1. On behalf of the RE-VERSE AD Investigators
Reversal of Dabigatran by its Specific Reversal Agent Idarucizumab in Patients with Uncontrolled Bleeding or Requiring Urgent Surgery/Procedures: Final Results of RE-VERSE AD
CV Pollack Jr, PA Reilly, J van Ryn, J Eikelboom, S Glund, RA Bernstein, R Dubiel, MV Huisman, EM Hylek, C-W Kam, PW Kamphuisen, J Kreuzer, JH Levy, FW Sellke, G Royle, J Stangier, T Steiner, P Verhamme, B Wang, L Young, JI Weitz
On behalf of the RE-VERSE AD Investigators

2. Idarucizumab specifically reverses the anticoagulant activity of dabigatran
Humanized Fab: binds free- and thrombin-bound dabigatran
High binding affinity for dabigatran (2pM); is essentially irreversible
No known off-target effects; does not reverse heparins or other anticoagulants
IV administration, immediate onset of action, short half-life (~45 min)
No intrinsic procoagulant or anticoagulant activity
Blood 2013;121: ; Circulation 2015;132: ; Lancet 2016;386: ; Thromb Haemost 2017;117:269-76

3. Multicentre, Prospective, Open-label, Single-arm Phase III Study
Dabigatran etexilate treated patients:
Group A: Uncontrolled bleeding
5 g idarucizumab (2 x 2.5 g IV)
N = 503
Group B: Emergency surgery or procedure
0–15 min
Hospital arrival
Baseline
Between vials
Patients treated based only on clinical presentation
173 sites in 39 countries
dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time
Thromb Haemost 2015;114:198–205; NEJM 2015:373:

4. Multicentre, Prospective, Open-label, Single-arm Phase III Study
Dabigatran etexilate treated patients:
Primary endpoint:
Blood sample time points
2 h
4 h
1 h
~20 min
Maximum reversal within 4 hrs with dTT and ECT measures
Group A: Uncontrolled bleeding
5 g idarucizumab (2 x 2.5 g IV)
N = 503
Group B: Emergency surgery or procedure
0–15 min
Hospital arrival
Baseline
Between vials
Patients treated based only on clinical presentation
173 sites in 39 countries
dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time
Thromb Haemost 2015;114:198–205; NEJM 2015:373:

5. Multicentre, Prospective, Open-label, Single-arm Phase III Study
Dabigatran etexilate treated patients:
Primary endpoint:
Blood sample time points
2 h
4 h
1 h
~20 min
Maximum reversal within 4 hrs with dTT and ECT measures
Secondary endpoints:
90 day follow-up
12 h
24 h
30 d
Determined
locally
Hemostasis within 24 hours (non-ICH)
Hemostasis during procedure /surgery
Group A: Uncontrolled bleeding
5 g idarucizumab (2 x 2.5 g IV)
N = 503
Group B: Emergency surgery or procedure
0–15 min
Hospital arrival
Baseline
Between vials
Patients treated based only on clinical presentation
173 sites in 39 countries
dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time
Thromb Haemost 2015;114:198–205; NEJM 2015:373:

6. Multicentre, Prospective, Open-label, Single-arm Phase III Study
Dabigatran etexilate treated patients:
Primary endpoint:
Blood sample time points
2 h
4 h
1 h
~20 min
Maximum reversal within 4 hrs with dTT and ECT measures
Secondary endpoints:
90 day follow-up
12 h
24 h
30 d
Determined
locally
Hemostasis within 24 hours (non-ICH)
Hemostasis during procedure /surgery
Group A: Uncontrolled bleeding
Thrombotic events
Restart of anticoagulation
Mortality
aPTT / TT
Drug levels
Immunogenicity
5 g idarucizumab (2 x 2.5 g IV)
N = 503
Group B: Emergency surgery or procedure
0–15 min
Hospital arrival
Baseline
Between vials
Patients treated based only on clinical presentation
173 sites in 39 countries
dTT, diluted thrombin time; ECT, ecarin clotting time, aPTT, activated partial thromboplastin time, TT thrombin time
Thromb Haemost 2015;114:198–205; NEJM 2015:373:

7. Patient Demographics Characteristic Group A (n=301) Group B (n=202)
Total (N=503)
Age (y)*
79 (24–96)
77 (21–96)
78 (21–96)
Male sex, n (%)
172 (57.1)
102 (50.5)
274 (54.5)
Creatinine clearance (mL/min)*
50.8 (6.1–216.9)
56.0 (7.9–198.7)
52.6 (6.1–216.9)
Comorbidities, n (%)
Congestive Heart Failure
117 (38.9)
65 (32.2)
182 (36.2)
Diabetes
95 (31.6)
57 (28.2)
152 (30.2)
Coronary Artery Disease
110 (36.5)
68 (33.7)
178 (35.4)
Prior Stroke / TIA
73 (24.3) / 27 (9.0)
36 (17.8) / 20 (9.9)
109 (21.7) / 47 (9.3)
Dabigatran, n (%)
Atrial fibrillation indication
288 (95.7)
190 (94.1)
478 (95.0)
Daily dose mg BID
94 (31.2)
151 (30.0)
110 mg BID
185 (61.5)
126 (62.4)
311 (61.8)
75 mg BID
16 (5.3)
8 (4.0)
24 (4.8)
Patient-reported time since last dose (hrs)*
14.6 (1.5, 90.4)
18.0 (2.6, 105.8)
15.6 (1.5, 105.8)
Elevated dTT at baseline, n (%)
244 (81.1)
152 (75.2)
396 (78.7)
Elevated dTT or ECT at baseline, n (%)
276 (91.7)
185 (91.6)
461 (91.7)
*Shown as median (range)

8. Group A: Site of Index Bleed and Severity (n=301)
Type of Bleeding*
N (%)
Intracranial
98 (32.6)
Subdural 39
Subarachnoid 26
Intracerebral 53
Gastrointestinal
137 (45.5)
Lower 47
Upper 52
Unknown 42
Intramuscular
9 (3.0)
Retroperitoneal
10 (3.3)
Intra-pericardial
7 (2.3)
Intra-articular
5 (1.7)
Intraocular
1 (0.3)
Other
52 (17.3)
Not identified
4 (1.3)
Other: epistaxis, hepatic bleed, hematuria, hematomas (such as abdominal wall, subcutaneous at ribs due to trauma), pelvic bleed with multiple pelvic fractures, fingers on right hand cut off by chainsaw.
*Bleeding may occur at more than one site.
GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis

9. Group A: Site of Index Bleed and Severity (n=301)
Type of Bleeding*
N (%)
Intracranial
98 (32.6)
Subdural 39
Subarachnoid 26
Intracerebral 53
Gastrointestinal
137 (45.5)
Lower 47
Upper 52
Unknown 42
Intramuscular
9 (3.0)
Retroperitoneal
10 (3.3)
Intra-pericardial
7 (2.3)
Intra-articular
5 (1.7)
Intraocular
1 (0.3)
Other
52 (17.3)
Not identified
4 (1.3)
Adjudicated ISTH Bleeding Severity:
88% Major and Life-threatening bleeding
Other characteristics:
38% Hemodynamic instability
20% Surgical intervention required
26% Trauma-related
Other: epistaxis, hepatic bleed, hematuria, hematomas (such as abdominal wall, subcutaneous at ribs due to trauma), pelvic bleed with multiple pelvic fractures, fingers on right hand cut off by chainsaw.
*Bleeding may occur at more than one site.
GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis

10. Group B: Indications for Surgery / Procedures (n=202)
(Percent of total shown at end of each bar)

11. Similar results were obtained with aPTT and TT
Primary Results
Median maximum reversal within 4 hours measured by dTT and ECT was 100% (95% CI, 100–100%)
Similar results were obtained with aPTT and TT
dTT normalized* within 4 hours in 241/244 patients (98.8%) in Group A and 150/152 patients (98.7%) in Group B
*at or below the upper limit of normal. All data measured in central laboratory, aPTT and TT outcomes were secondary endpoints

12. Results: Diluted Thrombin Time Assessment of Dabigatran Reversal
dTT diluted thrombin time

13. Results: Dabigatran Reversal Measured as Unbound Dabigatran and aPTT
aPTT activated Partial Thromboplastin Time

14. Group A (n=301): Hemostasis (bleeding cessation) in 24 hours
Time to Locally Reported Hemostasis (Bleeding Cessation)*
Non-ICH bleeding: 203 patients
(assessable in 198)
120 Gastrointestinal (GI) bleeds
78 Non-GI, non-ICH bleeds
Evaluated in
134 /198 (67.7%) patients within 24 (+2) hours
25 /198 (12.6%) patients after 24 hours
Not evaluated in
39 /198 (19.7%) patients
(bleeding location could not be identified)
2.5 (2.2 – 3.9) hours (median, 95% CI)
Intracranial hemorrhage (ICH):
98 patients
non-interpretable: serial CT scans not mandated by protocol
*Based on visualization where possible, or changes in hemoglobin / hematocrit within 24 hrs of idarucizumab administration by the local investigator

15. Group B: Peri-procedural Hemostasis
197 of 202 (97.5%) patients underwent anticipated surgery/procedures
Median time from administration of first vial to procedure was 1.6 hours
Adequacy of hemostasis during surgery determined locally
93.4%
Normal:
as if anticoagulation were absent
Abnormal:
Mild – oozing, not requiring intervention
Moderate – controlled with local intervention Severe – refractory hemorrhage
5.1%
1.5%
0.0%
Normal
Mildly
Abnormal
Moderately Abnormal
Severely Abnormal

16. Adjudicated Thrombotic Events Occurring Post-Reversal
Events n (%)
Group A (n=301)
Group B (n=202)
Total (n=503)
30 days
14 (4.6)
10 (5.0)
24 (4.8)
90 days
19 (6.3)
15 (7.4)
34 (6.8)
At 72 hours post idarucizumab, 22.9% of Group A and 66.8% of Group B had re-started anticoagulation or antiplatelet therapy
By 90 days antithrombotic therapy had been re-started in 72.8% of Group A and 90.1% of Group B patients
Patients restarted on dabigatran: % in Group A (median time 16 days) % in Group B (median time 6 days)

17. Mortality
Within 5 days of idarucizumab treatment, 19 deaths occurred in Group A (6.3%) and 16 deaths occurred in Group B (7.9%)
Kaplan–Meier rates at 30 and 90 days:
Group A (n=301)
Group B (n=202)
30 days
Patients at risk, n
254
169
Mortality, %
13.5
12.6
90 days
152
109
18.8
18.9
See table S1 in supplement. This lists all deaths in the 5 day time frame, most are related to the index event. Later deaths (30, 90 days) are more related to other comorbidities or independent events.

18. Patients Receiving a Second Dose
9 patients* received a second dose (1.8%)
4 in Group A due to re-bleeding ≥ 24 hours post first-dose of idarucizumab
4 in Group B due to post-operative bleeding or requiring a new procedure ≥ 12 hours post first-dose of idarucizumab
Group
Age/ Gender
Dose of Dabigatran (bid)
Index event
Unbound dabigatran (ng/mL)
Creatinine Clearance (mL/min)
Approximate Time to Additional dose
Reason for additional dose A
60 M
110
Gastrointestinal bleed
955
25.7
48 hr
Recurrent bleeding
79 M
325
43.4
36 hr
76 M
Hematuria
1360
15.2
24 hr
73 M
329
29.0 B
85 F 75
Intestinal occlusion 51
31.2
5 days
New procedure
73 F
150
Ischemic large bowel
1630
34.0
12 hr
Postoperative bleeding
82 F
Catheter placement for dialysis
271
8.0
6 days
70 M
240
18.6
3 days (dose 2) 8 days (dose 3)
Postoperative bleeding and new procedure
Suggestions to discuss verbally: spectrum of doses the patients received and wide range of plasma levels, lower creatinine clearance (took this out as a bullet point), and fact that second (or third dose quite a few hours later so there is time to perform assays etc)
*one patient received a second dose in error and is not included in this analysis

19. Discussion Open label cohort study
Currently no approved treatment for comparison
Inclusive pragmatic study
Clinical condition and bedside evaluation drive treatment decision
Provides a broad and heterogeneous emergency patient population, including patients requiring urgent surgery and interventions
Fixed dose based on anticipated dabigatran loads
Overdose or acute renal failure could result in higher dabigatran levels
Some patients show re-appearance of low levels of dabigatran at hours, usually without clinical consequences
May be due to mobilization of dabigatran from tissues or extracellular fluid

20. Conclusions
In a cohort of elderly, multi-morbid patients taking dabigatran etexilate who presented with life-threatening emergencies:
5 g of idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulation
Median time to cessation of extracranial bleeding in Group A was hours after reversal
Median time to invasive procedure after reversal was 1.6 hours
Intraoperative hemostasis was “normal” in 93% of Group B patients
Prompt re-initiation of antithrombotic therapy post-procedure was safe
No safety concerns identified to date

21. Thank you to all the investigators involved and to the patients in this study