Novel Oral Anticoagulants and Lack of Reversibility
Novel oral anticoagulants (NOACs) are being increasingly utilized in patients with atrial fibrillation for the prevention of stroke and systemic embolization. Among them is dabigatran etexilate, a direct thrombin inhibitor which was superior to the vitamin K antagonist warfarin for stroke and systemic embolization prophylaxis at a dose of 150 mg twice-daily (1.11% vs. 1.69% per year, RR 0.66, 95% CI 0.53-0.82, P<0.001 for superiority), and non-inferior to warfarin at 110 mg twice-daily (1.53% vs. 1.69% per year, RR 0.91, 95% CI 0.74-1.11, P<0.001 for non-inferiority) in the Randomized Evaluation of the Long-Term Anticoagulation Therapy (RE-LY) trial.1 Patients receiving dabigatran 110 mg experienced a lower annual rate of major bleeding (2.71%) as compared to those treated with warfarin (3.36%, P=0.003), while the rate of major bleeding in patients receiving dabigatran 150 mg did not differ from warfarin-treated patients (P=0.31).1 However, this may not be the case for all patients. Patients ≥75 years old experienced similar rates of major bleeding on dabigatran 110 mg as compared to warfarin (4.43% vs. 4.37%, P=0.89), but tended to experience higher rates of major bleeding with dabigatran 150 mg versus warfarin (5.10% vs. 4.37%, P=0.07).2 While a recent mini-sentinel analysis did not find an increased risk of bleeding in patients who received dabigatran compared to warfarin based on post-marketing reports,3 bleeding events on novel oral anticoagulants pose a particular challenge because no means of reliable reversal currently exist, and laboratory means of monitoring the anticoagulant effects of traditional agents are less reliable when applied to the novel oral anticoagulants.
While the more predictable pharmacokinetics, wider therapeutic window, and shorter half-life of dabigatran make routine laboratory monitoring of its anticoagulant effect unnecessary, such monitoring could prove beneficial for patients at high risk for bleeding. However, none of the standard laboratory tests can be used to accurately measure the anticoagulant effect of dabigatran, particularly at higher concentrations. Several case reports have described dabigatran over-anticoagulation in the elderly,4-12 a population at high risk for adverse pharmacologic events. Given that dabigatran is primarily excreted renally, patients with renal impairment or susceptibility to changes in creatinine clearance may also benefit from monitoring. While the RE-LY trial excluded patients with a creatinine clearance less than 30 mL/min, the FDA approved 75 mg dabigatran twice-daily for prevention of stroke and systemic embolization in atrial fibrillation patients with severe renal impairment (CrCl 15-30 mL/min) based on pharmacokinetic population data which showed a similar safety profile as patients with normal renal function administered 150 mg dabigatran twice-daily.1,13,14
The international normalized ratio (INR) used for warfarin monitoring is insensitive to therapeutic dabigatran levels.15-18 While activated partial thromboplastin time (aPTT) initially bears a curvilinear relationship to increasing dabigatran concentrations, the aPTT plateaus around peak therapeutic levels and therefore may not enable differentiation between patients who are therapeutically- versus over-anticoagulated.4,15-17,19,20 By some assays, an aPTT value greater than 80 seconds obtained at the drug's trough is predictive of higher bleeding risk in patients taking 150 mg twice-daily, but given significant inter-reagent variability this may not be true for all available reagents.18 Similarly, thrombin time (TT) is a sensitive test for detecting the presence of circulating dabigatran, but concentrations above 600 ng/mL exceed the maximum measurement time of most coagulometers.15,19 However, the diluted TT assay continues to rise linearly even at high dabigatran levels and, in turn, dabigatran concentrations can be approximated using dabigatran standards to run a calibration curve.15,21 The Rapid Thromboelastrographic-derived activated clotting time, activated clotting time (ACT), and ecarin clotting time (ECT) are other promising laboratory tests that remain to be tested in the clinical setting.4,15-18,22,23
Even if excess anticoagulation due to dabigatran is identified, no proven means of expedient reversal exists to treat life-threatening bleeding or minimize the bleeding risk prior to emergent procedures. If time permits, plasma dabigatran levels will fall below 100 ng/mL within 12 hours in patients with normal renal function taking 150 mg of twice-daily dabigatran, and supportive care can be employed while patients eliminate the drug on their own.15 In patients with oliguric renal failure, promoting diuresis should be the first consideration.4 Hemodialysis can remove 62% of the drug in two hours and is a method that has been explored in case reports.7,8,10,11,24-27
Products used for reversal of other anticoagulants including vitamin K, protamine, fresh frozen plasma, and cryoprecipitate have not been shown to be effective in the context of dabigatran in the limited data available.11,15,19,24,25,28 Recombinant activated factor VII (rFVIIa) can directly activate thrombin in the absence of tissue factor and thus holds the potential to reverse dabigatran's anticoagulant effects, but its clinical utility is still a topic of investigation and its possible pro-thrombotic effect is a potential draw-back.15,19,28,29
Much interest has centered on utilization of prothrombin complex concentrates (PCC), of which there is a three-factor concentrate (containing factors II, IX, and X) and a four-factor concentrate (with added factor VII), both of which are now available in the United States. A small randomized trial of 12 healthy male volunteers failed to demonstrate reversal of dabigatran as measured by the aPTT, ECT, or TT using 50 IU/kg of Cofact® (four-factor PCC; Sanquin Blood Supply, Amsterdam, the Netherlands).30 Another study of ten healthy, white male patients receiving a one-time dose of dabigatran 150 mg found that low-doses of four-factor PCC nearly restored endogenous thrombin potential to baseline, while higher doses resulted in increased thrombin generation.31 Factor Eight Inhibitory Bypassing Activity (FEIBA®, Baxter, West Lake Villiage, CA, USA) is an activated PCC concentrate that contains factors II, IX, X, and activated VII. In the same study of 10 healthy white male patients, FEIBA® also restored thrombin generation at low doses and increased it at higher doses.31 This small study suggests that PCC, rFVIIa, and FEIBA® may be effective in reversing dabigatran's anticoagulant effect, a hypothesis that requires larger study.
A number of targeted reversal agents are currently in development for dabigatran. There is a humanized monoclonal antibody fragment developed against dabigatran that has successfully inhibited the drug's anticoagulant effect in human plasma and whole blood.32 PER977 is a potential antidote to factor Xa and IIa inhibitors for which phase 1 testing is on the horizon.33,34 Finally, PRT064445 is an inactive form of factor Xa shown to neutralize factor Xa inhibitors both in vitro and in vivo without any pro- or anticoagulant effect, and is currently in phase 2 study.33,35-37
While the clinical utilization of novel oral anticoagulants continues to grow, there is an unfortunate paucity of data to guide the management of bleeding and over-anticoagulation. More rigorous identification of risk factors for bleeding is necessary in order to target patients who may benefit from prevention strategies. Reliable laboratory tests sensitive to supratherapetic levels of dabigatran are required in order to monitor the anticoagulant effect in high-risk patients, identify cases of over-anticoagulation, approximate concentrations of circulating dabigatran, and monitor the success of potential therapies. Finally, reliable means of reversing novel oral anticoagulants are crucial to the care of patients with bleeding events, either through more rigorous clinical study of available agents or development of novel targeted antidotes. As the interest in developing and utilizing novel oral anticoagulants grows, so should the interest in developing reliable means of reversing these agents in the case of serious bleeding events.
- Connolly SJ, Ezekowitz MD, Yusuf S, RE-LY Steering Committee and Investigators, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
- Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2011;123:2363-72.
- Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013;268:1272-4.
- Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012;126:2428-32.
- Bene J, Said W, Rannou M, Deheul S, Coup P, Gautier S. Rectal bleeding and hemostatic disorders induced by dabigatran etexilate in 2 elderly patients. Ann Pharmacother 2012;46:e14.
- Legrand M, Mateo J, Aribaud A, et al. The use of dabigatran in elderly patients. Arch Intern Med 2011;171:1285-6.
- Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother 2012;46:e10.
- Maddry JK, Amir MK, Sessions D, Heard K. Fatal dabigatran toxicity secondary to acute renal failure. Am J Emerg Med 2013;31:462.e1-2.
- Fellows SE, Rosini JM, Curtis JA, Volz EG. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med 2013;44:e221-5.
- Louet L-L, Wolf M, Soufir L, et al. Life-threatening bleeding in four patients with an unusual excessive response to dabigatran: implications for emergency surgery and resuscitation. Thromb Haemost 2012;188:583-5.
- Harinstein LM, Morgan JW, Russo N. Treatment of dabigatran-associated bleeding: case report and review of the literature. J Pharm Pract 2013;26:264-9.
- Sarma A, Rossi JE, Connors JM, Giugliano RP. Dabigatran excess: case report and review of the literature. Cardiol Ther 2013;2:111-24.
- U.S. Food and Drug Administration. Pradaxa prescribing information. December 2012. http://www.pradaxa.com (Accessed 8 June 2013).
- Lehr T, Haertter S, Lisenfeld KH, Staab A, Clemens A, Reilly PA, Friedman J. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol 2012;52:1373-1378.
- Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27.
- Baglin T, Keeling D, Kitchen S. Effects on routine coagulation screens and assessment of anticoagulation intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British committee for standards in haematology. Br J Haematol 2012;159:427-9.
- Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011;7:281-7.
- Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogne JM. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012;107:985-97.
- Lal Y, Van Heukelom J. Dabigatran, a cause of hematologic emergency. Am J Med Sci 2013;346:190-3.
- Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol 2010;30:1885-9.
- Avecilla ST, Ferrell C, Chandler WL, Reyes M. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol 2012;137:572-4.
- Dager WE, Gosselin RC, Kitchen S, Dwyer D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 2012;46:1627-36.
- Davis PK, Musunuru H, Walsh H, Mitra R, Ploplis V, Castellino FJ. The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine. Thromb Haemost 2012;108:586-8.
- Obeng-Gyasi S, Loor MM, Samotowka MA, Moorman ML. Management of dabigatran-induced anticoagulation in trauma and acute care surgery patients. J Trauma Acute Care Surg 2012;73:1064-9.
- Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombination factor VIIa (rFVIIa) and hemodialysis to management massive dabigatran-associated postcardiac surgery bleeding. Blood 2012;119:2172-4.
- Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol 2012;35:730-7.
- Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012;46:e21.
- Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013;34:489-98b.
- Novo Nordisk. NovoSeven RT Coagulation Factor VIIa (recombinant) Prescribing Information; 2010. http://www.novosevenrt.com/pdfs/PI_novosevenrt.pdf (Accessed 8 June 2013).
- Erenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9.
- Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomized crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217-24.
- Van Ryn J, Litzenburger T, Waterman A, et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 2011;57(Suppl 1):E1130.
- Dolgin E. Antidotes edge closer to reversing effects of new blood thinners. Nat Med 2013;19:251.
- Laulicht B, Bakhur S, Lee C, Baker C, Jiang X, Mathiowitz E, Costin J, Steiner S. Small molecule antidote for anticoagulants. Circulation 2012;126:A11395.
- Lu G, Deguzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446-51.
- Lu G, Luan P, Hollenbach SJ, et al. Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost 2009;5(Suppl 2):Abstract OC-TH-107.
- Hollenbach SJ, Genmin L, Siusze T, Lee G, Athiwat H, Inagaki M, Sinha U. PRT064445 but not recombinant FVIIa reverses rivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. Blood 2012;120:3414.
Keywords: Anticoagulants, Antithrombins, Atrial Fibrillation, Benzimidazoles, Pyridines, Stroke, Vitamin K, Warfarin, beta-Alanine
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