1. Perioperative anticoagulation: DOACs
P Albaladejo, MD, PhD
Department of Anesthesia and Critical Care
Grenoble-Alpes University Hospital
France
Disclosures: Bayer Healthcare, Boehringer Ingelheim, BMS-Pfizer, Sanofi, Daiichi Sankyo, LFB, CSL Behring, Octapharma, BBraun, Sandoz, Portola

2. 33% renal (active) 33% renal (inactive) 33% hepatic
DOACs
Elimination
½ life
Tmax
Dabigatran anti-IIa
14-17h
0.5 à 2 h
80% renal 20% hepatic
Rivaroxaban
anti-Xa
7-13h
2-4h
33% renal (active) 33% renal (inactive) 33% hepatic
Apixaban anti-Xa
8-15h
3-4h
25% renal 75% hepatic
Edoxaban anti-Xa
10-14h
1.5h
35% renal
PRADAXA
XARELTO
ELIQUIS
LIXIANA

3. VTE prevention in major orthopedic surgery
Dabigatran
75 mg then 150 mg OD
110 mg then 220 mg OD
Rivaroxaban
10 mg OD
Apixaban
2,5 mg BID
Edoxaban
(not approved)
The first indication for these drugs is VTE prevention in major orthopedic surgery.
With low doses and specific schemes, particularly for the first administration after surgery

4. (non valvular) Atrial fibrillation - VTE treatment
Dabigatran
Atrial fibrillation
110 mg BID
150 mg BID
VTE treatment
Rivaroxaban
15 mg/j (Cockcroft ml/min)
20 mg/j (Cockcroft > 50 ml/min)
15 mg BID for 3 weeks
15 or 20 mg OD (Cockcroft)
Apixaban
5 mg BID
2.5 mg BID (if bleeding risk factors)
10 mg BID for 7 days
5 mg or 2.5 mgBID
Edoxaban
60 mg OD
30 mg OD (if bleeding risk factors)
Pour les indications fibrillation atriale et traitement de la MTEV, on note que pour les AntiXa, les doses sont globalement 2 x fois la dose de prévention en orthopédie.
La question posée ici est comment gérer les patients traités par ces doses de médicaments pour une chirurgie programmée dans un premier temps.
Le schéma précédent ne s’applique pas, car on fait 3 constats

5. DOACs Age Weight Creatinin Cockcroft Comedications Scheme Indication
Last intake
Age
Weight
Creatinin
Cockcroft
Comedications

6. Cockcroft= Age + Weight + Creatinine
Factors that may affect bleeding risks while on DOACs
Cockcroft= Age + Weight + Creatinine
Verapamil/dronedarone
Macrolids
-Azole
-Navir
Rifampicin
Immunosuppressive drugs
And aspirin, clopidogrel…Etc…
Never, Never, Never…..overlap with other anticoagulants

7. DOACs and coagulation assays
European Heart Journal 2018; 39: 1330–1393

8. POC and DOACs?
Semin Thromb Hemost 2017

9. Is the lab useful? Lab monitoring is not required….
Lab monitoring may be useful in difficult cases
Urgent surgery
Bleeding
Specific assays are not available everywhere, everytime.
PT and/or aPTT may be normal despite high plasma concentration (but still useful)
……….all depends on the question….

10. How to manage a RABBIT treated with dabigatran, with a kidney trauma, admitted to the ER?
J Thromb Haemost 2012; 10: 1841–8

11. Rivaroxaban
Dabigatran
Thromb Haemostasis 2012

12. Anesthesiology 2017; 127:

13. European Heart Journal 2018; 39: 1330–1393

14. Idarucizumab: PRAXBIND®
Une fraction Fab pour le dabigatran
Nat Rev Cardiol May;15(5):

15. Key Measurements before and after the Administration of Idarucizumab.
Figure 1 Key Measurements before and after the Administration of Idarucizumab. The diluted thrombin time in 293 patients who had uncontrolled bleeding and in 195 patients who were about to undergo urgent surgery or intervention are shown in Panels A and B, respectively. Panel C shows the plasma concentration of unbound dabigatran in the 485 patients in groups A and B who could be assessed. Panel D shows the activated partial-thromboplastin time in the 486 patients in groups A and B who could be assessed. The arrows show the timing of the two infusions of idarucizumab. Blood samples were obtained at baseline, after the first infusion, and between 10 and 30 minutes and at 1, 2, 4, 12, and 24 hours after the second infusion. Data are presented as box-and-whisker plots, in which the top and bottom of the rectangles indicate the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles indicate the 50th percentile; the lines above and below the rectangles indicate the 90th and 10th percentiles, respectively; and the dots above and below the lines indicate the 95th and 5th percentiles, respectively. The shaded areas show the normal ranges for each of the measures, which are based on data from 208 volunteers. The upper limits of the normal range for diluted thrombin time and activated partial-thromboplastin time are 35.5 seconds and 39.8 seconds, respectively.
2 x 2,5 g (15 minutes)
N Engl J Med 2017;377:

16. Dose totale: 15 g Br J Anaesth 2018; 121: 505-508
An 81-yr-old woman (70 kg, 165 cm) presented with sustained lower gastrointestinal bleeding under a twice-daily regimen of 110 mg dabigatran for secondary prevention after unprovoked pulmonary embolism.
Dose totale: 15 g
Br J Anaesth 2018; 121:

17. Andexanet Nat Rev Cardiol. 2018 May;15(5):273-281
Une fraction Fab pour le dabigatran
Nat Rev Cardiol May;15(5):

18. Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban
daily. For each factor Xa inhibitor, a two-part randomized placebocontrolled
study was conducted to evaluate andexanet administered as a bolus or
as a bolus plus a 2-hour infusion. The primary outcome was the mean percent
change in anti–factor Xa activity, which is a measure of factor Xa inhibition by the
anticoagulant.
Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in
older healthy participants within minutes after administration and for the duration
of infusion, without evidence of clinical toxic effects.
N Engl J Med. 2015; 373: 19

19. N Engl J Med 2016;375:

20. FDA Approves First Factor Xa Inhibitor Antidote, Andexxa - Medscape - May 04, 2018.
N Engl J Med 2016;375:

21. PCC and aPCC seem to be efficient…at high doses
Idarucizumab on the shelves
Andexanet….. FDA approval, EMA pending

22. To wait ?
To delay ?
To dose ?
To reverse ?

23. Management of DOACs Regional anesthesia ? Elective surgery ?
Urgent surgery ?
Bleeding while on NOACs ?

24. Management of DOACs Michael Langerkranser Regional anesthesia ?
Elective surgery ?
Urgent surgery ?
Bleeding while on DOACs ?
Michael Langerkranser

25. Management of NOACs Regional anesthesia ? Elective surgery ?
Urgent surgery ?
Bleeding while on NOACs ?

26. Venous Thrombo Embolism
Mechanical Cardiac
Valves
(Non valvular) Atrial Fibrillation
Venous Thrombo Embolism
(No DOACs)
VKA
VKA
DOACs
VKA
DOACs
Stroke ?
< 3 months ?
Yes No
Yes No
Bridging
Bridging
No Bridging
Bridging
No bridging

27. DOACs in elective surgery
European Heart Journal 2018; 39: 1330–1393

28. Eur J Anaesthesiol 2017; 34:332–395

29. Anaesth Crit Care Pain Med. 2017; 36: 73-76
Low hemorrhagic risk
High hemorrhagic risk
Before the
procedure
No DOA the evening before and the morning of the procedure
rivaroxaban
apixaban
edoxaban
Cockcroft
≥ 30 ml/mn
Last DOA on D-3
dabigatran
≥ 50 ml/mn
Last DOA on D-4
30-49 ml/mn
Last DOA on D-5
No bridging
No dosage
After the procedure
Resumption at the usual time but at least 6h after the procedure
« Prophylactic » dose of anticoagulant
At least 6 hours after the procedure if venous thromboprophylaxis is indicated
« Therapeutic » dose of anticoagulant
as soon as the hemostasis allows it
(between 24 and 72 hours)
Anaesth Crit Care Pain Med. 2017; 36: 73-76

30. Management of NOACs Regional anesthesia ? Elective surgery ?
Urgent surgery ?
Bleeding while on NOACs ?

31. (ressuscitation needed simultaneously)
Is it really urgent ?
Type A
Aortic Dissection
(ressuscitation needed simultaneously)
Peritonitis?
(no resuscitation needed)
Hip fracture
Antagonize
Antithrombotics
(but when)
Comments:
Is it really bleeding ?
Already bleeding

32. GIHP-NACO Observatory
Urgent Surgery
GIHP-NACO Observatory
41 centres
30 months
478 patients admitted and hospitalised for urgent invasive procedure while on DOACs %
Conc DOAC ?
Conc (median)
(ng/ml)
Delay (median)
(LI-Surgery)
Immediate 5%
56% 98
16h
Urgent
45%
67% 72
20h
Expedited
50% 49
27h
(unpublished data,. GIHP working group)
Abnormal bleeding
(a)PCCs
MACCE
30 days mortality
Immediate
42%
26%
Urgent
12% 5%
7.5%
6.4%
Expedited 1%
6.8%
2.6%

33. European Heart Journal 2018; 39: 1330–1393

34. Anaesth Crit Care Pain Med. 2018; 37: 391-399

35. Management of NOACs Regional anesthesia ? Elective surgery ?
Urgent surgery ?
Bleeding while on NOACs ?

36. Bleeding in patients treated with NOACs
Always consider:
Symptomatic and supportive therapies
Compression
Surgery
Embolisation
Specific procedures
Fluids
Transfusion
Clotting factors
FFP
PCCs
Options:
Alter the PK of the DOA
Time
Antidotes: idarucizumab
Dialysis (dabigatran)
Charcoal
Clotting factors
4F-PCC First-line
aPCC First- or second-line
(rFVIIa)
This slide shows obvious things
In front of a patient bleeding while treated by any anticoagulant, we must always consider the use of appropriate supportive and symptomatic treatment,
And when all these treatments are done, we have several options to specifically reverse either VKA or NOACs 37

37. European Heart Journal 2018; 39: 1330–1393

38. Anaesth Crit Care Pain Med. 2018; 37: 391-399

39. DOACs widely used (with some complex combinations)
Type, dose, indication, Cockcroft, comedication
Bleeding risk of the procedure
No bridging, no dosage for elective surgery
Delay ± dose ± reverse (antidotes, PCCs) for urgent procedures
Protocols and aids (referent)