Download REVERSE-AD: Reversal Effects of Idarucizumab on Active

REVERSE-AD: Reversal Effects of Idarucizumab on Active Dabigatran
Ted Berei, Pharm.D., MBA | Mentor: Jeff Langford, Pharm.D., BCPS
Trial Summary
The REVERSE-AD (Reversal Effects of Idarucizumab on Active Dabigatran) trial is an ongoing, nonrandomized, multi-center/national, prospective, cohort trial. We were offered a snapshot cohort of 90
patients in the 2015 New England Journal of Medicine article “Idarucizumab for Dabigatran Reversal”1.
Idarucizumab represents the first novel oral anticoagulant (NOAC) reversal agent approved by the
United States Food and Drug Administration (FDA), ultimately making it to the market in late 2015. It will
soon be followed by Andexanet Alfa, a reversal agent for Factor Xa inhibitors, which has shown clinical
efficacy in phase II proof-of-concept testing.2 This new wave of reversal agents will have considerable
clinical implications for patients presenting with major bleeding or the need for anticoagulation reversal
prior to emergent surgery in addition to other miscellaneous clinical indications. The pharmacoeconomic
burden also has the potential to be significant.
Currently there is no clinically accepted or guideline recommended reversal method for the NOACs. If a
patient has ingested dabigatran within the past two hours, activated charcoal should be administered.
Use beyond two hours is futile as dabigatran rapidly reaches peak serum concentrations within this time
period. Fresh frozen plasma (FFP) can aid in normalizing coagulation, but the amount necessary to do so
would be clinically irrational. In addition, FFP takes time to thaw, ABO cross-match, and can cause fluid
overload in hemodynamically unstable patients in addition to the inherent infection risk and
allosensitization potential (considerable for transplant candidates). The concentrated factor products
have shown limited utility in small clinical trials and anecdotally through case reports.3 Considering their
pro-thrombotic nature and lack of established effectiveness in reversing NOACs, careful use is
recommended. Finally, hemodialysis is an attractive option, but the practicality of rapid use in
hemodynamically unstable patients questions its true utility. Given dabigatran’s low protein binding,
however, it may be extremely useful in overdose situations.
REVERSE-AD is enrolling patients in two specific groups: A – those with uncontrolled, clinically overt, lifethreatening bleeding (see the supplementary appendix for more information); B – those requiring
emergent surgery (within 8 hours or less). Those meeting inclusion and exclusion criteria receive 2 – 2.5g
boluses of Idarucizumab for a total dose of 5g. The boluses must be separated by no less than 15
minutes, which mirrors current package insert instructions. Clinical efficacy is based off the maximum
ability of Idarucizumab to normalize diluted thrombin time (dTT) and ecarin clotting time (ECT) within 4
hours of the last vials administration. These assays were chosen due to their excellent correlation with
dabigatran concentrations; however, most institutions lack the ability to perform either analysis in a
timely fashion. It should be noted that patients were enrolled based on clinical presentation and not on
clotting assay results, as this information was not made available to practitioners in real time to guide
therapy. Nearly 90% of the first 90 enrollees were utilizing dabigatran for means of stroke prevention
secondary to a diagnosis of atrial fibrillation. The median maximum percentage reversal for patients in
groups A and B was 100% (95% CI, 100 to 100). Furthermore, within 4 hours of the initial infusion the
median concentration of unbound dabigatran was approximately 1 ng/mL and at 24 hours post-dose
nearly 80% of patient’s plasma concentrations were less than 20 ng/ml, which produces minimal
anticoagulant activity. Interestingly, clinicians were asked to assess when patients in Group A reach
adequate hemostasis. The median time for this was 11.4 hours, which is discordant with the immediate
reversal we saw according to laboratory parameters. This warrants further investigation and explanation
once final trial results are published. Ultimately, institutions need to determine how this novel agent will
REVERSE-AD: Reversal Effects of Idarucizumab on Active Dabigatran
Ted Berei, Pharm.D., MBA | Mentor: Jeff Langford, Pharm.D., BCPS
be best utilized. Considerable thought should be directed towards determining if Idarucizumab is
necessary based on the patient’s age, renal function, time since last dose, and thrombin time/aPTT. Lest
we not forget placing patient’s on appropriate NOACs from the onset of therapy to mitigate the
potential for serious bleeds and the necessity of dose adjustments based on renal function.
Follow-up Questions
1. Knowing that TT is very sensitive to dabigatran, would you use praxbind for patients with normal TT
who need emergent procedure?
Response: The patient must be looked at holistically in every clinical situation. Yes, the thrombin
time is sensitive for detecting if there is a “clinically significant” amount of dabigatran present and
nothing more. It does not correlate to serum concentration or the degree of anti-coagulation. So, in
theory, a normal TT may suggest that dabigatran is not playing a role in an active bleed or is not a
target for reversal in emergent situations. However, TT can also be impacted by ongoing
coagulopathies, liver disease, and blood loss; utility is thus limited to being a singular tool in our
clinical belt. More importantly, it would be prudent to assess when the patient received their last
dose and current renal function when making the decision of dabigatran necessity. Having said all of
this, individual institutions need to clearly define appropriate use within the scope of their current
hemostasis guidelines. Otherwise, pharmacists likely will be placed in precarious situations, such as
this.
2. Given the median time of bleeding cessation in this study, at what point would you consider giving
PCC in addition to Idarucizumab?
Response: Quite simply, I would never administer PCC to a patient needing dabigatran reversal. Now
having Idarucizumab and knowing it does not pre-dispose someone to hypercoagulability (like PCC
does)/minimal side effects, I would much rather re-dose it off label. Furthermore, PCC has been
studied in healthy males (50 units/kg dose) that were given 150mg BID of dabigatran.3 It was found
to have minimal impact on the aPTT, TT, or ECT. Its utility seems extremely sparse as the inherent
risks outweigh any potential clinical benefit for this patient population in my opinion.
3. Can you comment on the amount of concomitant blood product utilized in Reverse-AD, and the
potential confounding of results?
Response: Detailed blood product use is exclusively found within the supplementary index. In terms
of confounding our results, the amount of FFP that would be necessary to impact the aPTT, TT, dTT,
or ECT is extremely substantial. Furthermore, we cannot prevent the use of standard care measures
for patients enrolled in the trial. The decrease in the dTT and ECT perfectly correlates with the
witnessed reduction in unbound dabigatran. To me, this signals that administration of our study
drug and not marginal blood product use is what truly aided in attaining normal coagulation
parameters. Additionally, if you look at case reports involving the use of FFP and PCC, they minimally
impact coagulation parameters. Thus, I think they have a marginal potential for confounding results.
REVERSE-AD: Reversal Effects of Idarucizumab on Active Dabigatran
Ted Berei, Pharm.D., MBA | Mentor: Jeff Langford, Pharm.D., BCPS
4. Based on the Phase I trials and the dTT and ECT values in group A in REVERSE-AD do you believe that
1 dose of 2.5g would be sufficient for these patients?
Response: It would be difficult to determine if this would be an effective strategy. If you look at
Phase I trial data variable dosing strategies were used, ranging from 0.5g to 8g total. Consistently, 5g
was found to be the most efficacious dose. Given the “creep” we saw in coagulation parameters at
24 hours, I would be hard pressed to use a 2.5g dose. Also, there is no solid clinical data to support
the use of this regimen from an efficacy standpoint.
5. Is there a reason why Idarucizumab is given in divided doses rather than one 5g bolus?
Response: From what I can ascertain this is done based on how the drug was originally tested in
phase I trials. Theoretically you may also reduce infusion related reactions with this approach.
6. Given the possible issues with lab results for TT and ECT, would you empirically administer
medication given clinically significant bleeding or emergent procedure?
Response: Given what we know and the clinical landscape, I think clinician’s will be forced to do this
for patient’s presenting with clinically significant bleeding or the need for an emergent procedure.
Given laboratory parameters take considerable time to result and may not be 100% reliable, the
patient will need to be assessed holistically. Consideration must be given to when their last
dabigatran dose was administered, renal function, age, and if surgical intervention would remedy
the situation as opposed to complete reversal of anticoagulation. As mentioned before, this
highlights the need for every institution to assess how Idarucizumab should be used and its role in
their local hemostasis protocol.
References:
1. Pollack, CV, Reilly, PA, Eikelboom, J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med,
2015, 373: 511-520
2. Siegal, D, Curnutte, J, Connolly, S. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N
Engl J Med, 2015, 373: 2413-2424
3. Nitzki-George, D, Wozniak I, Caprini, J. Current State of Knowledge on Oral Anticoagulant Reversal
Using Procoagulant Factors. Ann of Pharm. 2013;47: 841-854.