab, is in development and was shown to immediately reverse the anticoagulant effect of dabigatran in volunteers and patients. However, it is unknown if administration of idarucizumab to reverse dabigatran results in any nonspecific effects on the action of rtPA. Thus this study was performed to determine the effect of dabigatran and its reversal with idarucizumab on rtPA-induced thrombolysis of a clot in human plasma in vitro. Blood was obtained from volunteers after written informed consent. Clots were produced by adding thromboplastin and 200mM CaCl2 to platelet rich plasma containing 594Alexa-labelled fibrinogen at 37°C for 60 min. Clots were then removed, washed and added to plasma from the same subject containing 150 IU/mL rtPA ± dabigatran (150 ng/mL) for 1 hr. Idarucizumab (3 mg/mL) was added after 60 min and incubated for a further 60 min at 37°C, all under continuous stirring. Lysis was measured as fluorescence released into plasma from the clot. Data shown as mean ± SD, n=5, were compared with ANOVA, p<0.05 was significant. Initial clot weight was similar (18±6 mg) across groups. Clots added to plasma containing only dabigatran or idarucizumab underwent no lysis. Incubation with rtPA resulted in 28±17, 34±18 and 61±18% lysis after 60, 65 and 120 min, respectively (p<0.001 vs control). Addition of dabigatran or idarucizumab alone did not significantly affect lysis in the presence of rtPA. Addition of dabigatran (at t=0) followed by idarucizumab (at t=60 min) to plasma resulted in similar rtPA-induced thrombolysis, 30±16, 34±14 and 55±17%, as compared to incubation with rtPA alone. Clot weight after 2 hrs was 6.3±2.2 mg with no difference across groups. These data show there are no non-specific interactions of idarucizumab with rtPA-induced thrombolysis in this in vitro model. It reinforces the specificity of idarucizumab for only dabigatran and its lack of binding to other substrates.

Abstract 213: Effect of Idarucizumab on Intracranial Bleeding in Dabigatran-treated Patients: Initial Results From RE-VERSE AD

Introduction: Dabigatran is a non-vitamin K antagonist oral anticoagulant (NOAC) licensed for stroke prevention in nonvalvular atrial fibrillation. In the RE-LY trial, both doses of dabigatran (110 mg and 150 mg bid) were associated with a significantly lower annualized rate of intracranial hemorrhage (ICH) than warfarin (0.23%, 0.32% and 0.76%, respectively). Nonetheless, the mortality rate with ICH in the context of any anticoagulation remains high, probably reflecting the effects of hematoma expansion. Whether a specific reversal agent for dabigatran will improve clinical outcomes in dabigatran-treated patients with ICH is unknown. RE-VERSE AD is an ongoing, open-label, phase 3, cohort study evaluating the extent to which idarucizumab, a humanized Fab fragment directed against dabigatran, reverses the latter’s anticoagulant effects in patients with serious bleeding or in those requiring urgent interventions. This study focuses on the results in patients with ICH. Hypothesis: Compared with historical controls, idarucizumab improves clinical outcomes in dabigatran-treated patients with ICH. Methods: Patients presenting with ICH were given intravenous idarucizumab 5 g as two 2.5 g bolus infusions administered no more than 15 minutes apart. The primary endpoint was the maximum reversal of the anticoagulant effect of dabigatran, based on central laboratory determination of the dilute thrombin time or ecarin clotting time. Results: In an interim analysis at 90 patients, 18 with ICH had been enrolled in RE-VERSE AD. Updated results on the effects of idarucizumab on coagulation parameters, imaging studies, and clinical outcomes in this patient subgroup will be presented. Conclusions: Currently, there are no specific reversal agents for the NOACs. We present the first data on the clinical outcomes for idarucizumab in dabigatran-treated patients who present with ICH.

Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring

Context: Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications – however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function. Case details: Two patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10 × 150 mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100 × 110 mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels. Conclusion: There is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.

Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo-controlled study.

There is growing interest in understanding the effects of adding an oral anticoagulant in patients on dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and clopidogrel represent the most broadly utilised oral anticoagulant and P2Y12 receptor inhibitor, respectively. However, VKAs can interfere with clopidogrel metabolism via the cytochrome P450 (CYP) system which in turn may result in an increase in platelet reactivity. Dabigatran is a direct acting (anti-II) oral anticoagulant which does not interfere with CYP and has favourable safety and efficacy profiles compared with VKAs. The pharmacodynamic (PD) effects on platelet reactivity and clot kinetic of adjunctive dabigatran therapy in patients on DAPT are poorly explored. In this prospective, randomised, double-blind, placebo-controlled PD study, patients (n=30) on maintenance DAPT with aspirin and clopidogrel were randomised to either dabigatran 150 mg bid or placebo for seven days. PD testing was performed before and after treatment using four different assays exploring multiple pathways of platelet aggregation and fibrin clot kinetics: light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA), kaolin-activated thromboelastography (TEG) and turbidimetric assays. There were no differences in multiple measures of platelet reactivity investigating purinergic and non-purinergic signaling pathways assessed by LTA, MEA and TEG platelet mapping. Dabigatran significantly increased parameters related to thrombin activity and thrombus generation, and delayed fibrin clot formation, without affecting clot structure or fibrinolysis. In conclusion, in patients on DAPT with aspirin and clopidogrel, adjunctive dabigatran therapy is not associated with modulation of profiles of platelet reactivity as determined by several assays assessing multiple platelet signalling pathways. However, dabigatran significantly interferes with parameters related to thrombin activity and delays fibrin clot formation.

Treatment of acute pulmonary embolism with dabigatran versus warfarin. A pooled analysis of data from RE-COVER and RE-COVER II.

Dabigatran was non-inferior to warfarin for prevention of recurrent venous thromboembolism (VTE), and dabigatran had a lower rate of bleeding compared with warfarin in two large-scale randomised trials, RE-COVER and RE-COVER II. In this study, we investigate the efficacy and safety of dabigatran versus warfarin according to the index event that qualified the patient for enrollment, either symptomatic pulmonary embolism (PE) with or without deep-vein thrombosis (DVT), or DVT alone. We then analyse the anticoagulant effect of dabigatran vs warfarin on patients enrolled with PE. The pooled dataset for the efficacy analysis consisted of 2553 and 2554 patients who were randomised to dabigatran and warfarin, respectively. Recurrent VTE/VTE-related death during the study period and additional 30-day follow-up occurred in 2.7 % of all patients on dabigatran and in 2.4 % on warfarin (hazard ratio [HR] 1.09 [95 % confidence interval 0.77, 1.54]). In patients with PE as their index event, recurrent VTE/VTE-related death occurred in 2.9 % vs 3.1 % of patients (HR 0.93 [0.53, 1.64]). There were significantly fewer major bleeding events in patients treated with dabigatran than with warfarin (HR 0.60 [0.36, 0.99]). The pattern was similar both in patients with PE and in those with DVT alone as the index event. These analyses of the pooled dataset from the RE-COVER and RE-COVER II trials indicate that dabigatran is as effective as warfarin in preventing recurrent VTE, regardless of whether patients present with symptomatic PE (with or without DVT) or with symptomatic DVT alone. Dabigatran was also associated with a lower risk of bleeding than warfarin, regardless of the index event.

Reversal of Dabigatran Using Idarucizumab in a Septic Patient with Impaired Kidney Function in Real-Life Practice.

Background. Immediate reversal of anticoagulation is essential when facing severe bleeding or emergency surgery. Although idarucizumab is approved for the reversal of dabigatran in many countries, clinical experiences are lacking, particularly in special patient-populations such as sepsis and impaired renal function. Case Presentation. We present the case of a 67-year-old male septic patient with a multilocular facial abscess and chronic kidney disease (GFR 36.5 mL/min). Thrombin time (TT) and activated partial thromboplastin time (aPTT) 15 hours after the last intake of 150 mg dabigatran were both prolonged (>120 sec, resp., 61 sec), as well as unbound dabigatran concentration (119.05 ng/mL). Before immediate emergency surgery dabigatran was antagonised using idarucizumab 2 × 2.5 g. Dabigatran concentration was not detectable 10 min after idarucizumab administration (<30 ng/mL). TT and aPTT time were normalised (16.2 sec, resp., 30.2 sec). Sepsis was controlled after surgery and kidney function remained stable. In the absence of postoperative bleeding, dabigatran was restarted 36 hours after admission. Conclusion. Idarucizumab successfully reversed the effect of dabigatran in real-life practice in a patient with sepsis and renal impairment and allowed emergency surgery with normal haemostasis. Efficacy and safety in real-life practice will nevertheless require prospective registries monitoring.

SPECIFIC ANTIDOTES TO NEW ORAL ANTICOAGULANTS

Safety profiles of the novel oral anticoagulants (NOAC) (rivaroxaban, apixaban, edoxaban, dabigatran) are better than that of warfarin. However, the risk (including lifethreatening) of bleeding is no less than 2.3–3.1% per year. Three specific antidotes to NOAC are currently in different phases of clinical trial and implementation. Idarucizumab is a monoclonal antibody which immediately and completely reverses the anticoagulation effect of dabigatran. Andexanet alfa is a recombinant, modified factor Xa molecule that binds and inhibits the effects of oral and parenteral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, fondaparinux, heparins). Andexanet is already in 3b Phase, and at the end of 2016 — beginning of 2017 it is expected to be approved for clinical use. Ciraparantag is a small molecule, non-covalently binding to factor Xa inhibitors, and dabigatran (i.e., a universal antidote). Recently, promising results of phase 1 trials involving aripazin were published. The article tells about the practical aspects of the use of antidotes, treatment approaches for life-threatening bleeding during treatment with NOAC.

Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism

ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis. Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this. To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation. Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE. Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice. We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect.

Dabigatran but not rivaroxaban or apixaban treatment decreases fibrinolytic resistance in patients with atrial fibrillation

IntroductionMost anticoagulants stimulate fibrinolysis in vitro through mechanisms dependent on and independent of thrombin activatable fibrinolysis inhibitor (TAFI). We evaluated the effect of dabigatran, rivaroxaban and apixaban treatment on plasma fibrinolysis in patients with non-valvular atrial fibrillation. Methods and resultsPatients treated with dabigatran etexilate (n=22), rivaroxaban (n=24) or apixaban (n=22) were studied. Plasma was obtained before (trough) and 2h after drug intake (peak). Fibrinolytic resistance of clots exposed to exogenous tissue plasminogen activator was significantly lower in peak than in trough samples and correlated with drug concentration only in dabigatran group. Moreover, fibrinolytic resistance at peak was lower in dabigatran than in rivaroxaban and apixaban groups. This difference disappeared if the TAFI pathway was inhibited. Thrombin generation and TAFI activation were markedly lower in peak than in trough samples in all three groups. However, TAFIa levels in trough and peak samples were significantly lower in dabigatran group than in rivaroxaban and apixaban groups. Circulating levels of prothrombin fragment F1+2 (reflecting in vivo thrombin generation) and plasmin-antiplasmin complex (reflecting plasmin generation) were not or barely influenced by drug levels in all groups. ConclusionsOur data suggest that dabigatran, contrary to rivaroxaban and apixaban, reduces fibrinolytic resistance by virtue of its greater impact on TAFI activation. The profibrinolytic effect of dabigatran may play a role locally, at sites of fibrin formation, by making the nascent thrombus more susceptible to plasminogen-dependent degradation.

Dabigatran Pharmacokinetics and Pharmacodynamics during Renal Replacement Therapy

Introduction: Dabigatran is an oral direct thrombin inhibitor approved for use in prevention and treatment of thromboembolism. There is currently no reliable strategy for reversing its anticoagulant effects. The use of activated prothrombin complex concentrates has been reported, however, the relationship between dabigatran concentration and anticoagulation parameters in this setting have not been formally assessed or documented. There are also few reports on the pharmacokinetics and pharmacodynamics of dabigatran in the context of renal replacement therapy. This report describes a case of dabigatran overdose and management with factor eight bypassing activity (FEIBA), and hemodialysis.Case Presentation: A 62-year-old man taking dabigatran 110 mg twice daily presented with hematemesis, shock, acute kidney injury, INR > 8 and PTT > 150 s, hemoglobin 104 g/L and creatinine 1675 µmol/L. Last dose of dabigatran was ingested within 10 hours of presentation. Additional complications included hematuria, pulmonary hemorrhage, gastrointestinal bleeding and cardiac arrest. The patient required multiple blood transfusions at presentation. In an attempt to reverse the anticoagulant effects of dabigatran, the patient received 42 units/kg of FEIBA. A dialysis catheter was placed approximately 2 hours later without complication. Conventional hemodialysis (CHD) was initiated for high clearances with blood flows of 200 mL/min over 4 hours, followed by continuous venovenous hemodialysis (CVVHD). No further blood transfusions were required following administration of dialysis. He had resolution of all hemorrhagic symptoms by day 5 and achieved partial recovery of kidney function. Dialysis was discontinued on day 3 and the patient was discharged to a rehabilitation facility on day 34.Results: Bloodwork drawn every 2 hours was analyzed for INR, PTT and dabigatran levels using HEMOCLOT® assay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two hours following FEIBA administration, INR and PTT decreased from 7.4 to 3.6 and 114 s to 100 s, respectively despite no significant change in dabigatran levels (1.26 µg/mL - 1.30 µg/mL). Plasma dabigatran half-lives were 5.4 hours during CHD, 28 hours with CVVHD and 65 hours post-dialysis. Dialytic clearance values for dabigatran were estimated with a pharmacometric model. Plasma dialysis clearance for CHD was 66 mL/min (plasma perfusion rate of 128 mL/min) while the plasma dialysis clearance for CVVHD was 20 mL/min (plasma perfusion rate of 101 mL/min).Conclusions: Information regarding management of dabigatran overdose is scarce. To the best of our knowledge, this is the first study to document the use of FEIBA in the acute management of dabigatran overdose with pharmacokinetic and pharmacodynamic testing. By use of HEMOCLOT® assay, we were able to demonstrate a rapid reversal of INR and PTT despite no significant change in dabigatran levels. This report supports the use of FEIBA for reversal of the anticoagulant effects of dabigatran for urgent procedures. This report also adds to literature demonstrating that dabigatran overdose should be initially treated with CHD rather than CVVHD. CHD with high flows and a high flux dialyzer is best, as it has greater efficiency of dabigatran clearance than CVVHD. DisclosuresLazo-Langner:Bayer: Honoraria; Pfizer: Honoraria.

Prothrombin Complex Concentrate Is Effective in Treating the Anticoagulant Effects of Dabigatran in a Porcine Polytrauma Model.

In the event of trauma, emergency reversal of anticoagulation therapy may be required. However, no specific reversal agents are routinely available for the direct oral anticoagulants such as dabigatran. The authors investigated four-factor prothrombin complex concentrate (PCC) for treating dabigatran-induced anticoagulation in a porcine polytrauma model. Dabigatran etexilate was given orally for 3 days and intravenously on day 4 to 32 pigs. Animals were randomized 1:1:1:1 to PCC (25, 50, or 100 U/kg) or saline. Study medication was administered 12 min after bilateral femur fractures and blunt liver injury. The primary endpoint was blood loss at 300 min. The mean plasma concentration of dabigatran was 487 ± 161 ng/ml after intravenous administration. Blood loss was 3,855 ± 258 ml in controls and 3,588 ± 241 ml in the PCC25 group. In the PCC50 and PCC100 groups, blood loss was significantly lower: 1,749 ± 47 ml and 1,692 ± 97 ml, respectively. PCC50 and PCC100 effectively reduced dabigatran's effects on coagulation parameters, whereas control and (to a lesser extent) PCC25 animals developed severe coagulopathy. Sustained increases in endogenous thrombin potential occurred with PCC50 and PCC100. Four-factor PCC (50 or 100 U/kg) is effective in reducing blood loss in dabigatran-anticoagulated pigs, but higher doses may induce a procoagulant state.

Idarucizumab: The Antidote for Reversal of Dabigatran.

Four non–vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, are currently licensed as alternatives to heparins and vitamin K antagonists for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with nonvalvular atrial fibrillation. Dabigatran is the only NOAC that inhibits thrombin; the others inhibit factor Xa. All of the NOACs are at least as effective as vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are associated with less life-threatening bleeding, in particular less intracranial hemorrhage.1,2 Nonetheless, serious bleeding can occur with NOACs. In addition, patients taking NOACs may sustain trauma and may require urgent surgery or interventions. Consequently, the availability of specific reversal agents for NOACs could improve patient management during these emergency situations. Idarucizumab is a humanized monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. In vitro and ex vivo studies have demonstrated that idarucizumab promptly restores dabigatran-prolonged coagulation parameters to baseline values,3–5 and studies in healthy volunteers and patients with life-threatening bleeding or requiring emergency surgery or invasive procedures show that it completely reverses the anticoagulant effects of dabigatran within minutes in the majority of patients. Idarucizumab was recently licensed in the United States and Europe. This article summarizes the pharmacology and clinical data on the use of idarucizumab to reverse dabigatran. The first step in the development of idarucizumab was to immunize mice with dabigatran-derived haptens coupled to carrier proteins to produce antibodies against dabigatran.3 Monoclonal antibodies exhibiting the highest affinity for dabigatran were selected, and the antigen-binding fragment (Fab) was isolated (Figure 1). Murine protein sequences were replaced …

Design and protocols of the GIRAF prevention trial: A randomized, prospective, parallel, two-center study to compare cognitive outcomes in subjects with atrial fibrillation using warfarin or dabigatran

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with cognitive impairment and dementia. Cognitive and functional impairments have been neglected in clinical trials with patients affected by AF. Dabigatran is a new drug, which can offer a more stable long-term anticoagulant therapy compared to warfarin. This advantage could be associated with a minor incidence of cognitive and functional decline. The objective of the study is to evaluate the effects of dabigatran compared with warfarin on cognitive and functional impairments, thrombin production, bleeding occurrence and cerebrovascular complications in elderly patients with AF.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A randomized, prospective parallel, two-center, active-controlled trial will be performed in a sample of 200 patients with AF randomly designated to take dabigatran (150 mg twice daily) or warfarin (once daily, dose controlled by INR between 2 and 3). After one and two years, subjects will be assessed considering cognitive outcomes. Additionally, patients will be submitted to brain magnetic resonance imaging (MRI) at the beginning and ending of study to identify possible cerebrovascular events, as well as carotid ultrasonography to search for atherosclerotic disease.&lt;/p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; The GIRAF study expects to provide data about prevention of cognitive and functional impairments among patients on anticoagulant therapy for AF, and to explore new concepts on potential prevention of cognitive decline and benefits for AF patients and their relatives.

Idarucizumab: First Global Approval

Idarucizumab (Praxbind(®)) is a fully humanized, monoclonal antibody fragment developed by Boehringer Ingelheim as a specific antidote to reverse the anticoagulant effect of the direct oral thrombin inhibitor dabigatran etexilate (Pradaxa(®)). Idarucizumab received its first global approval, in the USA, in October 2015 for use in adult patients treated with dabigatran etexilate when rapid reversal of its anticoagulant effects is required for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding. Regulatory applications have been submitted in Canada and in the EU, where it has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use. This article summarizes the milestones in the development of idarucizumab leading to this first approval for reversing the anticoagulant effects of dabigatran in adults.

Heart Failure and Mortality in Patients With Nonvalvular Atrial Fibrillation Started on Novel Oral Anticoagulant Therapy: A Single-Center Experience.

Heart failure (HF) is the leading cause of in-hospital morbidity and mortality in the elderly population. Coexistence of HF and atrial fibrillation (AF) increases the risk of thromboembolic events. Oral anticoagulant therapy reduces the risk of thromboembolic events in patients with AF. Novel oral anticoagulants (NOACs) have been introduced as an alternative drug for prevention from thromboembolic events in patients with nonvalvular AF. The primary aim of this study is to investigate the clinical effects of warfarin, dabigatran, and rivaroxaban in patients with nonvalvular AF. The secondary aim of this study is to reveal the predictors of all-cause mortality in patients with nonvalvular AF undergoing NOACs therapy. The study population consisted of 171 patients with nonvalvular AF. Patients were divided into 3 groups according to the usage of oral anticoagulant therapy including coumadin (51 patients), dabigatran (52 patients), and rivaroxaban (68 patients). Although CHA2DS2-VASc score was similar between groups, HAS-BLED score was significantly higher in patients using rivaroxaban. Dyspepsia and itching were more common in patients using dabigatran. Heart failure and vascular disease were more common in the nonsurviving group (10 patients) than in the surviving group (110 patients) in patients using NOACs. Among age, sex, HF, hypertension, vascular disease, and CHA2DS2-VASc, which were included in the regression model, only the presence of HF was an independent predictor of all-cause mortality in patients using NOACs. In conclusion, the mortality rate is significantly higher in patients with HF using NOACs. Moreover, HF is an independent predictor of all-cause mortality in patients using NOACs.

Abstract 12862: Predictors of Hospitalization and Effects of Dabigatran and Warfarin on Hospitalization Rates: An Analysis From The Re-ly Trial

Introduction: Hospitalization is common in patients with atrial fibrillation (AF), and predicts poor prognosis, but is poorly understood. Aim: We evaluated predictors of hospitalization in patients with AF treated with dabigatran etexilate (DE) or warfarin in RE-LY to understand predictors of hospitalization and to further evaluate the effects of anticoagulant choices on hospitalization. Methods: A multivariate regression model was developed to determine predictors of hospitalization. Hospitalization due to bleeding events were identified and rates were compared between DE and warfarin. Results: Of 18,113 patients in RE-LY, 7,200 (39.8%) were hospitalized at least once during mean follow up of 2 years, with 14,025 total hospitalizations. Compared to patients not hospitalized, patients with hospitalizations were older, more often had coronary artery disease, prior MI, a history of heart failure, moderate renal impairment, hypertension, diabetes and higher CHADS 2 scores. Multivariate analysis identified peripheral artery disease (PAD; HR 1.44, 95% CI 1.22-1.69), a CHADS 2 score of ≥ 3 (HR 1.29, CI 1.11-1.51), VKA-naïve (HR 1.28, CI 1.19-1.37), left ventricular ejection fraction (EF) ≤ 40% (HR 1.24, CI 1.12-1.36), and renal impairment with CrCL ≤ 50mL/min (HR 1.12, CI 1.02-1.23) as predictors of hospitalization. First hospitalization rates were 39.5%, 41.6% and 42.6% for DE 110 mg bid, DE 150 mg bid and warfarin, respectively. The treatment effects of both DE doses compared to warfarin were consistent, between patients hospitalized and those not. Hospitalization occurred less often with DE 110 compared to warfarin (RR = 0.93, CI 0.87-0.99) and compared to DE 150 (RR=0.95, CI 0.89-1.01). Hospitalizations for bleeding events occurred less often with DE 110 (3.5%) compared both to warfarin (4.6%) (p=0.02) and to DE 150 (5.2%) (p&lt;0.001); rates were statistically similar between DE 150 and warfarin (p=0.07). Conclusion: Predictors of hospitalization included common comorbidities of an elderly AF population, such as PAD, higher CHADS 2 scores, low EF and renal impairment. DE 110 mg bid was associated with significantly fewer hospitalizations compared to both warfarin and DE 150 bid; in part due to reduction in hospitalizations for bleeding events.

Abstract 16418: Reinitiation of Antithrombotic Therapy After Emergency Procedures or After an Uncontrolled or Life Threatening Bleeding Event. Initial Experience From the Re-verse Ad Trial

Background: In AF patients, oral anticoagulation is effective for stroke risk reduction, but there is uncertainty on how to manage re-initiation of anticoagulation after a bleeding complication. Ideally, therapy would be stopped immediately and reinitiated as soon as possible after the bleeding has resolved. In clinical trials comparing dabigatran to warfarin, urgent interventions were linked to higher rates of both bleeding and thromboembolic events than elective interventions. Idarucizumab immediately reverses the anticoagulant effects of dabigatran without prothrombotic effect. Due to idarucizumab’s specificity to dabigatran, other drug-drug interaction is not expected, allowing the clinician flexibility in managing antithrombotic therapy during and after the event. Methods: In the ongoing phase III RE-VERSE AD study, dabigatran-treated patients with uncontrolled bleeding (Group A) or who require emergency surgery (Group B) are given 5 g of idarucizumab IV. The primary endpoint was median maximum reversal of the anticoagulant effect of dabigatran, based on dilute thrombin time (dTT) or ecarin clotting time (ECT) within 4 h of study drug infusion. Data collection on re-initiation of antithrombotic therapy was studied as a secondary endpoint. Results: In the interim analysis of 90 patients, median maximum reversal of the anticoagulant effect of dabigatran was 100%. For antithrombotic re-initiation data, see Table. Conclusions: Idarucizumab is an immediate-acting, specific reversal agent for dabigatran. Preliminary results from RE-VERSE AD suggest that idarucizumab facilitates the periprocedural management of dabigatran-treated patients. Of note is that after an acute event, alternative antithrombotic therapy can be initiated at any time after idarucizumab application. Reintroduction of dabigatran was possible as early as 24 h after idarucizumab treatment. This is desirable to protect patients from their underlying thromboembolic risk.

Dabigatran etexilate and reduction in serum apolipoprotein B

ObjectiveCarboxylesterases, which convert dabigatran etexilate to its active form, dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism...

The addition of idarucizumab to plasma samples containing dabigatran allows the use of routine coagulation assays for the diagnosis of hemostasis disorders

The anticoagulant effect of dabigatran can be approximated by its prolongation of routine coagulation assays. Consequently, dabigatran also interferes with thrombophilia screening or with diagnosing hemostasis disorders that have developed after the initiation of anticoagulant treatment, such as vitamin K deficiency or acquired hemophilia A. This study was carried out to determine whether idarucizumab, a humanized antibody fragment that binds dabigatran, could fully neutralize dabigatran in routine diagnostic coagulation assays conducted in vitro, thereby preventing false-positive or false-negative diagnostic readouts. Preliminary experiments identified coagulation assays that were sensitive to dabigatran, and identified a concentration of idarucizumab that neutralized the effects of dabigatran. These assays were then carried out with patient and control plasma samples spiked with dabigatran, with or without a molar excess of idarucizumab. Dabigatran altered the prothrombin time, activated partial thromboplastin time and thrombin time, and the measurement of intrinsic and extrinsic factor levels. Screening and confirmation tests used for lupus anticoagulant detection were prolonged by dabigatran, falsely suggesting the presence of lupus anticoagulant. Conversely, the addition of dabigatran falsely corrected an abnormal activated protein C resistance ratio. Addition of idarucizumab completely normalized these measurements, and allowed the correct identification of normal and abnormal samples with these assays. In vitro addition of idarucizumab to plasma samples containing dabigatran fully neutralizes the drug, and facilitates the use of routine coagulation assays to allow the diagnosis of hemostasis disorders that may be concurrently present in patients taking dabigatran.

Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects

Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects -