Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for ...long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug-drug and drug-food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate.
The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment.
Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.
Abstract only 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.
Background: A proportion of trauma patients presenting with coagulopathy also receive anticoagulant therapy, which can exacerbate coagulopathy and increase bleeding. Emergency reversal of ...anticoagulation therapy may require therapy with specific reversal agents, as with idarucizumab for dabigatran or non-specific reversal agents, such as prothrombin complex concentrates (PCC).
Methods: Using a lethal polytrauma model under dabigatran anticoagulation, we investigated the mechanism and procoagulant properties of a four-factor PCC or idarucizumab in dabigatran-anticoagulated pigs following multiple injuries. Blood markers of coagulation associated with procoagulant effects, platelet activation and hyperfibrinolysis were determined over time and related to blood loss.
After ethical approval, dabigatran etexilate was given orally for 3 days and iv on day 4 to 18 pigs after anesthesia. Animals were randomized to receive idarucizumab (60 mg/kg), PCC (50 IU/kg) or saline (control), administered 15 minutes after bilateral femur fracture and blunt liver injury. Plasma dabigatran was determined using diluted thrombin time. Thrombin-antithrombin (TAT) complexes and fibrinopeptide A (FPA) were quantified using ELISA and D-Dimer with a clotting assay. Thrombin generation (ETP) in plasma was measured using Calibrated Automated Thrombogram. Platelet function was evaluated as aggregation using platelet-rich plasma in response to tissue factor, collagen, or adenosine diphosphate (ADP) agonism using light transmission aggregometry.
Results: Mean dabigatran levels were 543±186 ng/ml prior to injury. Blood loss was 4056±537 mL after saline treatment (control), 1822±222 mL after PCC (P<0.0001 vs. control) and 1086±134 mL after idarucizumab (P<0.0001 vs. all). All controls developed severe coagulopathy and exsanguinated with a mean survival time of 93 min (range: 62-146 min). Post-injury and after PCC infusion, TAT, D-dimers and FPA were significantly increased vs idarucizumab and control and remained elevated over 300 minutes. Similarly thrombin generation (baseline ETP 267±84 nM*min) increased immediately after PCC administration and persisted elevated 848±114 nM*min at 120 min. In contrast, following therapy with idarucizumab ETP was restored to baseline values. Thrombin-dependent tissue factor-induced platelet aggregation was inhibited with dabigatran, partially restored with PCC and fully restored with idarucizumab. There was no effect with thrombin-independent collagen- and ADP-induced aggregation.
Conclusion: Although four-factor PCC (50 IU/kg) is effective in reducing blood loss, its efficacy is less than therapy with idarucizumab (60 mg/kg). Most importantly the activation of coagulation is explained by different mechanisms. Supernormal activation of coagulation (e.g. TAT, FPA, ETP) was evident after PCC administration, whereas idarucizumab normalized ETP to baseline values. Since thrombin is a potent activator of platelets via PAR, restoration of active thrombin after PCC also partially restored aggregation. In contrast, idarucizumab binds dabigatran and forms an irreversible complex, inactivating dabigatran in plasma, thereby restoring hemostatic function. This difference may influence the choice of therapy when idarucizumab is clinically available.
van Ryn:Boehringer Ingelheim: Employment. Grottke:NovoNordisk: Research Funding; Portola Pharmaceuticals: Consultancy; CSL Behring: Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Biotest: Research Funding.
This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B(2) endpoints in ...healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB(2). These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2) levels, and that meloxicam is selective for COX-2.
Dabigatran etexilate, the oral direct thrombin inhibitor, has now been successfully introduced into the clinic for the reduction of stroke in patients with atrial fibrillation in many countries ...around the world. In addition, it has found a role in 83 countries world wide in the prevention of venous thromboembolism after orthopedic hip and knee surgery. Dabigatran is a potent, selective and reversible inhibitor of thrombin that was developed by classical medicinal chemistry techniques in the early-mid 1990s. The resulting pharmacological profiling of the compound demonstrated potent anticoagulant and antithrombotic activity in various venous and arterial thrombosis models. In addition, no effect of vitamin K supplementation on its antithrombotic actions was found, in contrast to warfarin. The bleeding profile of this compound was very favorable when measured as safety margin over antithrombotic activity and as compared to warfarin. Dabigatran has also shown efficacy as an antithrombotic agent in models with mechanical heart valves, both in vitro and in vivo. In addition, the effect of thrombin inhibition by dabigatran on PAR1-mediated pathophysiology is also being elucidated. Chronic treatment of dabigatran etexilate in a mouse model of breast cancer has shown beneficial effects in reducing tumor growth progression and metastases. Fibrosis in the lungs induced by bleomycin was also attenuated in an animal model of pulmonary fibrosis after chronic treatment with dabigatran etexilate. In addition, atherosclerosis progression has been reduced in several models of atherosclerosis in mice after treatment of dabigatran for up to 20 weeks. These studies imply that thrombin may be a mediator between coagulation and inflammation and other proliferative processes and its direct inhibition by dabigatran may provide an added benefit, in addition to its antithrombotic and anticoagulant properties.
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 (nonanticoagulated31%; dabigatran35% versus warfarin55%; 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.
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.
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.
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