Dabigatran Reversal With Idarucizumab in Patients Requiring Urgent Surgery: A Subanalysis of the RE-VERSE AD Study.

OBJECTIVE: To further examine anticoagulation reversal and clinical outcomes in dabigatran treated patients requiring urgent surgery or procedural interventions. BACKGROUND: Idarucizumab, a humanized monoclonal antibody fragment, reverses dabigatran anticoagulation. METHODS: Data from surgical and procedural patients in RE-VERSE AD, a multicenter, open-label, single-arm, prospective cohort of dabigatran reversal were evaluated. A total of 202 patients in this group received 5 g of idarucizumab before surgery or procedures. RESULTS: The interventions included 49 abdominal, 45 orthopedic, 34 vascular, 8 neurologic, and 4 genitourinary surgical procedures, or 29 catheter-based cases, 20 cases for drainage, and 8 diagnostic procedures. Five patients did not undergo their intended intervention after receiving idarucizumab. Complete reversal of the dabigatran anticoagulant effect occurred within minutes in almost all patients, with normal hemostasis in more than 91% of patients. The median time from the first vial of idarucizumab to surgery or procedures was less than 2 hours in all groups except neurosurgery, where it was 3.3 hours. Fresh frozen plasma and packed red cells were the most frequently transfused blood products. Postreversal thromboembolic events occurred in 10 (5%) patients at 30 days, 5 of whom had restarted anticoagulation before the event. Overall 30-day mortality was 12.6%. There were no serious adverse safety signals due to idarucizumab dosing. CONCLUSIONS: Idarucizumab facilitates management of patients requiring urgent procedures by providing rapid dabigatran reversal, and is the only agent of its class studied in surgical patients.

Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding.

BACKGROUND: Although dabigatran has a favorable risk-benefit profile compared with vitamin K antagonist therapy for venous thromboembolism and nonvalvular atrial fibrillation, major bleeding events, including gastrointestinal (GI) bleeding, may occur. Therefore, our aim was to provide insights into the efficacy and safety of idarucizumab for urgent dabigatran reversal in patients with major GI bleeding. METHODS: Patients with uncontrollable GI bleeding requiring reversal were enrolled from June 2014 through July 2016 in the RE-VERSE AD study (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab), a prospective, multicenter, open-label study of idarucizumab, and were followed up for 90 days for primary and secondary outcomes. Patients were to receive a 5-g dose of intravenous idarucizumab, administered as 2 bolus infusions of 2.5 g no more than 15 minutes apart. The primary end point was the maximum reversal of dabigatran anticoagulation within 4 hours after administration of idarucizumab as measured by the dabigatran-specific assays diluted thrombin time and ecarin clotting time. Further end points included investigator-reported bleeding cessation within the first 24 hours and incidence of rebleeding, thromboembolic events, or mortality. RESULTS: GI bleeding occurred in 137 patients enrolled in RE-VERSE AD, of which 84% was adjudicated as major or life-threatening, 48 (35.0%) was upper GI tract in origin, 43 (31.4%) was lower GI in origin, and 46 (33.6%) was either both or unknown. Complete reversal of dabigatran was observed in 118 of 121 patients (97.5%) with an elevated diluted thrombin time at presentation and 95 of 131 patients (72.5%) with an elevated ecarin clotting time and was similar for upper and lower GI bleeding. Bleeding cessation within 24 hours was reported in 92 of 134 evaluable patients (68.7%) after a median duration of 2.4 hours (interquartile range, 2.0-3.9 hours). During the 90-day follow-up, 6 patients (4.4%) had a postreversal thromboembolic event, and 20 patients (14.6%) died. CONCLUSIONS: Idarucizumab showed a rapid and complete reversal of dabigatran activity in nearly all patients presenting with GI bleeding, facilitating emergency patient care without the additional presence of anticoagulation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02104947.

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).

Idarucizumab, but not procoagulant concentrates, fully restores dabigatran-altered platelet and fibrin components of hemostasis.

BACKGROUND: Comparative studies on the restoration of hemostasis with different reversal agents after dabigatran therapy have not been performed. We compared the efficacy and prothrombotic potential of the specific antidote idarucizumab with that of previously recommended non-specific procoagulant concentrates. STUDY DESIGN AND METHODS: We explored the in vitro effects of dabigatran (184 ng/mL) on fibrin and platelet-aggregate formation onto a damaged vessel under flow conditions (600 s-1 ). The reversal mechanisms and efficacy of idarucizumab (0.3-3 mg/mL) were compared with that of the non-specific procoagulant concentrates aPCC (25-75 U/Kg), PCC (70 U/Kg), or rFVIIa (120 µg/Kg). Generation of thrombin and prothrombin fragment (F1 + 2), and thromboelastometry parameters of clot formation were measured. RESULTS: Dabigatran caused pronounced reductions in fibrin (87%) and platelet interactions (36%) with damaged vessels (p < 0.01) and significantly impaired thrombin generation and thromboelastometric parameters (delayed dynamics and reduced firmness). Idarucizumab completely normalized rates of fibrin and platelet coverage to baseline values in flow studies; and reversed the alterations in thrombin generation, F1 + 2 and thromboelastometry parameters produced by dabigatran. In comparison, aPCC and PCC only partially compensated for the dabigatran-induced alterations in fibrin deposition, but were unable to fully restore them to baseline values. Reversal with aPCC or PCC improved the majority of alterations in coagulation-related tests, but tended to overcompensate thrombin generation kinetics and significantly increased F1 + 2 levels. CONCLUSION: Idarucizumab antagonizes alterations of direct and indirect biomarkers of hemostasis caused by dabigatran. In our studies, idarucizumab was clearly more efficacious than strategies with non-specific procoagulant concentrates and devoid of the excessive procoagulant tendency observed with the latter.

Cerebral Microbleeds in Murine Amyloid Angiopathy: Natural Course and Anticoagulant Effects.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) predispose patients to intracerebral hemorrhage. Preclinical models to examine the effects of antithrombotic treatments on the development of clinically overt intracerebral hemorrhage are needed. We examined the natural course of CMB development and the effects of long-term anticoagulation with warfarin or dabigatran on cerebral micro- and macrohemorrhage in mice overexpressing the APP23 (amyloid precursor protein). METHODS: Repeated susceptibility-weighted magnetic resonance imaging was performed in APP23 mice at the age of 18 and 21 months, respectively. After establishing stable long-term anticoagulation effects of warfarin and dabigatran on number and total volume of CMBs, the outcome parameters were compared with nonanticoagulated control. RESULTS: CMBs were equally located in lobar and deep brain regions, and number and total volume of CMBs increased over time. Anticoagulation with either warfarin or dabigatran did not increase CMBs in APP23 significantly. Mice treated with warfarin numerically had a higher mortality (nonanticoagulated: 31%; dabigatran: 35% versus warfarin: 55%; P=0.21). In postmortem brains of prematurely dying animals warfarin caused significantly more frequently large intracerebral hemorrhage than control and dabigatran. CONCLUSIONS: Anticoagulation with warfarin or dabigatran for 3 to 4 months does not promote the formation of CMBs in aged APP23 mice. Nevertheless, warfarin but not dabigatran is associated with a higher risk of extensive intracerebral hemorrhage, suggesting that this model may allow preclinical safety evaluation of antithrombotic therapies.

Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.

Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran.

Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease.

Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD.

Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects.

The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab-dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.

Characterization of thrombin-bound dabigatran effects on protease-activated receptor-1 expression and signaling in vitro.

Thrombin, the key effector protease of the coagulation cascade, drives fibrin deposition and activates human platelets through protease-activated receptor-1 (PAR1). These processes are critical to the progression of thrombotic diseases. Thrombin is the main target of anticoagulant therapy, and major efforts have led to the discovery of new oral direct inhibitors of thrombin. Dabigatran is the first oral anticoagulant licensed for the prevention of thromboembolisms associated with orthopedic surgery and stroke prevention in atrial fibrillation. Dabigatran is a direct thrombin inhibitor that effectively blocks thrombin's catalytic activity but does not preclude thrombin's exosites and binding to fibrinogen. Thus, we hypothesized that catalytically inactive thrombin retains the capacity to bind to PAR1 through exosite-I and may modulate its function independent of receptor cleavage and activation. Here, we report that dabigatran at clinically relevant concentrations is an effective and acute inhibitor of thrombin-induced PAR1 cleavage, activation, internalization, and ß-arrestin recruitment in vitro. Interestingly, prolonged exposure to catalytic inactive thrombin incubated with dabigatran at 20-fold higher therapeutic concentration resulted in increased PAR1 cell-surface expression, which correlated with higher detectable levels of ubiquitinated receptor. These findings are consistent with ubiquitin function as a negative regulator of PAR1 constitutive internalization. Increased PAR1 expression also enhanced agonist-induced phosphoinositide hydrolysis and endothelial barrier permeability. Thus, catalytically inactive thrombin appears to modulate PAR1 function in vitro by stabilizing receptor cell-surface expression; but given the high clearance rate of thrombin, the high concentration of dabigatran required to achieve this effect the in vivo physiologic relevance is unknown.

A specific antidote for dabigatran: functional and structural characterization.

Dabigatran etexilate is a direct thrombin inhibitor and used widely as an anticoagulant for the prevention of stroke in patients with atrial fibrillation. However, anticoagulation therapy can be associated with an increased risk of bleeding. Here, we present data on the identification, humanization, and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab). The X-ray crystal structure of dabigatran in complex with the antidote reveals many structural similarities of dabigatran recognition compared with thrombin. By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is ~350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, the antidote does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. In addition we demonstrate that the antidote rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the first report of a specific antidote for a next-generation anticoagulant that may become a valuable tool in patients who require emergency procedures.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation.

BACKGROUND: Dabigatran is a potent oral anticoagulant. Like any anticoagulant, there is an increased risk of bleeding associated with its use, and reversal may be needed in cases of severe bleeding. METHODS: In this study, six coagulation factor concentrates (CFCs) were tested for their ability to reduce bleeding induced by oral dabigatran etexilate (30 mg/kg) in a rat-tail bleeding model (n = 5 to 8 per group): three-factor (Profilnine [Grifols Biologicals Inc., Los Angeles, CA] and Bebulin [Baxter BioScience, Westlake Village, CA]) and four-factor prothrombin complex concentrates (Beriplex [CSL Behring, Marburg, Germany] and Octaplex [Octapharma AG, Lachen, Switzerland]), activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Activity; Baxter AG, Vienna, Austria), and recombinant factor VIIa (NovoSeven; NovoNordisk, Bagsværd, Denmark). The effect of CFCs on prolongation of coagulation assays was measured. Thrombin generation after administration of each CFC was compared in vitro using human plasma (n = 5) spiked with dabigatran in concentrations corresponding to median peak (200 ng/ml) and supratherapeutic values (600 and 1,000 ng/ml). RESULTS: Dabigatran resulted in an approximately three-fold increase in bleeding time, consistent with supratherapeutic dabigatran plasma levels. Beriplex (35 and 50 IU/kg), Octaplex (40 IU/kg), Profilnine (50 IU/kg), Bebulin (60 IU/kg), Factor Eight Inhibitor Bypassing Activity (100 U/kg), and NovoSeven (500 µg/kg) significantly decreased this prolonged bleeding time over 30 min (P < 0.001). The coagulation assays were prolonged three- to eight-fold over baseline (P = 0.01). None of the CFCs produced a consistent change in these assays that was predictive of reduced bleeding. Thrombin generation reversal was dependent on the concentration of dabigatran and each CFC; normalization occurred at the lower concentration of dabigatran with most CFCs, but not at higher concentrations. CONCLUSIONS: In this animal model, bleeding induced by high doses of dabigatran can be reduced by CFCs. However, routine coagulation assays do not predict this effect.

Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model.

INTRODUCTION: New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran. METHODS: Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 µg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time. RESULTS: Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab. CONCLUSION: In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

Background: Dabigatran is effective and safe for stroke prevention in patients with atrial fibrillation and for venous thromboembolism prevention and treatment. In Canada, APO-dabigatran, a generic formulation, has been approved based on a bioequivalence study, but its bioavailability in settings of reduced gastric acidity has not been examined. Methods: Treatment With APO-Dabigatran Absorption (TADA) was an open-label crossover study in 46 healthy male volunteers, comparing the absorption of APO-dabigatran (150 mg) with vs without rabeprazole. The primary outcome was the 24-hour total dabigatran exposure as measured by area under the curve (AUC) and peak concentration (Cmax). Results: Compared with no rabeprazole pretreatment, the total dabigatran AUC (geometric mean [gmean] AUC0-tz: 567.2 vs 804 ngh/mL, and gmean AUC0-∞: 609.7 vs 804) and Cmax (gmean: 64.1 vs 104.4 ng/mL) were significantly reduced with rabeprazole. The percent gmean ratios for AUC0-tz, AUC0-∞, and Cmax (with rabeprazole vs without) were 70.5% (95% confidence interval [CI]: 51.9% to 95.7%), 71.8% (95% CI: 53.1% to 96.9%), and 61.4% (95% CI: 44.1% to 85.5%), respectively. With rabeprazole, the proportions of participants with > 50% reduction in AUC0-tz, AUC0-∞, and Cmax were 32.6%, 30.4%, and 39.1%, respectively. Conclusions: When APO-dabigatran is administered with rabeprazole, the exposure to dabigatran is reduced by about 30%, which is similar to the level observed with Pradaxa when it was co-administered with a proton pump inhibitor. However, the finding that one-third of participants had a > 50% reduction in exposure is concerning, and it highlights the need for caution in patients who have, or are at risk of, reduced gastric acidity.

Contexte: Le dabigatran est une option thérapeutique sûre et efficace pour prévenir les accidents vasculaires cérébraux chez les patients atteints de fibrillation auriculaire et pour prévenir et traiter les thromboembolies veineuses. Au Canada, APO-dabigatran (une version générique) a été homologué sur la base d'une étude de bioéquivalence, mais sa biodisponibilité en contexte d'acidité gastrique réduite n'a pas été évaluée. Méthodologie: L'étude TADA ( T reatment with A PO- D abigatran A bsorption) est une étude croisée menée en mode ouvert auprès de 46 hommes volontaires en bonne santé, afin de comparer l'absorption d'APO-dabigatran (à 150 mg) avec et sans rabéprazole. Le critère d'évaluation principal était l'exposition totale sur 24 heures au dabigatran, telle que mesurée par la surface sous la courbe (SSC) et la concentration maximale (Cmax). Résultats: Par rapport à une administration sans prétraitement par rabéprazole, une réduction significative de la SSC totale du dabigatran (moyenne géométrique [MG] SSC0-tz : 567,2 par rapport à 804 ngh/ml; MG SSC0-∞ : 609,7 par rapport à 804 ngh/ml) et de la Cmax (MG : 64,1 par rapport à 104,4 ng/ml) a été observée avec la prise de rabéprazole. Les ratios des MG en pourcentage de la SSC0-tz, de la SSC0-∞, et de la Cmax (avec et sans rabéprazole) étaient de 70,5 % (intervalle de confiance [IC] à 95 % : 51,9 % à 95,7 %), 71,8 % (IC à 95 % : 53,1 % à 96,9 %) et 61,4 % (IC à 95 % : 44,1 % à 85,5 %), respectivement. Les proportions de participants chez qui une réduction de > 50 % de la SSC0-tz, de la SSC0-∞ ou de la Cmax a été notée avec l'administration du rabéprazole s'élevaient à 32,6 %, 30,4 % et 39,1 %, respectivement. Conclusions: Lors de l'administration d'APO-dabigatran en concomitance avec le rabéprazole, l'exposition au dabigatran était réduite d'environ 30 %, une valeur comparable à la réduction observée lors de l'administration de Pradaxa en concomitance avec un inhibiteur de la pompe à protons. La réduction de > 50 % de l'exposition médicamenteuse chez le tiers des participants n'en est pas moins préoccupante et démontre la nécessité de faire preuve de prudence lorsque l'acidité gastrique est réduite ou risque d'être réduite chez un patient.

Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.

OBJECTIVE: Activation of the coagulation cascade leading to generation of thrombin has been documented extensively in various forms of lung injury, including that associated with systemic sclerosis. We previously demonstrated that the direct thrombin inhibitor dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study was undertaken to test whether dabigatran etexilate attenuates lung injury in a murine model of interstitial lung disease. METHODS: Lung injury was induced in female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 of bleomycin instillation (early treatment, study of antiinflammatory effect) or on day 8 following bleomycin instillation (late treatment, study of antifibrotic effect). Mice were killed 2 weeks or 3 weeks after bleomycin instillation, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were investigated. RESULTS: Both early treatment and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of transforming growth factor ß1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. Histologically evident lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, connective tissue growth factor, and α-smooth muscle actin expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins. CONCLUSION: Inhibition of thrombin using the oral direct thrombin inhibitor dabigatran etexilate has marked antiinflammatory and antifibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung disease.

Switching from enoxaparin to dabigatran etexilate: pharmacokinetics, pharmacodynamics, and safety profile.

PURPOSE: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran. METHODS: Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase-induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). RESULTS: PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0-110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC0₋48) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC0₋48 of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment. CONCLUSION: Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate.

Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.

BACKGROUND AND PURPOSE: Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. METHODS: In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 µL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. RESULTS: DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. CONCLUSIONS: The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.

Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin.

Dabigatran is a highly selective, reversible, and potent thrombin inhibitor and is orally available as the prodrug, dabigatran etexilate. It has shown antithrombotic efficacy in animal models of thrombosis, with a rapid onset of action and predictable pharmacodynamic response. Peak plasma concentrations of dabigatran occur 1 to 2 hours after ingestion of the prodrug. The terminal half-life of dabigatran is 12 to 14 hours in elderly volunteers. Dabigatran is not metabolized by cytochrome P450 isoenzymes and does not interact with food. Dabigatran has a low potential for drug-drug interactions and is predominantly renally excreted. Dabigatran etexilate as chronic therapy effectively prevents the recurrence of venous thromboembolism and cardioembolic stroke. For the first time, it has been demonstrated clinically that there may be an effective and safe alternative to warfarin.