Transcript N Engl J Med, 2015, 373: 511-520

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Idarucizumab for Dabigatran Reversal
Ted Berei, PharmD, MBA
PGY2 Cardiology Resident
Abbott Northwestern Hospital, Minneapolis Heart Institute
Minneapolis, MN
Disclosures
Presenters have no conflicts to report related to financial
or personal relationships with commercial entities (or
their competitors) that may be referenced in this
presentation
Background
• Dabigatran is FDA approved for the treatment of DVT/PE, non-valvular atrial
fibrillation, and DVT prophylaxis
• Clinical situations occur (i.e. major bleeds, emergent surgery, etc.) where complete
reversal of anticoagulation is desirable
• Idarucizumab (Praxbind®) is a first-in-class monoclonal antibody that binds both
free and thrombin-bound Dabigatran (as well as glucuronide metabolites)
Dabigatran [package insert]. Available at: http://www.uptodate.com/contents/dabigatran-druginformation?source =search_result&search=dabigatran&selectedTitle=1~112.
Idarucizumab [package insert]. Available at: http://www.uptodate.com/contents/ idarucizumab-drug-information?source =search_result&search=idarucizumab&selectedTitle =1~16.
Current Reversal Practices
• No current practice standard when it comes to reversing dabigatran
• Dilute thrombin time (dTT) and chromogenic ecarin clotting time (ECT) can be calibrated
to correlate with serum Dabigatran levels
• Thrombin time and aPTT can also be used to detect “presence” of dabigatran
• Mixed results with using a variety of methods:
• Hemodialysis
• Four-Factor Prothrombin Complex Concentrate (PCC)
• Recombinant Factor VIIa (rFVIIa)
• Fresh Frozen Plasma (FFP)
Ann of Pharm. 2013;47: 841-854.
Idarucizumab (Praxbind®)
Property
• Phase I and II trials in > 200 patients
established Idarucizumab was well
tolerated (doses up to 8g)
Administration
Dosing
• Affinity for dabigatran ~ 350x higher than
Dabigatran’s affinity for thrombin
5g total (2 – 2.5 g boluses
separated by NO more than
15 minutes)
T1/2
Biphasic; initial = 45 minutes,
terminal = ~ 4.4-8.1 hours
• Once bound, idarucizumab neutralized
dabigatran’s anticoagulant effect
Thromb Haemost. 2015;113:943-951
Blood. 2014;124
Circulation. 2015;132:2412-2422
Onset of Action
Route of Elimination
Intravenous
1-2 minutes
Renal
Storage
Requires refrigeration
Stability
2 years
FDA Approval & Availability
• Approved by the FDA in October 2015
• FDA labeling:
• Reversal of dabigatran for emergency surgery/urgent procedures or in lifethreatening or uncontrolled bleeding
• Supplied as 2.5g vials (5g total dose)
• Cost = ~ $ 4,200 for 5g dose
REVERSE-AD: Background
• Funded by Boehringer Ingelheim (manufacturers of dabigatran)
• Multi-center, prospective, cohort study
• Will enroll 300 total patients
• 400 centers, 38 countries
• NO randomization or placebo arm
• Analysis of the first 90 patients enrolled in REVERSE-AD was presented
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Study Objectives
Demonstrate the efficacy and safety of idarucizumab
for the reversal of the anticoagulant effects of
dabigatran in patients who presented with serious
bleeding or who require urgent surgery or
intervention
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Trial Design
300 patients total
• 90 patients analyzed for this
cohort snapshot
N Engl J Med, 2015, 373: 511-520
Groups
Idarucizumab
• A (n = 51)
• Overt, uncontrollable, or lifethreatening bleeding
• B (n = 39)
• Emergent procedure or surgery
required within 8 hours
• Administered as 2- 2.5g boluses (5g
total dose, 50 mL each)
• Boluses administered within 15
minutes of one another
REVERSE-AD: Trial Design, Laboratory Monitoring
Circulation. 2015;132:2412-2422.
REVERSE-AD: Primary Endpoint
Maximum % reversal of the anticoagulant effect of dabigatran within
4 hours, based on central laboratory determination of the dTT or ECT
Calculated as:
([Pre-dose test result (seconds) – Minimum post-dose test result
(seconds)]/ [Pre- dose test result (seconds) – Upper limit of normal
range (seconds)] x 100)
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Patient Population (Group A)
Overt major or life-threatening bleeding judged by the physician to require a reversal agent
Inclusion Criteria
Exclusion Criteria
- Age ≥18 years
- Currently taking dabigatran etexilate
- Bleeding associated with hypotension requiring use of
intravenous inotropic agents
- Patients with minor bleeds (epistaxis,
hematuria) who can be managed with standard
supportive care
- Fatal bleeding
- Symptomatic intracranial bleeding
- Bleeding necessitating surgical intervention
- Patients with no clinical signs of bleeding
- Reduction in hemoglobin of at least 5 g/dL
- Transfusion of at least 4 units of blood or packed cells
- Contraindications to study medication
including known hypersensitivity to the drug or
its excipients.
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Patient Population (Group B)
Requiring emergency surgery or procedure for a condition other than bleeding (within 8 hours)
Inclusion Criteria
Exclusion Criteria
- Current treatment with dabigatran
- A surgery or procedure which is elective or
where the risk of uncontrolled or unmanageable
bleeding is low
- Age ≥18 years
- Contraindications to study medication including
known hypersensitivity to the drug or its
excipients (such as subjects with hereditary
fructose intolerance who may react to sorbitol)
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Baseline Characteristics
Characteristic
Group A
(N = 51)
Group B
(N = 39)
Total
(N = 90)
Age (yr, median)
77
76
76.5
Male
32
18
50
Atrial Fibrillation as indication for dabigatran
47
39
86
< 12 hr
17
15
32
12 to , 24 hr
21
10
31
24 to , 48 hr
12
10
22
> 48 hr
1
4
5
Elevated ECT at baseline
40
28
68
Elevated dTT at baseline
47
34
81
Intracranial
18
-
18
Trauma-related
9
-
9
GI
20
-
20
Other
11
-
11
150mg BID
14
15
29
110mg BID
34
24
58
75mg BID
1
0
1
Time since last intake of Dabigatran
Type of Bleeding
Dose of Dabigatran
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Results
• Median maximum percentage reversal in the patients in group A and in those
in group B was 100% (95% confidence interval, 100 to 100)
• 22 patients with a normal dTT and 9 with a normal ECT based on central
laboratory testing
• Excluded from final efficacy analysis
• dTT = 68 patients assessed  (40 patients Group A, 28 patients Group B)
• ECT = 81 patients assessed  (47 patients Group A, 34 patients Group B)
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Results (Primary Outcome)
* Dilute Thrombin Time (dTT) *
Group A
Group B
Mean dTT at baseline
54.1 (n=51, SD=23.6)
53.2 (n=39, SD=38.5)
Mean dTT between vials
29.7 (n=51, SD=2.46)
32.9 (n=39, SD=20.9)
Mean dTT 10-30 min after second vial
29.8 (n=51, SD=2.42)
31.3 (n=39, SD=12.4)
Mean dTT 4 h +/- 30 min after second vial
29.6 (n=46, SD= 2.59)
35.8 (n=37. SD=25.5)
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Results (Primary Outcome)
* Ecarin Clotting Time (ECT) *
Group A
Group B
Mean ECT at baseline
113 (n=51, SD= 79.0)
111 (n=39, SD=97.1)
Mean ECT between vials
38.2 (n=51, SD=6.00)
45.3 (n=39, SD=44.0)
Mean ECT 10-30 min after second vial
39.3 (n=51, SD=6.72)
Mean ECT 4 h +/- 30 min after second vial
37.7 (n=47, SD=4.06)
N Engl J Med, 2015, 373: 511-520
44.6 (n=39, SD=43.5)
59.0 (n=37, SD=85.3)
REVERSE-AD: Results (Secondary Outcome)
* Unbound (free) dabigatran [ng/mL] *
Mean unbound dabigatran at baseline
Mean unbound dabigatran between vials
Group A
Group B
161 (n=48, SD=166)
218 (n=39, SD=503)
1.11 (n=48, SD= 0.288)
34.6 (n=39, SD=206)
Mean unbound dabigatran 10-30 min
after second vial
1.08 (n=48, SD=0.431)
18.5 (n=39, SD=107)
Mean unbound dabigatran 4 h +/- 30 min
after second vial
1.01 (n=46, SD=0.0516)
63.9 (n=38, SD=277)
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Results (Secondary Outcomes)
** Time to cessation of bleeding (for Group A only)
• Median investigator-reported time to the cessation of bleeding for patients
was 11.4 hours
Occurrence of major bleeding (for group B only) intraoperatively and up to
24 hours post-surgery
• Of the 36 patients who received a procedure:
• Normal intraoperative hemostasis was reported in 33 (92%) patients
• Mildly abnormal hemostasis during the procedure was reported in 2 patients
• Moderately abnormal hemostasis reported in 1 patient
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Results (Adverse Events)
Deaths
• 18 total (9 in each group)
• 10 due to vascular causes (5 fatal bleeds)
• 9 deaths occurred > 96 hours after
treatment and appear related to index
event
Thrombotic Events
Occurred in five patients overall (none were on
any anti-thrombotic agents at the time of these
events)
N Engl J Med, 2015, 373: 511-520
N Engl J Med, 2015, 373: 511-520
REVERSE-AD: Author’s Conclusions
Idarucizumab is safe and effective for reversing the
anticoagulant effects of dabigatran for patients presenting
with overt, uncontrollable, life-threatening bleeding or
needing urgent surgery or procedure within 8 hours
REVERSE-AD: Reviewer’s Conclusions
• Small population analyzed in a non-randomized way without placebo or alternative
intervention
• dTT and ECT are not readily available at most institutions
• Idarucizumab was effective at mitigating dabigatran’s anticoagulant effect
• Deaths appear related to index admission as opposed to drug
• Rebound effect of dabigatran at 24 hours witnessed in both A and B group
• Median investigator-reported time to the cessation of bleeding for group A patients
was 11.4 hours
REVERSE-AD: Takeaways
• Demonstrated that idarucizumab safely and efficaciously reverses anticoagulation induced by dabigatran
administration
• Standardization of laboratory testing and monitoring will be necessary on an institution-to-institution basis
• dTT vs. ECT vs. TT vs. aPTT
• Consideration must be given to time of last dabigatran dose and native renal function when deciding
whether idarucizumab is appropriate
• T1/2 : 12-17 hours; Elderly: 14-17 hours; Mild/moderate: 15-18 hours; Severe: 28 hours
• Must be vigilant about perioperative DOAC use
• CrCl ≥ 50 mL/min = 1-2 days | CrCl < 50 mL/min = 3-5 days
• i.e. discontinuation at the appropriate time depending on renal function
• Local hemostasis protocols need to clearly define how idarucizumab should be used based on the clinical
situation in conjunction with other reversal options
Potential Pathway for Utilization
Patient Presentation
Attempt to determine dabigatran presence (i.e. local clotting assays)
Consider: Last dose, renal function, age
Non Life-Threatening
Bleeding
Life-Threatening or
Urgent Bleeding
Urgent Surgery or
Procedure
Activated
Charcoal?
Idarucizumab 5g +/- other interventions
Local Hemostasis Protocol (utilization of PCC, rFVIIa,
FFP, hemodialysis, etc.)
Coags
monitoring for
normalization
Resume anticoagulation as soon as possible depending on patient specific factors
Circulation. 2015;132:2412-2422.
Clinical Questions
• Where does idarucizumab fit into local hemostasis protcols?
• Which coagulation assays should be used?
• How often should we monitor them?
• Do we have thresholds for determining the appropriateness of idarucizumab
administration based on these?
• Is re-dosing necessary? If so, how often and how much?
• Can we use idarucizumab to allow for thrombolytic qualification in TIA patients?
Looking Ahead…….
• Complete trial enrollment for REVERSE-AD is expected by 2017
• Aripazine (PER977) - universal reversal agent for oral direct thrombin and
factor XA inhibitors, injectable UFH, LMWH, and fondaparinux
•
•
•
•
Synthetic molecule
IV administration
Stored at room temp
Currently only phase II trials underway
References
1.
2.
3.
4.
5.
6.
7.
Dabigatran [package insert]. Available at: http://www.uptodate.com/contents/dabigatran-druginformation?source
=search_result&search=dabigatran&selectedTitle=1~112. Accessed February 17, 2016.
Idarucizumab [package insert]. Available at: http://www.uptodate.com/contents/ idarucizumab-druginformation?source =search_result&search=idarucizumab&selectedTitle =1~16. Accessed February 17, 2016.
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.
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;113:943951.
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. Blood. 2014;124.
Eikelboom JW, Quinlan DJ, van Ryn J, et al. Idarucizumab: The antidote for reversal of dabigatran. Circulation.
2015;132:2412-2422.
Pollack, CV, Reilly, PA, Eikelboom, J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med, 2015, 373: 511-520
Acknowledgements
• Journal Club Mentor
• Jeff Langford, PharmD, BCPS
• Program Director
• Matthew Lillyblad, PharmD, BCPS
• ACC Cardiology PRN Journal Club Coordinator
• Craig Beavers, PharmD, FAHA, AACC, BCPS AQ-Cardiology, CACP
Idarucizumab for Dabigatran Reversal
Ted Berei, PharmD, MBA
PGY2 Cardiology Resident
Abbott Northwestern Hospital, Minneapolis Heart Institute
Minneapolis, MN
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