Over the past decade, novel oral anticoagulants (NOACs) have become more commonly used for prevention of venous thromboembolism (VTE), and management of stroke risk in patients with atrial fibrillation (AF). These drugs were developed to eliminate the need for routine blood monitoring with anticoagulants such as warfarin, and to achieve standard drug dosing with predictable pharmacokinetics.¹

In 2008, the European Commission approved dabigatran etexilate, a reversible direct thrombin inhibitor, for stroke and systemic embolization risk reduction in patients with non-valvular AF; it was subsequently approved by the U.S. Food and Drug Administration (FDA) in 2010, with indications broadened to the prevention and treatment of VTE. Although dabigatran and the other NOACs have been extremely useful in the clinical setting, two major clinical issues remained unsettled: the lack of a reliable reversal agent, and difficulty with laboratory monitoring due to inter-patient variability in commonly assayed coagulation parameters. However, recent studies have shown promise of specific reversal agents for various NOACs, including dabigatran. This article reviews the current literature on reversing dabigatran function, with special focus on idarucizumab and the Reversal of Dabigatran Anticoagulant Effect With Idarucizumab (RE-VERSE AD) trial.

A few key points on dabigatran's formulation and pharmacokinetics are critical to this discussion. Dabigatran is a prodrug, requiring hydrolysis to become active; it binds to both free and clot-bound thrombin.² Its activity peaks between 30-120 minutes after administration and rapidly decreases by approximately 70% over four to six hours.³ The half-life of dabigatran is 12-17 hours, warranting twice-daily dosing.^2,3 It is primary renally-excreted (80%), an important consideration in patients with chronic renal impairment.¹

With regard to assays available to monitor the anticoagulant activity of dabigatran, while prothrombin time (PT) and international normalized ratio (INR) are commonly used to monitor warfarin-mediated anticoagulation, they have significant variability in monitoring direct thrombin inhibitors such as dabigatran. This may be due to the high concentration of tissue factor in PT reagents, resulting in activation of the coagulation cascade and production of additional Factor Xa and thus thrombin.³ Another assay, thrombin time (TT), has a dose-dependent prolongation with dabigatran; however, it is exquisitely sensitive to low levels of the drug.^3,4 As a result, maximum assay levels (>200 sec) are often achieved before reaching therapeutic levels of dabigatran, making it a suboptimal test.

The dilute thrombin time (dTT) and ecarin clotting time (ECT) have both been suggested as better laboratory parameters for this purpose. The dTT assay measures conversion of fibrinogen to fibrin. One such assay, the HEMOCLOT Thrombin Inhibitor, has demonstrated a linear response with increasing doses of dabigatran.⁴ Notably, it circumvents the issue of TT oversensitivity to low dabigatran levels through a 1:8 dilution of samples prior to assay. In the ECT assay, prothrombin is converted to meizothrombin which is inhibited by dabigatran. Meizothrombin is a precursor to thrombin and also converts fibrinogen to fibrin; thus dabigatran levels can be estimated by measurement of clotting time.^3,4 While these assays are the best to date, there is limited access to them in most clinical settings. Additionally, large-scale trials have not validated their efficacy, and they are currently not FDA-approved for monitoring dabigatran anticoagulant activity.³

Brief Overview of Data Supporting Dabigatran's Efficacy

The 2009 Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared the efficacy of low dose (110 mg twice daily) and high dose (150 mg twice daily) dabigatran to warfarin (goal INR 2-3) in preventing stroke or systemic embolism in patients with non-valvular AF.⁵ While the warfarin and low-dose dabigatran groups had similar rates of stroke or systemic embolism, high dose dabigatran was superior to warfarin. Following this seminal trial, the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER) and Phase III Study Testing Efficacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symp Venous Thromboembolism (VTE) (RE-COVER II) trials compared the reduction of VTE with high-dose dabigatran versus warfarin.^6,7 In a pooled analysis, dabigatran was non-inferior to warfarin with similar risk of major bleeding. Based on these trials, the AHA/ACC/HRS AF guidelines and the European Society of Cardiology (ESC) have recommended dabigatran as an option for anticoagulation in patients with non-valvular AF and acute VTE, respectively.^8,9

Brief Summary of Dabigatran Reversal Strategies to Date

Several methods have been studied for reversal of dabigatran.¹ Ex vivo experiments have shown limited efficacy of charcoal in reversing dabigatran function; due to its lipophilic nature, it binds to the surface of activated charcoal, reducing the amount of drug that is systemically absorbed.¹ However, charcoal is only effective at chelating circulating dabigatran if administered within two hours of the drug, as dabigatran's concentration peaks within this timeframe.

Another method is hemodialysis; since only a fraction of dabigatran is protein-bound, it is easily dialyzed using a charcoal filter. A parallel-group, single-center study in end-stage renal disease patients on maintenance hemodialysis who were given one dose (50 mg) of dabigatran showed a 62% to 68% reduction of circulating drug after hemodialysis.¹⁰ Another single-center case series of five patients on dabigatran 150 mg twice-daily with life-threatening bleeding found that dabigatran levels decreased by 52% to 77% after hemodialysis, but increased back to 87% of initial levels two hours later, likely due to the drug's large volume of distribution.¹¹ Although this method is useful in patients already on hemodialysis, it is not as useful in others, as central venous access and access to hemodialysis machines would be difficult to obtain rapidly, especially in the setting of hemodynamic instability. Additionally, the partial and short-lived reversal makes it a suboptimal option.¹² Hemodialysis is therefore most applicable in the setting of dabigatran overdose.¹

Finally, since direct thrombin inhibitors like dabigatran act on circulating and activated thrombin, it has been believed that increasing the concentration of thrombin would reverse the action of dabigatran. At present, however, synthetic or natural thrombin concentrates are not available for rapid repletion. Studies looking at prothrombin complex concentrates (PCC), activated PCC, and Factor VIIa have shown conflicting results.^1,12,13 A recent in vitro study by Levin et al, studying the efficacy of aminocaproic acid and tranexamic acid in reversing the effects of dabigatran in rats, measured by the activated clotting test, showed no significant benefit.¹⁴ In summary, there has been a lack of reliable methods for reversing dabigatran's anticoagulant activity to date.

Idarucizumab for Dabigatran Reversal

Recently, Boehringer Ingelheim developed idarucizumab, a humanized monoclonal antibody fragment with >350 times the affinity for dabigatran compared to thrombin, as a specific antidote for dabigatran-associated coagulopathy.^15-17 Initial studies to characterize the structure and function of idarucizumab confirmed that the antibody fragment alone did not have thrombin-like functions, despite its structural similarity to thrombin.² Specifically, idarucizumab did not shorten the clotting time, indicating no independent procoagulant activity; it did not increase the concentration of fibrin, indicating lack of conversion of fibrinogen to fibrin; finally, it did not increase platelet aggregation.² It also rapidly reversed the anticoagulant effect of dabigatran.²

Based on these studies in rats, a three-part Phase I randomized, placebo-controlled, double-blind study was undertaken to test the safety, tolerability, and efficacy of idarucizumab in reversing dabigatran activity in humans.^15,17,18 Part one, the safety analysis, included 110 healthy subjects who were randomized to placebo or a predetermined idarucizumab dose ranging from 20 mg to 8 g, delivered over either a one-hour or five-minute infusion.¹⁷ No adverse events occurred, and the drug was well-tolerated. Plasma drug concentrations peaked toward the end of the infusion in all cases, suggesting that the drug would have a favorable bioavailability profile in the setting of emergency reversal.

Part two, the proof-of-concept analysis, aimed to evaluate the safety and efficacy of idarucizumab in reversing dabigatran-associated coagulopathy.¹⁵ In this study, 47 healthy, young male volunteers received four doses of high-dose dabigatran (220 mg twice-daily) over four days, achieving similar median dabigatran concentrations as in the RE-LY trial.¹⁵ Subsequently, they received idarucizumab infusions (1 g, 2 g, or 4 g over five minutes, or 5 g plus 2.5 g over two minute-minute infusions) or placebo within two hours of receiving the final dabigatran dose, due to the short peak-time of dabigatran. For the primary endpoint of drug-related adverse events, seven of 47 participants experienced minor complications such as infusion site erythema, hematoma, or hematuria, none of which required termination of therapy; a dose-dependent pattern was not appreciated on this outcome. The secondary endpoint was reversal of drug function, assessed by dTT HEMOCLOT, ECT, TT, and activated partial thromboplastin time (aPTT). Immediate and complete reversal of dabigatran-induced anticoagulation was achieved in a dose-dependent fashion, with 5 g plus 2.5 g over two infusions being most effective (99% reduction on dTT assay). The dTT assay was followed over a 72-hour period after initial reversal and showed sustained reversal in all groups except for the 1g dose, unlike follow-up assays after hemodialysis. Similar results were achieved with other clotting parameters. Interestingly, idarucizumab has a small volume of distribution, and is mostly present within the circulating blood. On the other hand, dabigatran has a large volume of distribution and equilibrates between circulating blood and tissues. Thus, idarucizumab not only binds to and inactivates circulating dabigatran, but is also believed to draw more of the drug out of the tissues and into the circulation until all free idarucizumab is dabigatran-bound. This may explain the dose-dependent magnitude of reversal.

Part three studied the efficacy of idarucizumab in dabigatran reversal in both healthy and elderly patients with renal impairment, as dabigatran is primarily renally-excreted.¹⁸ A randomized, double-blind, placebo-controlled two-way crossover study enrolled 46 male and female volunteers.¹⁸ Healthy volunteers received 220 mg twice-daily, while patients with mild to moderate renal impairment (CrCl 60-90 mL/min or CrCl 30-60 mL/min) received 150 mg twice-daily over four days. Within two hours of the last dose, infusions of 1 g to 5 g of idarucizumab were administered. dTT, ECT, and aPTT assays were measured for anticoagulation reversal. All doses above 2.5 g showed rapid, complete, and sustained dabigatran reversal, including in patients with impaired renal function, with 5 g being most efficacious; no significant adverse effects were noted.¹⁸

With the promising data from this Phase I trial, the RE-VERSE AD Phase III trial was launched to study idarucizumab-mediated dabigatran reversal in patients with serious bleeding or requiring an urgent procedure.¹⁶ An interim analysis was recently published by Pollack et al. due to its favorable results. In this prospective cohort study, 90 patients on dabigatran, with either serious bleeding (Group A) or requiring an urgent procedure (Group B), received two infusions of idarucizumab 2.5 g within 15 minutes of each other. The majority of patients were on dabigatran for stroke risk reduction in the setting of non-valvular AF.

The primary endpoint was the maximum percentage reversal of dabigatran anticoagulation within four hours of the second infusion of idarucizumab, quantified by the dTT and ECT assays. At baseline, only 68 of the 90 total patients had evidence of anticoagulation by dTT assay, and 81 had evidence of anticoagulation by ECT assay. 98% of patients in Group A and 93% of patients in Group B had normalization of dilute thrombin time immediately after the second idarucizumab infusion; 89% in Group A and 88% in Group B had immediate normalization of ECT. Thereafter, median maximum percentage reversal was 100% (95% confidence interval [CI], 100 to 100) by both assays, and sustained reversal was demonstrated over the next 12-24 hours.

The secondary endpoint of the study was clinical outcomes determined by providers. Among the 51 patients in Group A, only 35 could be assessed due to location of bleeding, and the median time to bleeding cessation was 11.4 hours. Among the 39 patients in Group B, 36 underwent urgent surgery, and normal intraoperative hemostasis was reported in 33 patients. One patient with dabigatran overdose did not require hemodialysis after reversal with idarucizumab. Five patients, in whom anticoagulation was not re-initiated, experienced thrombotic complications including deep vein thrombosis, pulmonary embolism, left atrial thrombus, NSTEMI, and ischemic stroke; one event occurred within 72 hours of idarucizumab infusion, while the other four occurred more than a week later. Overall, 18 patients died, with 5 events due to fatal bleeding.

A major strength of this analysis was the broad inclusion criteria for participation in the study. Realistically, reversal agents such as vitamin K or fresh frozen plasma are only used in acutely ill patients with active bleeding or an emergent need for a procedure requiring normalization of coagulation parameters. By studying these two populations and including elderly patients, the study authors mimicked the most common use cases as closely as possible. Additionally, 65% of the patients had mild to severe renal function impairment, defined by a creatinine clearance <80 mL/min; yet, the trial achieved impressive, sustained anticoagulant reversal.¹⁶ This is another key strength, as dabigatran is primarily renally-excreted and thus supra-therapeutic levels are more likely to occur in these populations.

Several questions remain after the RE-VERSE AD trial. First, the time between receiving the final dabigatran dose and initiation of idarucizumab infusion was longer than the two-hour interval studied in the Phase 1 trials. Of the 90 patients, 64% had taken their last dose of dabigatran more than 12 hours prior to idarucizumab infusion. Of these, 30% had taken it greater than 24 hours prior. Since the half-life of dabigatran is 12 to 17 hours, this raises the question of whether patients were truly anticoagulated at the time of idarucizumab infusion.^3,10 The results of RE-VERSE AD indicate that prior to infusion, 68 patients had elevated dTT, and 81 patients had elevated ECT, indicating anticoagulation; only these patients were included in the efficacy analysis.¹⁶ However, yet another question arises: do these lab parameters accurately measure dabigatran anticoagulant activity? Strong, conclusive data in this area are currently lacking, as discussed previously.^3,19

A second major point involves the study design. As a prospective cohort study, RE-VERSE AD lacked a control group. A placebo-controlled, double-blinded trial design may have answered the question about true anticoagulation status of patients prior to idarucizumab infusion. In addition, such a design would have provided critical information in differentiating the contribution of normal renal clearance of dabigatran versus true reversal with idarucizumab. Pollack et al report ethical considerations of randomizing patients to a control group with placebo or no active treatment, when a standard-of-care dabigatran reversal agent does not exist.¹⁶ While this is, indeed, a valid consideration, it is interesting to note that the ongoing trial evaluating the efficacy of andexanet alfa in reversing rivaroxaban-induced coagulopathy is a randomized, placebo-controlled trial.²⁰

Although the RE-VERSE AD trial had several notable limitations, the data on idarucizumab as a specific antidote to dabigatran-induced coagulopathy are promising. RE-VERSE AD is the first Phase III trial to show rapid and sustained reversal of a NOAC drug in critically ill patients requiring emergent reversal. Other small molecule antidotes to Factor Xa inhibitors such as apixaban and rivaroxaban are actively being studied. Andexanet alfa, a modified recombinant form of Factor Xa, has been shown to reverse the anticoagulant effects of both rivaroxaban and apixaban.¹² Recently, Portola Pharmaceuticals announced the initiation of the Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors – Rivaroxaban (ANNEXA™-R) Phase III randomized, double-blind, placebo-controlled trial studying andexanet alfa's ability to reverse rivaroxaban-induced coagulopathy, with results expected later this year.²⁰ Another drug, aripazine (PER977), developed by Perosphere, has been successfully shown to reverse coagulopathy associated with NOACs such as rivaroxaban, apixaban, and dabigatran, as well as other parenteral anticoagulants (unfractionated heparin, low-molecular-weight heparin, fondaparinux), in preclinical rat models. A Phase I trial is underway to study the safety of aripazine in reversing edoxaban-induced coagulopathy.¹² These small-molecule drugs have begun to pave the way for NOACs as the future standard in anticoagulation therapy.

References

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4. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23:138-43.
5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
6. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-52.
7. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-72.
8. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-104.
9. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033-69,3069a-k.
10. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259-68.
11. Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol. 2013;8:1533-9.
12. Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015;35:198-207.
13. Lindahl TL, Wallstedt M, Gustafsson KM, Persson E, Hillarp A. More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate. Thromb Res. 2015;135:544-7.
14. Levine M, Huang M, Henderson SO, Carmelli G, Thomas SH. Aminocaproic Acid and Tranexamic Acid Fail to Reverse Dabigatran-Induced Coagulopathy. Am J Ther. 2015 Jun 3 [Epub ahead of print].
15. 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. Published online June 16, 2015. Available at http://dx.doi.org/10.1016/S0140-6736(15)60732-2.
16. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373:511-20.
17. 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;113:943-51.
18. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood. 2014;124.
19. Gehrie E, Tormey C. Novel oral anticoagulants: efficacy, laboratory measurement, and approaches to emergent reversal. Arch Pathol Lab Med. 2015;139:687-92.
20. Portola Pharmaceuticals. 2015. Portola Announces Phase 3 ANNEXA-R Study of Andexanet Alfa and Factor Xa Inhibitor XARELTO(R) (rivaroxaban) Met Primary Endpoint With High Statistical Significance. Available at: http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=2005429. Accessed 09/24/2015.

Keywords: Aged, Aminocaproic Acid, Anticoagulants, Antidotes, Antithrombins, Atrial Fibrillation, Benzimidazoles, Biological Availability, Blood Coagulation Factors, Charcoal, Cohort Studies, Confidence Intervals, Control Groups, Creatinine, Critical Illness, Cross-Over Studies, Double-Blind Method, Embolism, Erythema, Factor VIIa, Factor Xa, Factor Xa Inhibitors, Fibrin, Fibrinogen, Follow-Up Studies, Half-Life, Healthy Volunteers, Hematoma, Hematuria, Hemodynamics, Heparin, Heparin, Low-Molecular-Weight, Hydrolysis, Immunoglobulin Fragments, Indicators and Reagents, International Normalized Ratio, Kidney Failure, Chronic, Morpholines, Partial Thromboplastin Time, Pharmaceutical Preparations, Platelet Aggregation, Polysaccharides, Prodrugs, Prospective Studies, Prothrombin, Prothrombin Time, Pulmonary Embolism, Pyrazoles, Pyridines, Pyridones, Renal Dialysis, Risk Reduction Behavior, Stroke, Thiazoles, Thiophenes, Thrombin Time, Thrombin, Thromboplastin, Tranexamic Acid, Venous Thromboembolism, Venous Thrombosis, Vitamin K, Warfarin, beta-Alanine

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