1. Management of Bleeding with NOACS in Era of Specific Reversal Agents
Christian T. Ruff, MD, MPH
TIMI Study Group
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA 1 1

2. RE-LY: Bleeding with Antiplatelet Therapy
Major Bleeding*
2.8
4.6
6.3
None
ASA
ASA + Clopidogrel
HR=1.50 (95%CI: 1.22, 1.86)
HR=2.34 (95%CI: 1.53, 3.57)
HR=1.81 (95%CI: 1.46, 2.24)
HR=2.16 (95%CI: 1.34, 3.47)
HR=1.53 (95%CI: 1.21, 1.92)
HR=2.39 (95%CI: 1.53, 3.74)
WARFARIN
2.6
4.3
5.5
Dabi 150
2.2
3.8
5.4
Dabi 110
*Adjusted for age, gender, warfarin experience, SBP, CAD, CHF, TIA, HTN, DM, CrCl, Statins
Dans AL, et al. Circulation. 2013; 127:

3. How to Approach Combination Antithrombotic Therapy3
Kirchhof P, et al. Eur Heart J [Epub ahead of print]

4. Discontinuing NOACs Prior to Procedures
Minor Bleeding Risk Endoscopy with biopsy, prostate or bladder biopsy, EPS/RFA for SVT, angiography, pacemaker or implantable cardioverter defibrillator (unless complex anatomic setting, such as congenital heart disease)
Major Bleeding Risk Complex left-sided ablation (AF, VT), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, TURP, kidney biopsy
Heidbuchel H, et al. Europace. 2015; 17(10):

5. Practical Suggestions
NOACs in CKD:
Practical Suggestions
Yearly
CrCl ≥60 ml/min
Every 6 mo.
Elderly (≥75 yrs) or frail patients
(especially if on dabigatran or edoxaban)
Every X mo.
CrCl ≤60 ml/min: recheck interval=CrCl/10
(Example: CrCl=30 ml/min; recheck every 3 months) 5
Heidbuchel H, et al. Europace. 2015; 17(10): 5

6. Coagulation Tests
Test
Apixaban/Rivaroxaban/Edoxaban
Dabigatran
Qualitative
Present / Absent PT
rivaroxaban>edoxaban>apixaban
[sensitivity depends on reagents]
TT>aPTT
Quantitative test
Chromogenic anti-FXa
[requires specific calibration to drug]
Dilute TT, chromogenic anti-FIIa
[requires specific calibration]
Normal PT or aPTT does not guarantee absence of anticoagulant effect
Quantitative tests are not standardized or approved
Tripodi A, et al. Thromb Haemost 2011; 105:
Barrett YC, et al. Thromb Haemost 2010; 104:
van Ryn J, et al. Thromb Haemost 2010; 103:
Stangier J, et al. Br J Clin Pharmacol 2007; 64:
Cuker A, et al. JACC 2014; 64(11): 6 6 6

7. Non-Specific Reversal Agents
Only After D/C drug and Supportive Care (fluids / transfusions)
Agent
Clotting Factors Replaced
Dose
4 Factor-PCC
Factors II, VII, IX, X
25-50 units/kg
3 Factor-PCC
Factors II, IX, X
aPCC
Factors II, VIIa, IX, X
80 units/kg
rFVIIa
FVIIa
90 ug/kg 7 7 7

8. Specific NOAC Reversal Agents
Ruff CT, et al. Circulation ; 134(3):

9. REVERSE-AD: Idarucizumab
Group A: Uncontrolled bleeding + dabigatran-treated
Group B: Emergency surgery or procedure + dabigatran-treated
N=300
0–15 minutes
90 days follow-up
0–24 hours
Hospital arrival
5 g idarucizumab
(two separate infusions of 2.5 g)
Pre-2nd vial
2 h
4 h
12 h
24 h
30 d
90 d
Pre-1st vial
1 h
Blood
samples
~20 min
Pollack CV, et al. Thromb Haemost 2015;114(1):

10. Reversal of Dabigatran with Idarucizumab
Median maximum reversal within 4 hours was 100% for both dTT and ECT (95% CI, 100–100), evident after first vial of idarucizumab
dTT normalized in 98% and 93% of Group A and B patients, respectively*
ECT normalized in 89% and 88% of Group A and B patients, respectively*
Similar results with central laboratory aPTT and TT
Pollack CV, et al. N Engl J Med 2015;373:511-20

11. Poor Outcomes Regardless of Reversal
Pollack CV, et al. N Engl J Med 2015;373:511-20

12. ANNEXA - A & R: Andexanet Alpha
Part I:
Andexanet Bolus Only
apixaban
________
rivaroxaban
apixaban- 400mg andexanet
rivaroxaban- 800mg andexanet R
n ~ 35 per Xa
Anti-fXa levels
(Biomarker endpoint)
Placebo
Andexanet Bolus + Infusion (x 2hrs)
Part 2:
apixaban
________
rivaroxaban
apixaban- 400mg + 480mg (4mg/min) andexanet
rivaroxaban- 800mg + 960mg (8mg/min) andexanet R
n ~ 35 per Xa
Placebo
Crowther M, ISTH 2015

13. Anti–FXa Activity before and after Andexanet
Figure 1. Time Courses of Anti–Factor Xa Activity before and after Administration of Andexanet. Anti–factor Xa activity among persons who had received anticoagulation treatment with apixaban or rivaroxaban was measured before and after the administration of andexanet or placebo on study day 4. Dashed lines indicate the end of administration of the bolus or infusion. Panel A shows data from participants in the apixaban study (ANNEXA-A) who received andexanet, as a 400-mg intravenous bolus, or placebo; Panel B participants in the rivaroxaban study (ANNEXA-R) who received andexanet, as an 800-mg intravenous bolus, or placebo; Panel C participants in the apixaban study who received andexanet, as a 400-mg intravenous bolus plus a 4-mg-per-minute infusion for 120 minutes, or placebo; and Panel D participants in the rivaroxaban study who received andexanet, as an 800-mg intravenous bolus plus a 8-mg-per-minute infusion for 120 minutes, or placebo. Different scales along the x axis in each graph are used to enable visualization of the immediate, short-term dynamics as well as the longer-term dynamics of anti–factor Xa activity after andexanet treatment. The points on the graph represent the mean anti–factor Xa activity level, and I bars indicate the standard error. There was a significant difference (P<0.05) in the percent change in anti–factor Xa activity (relative to the pre-bolus activity level) between andexanet and placebo until 2 hours after administration of the bolus or infusion.
Siegal DM et al. N Engl J Med 2015 Nov 11 [Epub ahead of prin]

14. Pre-PER977, 2.75 hrs post 60 mg p.o. edoxaban
Ciraparantag
Scale Bar: 1 inch
BASELINE
(Pre-edoxaban)
ANTICOAGULATED
(Pre-PER977, hrs
60 mg edoxaban p.o.)
REVERSED
(1 hr post 100 mg i.v. bolus PER977)
*** ** *
Pre-edoxaban
baseline
Pre-PER977, 2.75 hrs post 60 mg p.o. edoxaban
1 hr post
100 mg i.v. PER977
Visual examination of blood clots from WBCT (whole-blood clotting time) assay pre- and postPER977.
Top, clot fibrin structure pre- and post- PER977 (upper and lower photos represent
lower and higher magnification).
Bottom, computer algorithm-based quantification of clot fibrin diameter. 15
Ansell JE, et al. NEJM. 2014; 371(22):

15. Management of NOAC-Related Bleeding
Ruff CT, et al. Circulation ; 134(3):

16. Management of NOAC Treated Patients who Require Invasive Procedures
Ruff CT, et al. Circulation ; 134(3):

17. Conclusions Serious bleeding is uncommon with NOACs
50% less compared to warfarin
Many bleeds are preventable
Stop unnecessary antiplatelet agents and NSAIDs
For most bleeds: temporarily stopping anticoagulation and supportive measures are all that is needed
Laboratory coagulation tests have limited utility
PCCs are the preferred non-specific reversal agent
Specific antidotes available for dabigatran and likely soon to be available for Fxa inhibitors: trauma, urgent surgery/procedures, stroke requiring lysis
Anticoagulation should be restarted in the majority of patients who experience a bleed once stabilized 18 18 18