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Review

Strategies for the prevention and treatment of bleeding in patients treated with dabigatran: an update

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Pages 1091-1102 | Received 11 May 2021, Accepted 03 Aug 2021, Published online: 18 Aug 2021

References

  • Larsen TB, Skjoth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2016;353:i3189.
  • Lopes LC, Spencer FA, Neumann I, et al. Bleeding risk in atrial fibrillation patients taking vitamin K antagonists: systematic review and meta-analysis. Clin Pharmacol Ther. 2013;94(3):367–375.
  • Chan N, Sobieraj-Teague M, Eikelboom JW. Direct oral anticoagulants: evidence and unresolved issues. Lancet. 2020;396:1767–1776.
  • Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.
  • Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178–2185.
  • Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949–956.
  • Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721–729.
  • Committee R-MW, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1–9.
  • Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352.
  • Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–718.
  • Schulman S, Kakkar AK, Goldhaber SZ, et al., Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 129(7): 764–772. 2014.
  • Majeed A, Goldhaber SZ, Kakkar A, et al. Bleeding events with dabigatran or warfarin in patients with venous thromboembolism. Thromb Haemost. 2016;115(2):291–298.
  • Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36(20):1264–1272.
  • Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114(8):774–782.
  • Sharma A, Hagstrom E, Wojdyla DM, et al. Clinical consequences of bleeding among individuals with a recent acute coronary syndrome: insights from the APPRAISE-2 trial. Am Heart J. 2019;215:106–113.
  • Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2020;76(5): 594–622.
  • Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin? Inhibitor Dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–295.
  • Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.
  • Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386–399.
  • Pollack CV Jr., Reilly PA, van Ryn J, et al., Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;377(5): 431–441.
  • Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–268.
  • Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513–1524.
  • Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015;131(2):157–164.
  • Sjoblom L, Hardemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32(11):2567–2574.
  • Murthy SB, Gupta A, Merkler AE, et al. Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis. Stroke. 2017;48:1594–1600.
  • Van Rein N, Heide-Jorgensen U, Lijfering WM, et al. Major bleeding rates in atrial fibrillation patients on single, dual, or triple antithrombotic therapy. Circulation. 2019;139(6):775–786.
  • Kent AP, Brueckmann M, Fraessdorf M, et al. Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation. J Am Coll Cardiol. 2018;72:255–267.
  • Peterson BE, Bhatt DL, Gabriel Steg P, et al. Evaluation of dual versus triple therapy by landmark analysis in the RE-DUAL PCI trial. J Am Coll Cardiol Intv. 2021;14:768–780.
  • Bohm M, Brueckmann M, Eikelboom JW, et al. Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial. Eur Heart J. 2020;41:2848–2859.
  • Biffi A, Anderson CD, Battey TW, et al. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA. 2015;314:904–912.
  • Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313:824–836.
  • Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2017;2018(71):e127–e248.
  • Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–3104.
  • Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018;320:2221–2230.
  • Moayyedi P, Eikelboom JW, Bosch J, et al. Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2019;157(403–412):e5.
  • O’Brien EC, Simon DN, Thomas LE, et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J. 2015;36:3258–3264.
  • Hijazi Z, Oldgren J, Lindback J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet. 2016;387:2302–2311.
  • Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol. 2011;58(4):395–401.
  • Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–1100.
  • Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713–719.
  • Douxfils J, Mullier F, Robert S, et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost. 2012;107:985–997.
  • Ebner M, Birschmann I, Peter A, et al. Emergency coagulation assessment during treatment with direct oral anticoagulants: limitations and solutions. Stroke. 2017;48:2457–2463.
  • Helin TA, Pakkanen A, Lassila R, et al. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem. 2013;59:807–814.
  • Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost. 2013;11:1493–1502.
  • Bliden KP, Chaudhary R, Mohammed N, et al. Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis. 2017;43:437–445.
  • Taune V, Skeppholm M, Agren A, et al. Rapid determination of anticoagulating effects of dabigatran in whole blood with rotational thromboelastometry and a thrombin-based trigger. J Thromb Haemost. 2018;16:2462–2470.
  • Taune V, Wallen H, Agren A, et al. Whole blood coagulation assays ROTEM and T-TAS to monitor dabigatran treatment. Thromb Res. 2017;153:76–82.
  • Chan NC, Weitz JI. Measuring dabigatran levels: what tests are available and what still needs to be done? Thromb Haemost. 2017;117:2213–2214.
  • Dager WE, Gosselin RC, Kitchen S, et al. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627–1636.
  • Jaffer IH, Chan N, Roberts R, et al. Comparison of the ecarin chromogenic assay and diluted thrombin time for quantification of dabigatran concentrations. J Thromb Haemost. 2017;15:2377–2387.
  • Ansell J, Laulicht BE, Bakhru SH, et al. Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants. Blood. 2021;137:115–125.
  • Glund S, Stangier J, Schmohl M, et al. 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. Lancet. 2015;386:680–690.
  • Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113:943–951.
  • Glund S, Stangier J, van Ryn J, et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib Study. Clin Pharmacokinet. 2017;56:41–54.
  • Pollack CV Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–520.
  • Singh S, Nautiyal A, Belk KW. Real world outcomes associated with Idarucizumab: population-based retrospective cohort study. Am J Cardiovasc Drugs. 2020;20:161–168.
  • van der Wall SJ, Van Rein N, van den Bemt B, et al. Performance of idarucizumab as antidote of dabigatran in daily clinical practice. Europace. 2019;21:414–420.
  • Barber PA, Wu TY, Ranta A. Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort. Neurology. 2020;94:e1968–e1972.
  • Beharry J, Waters MJ, Drew R, et al. Dabigatran reversal before intravenous tenecteplase in acute ischemic stroke. Stroke. 2020;51:1616–1619.
  • Simon A, Domanovits H, Ay C, et al. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran. J Thromb Haemost. 2017;15:1317–1321.
  • Gendron N, Gay J, Lemoine M, et al. Usefulness of initial plasma dabigatran concentration to predict rebound after reversal. Haematologica. 2018;103:e226–e229.
  • Kanjee Z, McCann ML, Freed JA. Availability of specific direct oral anticoagulant reversal agents in US hospitals. JAMA Network Open. 2021;4:e2110079.
  • Jarrett JB, Gimbar RP. Idarucizumab (Praxbind) for dabigatran (Pradaxa) anticoagulant reversal. Am Fam Physician. 2017;95:798–800.
  • Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–1579.
  • Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217–224.
  • Herrmann R, Thom J, Wood A, et al. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2014;111:989–995.
  • Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm. 2012;69:1646–1650.
  • Billoir P, Girault C, Barbay V, et al. Management of dabigatran after overdosage: two case reports and suggestions for monitoring. Blood Coagul Fibrinolysis. 2018;29:653–655.
  • Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106:429–438.
  • Grottke O, van Ryn J, Spronk HM, et al. 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. Crit Care. 2014;18:R27.
  • Solbeck S, Nilsson CU, Engstrom M, et al. Dabigatran and its reversal with recombinant factor VIIa and prothrombin complex concentrate: a Sonoclot in vitro study. Scand J Clin Lab Invest. 2014;74:591–598.
  • Warkentin TE, Margetts P, Connolly SJ, et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119:2172–2174.
  • Jourdi G, Delrue M, Stepanian A, et al. Potential usefulness of activated charcoal (DOAC remove(R)) for dRVVT testing in patients receiving Direct Oral AntiCoagulants. Thromb Res. 2019;184:86–91.
  • Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109:596–605.
  • Fuhr LM, Hanke N, Meibohm B, et al. Effective removal of dabigatran by idarucizumab or hemodialysis: a physiologically based pharmacokinetic modeling analysis. Clin Pharmacokinet. 2020;59:809–825.
  • Chai-Adisaksopha C, Hillis C, Lim W, et al. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13:1790–1798.
  • Ottosen TP, Grijota M, Hansen ML, et al. Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral hemorrhage. Stroke. 2016;47:1837–1843.
  • Nielsen PB, Larsen TB, Skjoth F, et al. Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and the impact on recurrent stroke, mortality, and bleeding: a nationwide cohort study. Circulation. 2015;132:517–525.
  • Lopez-Lopez JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.

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