Dabigatran Levels Research Articles

Removal of Dabigatran by Hemodialysis

Dabigatran is a newly available oral direct thrombin inhibitor approved for anticoagulation therapy to prevent strokes in patients with nonvalvular atrial fibrillation. Unlike warfarin, dabigatran's observed therapeutic window and minimal drug-to-drug interaction suggest that invasive laboratory testing and dose adjustment is not necessary. In circumstances of excessive anticoagulation, such as overdoses, decreased kidney function, or instances of significant bleeding, reversing dabigatran's effects may be necessary. Unlike warfarin, no rapid-acting antidote to reverse the effects of dabigatran is known. However, hemodialysis has been suggested as a method of removing dabigatran and thereby reducing its anticoagulant effect. We describe a case in which hemodialysis was used in an attempt to remove dabigatran in a patient with excessive anticoagulation from dabigatran and severe intracranial hemorrhage. Serial dabigatran levels suggested that hemodialysis removed the drug. However, given the large volume of distribution of dabigatran in the terminal phase of elimination, a rebound in drug level was noted. We suggest that a longer duration of therapy or more continuous modality of hemodialysis may be needed in conjunction with the initial hemodialysis treatment of dabigatran coagulopathy.

Abstract 9928: Reversal of Anticoagulant Activity of Dabigatran and Dabigatran-induced Bleeding in Rats by a Specific Antidote (Antibody Fragment)

Dabigatran etexilate (DE) is the prodrug of dabigatran, a direct potent thrombin inhibitor, approved as an alternative to warfarin for prevention of strokes in patients with atrial fibrillation. However, as with any anticoagulant, bleeding risks are associated with its use. Though there is no specific antidote available, an antibody fragment (Fab) against dabigatran is currently in development to neutralize its activity. Inhibition of dabigatran and its metabolites was tested in vitro using a diluted thrombin time assay. The ability of the Fab alone to induce coagulation was tested in various assays in human plasma including endogenous thrombin potential (ETP, 5 pM tissue factor) and ecarin chromogenic assay (ECA). Dabigatran etexilate (DE), 30 mg/kg was given orally to rats every 8 hrs to achieve supratherapeutic levels of dabigatran and induce bleeding in a rat tail bleeding model. 45 min after the last dose increasing i.v. Fab doses were given to test for bleeding reversal. Ex vivo clotting and plasma levels of dabigatran and Fab were measured. The Fab potently binds dabigatran (Kd 2 pM). Anticoagulant activity of dabigatran and its metabolites was inhibited with an IC 50 of 3.5 and 2.0 nM in human plasma. Fab had no effect on thrombin generation (ETP, 0.89-fold of control), in contrast FEIBA resulted in ∼2-fold increase in ETP. ECA was not elevated with Fab vs control. DE (30 mg/kg p.o.) was given in 8 hr intervals to achieve steady state levels in the rat, with supratherapeutic plasma levels (1500 nM or ~750 ng/mL). This resulted in ~2-fold increase in tail cut bleeding time. There was a rapid, dose-dependent decrease in blood loss after i.v. injection of Fab, which was maintained for 6 hrs after the highest dose of Fab. aPTT, TT and ECT were all reversed. Treating rats with warfarin (0.5 mg/kg p.o.) over 3 days resulted in a 2-fold elevation of blood loss. Similar doses of Fab had no effect on reversing this elevated blood loss. These data show the specificity and selectivity of the antibody fragment for dabigatran. Administration of the Fab after DE resulted in a safe and rapid reversal of blood loss, which correlated with reversal of ex vivo clotting tests. Thus this agent holds promise for reversing dabigatran-induced anticoagulation and bleeding effects.

Dabigatran Monitoring: Observations From the Initial 127 Patients Tested

AbstractAbstract 4366 Introduction:Dabigatran is the first oral anticoagulant since warfarin to be approved by the FDA for prevention of stroke in patients with non-valvular atrial fibrillation. Unlike warfarin, dabigatran monitoring has not yet been recommended. However, dabigatran accounted for 3781 serious adverse events (including 542 deaths) as reported in QuarterWatch by the Institute for Safe Medicine Practices in 2011. This has prompted clinicians to consider situations in which drug level measurements may provide clinically useful information to guide dosage. Aside from managing the acutely bleeding patient, drug level monitoring may be useful in the outpatient setting. For example, establishing a baseline drug level may be relevant given the direct correlation with bleeding risk, especially in patients with decreased creatinine clearance. It can also assess patient compliance given the short half-life of the drug. We performed a retrospective analysis of patient samples that were tested for dabigatranlevels at our facility to determine whether drug levels were within the therapeutic range. Method:Dabigatran levels were assayed for 172 frozen, citrated plasma samples from 127 patients (25 patients had multiple samples). The assay is a laboratory-developed, dilute thrombin clotting time test (CV ≤7.3%) that was validated by LC-MS/MS and is performed using drug-specific calibrators (Clin Chem 2012 abstract, in press). Specimens should be collected 90 to 120 minutes after the last dose and after ≥3 doses. The therapeutic range (64–443 ng/mL) was derived from the PETRO trial (van Ryn et al Throm Haemost2010). Patient demographics were correlated with drug levels, but clinical history was not available. Results:Dabigatran levels were within the therapeutic range for 76 samples (44.2%), in the subtherapeutic range for 82 samples (47.7%), and in the supratherapeutic range for 14 (8.1%) samples. The median dabigatran level for the samples within the therapeutic range was 152 ng/mL. These samples also had a skewed distribution such that 44 (57.9%) were within the lowest quartile and 62 (81.6%) were within the lower half.Table 1 shows the distribution of dabigatranlevels by age and gender. Women ≥65 years of age were the most likely to have levels in the therapeutic range. Independent of gender, people aged <65 years were less likely to have levels in the therapeutic range. Four patients were not classified by age or gender.Table 1Distribution of DabigatranLevels by Age or Gender in 123 Patients*GroupSubtherapeuticTherapeuticSupratherapeuticAge ≥65 (n=82)28 (34.1%)49 (59.8%)5 (6.1%)Age <65 (n=41)26 (63.4%)12 (29.3%)3 (7.3%)Male (n=56)31 (55.4%)24 (42.9%)1 (1.8%)Female (n=67)24 (35.8%)36 (53.7%)7 (10.4%)Male, ≥65 (n=35)16 (45.7%)18 (51.4%)1 (2.9%)Male, <65 (n=21)15 (71.4%)6 (28.6%)0 (0.0%)Female, ≥65 (n=47)13 (27.7%)30 (63.8%)4 (8.5%)Female, <65 (n=20)11 (55.0%)6 (30.0%)3 (15.0%)*For patients with multiple samples, only the initial level was included.Of the 25 patients with multiple samples (2–6 samples/patient), 17 patients were consistently in or out of range: 8 therapeutic, 7 subtherapeutic, and 2 supratherapeutic. The remaining 8 patients were variable (Table 2).Table 2Patients with Multiple Data Points Showing Variable Drug LevelsPatientGenderAge (years)Initial drug level (ng/mL)# days from 1st to last sample collectionTrend1M33701545 sub tx, 1 tx2F4864372 sub tx, 1 tx3F74>500 H11 sub tx, 1 tx, 3 supra tx4M64<45 L52 sub tx, 1 tx5M65152562 sub tx, 1 tx6F4060 L472 sub tx, 1 tx7F89129871 tx, 1 supra tx8M87445 H531 sub tx, 2 tx, 1 supra txSub tx, subtherapeutic; tx, therapeutic; supra tx, supratherapeutic; H, high (above therapeutic range); L, low (below therapeutic range) Conclusions:(1) A surprisingly high percentage of patients taking dabigatran were subtherapeutic. (2) The cause of the subtherapeutic levels is not readily discernable given the lack of clinical history, but may be explained by poor compliance, improper collection time, drug interactions, or decreased absorption (anecdotal evidence). Disclosures:No relevant conflicts of interest to declare.

Partial Reversal of Dabigatran Effect by a Prothrombin Complex Concentrate in a Model of Thrombin Generation

Abstract 3420Dabigatran etexilate (Pradaxa) is a prodrug that is metabolised to a small molecule direct thrombin inhibitor. It has some more desirable charactersitics than warfarin for long-term anticoagulation of patients with atrial fibrillation, particularly the fact that it does not routinely need laboratory monitoring. However, it has the drawback that it is not readily reversable. While the package insert suggests administration of fresh frozen plasma or recombinant FVIIa as “antidotes”, there is no good theoretical or experimental basis to support this recommendation. Several sutdies have suggested that prothrombin complex concentrates (PCCs) can partially reverse the effects of dabigatran on laboratory assays. However, there is still much controversy over the potential of PPCs to reverse dabigatran anti-coagulation. The goal of our studies was to assess the effects of a 4-component PCC (Beriplex, CSL-Behring) on parameters of thrombin generation in PRP and a cell-based model. This allow us to use varying levels of dabigatran and varying levels of PCC, a cell-associated source of tissue factor (TF), fresh platelets, and either plasma or plasma levels of coagulation factors. Thrombin generation was assessed continuously using a fluorogenic thrombin substrate in a fluorescent plate reader. Dabigatran (Selleck Chemicals) was dissolved in DMSO and added to the test plasma at concentrations from 189–944 ng/mL. Beriplex was added to test plasma at concentrations from 0.25 FIX units/mL to 2.0 FIX units/mL. As others have reported for conventional calibrated automated thrombogram (CAT) assays, we found that dabigatran prolonged the lag before onset of thrombin generation. It also progressively depressed the rate and peak level of thrombin production. We found that the addition of Beriplex increased the rate and peak level of thrombin generation in a dose-dependent manner, but had little effect on the lag. This effect was seen at all levels of dabigatran tested, with a level of 1 U/mL restoring the rate and peak levels of thrombin generation, as well as the area-under-the-curve, to normal levels. The addition of FIX alone at 1 U/mL had no significant effect on thrombin generation in the presence of dabigatran. The effects of Beriplex were similar, though not identical, to the pattern seen when prothrombin alone was added to this model. Thus, we hypothesize that Beriplex has its dominant effect on reversal of dabigatran effects by a prothrombin-mediated mechanism. This increases the burst of platelet surface thrombin generation. However, this unactivated PCC does not reverse the inhibitory effect of dabigatran on the amplification phase of hemostasis as reflected in the lag time before the onset of thrombin generation. Thus, Beriplex corrects some, but not all, parameters all of thrombin generation affected by dabigatran in this model. Disclosures:Hoffman:CSL Behring: Research Funding.

In Vitro Characterization, Pharmacokinetics and Reversal of Supratherapeutic Doses of Dabigatran-Induced Bleeding in Rats by a Specific Antibody Fragment Antidote to Dabigatran

AbstractAbstract 3418 Background:The new oral anticoagulants have demonstrated efficacy and safety in preventing stroke in patients with atrial fibrillation; however, one feature they all share is the lack of a specific antidote in cases of emergency, such as excess bleeding or emergency surgical interventions. A fully humanized monoclonal antibody fragment (Fab) against dabigatran is currently in development for use in the clinic. Methods:The Fab was characterised for binding to dabigatran using Kinexa technology. The dissociation constant (KD) and on-rate (kon) were determined experimentally; the off-rate (koff) was calculated. Inhibition of glucuronidated dabigatran metabolites was tested using a diluted thrombin time assay. Any prothrombotic activity of the Fab was determined by testing the ability to induce coagulation in various assays in human plasma including endogenous thrombin potential (ETP, 5 pM tissue factor) and ecarin chromogenic assay (ECA). Animal studies were approved by local ethics committee and followed principles of laboratory animal care. Pharmacokinetics (PK) of Fab with dabigatran was determined by measuring functional dabigatran, total dabigatran and total Fab in the rat. Dabigatran etexilate (DE) was given to rats every 8 hrs to achieve supratherapeutic levels of dabigatran and induce bleeding. Increasing Fab doses were given to test for bleeding reversal in this rat tail bleeding model. Associated ex vivo clotting and plasma levels of dabigatran and Fab were measured. Results:The Fab has a very tight binding affinity to dabigatran, with a Kd of 2 pM, ∼350-fold more potent than the 0.7 nM Kd of dabigatran binding to thrombin. This binding has a rapid kon (1.5×106 M−1s−1) and a slow koff (3×10−6s−1), resulting in a calculated complex half life (t½) of ∼64 hrs. IC50 of Fab inhibition of 7nM dabigatran was 3.5 nM. Acylglucuronidated dabigatran (7nM) was inhibited by an IC50 of 2nM Fab. There was no effect on thrombin generation when concentrations up to 3 mg/mL Fab were added to plasma (ETP, 0.89-fold of control), in contrast an activated prothrombinase complex concentrate, FEIBA, resulted in 2.06 increase of ETP with 0.8 U/mL. ECA was also not elevated vs control.The PK of the Fab in rats showed a short initial phase t1/2 (0.24 h) and a longer terminal phase t1/2 (5.8 h). Clearance was low (1.95 mL/min/kg), and the steady-state volume of distribution small (0.0688 L/kg; only slightly larger than plasma volume). The PK of the Fab was not affected by dabigatran.DE (30 mg/kg p.o.) given in 8 hr intervals achieved steady state levels in the rat, with dabigatran plasma levels of 1500 nM (∼750 ng/mL), and resulted in an ∼2-fold prolongation of tail cut bleeding time. There was a rapid, dose-dependent decrease in blood loss after i.v. injection of Fab, which was maintained for 6 hrs after the highest dose of Fab. Anticoagulation (clotting ex vivo) was also reversed. Treating rats with warfarin (0.5 mg/kg p.o.) over 3 days resulted in a 2-fold elevation of blood loss. As expected, similar doses of Fab had no effect on reversing this elevated blood loss. Conclusions:These data show the specificity and selectivity of the antibody fragment for dabigatran. Administration of the Fab after DE resulted in a safe and rapid reversal of blood loss, which correlated with reversal of ex vivo clotting tests. Thus this agent holds promise for reversing dabigatran-induced anticoagulation and bleeding effects. It is currently under development for clinical use. Disclosures:van Ryn:Boehringer Ingelheim: Employment. Litzenburger:Boehringer Ingelheim: Employment. Gan:Boehringer Ingelheim: Employment. Coble:Boehringer Ingelheim: Employment. Schurer:Boehringer Ingelheim: Employment.

Antidotal Effects of Non-Specific Reversal Agents On Anticoagulant-Induced Inhibition of Thrombin Generation.

AbstractAbstract 2273 IntroductionReversal of pharmacologic anticoagulation is an issue that arises when an anticoagulated patient has a major bleeding or when an emergency surgery needs immediate correction of coagulation. However, the new oral anticoagulants (NOAC) Rivaroxaban (anti-FXa) and Dabigatran (anti-FIIa) lack specific antidotes and only limited data is available regarding the antidotal effect of non-specific haemostatic agents. Therefore, in this ex vivo study reversal of anticoagulant activity after the administration of either 20mg Rivaroxaban or 150mg Dabigatran was tested in vitro using two different PCC (Beriplex®, Cofact®), aPCC (FEIBA®; factor eight inhibitor bypassing activity) or rFVIIa (NovoSeven®) at various concentrations.Patients and Method Subjects10 healthy caucasian subjects (female: n=5; male: n=5) were first randomized to receive either 20 mg Rivaroxaban or 150 mg Dabigatran in one oral dose. The patients had to abide a 7-day wash-out period before administration of the respective second drug. MethodsCitrated venous blood was taken right before (T0) and 2 hours after administration (T2) of either Dabigatran or Rivaroxaban. The potential of 4 commercially available haemostatic agents to reverse the anticoagulant effect of the NOACs was evaluated.• Beriplex: 0.25; 0.5 (corresp. to 25 U/kg); 1; 2 U/mL• Cofact: 0.25; 0.5 (corresp. to 25 U/kg); 1; 2 U/mL• FEIBA:0.25; 0.5; 1 (corresp. to 80 U/kg); 2 U/mL• NovoSeven: 1.25; 2.5; 5; 10 μg/mL (a dose of 90–100 μg/kg corresponds to a plasma level of about 2 μg/mL)Thrombin generation using Calibration Automated Thrombinography (CAT) was the primarily applied assay, along with the parameters aPTT, PT, thrombin time, Rivaroxaban- and Dabigatran levels and Ecarin time. Parameters of interest concerning the thrombin generation assay (TGA) were the endogenous thrombin potential (ETP), Peak (maximum reaction velocity) and Lag time (LT; length of the latent phase). Thrombin generation in platelet poor plasma was initiated by adding 1 pM tissue factor and 4 μM phospholipids. Results2 hours after administration (T2), Rivaroxaban showed remarkable inhibitory effects on the investigated TGA parameters ETP, Peak and Lag time, with a more pronounced inhibitory effect on the Peak. In contrast, Dabigatran at T2 only showed a slight effect on ETP and no effect on the Peak whereas LT was significantly prolonged (fourfold).Rivaroxaban-induced inhibition of ETP and Peak were reversed by FEIBA in a concentration dependent manner with an over-correction for the two highest concentrations (1 and 2 U/mL). Cofact and rFVIIa restored ETP dose-dependently and both reached baseline T0 at their highest concentrations. Compared to FEIBA, rFVIIa and Cofact only had a slight but dose-dependent effect on the Peak. Interestingly, the other PCC, Beriplex, did not show any reversal effects on ETP and Peak.Regarding Rivaroxaban-prolonged LT all concentrations of rFVIIa and FEIBA were responsible for a significant LT-reduction close to baseline, whereas both PCCs did not correct prolonged LT.Regarding Dabigatran, all doses of rFVIIa, Cofact and FEIBA reduced the LT, with a more pronounced and dose-dependent effect of Cofact and FEIBA. For Beriplex only a slight reduction in LT was observed. ConclusionFEIBA and rFVIIa showed significant reversal of anticoagulant activity already at low therapeutic concentrations for both anticoagulants in TGA. Surprisingly, regarding both investigated PCCs, only Cofact showed an antidotal effect on TGA parameters, especially in higher therapeutic concentrations (1 and 2 U/mL). Considering that the main difference between the two PCCs is that Beriplex contains small amounts of heparin and Cofact does not, it is conceivable that this may explain the observed differences in TGA. Further clinical validation is needed. Disclosures:No relevant conflicts of interest to declare.

Acceleration of Dabigatran Elimination by Activated Charcoal Perfusion and Hemodialysis in a Pig Model.

AbstractAbstract 2272 Background and Aim:Dialysis based approaches can provide rapid removal of dabigatran in cases of emergency due to its low protein binding of ∼35%. However the in vitro properties of these filtration devices have not yet been characterized in detail. This study in the porcine system (both in vitro and in vivo) was performed to evaluate dabigatran elimination by hemodialysis and activated charcoal perfusion as compared to normal renal elimination. Methods:Porcine blood (5L) was supplemented with 1000 ng/mL dabigatran and circulated through an circuit of tubing allowing attached to an activated charcoal filter (Absorba 300 C, Gambro). Further supplementation of dabigatran allowed the determination of maximum binding capacity of the filter. A similar set up was used to also test dialysis (Polyflux 140H, Gambro) and determine the dependence of the flow rate on dabigatran removal. Dialysate flow rates were increased up to 500 ml/min. Anesthetized pigs (Domestic swine, female, ∼60 kg) were attached to an activated charcoal column or a High-Flux hemodialysis filter with a blood flow rate of 200 ml/min. Animals were given an initial i.v. infusion of dabigatran (7.5 mg in 15 min) and then reduced to 5 mg/hr to achieve steady state dabigatran over 1hr. Infusion was then stopped and elimination methods were applied over 4 hrs. An observation time of 1 hr followed. Dabigatran plasma levels were quantitated with diluted thrombin time. Preliminary settings/flow rates were obtained in vitro using 5L citrated porcine whole blood exposed to different AC or HD conditions. Results:Activated charcoal completely removed dabigatran within 1 hr from the 5L whole blood supplemented with 1000 ng/mL dabigatran, with a clearance rate of 100%. By repeatedly reapplying dabigatran, it was shown the active charcoal filter had a maximum binding capacity of ∼30 mg drug. Upon saturation there was no further clearance of dabigatran. Hemodialysis removed dabigatran with increasing clearance rates depending on dialysate flow rates (100 ml/min-35%, 200 ml/min-60%, 300 ml/min-65%) reaching a plateau of ∼65%. Further increases of dialysate flow to 500 ml/min had no further effect on drug clearance.Initial plasma levels of dabigatran ranged between 200–450 ng/mL after 60 min infusion in pigs. Exposure to activated charcoal or hemodialysis (dialysate flow 300 ml/min) resulted in 75–80% reduction in circulating dabigatran after 1 hr as compared to ∼25% reduction untreated controls after 1 hr. After 2 hrs dabigatran levels were below the detection limit using both elimination methods. Conclusions:Dabigatran can effectively be removed from the circulation in this in vivo porcine model using dialysis based approaches, which results in a restoration of blood coagulation. Active charcoal perfusion was fast and effectively removed dabigatran, but may be saturated if dabigatran plasma levels are too high (human body load for 150 mg dose in steady state is ∼14g). Stationary hemodialysis with sufficiently high dialysate flows achieves similar results in this model without saturation limitations; however, the set up for dialysis is much more specialized than the simpler approach of activated charcoal filtration. Disclosures:Formella:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. van Ryn:Boehringer Ingelheim: Employment. Schenk:Boehringer Ingelheim: Research Funding.

Neue Antikoagulantien - die direkten Thrombininhibitoren

Direct thrombin-inhibitors inactivate not only free but also fibrin-bound thrombin. The group of parenteral direct thrombin-inhibitors includes the recombinant hirudins lepirudin and desirudin, the synthetic hirudin bivalirudin, and the small molecule argatroban. All these compounds do not interact with PF4/heparin-antibodies. Therefore, argatroban as well as bivalirudin are currently used to treat heparin-induced thrombocytopenia (HIT). The oral direct thrombin-inhibitor dabigatran etexilate is already licensed in many countries for the treatment of non-valvular atrial fibrillation. Dabigatran etexilate reveals a stable and predictable effect that allows a medication without dose adjustment or monitoring. The substance shows only few interactions with other drugs but strong inhibitors of p-glycoprotein can increase plasma levels of dabigatran substantially. After oral intake, the prodrug dabigatran etexilate is cleaved by esterase-mediated hydrolyses to the active compound dabigatran. Elimination of dabigatran is predominantly renal. Safety and efficacy of dabigatran etexilate were tested in an extensive clinical study program. Non-inferiority compared to current standard treatments was shown for prophylaxis of venous thromboembolic events after total knee and hip replacement, for stroke prevention in atrial fibrillation, and for treatment of acute venous thromboembolism. In daily practice, Dabigatran etexilate competes against the new direct factor Xa-inhibitors. In the absence of direct comparative clinical trials, it is not yet clear if one class of substances has distinct advantages over the other.

A Survey of a Single Centerʼs Experience with Dabigatran (Pradaxa®) and Physicianʼs Knowledge in Management of Related Gastrointestinal Bleeding

Purpose: In 2010, the United States Food and Drug Administration approved dabigatran (Pradaxa®), a new oral anticoagulation drug. In addition to gaining FDA approval for use in atrial fibriliation, the RELY trial also demonstrated that patients taking dabigatran were 1.5 times more likely to have a major gastrointestinal (GI) bleeding event. To date, although there are proposed recommendations for withholding dabigatran peri-operatevily, clear evidence based guidelines on the timing of dabigatran administration both prior to and after an endoscopic procedure are lacking. We aimed to review clinicians' clinical experiences with and management approach to dabigatran related gastrointestinal bleeding events. Methods: We created a 12 question anonymous survey to assess clinicians' clinical experiences, level of knowledge of proper dabigatran administration and preferred management approach to any related GI bleeding events (Table 1). Included in the study were all internal medicine house staff, medical attendings, gastroenterology fellows and attendings employed in 2011 at the Beth Israel Medical center, New York, NY.Table: Respondent level of training ( N =71)Results: During the study period, a total of 71 physicians responded to our survey. The majority (70%) of respondents had cared for at least 1 patient taking dabigatran during the past year. Notably, 22.4% of respondents have cared for patients with GI bleeding secondary to dabigatran. The location of bleeding was essentially equally divided between upper (53.8%) and lower (46.2%) GI anatomy. Only half of the respondents (56.3%) believe that no serum marker is currently available to monitor dabigatran levels. Surprisingly, only 42% of respondents take into account renal function when making recommendations regarding holding dabigatran peri-endoscopy. While the majority (73.2%) of respondents would attempt optimal supportive care as a primary treatment for bleeding complication, approximately 40% of respondents would choose fresh frozen plasma as treatment for life threatening gastrointestinal hemorrhage. Finally, the majority (34%) of respondents would hold dabigatran 1-2 days prior to elective endoscopy, while the most common answer given for timing to withholding dabigatran post-endoscopy was “I don't know.” Conclusion: Despite our centers' growing experience with dabigatran use, we observed a wide range in knowledge and perception of peri-endoscopic dabigatran administration and any related GI bleeding complications. As the utilization and popularity of dabigatran continues to expand, there is an increasing need for more objective algorithms outlining the proper periendoscopic administration of dabigatran and management of any related GI bleeding complications.Table: [1429] Survey responses

Pharmakologie der neuen oralen Antikoagulanzien

New oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and edoxaban display pharmacologic and pharmacodynamic data similar to low molecular weight heparins. Peak levels are found 2-4h after oral ingestion and elimination half-lives are in the range of 7-14h. The drugs differ primarily concerning renal elimination. Dose adjustment is only performed in patients with impaired renal function, high risk of bleeding and patients with co-medications which influence the metabolism or anticoagulant effect of the drugs. Due to the short half-life, perioperative bridging is not necessary. Currently, no specific antidotes are available: however, assay systems are available for measuring the plasma concentration of dabigatran and rivaroxaban. In emergency cases a normal thrombin time excludes relevant levels of dabigatran, whereas a normal anti-factor Xa assay result excludes relevant levels of factor Xa inhibitors.The new anticoagulants are being used for prophylaxis of venous thrombosis in elective hip and knee surgery, as well as for treatment of venous thrombosis and for prevention of stroke and systemic embolism in patients with atrial fibrillation. Additional indications are to follow. Dabigatran is given at a dose of 110mg initially 1-4h after surgery followed by 220mg once daily for prophylaxis of thrombosis and at doses of 110mg or 150mg twice daily for therapeutic anticoagulation. The prophylactic and therapeutic doses of rivaroxaban are 10 and 20mg and, of apixaban 2.5mg and 5mg twice daily, respectively.

Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests

Dabigatran etexilate is a new oral anticoagulant for the therapy and prophylaxis of venous thromboembolism and stroke prevention in patients with atrial fibrillation. To investigate the extent of interactions of this new anticoagulant with frequently used coagulation assays, we completed a multicenter in vitro trial with Conformité Européenne(CE)-labeled dabigatran-spiked plasma samples. Lyophilized plasma samples with dabigatran concentrations ranging from 0.00 to 0.48 μg/mL were sent to the coagulation laboratories of six major Austrian hospitals for evaluation. Coagulation assays were performed under routine conditions using standard reagents and analyzer. Dabigatran led to a dose-dependent prolongation of the clotting times in coagulometric tests and influenced the majority of the parameters measured. Statistically significant interference could be observed with the prothrombin time (PT), activated partial thromboplastin time (aPTT) and PT/aPTT-based assays (extrinsic/intrinsic factors, APC-resistance test) as well as lupus anticoagulant testing. Even non-clotting tests, such as the colorimetric factor XIII activity assay and to a minor extent the amidolytic antithrombin activity assay (via factor IIa) were affected. This multicenter trial confirms and also adds to existing data, demonstrating that laboratories should expect to observe strong interferences of coagulation tests with increasing concentrations of dabigatran. This finding might become particularly important in the elderly and in patients with renal impairment as well as patients whose blood is drawn at peak levels of dabigatran.

Measurement of Dabigatran in Serum and Urine and As Point of Care Method in Urine,

Abstract 3352The oral direct thrombin inhibitor dabigatran prevents development of arterial and venous thromboembolism. Dabigatran is determined in plasma by coagulation and chromogenic methods. Renal excretion plays an important role in the metabolism. We aimed to determine dabigatran in urine by means of a quantitative measurement in serum and urine and as qualitative determination in urine as point of care method.Serum and urine (patent pending) from healthy donors were spiked with dabigatran (50ng/ml to 1000 ng). Thrombin inhibition was determined by means of a chromogenic substrate method comparing the results obtained from plasma. The reagents were lyophilized on mini-strips and incubated with urine (patent pending). The concentration of dabigatran was determined from plasma, serum, and urine and qualitatively by the mini-strips from 15 patients on treatment with dabigatran.The concentrations of dabigatran spiked to plasma, serum and urine were independent of the medium (correlation between r=0.80 and 0.93). Patients on treatment with dabigatran showed a high correlation of plasma and serum values (r=0.9). The correlation to urine samples was lower do to the time dependence of drug intake. The qualitative mini-strips detected dabigatran in all samples independently of drug intake. There were no false positive or false negative detections of dabigatran by the mini-strips.Detection of dabigatran in serum avoids separate blood sampling to obtain plasma. Detection in urine avoids blood sampling at all and allows point of care testing also by the patient him/herself. Control of intake and early detection of low urinary excretion leading to increased plasma levels of dabigatran may improve and facilitate patient care. Disclosures:No relevant conflicts of interest to declare.

Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity

Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.

Adsorption of Dabigatran Etexilate in Water or Dabigatran in Pooled Human Plasma by Activated Charcoal in Vitro.

Abstract 1065Poster Board I-87Dabigatran etexilate is a prodrug, which is rapidly converted in vivo to the active moiety dabigatran, a potent, direct thrombin inhibitor. This drug has been evaluated as an alternative to oral vitamin K antagonists for sustained prevention of ischemic and hemorrhagic strokes in patients with atrial fibrillation. As with any anticoagulant, there are bleeding risks with its use. Thus, the adsorption of drug to activated charcoal to allow for potential neutralization in emergency situations was tested in vitro. Binding of dabigatran etexilate to activated charcoal in water simulates recent ingestion (2-3 hrs) of large amounts of dabigatran etexilate in the stomach fluid. Binding of dabigatran to activated charcoal in plasma simulates situations where dabigatran was absorbed after ingestion and present in high concentrations in plasma.The contents of 5, 10 and 20 capsules (150 mg/capsule) of dabigatran etexilate were suspended in 100 ml water (approx. stomach volume, pH 2.7, 2.5 and 2.4, respectively). Each suspension was divided in half. To one portion a freshly prepared activated charcoal suspension (125 mg/ml, Ultracarbon®, Merck) was added. Both suspensions (with and without charcoal) were filtered and dabigatran etexilate concentrations were assessed via HPLC.Levels of 8.3, 15.6 and 29.6 mg/ml dabigatran etexilate were recovered by HPLC in the untreated suspensions in water. In the charcoal-treated suspensions, the dabigatran etexilate peak was no longer detectable, this indicated that >99.9 % of dabigatran etexilate was adsorbed by the activated charcoal for all three tested concentrations.In the plasma experiments, dabigatran was added to a human plasma pool at concentrations of 470 and 940 ng/ml. The sample was then split, and active charcoal was added to half at the manufacturer's specified concentration (125 mg/ml), or 1:11 dilution of this. Dabigatran plasma levels were measured by a validated LC-MS/MS method. After adding dabigatran active substance to plasma, values of 394 ± 19.4 and 824 ± 39.3 ng/ml (mean ± SD) were obtained in untreated plasma. Addition of activated charcoal at both concentrations reduced levels of dabigatran to <1.01 ng/ml (i.e. close to or below lower limit of quantification of the assay).These preliminary in vitro studies demonstrate that the prodrug dabigatran etexilate, and the active moiety, dabigatran, bind activated charcoal and can be removed from water or plasma. Clinical implications may be that oral activated charcoal could be used to neutralise recent ingestion of overdose quantities of dabigatran etexilate before it is absorbed in the gut. In addition, dabigatran could theoretically be adsorbed from plasma via hemoperfusion over a charcoal filter. However, further testing in more clinically relevant models, is required before this can be recommended in patients. Disclosures:van Ryn:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Sieger:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Kink-Eiband:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Gansser:Boehringer Ingelheim Pharma GmbH & Co K: Employment. Clemens:Boehringer Ingelheim GmbH: Employment.

Dabigatran/Dabigatran etexilate

Because of the crucial role of thrombin in the coagulation cascade and platelet activation, the enzyme is a primary target for the development of anticoagulant and antithrombotic drugs. The peptidomimetic dabigatran and its oral double prodrug dabigatran etexilate are univalent direct thrombin inhibitors. Pharmacological studies indicate that dabigatran potently interferes with the coagulation cascade, being highly selective for thrombin over most other serine proteases. Dabigatran and dabigatran etexilate have proven to be well tolerated in vivo in animal models. Pharmacokinetic studies indicate that thrombin activity is dose-dependently inhibited following administration of the prodrug. Pharmacokinetic and pharmacodynamic parameters increase proportionally with dose. Food delays but does not affect the extent of absorption of the agent. Clinical studies indicated good safety. Higher plasma levels of dabigatran were associated with a lower incidence of deep venous thrombosis (DVT). Moreover, dabigatran etexilate at the doses examined has proven to be safe and effective in the treatment of venous thromboembolism (VTE) compared with other anticoagulants such as warfarin.