Sunday, October 25, 2015

Dabigatran reversal with idarucizumab (Praxbind)

A 77 year old black patient is admitted to the hospital for a gastrointestinal bleed.  He has a past medical history of CAD (MI 15 years ago), CKD (stage 4), atrial fibrillation, PUD, and hyperlipidemia for which he is taking ASA 81 mg daily, metoprolol tartrate 50 mg twice a day, atorvastatin 20 mg daily, lisinopril 20 mg daily, omeprazole 20 mg daily, and dabigatran 75 mg orally twice a day.  Initial labs indicate an aPTT of 95 seconds, hemoglobin of 6.8 g/dL, and serum creatinine 2.3 mg/dL.


How dabigatran works

Dabigatran is a highly selective, reversible, orally administered anticoagulant that directly binds to the active site of thrombin (IIa).  This prevents thrombin from performing its usual activity of cleaving fibrinogen to fibrin, activating factor XIII (which leads to the covalent bonding and cross-linking of fibrin), activating other factors (causing a positive feedback loop and therefore its own synthesis), and platelet activation.

It is more dependent on renal function for elimination (about 80% of total clearance) than any of the other direct oral anticoagulants.  For stroke prevention in atrial fibrillation it is dosed 150 mg twice a day if the ClCr >30 mL/min and 75 mg twice a day if the ClCr 15-30 mL/min.  No dosing recommendation is made for ClCr <15 mL/min or for those on dialysis though patients with ClCr ≤30 mL/min were not included in the RECOVER or RELY studies.

Dabigatran has the following effects on coagulation tests:
Coagulation test
Effect of dabigatran
Clinical utility
DTT & ECT (diluted thrombin time & ecarin clotting time)
Linear relationship to unbound (functional) dabigatran
Most suitable for assessing anticoagulant activity but not routinely available
aPTT
Elevated, but more variable than DTT & ECT
No therapeutic range
INR
May be elevated but relatively insensitive
Not useful for clinical decision-making


How idarucizumab (Praxbind) works

Idarucizumab (Praxbind) is a humanized monoclonal antibody fragment that binds specifically to dabigatran.  Dabigatran has a 350-fold higher binding affinity for idarucizumab than it does for binding thrombin.  This 1:1 complex, once formed, is essentially irreversible due to the very slow dissociation of dabigatran from idarucizumab.  Then, the complex seems to be eliminated by protein catabolism, mainly in the kidney.  It specifically reverses dabigatran with no impact on the effect of other anticoagulant or antithrombotic therapies.  Additionally, because idarucizumab does not affect thrombin in any direct way, its use does not affect the coagulation cascade itself and therefore does not place the patient in a hypercoagulable state.


Bleeding from dabigatran

When dabigatran was approved, it was known from the RELY trial that major bleeding rates were similar to warfarin with dabigatran having more gastrointestinal bleeds but less intracranial hemorrhages.  A recent study of post-market Medicare patients found that bleeding rates were higher with dabigatran compared to warfarin.  This included:
  • Any bleeding: 32.7% vs 26.5% (p<0.001)
  • Major bleeding: 9% vs 5.9% (p<0.001)
  • Minor bleeding: 28.6% vs 23.6% (p<0.001)
The only exceptions to this were both decreased intracranial bleeding and epistaxis with dabigatran (about 1% each in favor of dabigatran).

There were also some demographic and clinical factors that associated dabigatran with increased risk of bleeding.  Those include:
  • Age ≥75 rather than <65
  • Blacks
  • Chronic kidney disease
  • Antiplatelet use


How to use idarucizumab (Praxbind)

Idarucizumab was studied and approved on the basis of its reduction of unbound dabigatran and normalization of coagulation parameters in health volunteers and an interim analysis of a phase 3 trial (RE-VERSE AD).  This analysis was of 90 patients who were taking dabigatran and experiencing either an overt, uncontrollable, or life-threatening bleed that was deemed to require reversal or who were undergoing surgery or an invasive procedure that required normal hemostasis.  Approval of idarucizumab is contingent on the ongoing results of the study.

Idarucizumab is given as a one-time 5 gram dose intravenously (2.5 gram vials administered <15 minutes apart - can be immediately one after the other) intended to reverse the total body load of dabigatran.  It is possible that the aPTT, if you decide to check it, can become elevated 12-24 hours after administration and if you see this PLUS clinically relevant bleeding, it's reasonable to consider giving an additional 5 gram dose.

In the RE-VERSE AD study, coagulation parameters (dTT and ECT) had a median reversal of 100% immediately after the idarucizumab infusion ended. At 12 and 24 hours, the dTT was still normal in >81% of patients and the ECT was still normal in 54% of patients.  Unbound serum concentrations of dabigatran were <20 ng/mL immediately after the infusion (this produces little or no anticoagulant effect) in all but one patient.  As far as bleeding outcomes, in the patient group who had an overt, uncontrollable, or life-threatening bleed  the median time to bleeding cessation was 11.4 hours.  In the patient group who were undergoing surgery or an invasive procedure, normal intraoperative hemostasis was reported in 92% of patients.


Back to the patient case

Looking at the patient's history, several risk factors for bleeding while on dabigatran are identified including age, race, CKD, and aspirin use.  His aPTT is elevated which suggests (and nothing else) that he is taking dabigatran and he may be hypocoagulable.  In conjunction with standard supportive measures, idarucizumab 5 grams intravenously can be administered if deemed medically necessary.  Bleeding should be expected to stop in about 11 hours and if clinically significant bleeding continues after that, another aPTT can be checked and if elevated, another dose administered.

Take home points:

  • Idarucizumab is the first antidote approved for a direct oral anticoagulant
  • It will only work for reversing dabigatran
  • Administer a one-time dose in addition to supportive care
  • Approval is based largely on response of coagulation tests and unbound drug concentrations, not clinical endpoints

References
1.  Licari LG, Kovacic JP.  Thrombin physiology and pathophysiology.  J Vet Emerg Crit Care  2009;19(1):11-22.
2.  Pradaxa (R) [package insert].  Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2015.
3.  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(680-90).
4.  Praxbind (R) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2015.
5.  Pollack CV, Reilly PA, Eikelboom J, et al.  Idarucizumab for dabigatran reversal.  N Engl J Med  2015;373:511-20.
6.  Boehringer Ingelheim.  FDA Approves Praxbind (R) (idarucizumab), Specific reversal agent for Pradaxa (R) (dabigatran etexilate mesylate) Available at: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2015/10-16-2015-fda-approves-praxbind-idarucizumab-specific-reversal-agent-pradaxa-dabigatran-etexilate-mesylate.html Published October 2015.  Accessed October 2015.

photo by Andrew Mason

3 comments:

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