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Authors

  1. O'Malley, Patricia Anne PhD, RN, CNS

Article Content

Despite the availability, safety, and efficacy of novel oral anticoagulants (NOACs) compared with warfarin, acceptance and use have been hampered by lack of a specific reversal agent. This may be part of the reason why anticoagulants remain widely underprescribed for stroke prevention in atrial fibrillation.1 The lack of an antidote to reverse NOACs in emergent situations such as life-threatening bleeding or emergent major surgery has been a significant clinical issue until now.2 The recent approval of idarucizumab (Praxbind; Boehringer Ingelheim, Ridgefield, Connecticut) to reverse the anticoagulant effects of dabigatran (Pradaxa; Boehringer Ingelheim) has resulted in the first and only NOAC with a specific reversal agent.3,4

 

Pradaxa was approved in 2010 to prevent stroke and systemic blood clots in patients with atrial fibrillation and for the treatment and prevention of deep venous thrombosis and pulmonary embolism without a specific reversal agent. Now, Praxbind has been approved specifically for Pradaxa under the FDA's accelerated approval program (http://www.fda.gov/ForPatients/Approvals/Fast/ucm405447.htm), which permits drug approval for serious conditions that is likely to provide a clinical benefit.4,5

 

Dabigatran Etexilate (Pradaxa)

Dabigatran has demonstrated effectiveness as an alternative to warfarin for prevention of stroke in atrial fibrillation and venous thromboembolism. The half-life is approximately 10 to 13 hours in patients with adequate renal function with a 75% decrease in anticoagulant effect within 24 hours.6 Dabigatran absorption can be modified with activated charcoal if administered shortly after ingestion and can be removed via hemodialysis. Other agents such as prothrombin have not demonstrated practical applicability in situations where emergency reversal is necessary.7

 

Idarucizumab (Praxbind)

Idarucizumab was created using direct recombinant expression technology to specifically target the direct thrombin inhibitor dabigatran. Crafted in a purified recombinant mammalian CHO cell line, idarucizumab is composed of a light chain of 219 amino acids and a heavy-chain fragment of 225 amino acids covalently linked by 1 disulfide bond. Once administered, the humanized antibody fragment (Fab) binds with dabigatran, the metabolites with a greater affinity than the affinity of dabigatran to thrombin, which neutralizes the anticoagulant effects.6,8 After intravenous administration of idarucizumab, a dabigatran-idarucizumab complex is created with dabigatran drawn from blood compartments and tissues. This binding is nearly irreversible. The result is a rapid and significant increase in plasma dabigatran, which represents amount of dabigatran-idarucizumab complex, which is inactive as an anticoagulant.6

 

Intravenous idarucizumab is indicated for reversal of anticoagulant effects of dabigatran for emergency surgery and life-threatening or uncontrolled bleeding. These indications were approved under an accelerated approval based on reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers. Continued approval for these indications may be contingent upon the results of an ongoing cohort case series study.4,8

 

Patients may require a second dose if clinically significant bleeding or re-elevation of coagulation indices recurs or if a second emergent surgery or procedure is needed. At this time, there are limited data regarding administration of a second dose beyond the first dose. Idarucizumab has an initial half-life of 47 minutes and a terminal half-life of 10.3 hours and is rapidly eliminated by the kidney. In a small number of subjects in clinical trials with mild renal impairment, total clearance was reduced. The median maximum reversal of anticoagulant effects in the first 4 hours after dosing of 5 g of idarucizumab was 100%, with effects evident immediately after administration. Greater than 89% of subjects achieved complete reversal.8,9

 

Risks

Reversing dabigatran therapy exposes patients to pretherapy thrombotic risks. Therefore, anticoagulant therapy should resume as soon as appropriate. Dabigatran activity was not affected when restarted 24 hours after idarucizumab. Patients with hereditary fructose intolerance may be at risk of adverse reactions with idarucizumab. Other frequently reported adverse events (in >=5% of patients treated with idarucizumab) included hypokalemia, constipation, delirium, fever, and pneumonia. At this time, any risks for pregnant and breast-feeding women as well as pediatric patients and patients with hepatic impairment are unknown. Renal impairment does not impact the reversal effects of idarucizumab.8,9

 

Recent Evidence

In 2013, male volunteers aged 18 to 47 years participated in a randomized, placebo-controlled, double-blind phase 1 trial that examined incidence of drug-related adverse events. Secondary end points included reversal of diluted thrombin time ecarin clotting time, activated partial thromboplastin time, and thrombin time.6

 

This first trial of idarucizumab in human beings resulted in immediate, complete, and sustained reversal of anticoagulation as a result of dabigatran therapy without serious or severe adverse events. There were no adverse events associated with discontinuation of treatment, and there were no differences in the incidence of adverse events between treatment groups. For doses 2 g or greater, the effect was sustained for more than 72 hours.6

 

The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study is a multicenter, prospective cohort study that examines the efficacy and safety of idarucizumab in patients who present with serious bleeding or who required urgent surgery or intervention receiving dabigatran. Patients are currently being recruited in more than 400 centers in 38 countries. Cohort A is composed of patients with life-threatening or uncontrollable bleeding judged by the treatment provider as requiring a reversal agent. Cohort B is composed of patients requiring surgery or other invasive procedures that could not be delayed for at least 8 hours and required normal hemostasis. The primary study end point is the maximum percentage reversal of the anticoagulant effect of dabigatran over several hours. Secondary end points include bleeding, hemodynamic stability, hemostasis, thrombotic events, or death (vascular or nonvascular) occurring within 90 days of infusion.10

 

Early results are favorable. More than 90% of the first 90 patients were receiving dabigatran for stroke prevention related to atrial fibrillation. Bleeding was related to events such as intracranial hemorrhage, gastrointestinal bleeding, and trauma. Similar to results found in healthy volunteers, idarucizumab reversed the anticoagulant activity of dabigatran in 88% to 98% of patients. Reporting all clinical outcomes for this study is beyond the scope of this article. However, no safety concerns have been revealed in this initial analysis, which included patients who received idarucizumab based on clinical grounds and were found later to have had normal clotting tests at baseline.10

 

The Future

The RE-VERSE AD trial, which began in May 2014, is planned to be completed by July 2017 with an estimated enrollment of 500 patients. You can check out the progress of this trial on the Web at https://clinicaltrials.gov/show/NCT02104949. For now, the company is required to continue to submit clinical information to confirm Praxbind benefits.4

 

Dabigatran as a direct thrombin inhibitor remains a part of emerging anticoagulant therapies. Other options include anti-Xa agents rivaroxaban (Xarelto; Bayer Healthcare), edoxaban (Savaysa, Lixiana; Daiichi-Sankyo), and apixaban (Eliquis; Bristol-Myers Squibb). These agents such as dabigatran do not require ongoing monitoring and dose changes. However, they lack a clinically available specific reversal agent, a worrisome prescribing issue.7,11,12

 

At this time, additional specific reversal agents are being explored. These include andexanet alfa (r-Antidote PRT064445; Portola Pharmaceuticals), a truncated form of enzymatically inactive factor Xa, which reverses the action of Xa inhibitors rivaroxaban, apixaban, and edoxaban. Another specific reversal agent is aripazine (PER-977, ciraparantag; Perosphere Inc), which is a synthetic small molecule that reverses oral Xa and thrombin inhibitors, as well as subcutaneous fondaparinux (Arixtra; GlaxoSmithKline Inc) and low-molecular-weight heparin in vivo.11,12

 

References

 

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4. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. U.S. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm October 16, 2015. Accessed December 17, 2015. [Context Link]

 

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6. 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 randomized, placebo-controlled, double-blind phase 1 trial. Lancet. 2015; 386(9994); 680-690. [Context Link]

 

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8. PRAXBIND(R) (Idarucizumab) Injection, for Intravenous Use [prescribing information]; initial U.S. Approval: 2015. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA US License No. 2006. Product of Germany. http://us.boehringer-ingelheim.com/content/dam/internet/opu/us_EN/documents/Medi. 10/2015. Accessed December 17, 2015. [Context Link]

 

9. Praxbind (Idarucizumab) Injection, for Intravenous Use [highlights of prescribing information]. Initial U.S. Approval: 2015. Revised 10/2015. http://us.boehringer-ingelheim.com/content/dam/internet/opu/us_EN/documents/Medi. Accessed December 17, 2015. [Context Link]

 

10. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015; 373(6): 511-520. [Context Link]

 

11. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Terleira-Fernandez AI, Vargas-Castrillon E. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov. 2014; 9(1): 2-10. [Context Link]

 

12. Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P, Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants. Expert Rev Cardiovasc Ther. 2015; 13(1): 95-103. [Context Link]