Idarucizumab

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Joanne Van Ryn - One of the best experts on this subject based on the ideXlab platform.

  • dabigatran reversal with Idarucizumab in patients requiring urgent surgery a subanalysis of the re verse ad study
    Annals of Surgery, 2019
    Co-Authors: Jerrold H. Levy, Paul A. Reilly, Stephan Glund, Jeffrey I. Weitz, Joanne Van Ryn, Amelie Elsaesser, Jorg Kreuzer, Frank W Sellke, Charles V. Pollack
    Abstract:

    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.

  • Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
    Journal of the American College of Cardiology, 2019
    Co-Authors: John W Eikelboom, Paul A. Reilly, Stephan Glund, Elaine M Hylek, Charles V. Pollack, Joanne Van Ryn, Amelie Elsaesser, Jeffrey I. Weitz
    Abstract:

    Abstract Background Dabigatran and Idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving Idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to  Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of Idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )

  • Idarucizumab but not procoagulant concentrates fully restores dabigatran altered platelet and fibrin components of hemostasis
    Transfusion, 2019
    Co-Authors: Eduardo Arellanorodrigo, Joanne Van Ryn, Victor Fernandezgallego, Irene Lopezvilchez, Patricia Molina, Maribel Diazricart, Urooj M Zafar, Juan J Badimon, Gines Escolar
    Abstract:

    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.

  • Volume replacement strategies do not impair the binding of dabigatran to Idarucizumab: Porcine model of hemodilution - Fig 4
    2019
    Co-Authors: Oliver Grottke, Joanne Van Ryn, Markus Honickel, Rolf Rossaint, Christian Zentai, Guanfa Gan, Hugo Ten Cate, Henri M. H. Spronk
    Abstract:

    Activated partial thromboplastin time (aPTT; A), activated clotting time (ACT; B), plasma fibrinogen concentration (C), and levels of D-dimers (D) after intravenous dabigatran, after hemodilution, and after Idarucizumab injection. Dotted black horizontal lines indicate median baseline values (n = 25). HD: hemodilution; IDA: Idarucizumab. Data are shown as median values; boxes extend from 25th to 75th percentiles and whiskers show minimum and maximum values (n = 5/group). *P

  • Volume replacement strategies do not impair the binding of dabigatran to Idarucizumab: Porcine model of hemodilution
    2019
    Co-Authors: Oliver Grottke, Joanne Van Ryn, Markus Honickel, Rolf Rossaint, Christian Zentai, Guanfa Gan, Hugo Ten Cate, Henri M. H. Spronk
    Abstract:

    BackgroundIdarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to Idarucizumab.MethodsTwenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer’s solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters.ResultsMean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with Idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups.ConclusionThis study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of Idarucizumab to dabigatran.

Stephan Glund - One of the best experts on this subject based on the ideXlab platform.

  • dabigatran reversal with Idarucizumab in patients requiring urgent surgery a subanalysis of the re verse ad study
    Annals of Surgery, 2019
    Co-Authors: Jerrold H. Levy, Paul A. Reilly, Stephan Glund, Jeffrey I. Weitz, Joanne Van Ryn, Amelie Elsaesser, Jorg Kreuzer, Frank W Sellke, Charles V. Pollack
    Abstract:

    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.

  • Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
    Journal of the American College of Cardiology, 2019
    Co-Authors: John W Eikelboom, Paul A. Reilly, Stephan Glund, Elaine M Hylek, Charles V. Pollack, Joanne Van Ryn, Amelie Elsaesser, Jeffrey I. Weitz
    Abstract:

    Abstract Background Dabigatran and Idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving Idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to  Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of Idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )

  • The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.
    Clinical and applied thrombosis hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis Hemostasis, 2018
    Co-Authors: Stephan Glund, Paul A. Reilly, Markus Honickel, Oliver Grottke, Guanfa Gan, Viktoria Moschetti, Joanne Van Ryn
    Abstract:

    Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of Idarucizumab and investigate the influence of Idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased Idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged Idarucizumab increased with increasing Idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of Idarucizumab was unaffected by dabigatran. In contrast, Idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by ...

  • rationale and design of a phase iii safety trial of Idarucizumab in children receiving dabigatran etexilate for venous thromboembolism
    Research and Practice in Thrombosis and Haemostasis, 2018
    Co-Authors: Manuela Albisetti, Stephan Glund, Arno Schlosser, Martina Brueckmann, Savion Gropper, Igor Tartakovsky, Leonardo R Brandao, Paul A. Reilly
    Abstract:

    Essentials There is no data on the use of Idarucizumab in children with venous thromboembolism (VTE). We present the design of a trial that will assess the safety of Idarucizumab in children with VTE. Patients will be recruited from two ongoing trials in children treated with dabigatran for VTE. Idarucizumab provides additional re-assurance when rapid reversal of dabigatran effects is needed. Background The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults. Objective and Methods This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of Idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0–≤18 years; n = ~5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive Idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of Idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post-dose and cessation of bleeding will also be assessed. Conclusion This study will report the safety of Idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

  • Idarucizumab for dabigatran reversal full cohort analysis
    The New England Journal of Medicine, 2017
    Co-Authors: Charles V. Pollack, Paul A. Reilly, Stephan Glund, Robert Dubiel, Richard A Bernstein, Menno V. Huisman, Elaine M Hylek, John W Eikelboom, Joanne Van Ryn
    Abstract:

    BackgroundIdarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. MethodsWe 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. ResultsA 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 ...

Paul A. Reilly - One of the best experts on this subject based on the ideXlab platform.

  • dabigatran reversal with Idarucizumab in patients requiring urgent surgery a subanalysis of the re verse ad study
    Annals of Surgery, 2019
    Co-Authors: Jerrold H. Levy, Paul A. Reilly, Stephan Glund, Jeffrey I. Weitz, Joanne Van Ryn, Amelie Elsaesser, Jorg Kreuzer, Frank W Sellke, Charles V. Pollack
    Abstract:

    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.

  • Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
    Journal of the American College of Cardiology, 2019
    Co-Authors: John W Eikelboom, Paul A. Reilly, Stephan Glund, Elaine M Hylek, Charles V. Pollack, Joanne Van Ryn, Amelie Elsaesser, Jeffrey I. Weitz
    Abstract:

    Abstract Background Dabigatran and Idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving Idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to  Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of Idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )

  • The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.
    Clinical and applied thrombosis hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis Hemostasis, 2018
    Co-Authors: Stephan Glund, Paul A. Reilly, Markus Honickel, Oliver Grottke, Guanfa Gan, Viktoria Moschetti, Joanne Van Ryn
    Abstract:

    Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of Idarucizumab and investigate the influence of Idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased Idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged Idarucizumab increased with increasing Idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of Idarucizumab was unaffected by dabigatran. In contrast, Idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by ...

  • rationale and design of a phase iii safety trial of Idarucizumab in children receiving dabigatran etexilate for venous thromboembolism
    Research and Practice in Thrombosis and Haemostasis, 2018
    Co-Authors: Manuela Albisetti, Stephan Glund, Arno Schlosser, Martina Brueckmann, Savion Gropper, Igor Tartakovsky, Leonardo R Brandao, Paul A. Reilly
    Abstract:

    Essentials There is no data on the use of Idarucizumab in children with venous thromboembolism (VTE). We present the design of a trial that will assess the safety of Idarucizumab in children with VTE. Patients will be recruited from two ongoing trials in children treated with dabigatran for VTE. Idarucizumab provides additional re-assurance when rapid reversal of dabigatran effects is needed. Background The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults. Objective and Methods This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of Idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0–≤18 years; n = ~5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive Idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of Idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post-dose and cessation of bleeding will also be assessed. Conclusion This study will report the safety of Idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

  • abstract 16489 Idarucizumab is effective and safe in the inhibition of dabigatran anticoagulation in patients presenting with a gastrointestinal bleeding insights from the re verse ad study
    Circulation, 2017
    Co-Authors: Menno V. Huisman, Paul A. Reilly, Joanne Van Ryn, Renato D Lopes, James Aisenberg, Eva Kleine, Sake J Van Der Wall, Charles V. Pollack
    Abstract:

    Background: Anticoagulant therapy with dabigatran is considered effective and safe as compared to warfarin; however, in rare cases of uncontrollable bleeding, the ability to rapidly reverse anticoagulation may further enhance patient care. Idarucizumab is a humanized monoclonal antibody fragment that specifically inhibits the anticoagulant effect of dabigatran. Methods: This sub-analysis focuses on patients enrolled with gastrointestinal (GI) bleeding in RE-VERSE AD™, which is a prospective, multicenter, single-arm, open label study. The primary endpoint was the maximum reversal of dabigatran anticoagulation within 4 hours after Idarucizumab dosing using the dabigatran-specific assays, diluted thrombin time, or ecarin clotting time. Secondary endpoints included restoration of hemostasis and safety evaluations of thromboembolic events and mortality, and any evidence of immunogenicity over the 90-day follow-up period. Data are presented as median (range: min–max). Results: Of the total 301 patients enrolled in the bleeding group, 137 (45.6%) were enrolled for GI bleeding; the second most frequent bleeding type was intracranial hemorrhage (32.6%). Overall, bleeding was considered major or life-threatening in 88% of patients. Median age was 80 years and creatinine clearance was 45.9 (8–180) mL/min in GI bleed patients versus 77 years and 55.9 (6–217) mL/min in non-GI bleed patients. There was a shorter time since the last drug intake, 12.5 versus 15.4 hours, in patients with GI bleeding compared with non-GI bleed patients, respectively. The primary endpoint of dabigatran reversal was 100% (100–100) 95% CI. Bleeding cessation was recorded as 2.4 hours post Idarucizumab. At 90 days, there was a thromboembolic event rate of 5.1% in those with GI bleeding and 6.3% in non-GI bleed patients. Mortality in the first 5 days post Idarucizumab was 6% in patients with GI bleeding versus 9% in non-GI bleed patients; at 90 days this was 16 and 23%, respectively. Conclusion: Our findings demonstrate that Idarucizumab is effective and safe in the inhibition of dabigatran anticoagulation in patients presenting with a GI bleeding event, and therefore, should help physicians in the management of this critical clinical setting.

Charles V. Pollack - One of the best experts on this subject based on the ideXlab platform.

  • dabigatran reversal with Idarucizumab in patients requiring urgent surgery a subanalysis of the re verse ad study
    Annals of Surgery, 2019
    Co-Authors: Jerrold H. Levy, Paul A. Reilly, Stephan Glund, Jeffrey I. Weitz, Joanne Van Ryn, Amelie Elsaesser, Jorg Kreuzer, Frank W Sellke, Charles V. Pollack
    Abstract:

    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.

  • Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
    Journal of the American College of Cardiology, 2019
    Co-Authors: John W Eikelboom, Paul A. Reilly, Stephan Glund, Elaine M Hylek, Charles V. Pollack, Joanne Van Ryn, Amelie Elsaesser, Jeffrey I. Weitz
    Abstract:

    Abstract Background Dabigatran and Idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving Idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to  Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of Idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )

  • abstract 16489 Idarucizumab is effective and safe in the inhibition of dabigatran anticoagulation in patients presenting with a gastrointestinal bleeding insights from the re verse ad study
    Circulation, 2017
    Co-Authors: Menno V. Huisman, Paul A. Reilly, Joanne Van Ryn, Renato D Lopes, James Aisenberg, Eva Kleine, Sake J Van Der Wall, Charles V. Pollack
    Abstract:

    Background: Anticoagulant therapy with dabigatran is considered effective and safe as compared to warfarin; however, in rare cases of uncontrollable bleeding, the ability to rapidly reverse anticoagulation may further enhance patient care. Idarucizumab is a humanized monoclonal antibody fragment that specifically inhibits the anticoagulant effect of dabigatran. Methods: This sub-analysis focuses on patients enrolled with gastrointestinal (GI) bleeding in RE-VERSE AD™, which is a prospective, multicenter, single-arm, open label study. The primary endpoint was the maximum reversal of dabigatran anticoagulation within 4 hours after Idarucizumab dosing using the dabigatran-specific assays, diluted thrombin time, or ecarin clotting time. Secondary endpoints included restoration of hemostasis and safety evaluations of thromboembolic events and mortality, and any evidence of immunogenicity over the 90-day follow-up period. Data are presented as median (range: min–max). Results: Of the total 301 patients enrolled in the bleeding group, 137 (45.6%) were enrolled for GI bleeding; the second most frequent bleeding type was intracranial hemorrhage (32.6%). Overall, bleeding was considered major or life-threatening in 88% of patients. Median age was 80 years and creatinine clearance was 45.9 (8–180) mL/min in GI bleed patients versus 77 years and 55.9 (6–217) mL/min in non-GI bleed patients. There was a shorter time since the last drug intake, 12.5 versus 15.4 hours, in patients with GI bleeding compared with non-GI bleed patients, respectively. The primary endpoint of dabigatran reversal was 100% (100–100) 95% CI. Bleeding cessation was recorded as 2.4 hours post Idarucizumab. At 90 days, there was a thromboembolic event rate of 5.1% in those with GI bleeding and 6.3% in non-GI bleed patients. Mortality in the first 5 days post Idarucizumab was 6% in patients with GI bleeding versus 9% in non-GI bleed patients; at 90 days this was 16 and 23%, respectively. Conclusion: Our findings demonstrate that Idarucizumab is effective and safe in the inhibition of dabigatran anticoagulation in patients presenting with a GI bleeding event, and therefore, should help physicians in the management of this critical clinical setting.

  • Idarucizumab for dabigatran reversal full cohort analysis
    The New England Journal of Medicine, 2017
    Co-Authors: Charles V. Pollack, Paul A. Reilly, Stephan Glund, Robert Dubiel, Richard A Bernstein, Menno V. Huisman, Elaine M Hylek, John W Eikelboom, Joanne Van Ryn
    Abstract:

    BackgroundIdarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. MethodsWe 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. ResultsA 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 ...

  • healthcare resource utilization in patients receiving Idarucizumab for reversal of dabigatran anticoagulation due to major bleeding urgent surgery or procedural interventions interim results from the re verse ad study
    Journal of Medical Economics, 2017
    Co-Authors: Charles V. Pollack, Paul A. Reilly, Robert Dubiel, Richard A Bernstein, Menno V. Huisman, Jerrold H. Levy, Fredrik Gruenenfelder, Chak Wah Kam, Eva Kleine, Frank W Sellke
    Abstract:

    AbstractAims: Patients treated with anticoagulants may experience serious bleeding or require urgent surgery or intervention, and may benefit from rapid anticoagulant reversal. This exploratory analysis assessed healthcare resource utilization (HCRU) in patients treated with Idarucizumab, a specific reversal agent for dabigatran etexilate.Materials and methods: RE-VERSE AD™ (NCT02104947), a prospective, multi-center open-label study, is evaluating Idarucizumab for dabigatran reversal in patients with serious bleeding (Group A) or undergoing emergency surgery/procedures (Group B). HCRU outcome measures evaluated in the first 90 patients enrolled were use of blood products and pro-hemostatic agents, length of stay (LOS) in hospital, and LOS in intensive care unit (ICU).Results: Blood products or pro-hemostatic agents were given to 63% (32/51) of patients in Group A and 23% (9/39) of patients in Group B on the day of/day after surgery. An overnight hospital stay was reported for 82% (42/51) of patients in Gr...

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  • Volume replacement strategies do not impair the binding of dabigatran to Idarucizumab: Porcine model of hemodilution - Fig 4
    2019
    Co-Authors: Oliver Grottke, Joanne Van Ryn, Markus Honickel, Rolf Rossaint, Christian Zentai, Guanfa Gan, Hugo Ten Cate, Henri M. H. Spronk
    Abstract:

    Activated partial thromboplastin time (aPTT; A), activated clotting time (ACT; B), plasma fibrinogen concentration (C), and levels of D-dimers (D) after intravenous dabigatran, after hemodilution, and after Idarucizumab injection. Dotted black horizontal lines indicate median baseline values (n = 25). HD: hemodilution; IDA: Idarucizumab. Data are shown as median values; boxes extend from 25th to 75th percentiles and whiskers show minimum and maximum values (n = 5/group). *P

  • Volume replacement strategies do not impair the binding of dabigatran to Idarucizumab: Porcine model of hemodilution
    2019
    Co-Authors: Oliver Grottke, Joanne Van Ryn, Markus Honickel, Rolf Rossaint, Christian Zentai, Guanfa Gan, Hugo Ten Cate, Henri M. H. Spronk
    Abstract:

    BackgroundIdarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to Idarucizumab.MethodsTwenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer’s solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters.ResultsMean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with Idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups.ConclusionThis study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of Idarucizumab to dabigatran.

  • reversal of dabigatran by intraosseous or intravenous Idarucizumab in a porcine polytrauma model
    BJA: British Journal of Anaesthesia, 2018
    Co-Authors: Necib Akman, Markus Honickel, Rolf Rossaint, Till Braunschweig, K Schutt, Herbert Schochl, Christian Stoppe, Oliver Grottke
    Abstract:

    Abstract Background Idarucizumab is licensed to reverse dabigatran in life-threatening haemorrhage. Establishment of venous access can be challenging, and the intraosseous (IO) route is a potentially life-saving alternative. In this study, we compared the efficacy and safety of IO or intravenous (i.v.) Idarucizumab for dabigatran reversal in a porcine polytrauma model. Methods Male pigs (n=21) received oral dabigatran etexilate (30 mg kg−1 bid) for 3 days. On the 4th day, animals received dabigatran infusion and were randomised 1:1:1 to receive IO saline (control), i.v. Idarucizumab (60 mg kg−1), or IO Idarucizumab (60 mg kg−1), or animals were included in a sham group (n=7). Study treatment was administered after polytrauma and the animals were monitored for 240 min, or until death. Coagulation status was monitored by thromboelastometry, thromboelastography, and thrombin measurements. Results Total blood loss was lowest in sham animals [521 (52) ml, P Conclusions Intravenous and intraosseous Idarucizumab were comparable for reversing dabigatran in a porcine trauma model. Dabigatran reversal could be monitored using fully automated thromboelastography.

  • The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.
    Clinical and applied thrombosis hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis Hemostasis, 2018
    Co-Authors: Stephan Glund, Paul A. Reilly, Markus Honickel, Oliver Grottke, Guanfa Gan, Viktoria Moschetti, Joanne Van Ryn
    Abstract:

    Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of Idarucizumab and investigate the influence of Idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased Idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged Idarucizumab increased with increasing Idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of Idarucizumab was unaffected by dabigatran. In contrast, Idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by ...

  • reversing dabigatran anticoagulation with prothrombin complex concentrate versus Idarucizumab as part of multimodal hemostatic intervention in an animal model of polytrauma
    Anesthesiology, 2017
    Co-Authors: Markus Honickel, Rolf Rossaint, Hugo Ten Cate, Till Braunschweig, Christian Stoppe, Oliver Grottke
    Abstract:

    Background:Although Idarucizumab is the preferred treatment for urgent dabigatran reversal, it is not always available. Prothrombin complex concentrate (PCC) may be an alternative and, with bleeding in trauma, additional hemostatic therapy may be required. The authors investigated multimodal treatme

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