Oral anticoagulation is a clinical therapeutic that is frequently prescribed by numerous providers in many medical settings. There are two different types of oral anticoagulation, including vitamin-K antagonists (VKAs), such as warfarin, and the new class of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and endoxaban.1 Until recently, warfarin has been the standard therapy for oral anticoagulation.2 However, according to the most recent CHEST guidelines on antithrombotic therapy for venous thromboembolism (VTE), experts in the field of anticoagulation agreed that DOACs provide advances in efficacy, overall safety, and patient and provider simplicity as the preferred anticoagulant when compared with warfarin in patients without cancer.3
This expert consensus was largely driven by multiple recent, large clinical trials that have established the efficacy and safety of DOACs for stroke prevention and VTE treatment and prevention. Since 2009, four large multicenter, randomized, double-blind, placebo-controlled trials demonstrated that DOACs were noninferior in the prevention of stroke in patients with nonvalvular atrial fibrillation and had a lower risk of bleeding compared with warfarin.4-7 Several other large phase 3 clinical trials have shown that DOACs were noninferior to warfarin regarding acute VTE treatment and prevention of recurrent VTE. In addition, DOACs had a lower risk of bleeding and similar risk of major fatal bleeding compared with warfarin.4,8-14 Furthermore, a recent systematic review and meta-analysis of 13 randomized control trials evaluated mortality data and showed that DOACs were associated with lower rates of fatal bleeding, cardiovascular mortality, and all-cause mortality compared with warfarin.15 These trials have even led to the recent update in guidelines on antithrombotic therapy for VTE released by the CHEST Guideline and Expert Panel in January 2016. The panel suggests that a DOAC should be used preferably over a VKA for initial and long-term therapy of VTE in patients without cancer (Grade 2B).3
Reversal agents for DOACs
Given these recent new guidelines, expert consensus statements, and multiple promising large trials, DOACs will be at the forefront of antithrombotic therapy. However, despite their non-inferior efficacy and lower risk of bleeding compared with warfarin, there is still a bleeding risk with any anticoagulant drug and a paucity of data regarding reversal agents for the new DOACs.16
Idarucizumab recently received accelerated approval to reverse the anticoagulant effects of dabigatran in patients requiring emergent surgery/urgent procedures or life-threatening/uncontrolled bleeding based on findings from the Reversal Effects of Idarucizumab on Active Dabigatran trial (RE-VERSE AD).17,18
Early trial results for idarucizumab
Schiele et al presented the first report of a specific antidote for DOACs, referred to as aDabi-Fab, now known as idarucizumab.18,19 The research group characterized aDabi-Fab as a monoclonal antibody fragment that binds and neutralizes the anticoagulant effects of dabigatran. They showed that the antidote exhibited a high affinity for dabigatran, roughly 350 times greater than for thrombin in vitro and in vivo. Additionally, the researchers showed that aDabi-Fab demonstrated quick reversal of dabigatran as measured by thrombin time (TT) and activated partial thromboplastin (aPTT) time in vivo in a rat model.19 These key findings were essential in the translation of idarucizumab as a humanized clinical therapeutic for future studies.
In March 2015, Glund et al conducted a two-part randomized, double-blind, placebo-controlled phase 1 trial on humanized idarucizumab. In the first part of the study, the group investigated the safety, tolerability, and pharmacokinetics of different doses of idarucizumab in 110 healthy male volunteers aged 18 to 45. They concluded that idarucizumab was safe and tolerable at all doses administered in the study. In addition, maximum concentrations of idarucizumab were achieved at the end of infusion followed by quick elimination without any effect on coagulation parameters.20 In the second part of the study, the group investigated the safety, tolerability, and efficacy of idarucizumab as a reversal agent for dabigatran in 47 men from the first part of the study. They showed that idarucizumab exhibited quick reversal of dabigatran with persistent effect at all doses tested without any major adverse events.21 Also, Glund et al concluded that idarucizumab was safe, tolerable, and exhibited persistent effect at all administered doses in elderly and renally impaired patients.22
Following the promising results from several studies on the safety, tolerability, and efficacy of idarucizumab, Pollack et al developed a multicenter, prospective cohort study, referred to as REVERSE-AD, to evaluate the safety of 5 grams of idarucizumab, which was given as two separate 2.5-gram infusions, and its ability to reverse dabigatran in patients who had serious bleeding (group A) or required an urgent procedure/surgery that could not be delayed for at least 8 hours and required hemostasis (group B). The study began in June 2014 and completed enrollment in July 2016. The primary outcome of the study was maximum reversal of dabigatran’s anticoagulant effects as measured by direct thrombin time (dTT) and ecarin clotting time (ECT) in the first 4 hours after initial infusion.
The maximum reversal was calculated as a percentage using the following equation: percentage reversal = (predose test result [in seconds] − minimum postdose test result [in seconds] ∕ (predose test result [in seconds] − upper limit of normal range [in seconds]) × 100. In an interim analysis of the first 90 patients enrolled, 68 patients with elevated dTT and 81 patients with elevated ECT at baseline were found to have maximum reversal of dabigatran’s anticoagulant effects of 100%, immediately after infusion of idarucizumab. Furthermore, dTT normalized in 98% of patients in group A and 93% of patients in group B
ECT normalized in 89% of patients in group A and 88% of patients in group B. The study found that similar maximum reversal and normalization findings of aPTT and TT were seen among each group. Furthermore, following the administration of idarucizumab, the concentration of unbound dabigatran was decreased to a level that produces little to no anticoagulant effect in all patients but one in the cohort. There were no safety concerns with administration of idarucizumab at the study dose.17
In August 2017, Pollack et al published the full cohort analysis of 503 patients from the REVERSE-AD trial. The robust findings validated the initial results from the interim analysis of 90 patients. In those patients receiving dabigatran with prolonged dTT and uncontrollable bleeding or need for an urgent procedure, idarucizumab reversed the anticoagulant activity of dabigatran in more than 98% of patients. The 30-day and 90-day mortality data were similar between the groups and were concluded to be due to the initial event or comorbid conditions and less likely as a result of idarucizumab effects.23
Following the interim analysis findings from the REVERSE-AD trial, idarucizumab received accelerated approval on October 16, 2015, for patients requiring emergent surgery/urgent procedures or life-threatening/uncontrolled bleeding. The recommended dose is 5 grams, given as two separate vials each containing 2.5 grams/50 milliliters.18 The wholesale acquisition cost of two vials of 2.5 grams of idarucizumab is about $3500.24 Even though the data have high impact, there are limitations to the study. First, most hospitals do not routinely use dTT or ECT levels, complicating the ability to measure the effects of idarucizumab on dabigatran reversal. The reason for their use in this study was based on their high correlation with unbound dabigatran levels.21 However, hospitals do routinely order aPTT as a coagulation parameter. Given that the study showed maximum reversal within the first few minutes and normalization of aPTT after idarucizumab administration, aPTT may be a potential coagulation parameter for monitoring idarucizumab. Second, there was no control group in the study; however, the authors acknowledge this limitation and state that it would be unethical to randomly assign patients to a placebo group given there are no approved alternatives to idarucizumab. Third, the REVERSE-AD trial did not evaluate any other specific indications for idarucizumab other than uncontrollable bleeding or need for urgent procedure. These data will need to be explored in future studies.
Potential alternative reversal agents
Three other potential methods have been evaluated as reversal agents for dabigatran. Khadzhynov et al conducted an open label, single center, phase 1 study to evaluate the elimination of dabigatran with renal replacement therapy in patients with end-stage renal disease. Their study findings showed that intermittent hemodialysis decreased plasma dabigatran concentrations by 48.8% to 59.3%.25 In 2011, Erenberg et al conducted a randomized, double-blind, placebo-controlled study evaluating the reversal effects of prothrombin complex concentrate (PCC) on rivaroxaban and dabigatran. They concluded that PCC quickly and completely reversed the effects of rivaroxaban but had no effect on dabigatran.26
In contrast, in 2012, Pragst et al conducted an open-label, placebo-controlled study evaluating the reversal effects of PCC among rabbits treated with dabigatran. They concluded that PCC decreased blood loss and increased hemostasis in a variety of dabigatran doses. Importantly, the doses used were similar to those used in clinical practice.27 Lastly, Lange et al showed that dabigatran can be removed via activated charcoal; 75% to 80% of circulating dabigatran was reduced after 1 hour and levels were undetectable after 2 hours. However, the maximum binding capacity for activated charcoal is 30 mg of drug, far less than the current recommended dose of dabigatran.28 Even though these studies may have promising potential, future large human randomized studies are warranted to determine their efficacy in reversing the effects of dabigatran as well as their efficacy when compared with idarucizumab.
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Given the recent updates on oral anticoagulation in the literature and findings from multiple large clinical trials showing the efficacy of DOACs, these drugs will become the leaders in antithrombotic therapy. Therefore, advances in new reversal agents will be a key piece to the puzzle for managing patients treated with DOACs to prevent major bleeding events. The promising data from the interim and full cohort analysis of the REVERSE-AD trial has put idarucizumab in the spotlight as the first approved DOAC reversal agent. However, future studies on idarucizumab are warranted to establish its potential indications in different patient populations.
Zachary Lavender, PA-C, MHS, and Peter S. Sandor, RRT, MHS, PA-C, DFAAPA, are critical care physician assistants based in Hartford, Conn., and faculty members at Quinnipiac University in Hamden, Conn.
- Barnes GD, Ageno W, Ansell J, Kaatz S. Subcommittee on the Control of Anticoagulation. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:1154-1156. doi: 10.1111/jth.12969.
- Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):e44S-88S. doi: 10.1378/chest.11-2292.
- Kearon C, Akl E, Ornelas J, et al. Antithrombotic therapy for VTE disease, Chest guideline and expert panel report. Chest. 2016;149:315-352. doi:10.1016/chest.11.026.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151. doi: 10.1056/NEJMoa0905561.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. doi: 10.1056/NEJMoa1009638.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. doi: 10.1056/NEJMoa1107039.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104. doi: 10.1056/NEJMoa1310907.
- 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. doi: 10.1056/NEJMoa0906598.
- Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772. doi: 10.1161/CIRCULATIONAHA.113.004450.
- Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718. doi: 10.1056/NEJMoa1113697.
- EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510. doi: 10.1056/NEJMoa1007903.
- EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297. doi: 10.1056/NEJMoa1113572.
- Hokusai-VTE Investigators, Buller HR, Decousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415. doi: 10.1056/NEJMoa1306638.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808. doi: 10.1056/NEJMoa1302507.
- Chai-Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13:2012-2020.
- Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: The RE-LY trial (randomized evaluation of long-term anticoagulation therapy). J Am Coll Cardiol. 2014;63:321-328. doi: 10.1016/j.jacc.2013.07.104.
- Pollack CV,Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520. doi: 10.1056/NEJMoa1502000.
- Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; revised October 2015.
- Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-3562. doi: 10.1182/blood-2012-11-468207.
- 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. doi: 10.1160/TH14-12-1080.
- 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. doi: 10.1016/S0140-6736(15)60732-2.
- 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. Oral presentation made at the 56th Annual Meeting of the American Society of Haematology and Exposition, San Francisco, 2014 (abstract).
- Pollack CV, Reilly RA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377:431-441. doi.10.1056/NEJMoa1707278
- Buchheit J, Reddy P, Connors JM. Idarucizumab (Praxbind) Formulary Review. Crit Pathw Cardiol. 2016;3:77-81. doi:10.1097/HPC.0000000000000076.
- 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. doi: 10.1160/TH12-08-0573.
- Eerenberg 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;124:1573-1579. doi: 10.1161/CIRCULATIONAHA.111.029017.
- Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (beriplex P/N) in a rabbit model. J Thromb Haemost. 2012;10:1841-1848. doi: 10.1111/j.1538-7836.2012.04859.x.
- Lange J, Thiel C, Thiel K, Klingert W, Klingert K, et al. Acceleration of dabigatran elimination by activated charcoal perfusion and hemodialysis in a pig model. Presentation made at the 2012 Annual Meeting of the American Society of Haematology. Abstracts. 120:2272.