Praxbind in Practice

On October 16th, the FDA approved the use of idarucizumab (Praxbind®), a monoclonal antibody developed by Boehringer Ingelheim Pharmaceuticals for the reversal of dabigatran. It proved effective in lab trials, but is it ready for prime time in the ED?

The prescription and use of target-specific oral anticoagulants (TSOACs) have sky-rocketed in the last five years as new agents have flooded the market. TSOACs have several benefits over the older vitamin K antagonist, warfarin: there are reportedly fewer serious bleeding complications, patients do not require frequent monitoring of coagulation, and there are no dietary restrictions.

Dabigatran (Pradaxa®) is a drug created by Boehringer Ingelheim Pharmaceuticals that was approved for use in the United States in 2010 for non-valvular atrial fibrillation, as well as for treatment and prevention of DVT and PEs [^1]. Patients taking dabigatran are at risk for serious hemorrhagic complications, and until recently, there was no available reversal agent [^2-5].

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Reversal of Dabigatran
Dabigatran is a direct thrombin inhibitor, so it cannot be reversed with vitamin K or fresh frozen plasma. Emergent hemodialysis can remove circulating dabigatran, but is not a rapidly available option in many cases [^3,6]. In dabigatran-related hemorrhagic emergencies, prothrombin complex concentrate (PCC) has been used in an attempt to reduce bleeding. However, a randomized, placebo-controlled study of PCC showed no effects on the anticoagulation effects of dabigatran [^3,6,7]. Despite the lack of evidence of efficacy, many health care facilities include the administration of PCC in their treatment protocols for life-threatening bleeding in patients taking dabigatran.

Enter: Praxbind
On October 16th, the FDA approved the use of idarucizumab (Praxbind®), a monoclonal antibody developed by Boehringer Ingelheim Pharmaceuticals for the reversal of dabigatran. The FDA approved idarucizumab through the accelerated approval program after the preliminary results of the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study indicated the complete reversal of dabigatran-induced elevations in dilute thrombin time (dTT) and ecarin clotting time (ECT) within minutes [^8]. This study, funded by Boehringer Ingelheim Pharmaceuticalsis, is an ongoing prospective cohort study with their initial results published after the effects were seen in 90 patients, with an on-going goal to reach up to 300 patients [^9]. However, it is important to note that the trial design was an observational cohort without a control arm to truly evaluate efficacy. The manufacturer had final say over the study and the authors of the paper had extensive commercial ties.

RE-VERSE AD Study Inclusions
The patients included were primarily white, about 70 yrs old, not obese, and with ‘normal’ renal function. CrCl ranged from 48-67ml/min, In addition, 22/90 or 24% had normal dilute thrombin times at study baseline.

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Indications to Treat with Idarucizumab
Idarucizumab was approved for use in patients who are anticoagulated with dabigatran in the following circumstances:

• In life-threatening or uncontrolled bleeding
• Requiring emergency surgery or urgent procedures within 8 hours [^10]

Dosage
Patients are to be treated with 5 g of intravenous idarucizumab, which should be administered as two 50-ml bolus infusions, each containing 2.5 g of idarucizumab, no more than 15 minutes apart [^10].

Half-life
The clearance of dabigatran is dependent on renal function. In healthy patients, the half-life of dabigatran is 12- 17 hours, although this can be prolonged in patients with decreased creatinine clearance [^1]. The half-life of idarucizumab is 10 hours, indicating that repeat dosing may be necessary depending on the timing and amount of the last dabigatran dose and the patient’s renal function [^10]. Also, in the RE-VERSE AD study, hemostasis in patients treated with idarucizumab was not achieved until approximately 11.4 hours after treatment [^9].

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Contraindications and Side Effects

• The most frequent side effect reported was headache, which is unlikely to be clinically significant when reversing dabigatran for a life-threatening, emergent bleed.
• Other adverse clinical outcomes included hypokalemia, delirium, pyrexia, pneumonia, right ventricular failure and pulmonary edema.
• There are no contraindications listed in the prescribing information, but since this is a monoclonal antibody, there is a risk for anaphylaxis.
• There is a risk of serious adverse reaction in patients with hereditary fructose intolerance because of the sorbitol contained in the product.
• Thrombosis is a risk. First, these patients were anticoagulated for some reason and should be placed back on anticoagulation when clinically indicated. Of the 90 patients studied, thrombotic events occurred in 5 patients within 30 days after administration of idarucizumab, including DVT, PE, NSTEMI and ischemic stroke [^9,10].

Cost
The U.S. price for the recommended 5 g dose of idarucizumab is $3500. This figure does not include the hospital charge to the patient, nor does it include the hospital charge to the patient. The product was launched on October 22nd and is available through specialty pharmacies [^11].

ANALYSIS
Clinical Effectiveness
While the authors of the RE-VERSE AD trial conclude that idarucizumab reversed the anticoagulant effect within minutes, the reversal outcome was measured using laboratory tests (dTT and ECT). The study design did not allow demonstration of any reduction in morbidity or mortality. The clinical relevance of using laboratory markers as a surrogate for effectiveness is unclear at this time as the evidence shows the decrease in free dabigatran concentrations but not necessarily the level of anticoagulation or clinically relevant bleeding. In addition, these tests are not routinely available to clinicians so cannot be used to measure laboratory effectiveness. Hemostasis was achieved after treatment with idarucizumab in patients with serious bleeding at approximately 11.4 hours after treatment, which is similar to the half-life of dabigatran. The much more rapid improvement in dTT and ECT likely indicates that these studies do not correlate well with degree of anticoagulation.

Hemostasis was reported as normal in 92% requiring urgent procedures, but the time from administration of idarucizumab to the time of procedure was not reported in the results of the study. Of the 90 patients studied, 13 of the patients had no hemostasis timing data and 18 of patients had intracranial hemorrhages with no way to measure actual cessation times [9].

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The dose of idarucizumab was calculated based on the amount required to reverse the total body load associated with the 99th percentile of dabigatran levels in the RE-LY trial. The dosing will likely need to be increased in patients with overdose, repeated supratherapeutic use, or decreased renal clearance [2,9].

With regards to the adverse events, it is difficult to discern the risks of this monoclonal antibody with only 90 patients’ results reported thus far. Despite treatment, 20% of the patients died, 5.6% had thrombotic events, and 23.3% had other adverse events. Post-marketing surveillance will be needed to clarify the true adverse risks [9].

The Bottom Line
The RE-VERSE AD trial was a study of laboratory effectiveness and was not designed to truly measure clinical effectiveness. While many emergent situations require the need to treat thrombin-inhibitor coagulopathy, it does not seem that there is enough evidence to universally implement this treatment. The current level of evidence on safety and efficacy must be considered an individual basis. A study that is designed with a control group, more patients, and measurement of clinical effectiveness rather than laboratory data would be ideal. Discussions amongst hospital pharmacists and specialists to include hematologists, emergency physicians and surgeons should help to guide the development of institutional indications for use of idarucizumab.

Opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Air Force, the Department of the Army, or the Department of Defense.

REFERENCES

1. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. October 2010.
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2009;361(12):1139-1151.
3. Fenger-Eriksen C, Munster AM, Grove EL. New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications. Acta Anaesthesiol Scand. 2014;58(6):651-659.
4. King AE, Szarlej DK, Rincon F. Dabigatran-Associated Intracranial Hemorrhage: Literature Review and Institutional Experience. Neurohospitalist. 2015;5(4):234-244.
5. 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(4):281-287.
6. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S12-21.
7. 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(14):1573-1579.
8. Fda.gov. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm.
9. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-520.
10. Praxbind [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. October 2015.
11. Dabigatran-Reversal Agent Price Set. NEJM Journal Watch. 2015:nejm-jw.FW110754.