1. Annual meeting of the Royal Belgian Society of Laboratory Medicine
New anticoagulants: influence on routine coagulation testing and how to detect an overdose
Prof. François Mullier
Université catholique de Louvain, CHU UCL Namur
Associate head of laboratory of clinical biology

2. No relevant conflicts of interest to declare Scientific Advisory Board
Research Support/P.I.
No relevant conflicts of interest to declare
Employee
Consultant
Major Stockholder
Speakers Bureau
Honoraria
Speaker fees for Boehringer Ingelheim, Bayer Healthcare and Bristol-Myers Squibb-Pfizer
Scientific Advisory Board 2

3. Take home message
2 key opinion leaders says: Registration by regulatory agencies and their widespread implementation in clinical laboratories are “urgently” needed
Dabigatran versus warfarin in patients with atrial fibrillation.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators.
N Engl J Med Sep 17;361(12):
Idarucizumab for Dabigatran Reversal.
Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI.
N Engl J Med Aug 6;373(6): 3

4. Outline Introduction Why to measure DOACs? When to measure DOACs?
- Measurement in the perioperative setting
- Measurement in urgent situations
How to measure DOACs?: International, national and regulatory recommendations
Influence of DOACs on other coagulation testing
Conclusions

5. PK and PD
rivaroxaban
apixaban
edoxaban
dabigatran 5

6. PK and PD dabigatran etexilate (PRADAXA®) rivaroxaban (XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
Target
Thrombin
Factor Xa
Bioavailability (%)
3-7%
Not affected by food
80 to 100% for the 10 mg
66% for the 15 and 20 mg (fasted)*
50%
62%
Prodrug
Yes – activated by esterase (CES1) No
Half-life (hours)
11-13
5-13
8-15
10-14
TMAX (hours)
Renal clearance
80%
33%
25%
Metabolism
P-gp
CYP3A4
CYP3A4/5, 1A2, 2J2
CYP3A4/5
* these dose regimen have to be taken with food. 6

7. Indications 7

8. Some figures in Belgium
Already patients on DOACs in 2014
Pharmanet, INAMI 8

9. Why to measure DOACs? 9

10. Why to measure DOACs? Cons: PK-PD studies: preditable response
All RCT were performed without monitoring
Large therapeutic range
Freyburger et al., 2011; Mani et al., 2013; Samama et al., 2013 10

11. Why to measure DOACs? Pros:
Correlation between clinical events and plasmatic dabigatran/edoxaban concentrations
Possible improvement of the B/R balance
Reilly PA et al., JACC 2013; Douxfils et al., Exp. Op. Drug Saf `; Ruff et al. The Lancet 2015. 11

12. Why to measure DOACs?
Interindividual variability (EMA SmPC 2013; Ten Cate, H. Thromb Haemost 2012; Ten Cate, H. Thromb J 2013; Reilly PA et al. JACC 2013; Chan et al. JTH 2015; Douxfils et al. JTH 2015; Douxfils et al. Exp. Op. Drug. Saf. 2015)
Mean (min-max) concentrations
Dabigatran 110mg (n=90)
Rivaroxaban 20 mg (n=37)
Apixaban 5 mg (n=73)
Trough
Peak
Trough
Peak
Trough
Peak
Testa S, Thromb Res 2016
High inter-individual variability
Variables: age, weight, renal function, CYP3A4 and P-gp modulators
Gong IY, Can J Cardiol 2013

13. Why to measure DOACs in the perioperative setting?
VKA:
discontinuation few days before surgery or invasive procedures
laboratory testing just before the procedure: INR should be lower than 1.5 (ACCP 2012)
DOACs:
Quick onset of action, relative short half-live
discontinuation of DOACs a few days before surgery or invasive procedures would be sufficient to allow clearance of these drugs from the circulation
 Is the laboratory measurement of residual drug levels needed?
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016.
Douketis J et al. Chest 2012 13

14. Why to measure DOACs in the perioperative setting?
Cons (against the laboratory strategy, in favor of the pharmacokinetic strategy):
Simpler: bleeding risk of the procedure, renal function,age, weight, other medications, dose of the DOAC, timing of the last DOAC administration
No precise guidance about which tests should be used
The specific assays are not readily available and require expertise
The specific assays are expensive
There are no reliable cut-off values for drug concentrations to make decisions on whether surgery or invasive procedures could be safely carried out.
Some procedures could be unnecessarily postponed based on borderline laboratory results that are difficult to interpret
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016. 14

15. Why to measure DOACs in the perioperative setting?
Cons (against the laboratory strategy, in favor of the pharmacokinetic strategy):
RELY,ROCKET-AF, ARISTOTLE : the pharmacokinetic strategy was adopted with no excess bleeding in comparison to warfarin
Feeling of some clinicians that the laboratory issue may undermine the implementation of DOAC
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016. 15

16. Why to measure DOACs in the perioperative setting?
Pros (in favor of the laboratory strategy, against the pharmacokinetic strategy):
Pharmacokinetic strategy is not so simple: recommendations based on renal function are not consistent with a risk of confusion and mismanagement
Pharmacokinetic strategy is not so simple: categorization into low bleeding risk or high bleeding risk is also not consistent
CrCl should be measured as close as possible to the performance of the procedure (as it may considerably over time)
The reliability of the dose and timing of the last DOAC administration are based on the assumption that the patient correctly reports the true dose of the drug, the exact timing of administration and the type of other concomitant drugs
Influence of genetic variation on the DOAC response is not well known,  clearence is not always what it is anticipated.
PK: surrogate information, Labo: direct information
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016. 16

17. Why to measure DOACs in the perioperative setting?
Pros (in favor of the laboratory strategy, against the pharmacokinetic strategy):
Laboratory strategy would presumably have a much stronger impact in the case of medical-legal issues
There are systematic reviews/guidance/guidelines (ISTH, British Society of Hematology) about which tests should be used
Specific assays are available from many commercial diagnostic companies and can be set up on regular coagulometers, where they can be run at any time without special expertise
The specific assays are not so expensive (15-20 EUR, > INR) and are limited to specific situations  no impact on the healthcare system (cost of DOAC < VKA)
Cut-offs?: clinical trials are still needed to establish these cut-offs with certainty but cut-offs are available from EMA, ISTH and GIHP (between 30 and 50ng/ml)
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016. 17

18. Why to measure DOACs in the perioperative setting?
Pros (in favor of the laboratory strategy, against the pharmacokinetic strategy):
Situations where laboratory data are difficult to interpret exist but solution should be based on common sense
Douketis et al. J Thromb Haemost 2016 Effect of standardized perioperative dabigatran interruption on residual anticoagulation effect at the time of surgery or procedure: 20% of patients had ‘abnormal’ test values at the time of the surgery/procedure is a cause of concern and should be seen as an indication to consider the laboratory strategy.
RELY,ROCKET-AF, ARISTOTLE : clinical trials are not entirely representative of the real life (strict control, many exclusion criteria,..)
Lab testing (if properly used) may help clinicians to better manage patients and would favor the implementation of DOACs
Tripodi J Thromb Haemost 2016
Spyropoulos et al J Thromb Haemost 2016. 18

19. Clinical trials on perioperative DOAC management with laboratory data
Schulman et al. 2015: first prospective study of periop management of patients on dabigatran etexilate without bridging: 48 hours may be not enough before high bleeding risk surgery
Godier et al CORIDA study (COncentrations of Rivaroxaban and Dabigatran): 48 hours not enough before high bleeding risk surgery
CORIDA 2: results in submission
PAUSE trial (Perioperative Anticoagulant Use for Surgery Evaluation Study (PAUSE) awaiting results for 2017
Schulman et al. Circulation 2015
Godier et al. Thromb Res 2015

20. When do we need to measure DOACs in urgent situations?
Bleeding or recurrence of thrombosis (to assessing the potential contribution of DOACs)
Before an invasive procedure (elective or urgent surgery at risk of bleeding, thrombolysis) to make decision about timing of these procedures or to determine whether patients with acute ischemic stroke can safely be given fibrinolytic therapy.
To select patients who will benefit from antidote administration
(RE-VERSE AD study; at baseline, 25 patients had a normal aPTT  more sensitive tests than the aPTT are needed to best identify patients who will benefit from idarucizumab and to monitor their response to treatment).
To monitor the extent of reversal achieved when reversal agents are given
Douxfils et al. Exp. Op. Drug. Saf
Weitz J, Eikelboom J. Circulation 2016 20 20

21. Assays sensitive to low plasma concentrations of dabigatran are required to assess the reversal by idarucizumab
RE-VERSE AD interim results: primary endpoint by dTT reversal
Assay upper limit of normal
Idarucizumab
2x 2.5 g
dTT (s)
130
110 70 60 50 40 30 20
120
100 90 80 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min
Time post idarucizumab
Uncontrolled bleeding
Emergency surgery or procedure
Idarucizumab
2x 2.5 g
dTT (s)
130
110 70 60 50 40 30 20
120
100 90 80 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min
Time post idarucizumab
Interim analysis includes data for the first 90 patients.
Pollack CV et al. N Engl J Med 2015:373:511–20

22. Idarucizumab for dabigatran reversal- Does one dose fit all?
The 5 g idarucizumab decreased dabigatran concentration from 3000ng/ml to 500 ng/mL. However, the dabigatran concentration
returned to 1126 ng/mL at 7 h after idarucizumab administration,
= rebound of drug levels
This case highlights the need for continued monitoring of dabigatran concentrations and coagulation parameters following idarucizumab administration.
Rottenstreich A et al. Thromb Res 2016
Miller L et al. J Emerg Med 2016

23. When do we need to measure DOACs in urgent situations?
For andexanet administration:
The dose is determined by which oral FXa inhibitor the patient is taking and the time from the last dose
This can lead to unnecessary administration or underdosing if the clinical information is incorrect
Ready access to rapidly available, calibrated tests is needed to ensure reversal agents are given appropriately
The cost of andexanet is estimated to be between 3000 and 4000 EUR per dose. Therefore, ready access to rapidly available, calibrated tests is needed to ensure that reversal agents are given appropriately.
Weitz J, Eikelboom J. Circulation 2016 23 23

24. Guidance of the SSC of the ISTH (2/2)
For the administration of reversal agents:
In patients with serious bleeding, a drug concentration, > 50 ng/mL is likely sufficiently high to warrant antidote administration whereas in those requiring an urgent intervention associated with a high risk of bleeding, antidote administration should be considered if the drug concentration exceeds 30 ng/mL
Note: This algorithm needs to be validated prospectively
Levy et al. J Thromb Hemost 2016

25. When it may be useful to measure DOACs in non urgent situations?
In patients with potential drug interactions that affect the pharmacokinetics of DOACs (P-gp)
In patients with extreme body weight (< 50 or > 110 kg)
In elderly patients (> 75 years of age) with renal failure
In case of accumulating interfering factors
Douxfils et al. Exp. Op. Drug. Saf
Weitz J, Eikelboom J. Circulation 2016
Martin et al. J Thromb Haemost 2016 25 25

26. How to interpret DOAC assays?
dabigatran etexilate (PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
TMAX (hours)
TTROUGH (hours)
12.0
24.0 26

27. How to interpret DOACs assays in urgent situations?
Use the appropriate assay! Limit of quantification, linearity and Interferences!
Safety threshold for surgery with high risk of bleeding
Drug reversal in case of serious bleeding
Risk of bleeding
Ischemic stroke: no consensus, IV thrombolysis in patients with 50 to 100 ng/mL
< 30 ng/mL
> 50 ng/mL
Trough measurement
200ng/ml
Levy JH, J Thromb Haemost 2016
Baglin T, J Thromb Haemost 2013
Pernod G, Arch Cardiovasc Dis 2013
Seiffge DJ, Circulation 2015 27 27

28. How to interpret DOACs assays in non urgent situations?
More complex! Absence of therapeutic range (concentrations associated with bleeding or thrombosis Expected plasma concentration or on-therapy range (5th percentile trough concentration - 95th percentile peak concentration)
Study population: atrial fibrillation
Through
conc. (ng/mL)
5th-95th
Peak
On-therapy range
(ng/mL)
Dabigatran
150 mg twice daily
64-443
31-225
31-443
Rivaroxaban
20 mg daily
6 - 87
Apixaban
5 mg twice daily
Edoxaban
60 mg daily 28
Kitchen S, et al. Br J Haematol. 2014; Cuker A, J Thromb Thrombolysis 2016; Samuelson BT Chest 2016 28

29. How to measure DOACs? Requirements
Readily available
24h/day and 7 days/week
Easily performed
short turnaround time
Reliable for measurement of
“low” and “high “ concentrations
< 30 to > 500ng/mL
Since measurement of the conc is most of the time require in emergency situation, the assay must be readily available and have a short….
Gold standard: liquid chromatography with tandem mass spectrometry (LC-MS/MS)
Baglin T, J Thromb Haemost 2014
Dale BJ, Br J Haematol 2015
Cuker A, J Thromb Thrombolysis 2016 29

30. Turn around time
38 consecutive patients with acute ischemic or hemorrhagic stroke under Rivaroxaban (last intake <48 h) in which RivLev determined by Biophen assay TAT:34 min (IQR 29–65 min).
similar for on-hours and off-hours-TATs as well as for early and late patient arrival
Feasible for use in emergency treatment
Further research to evaluate the role of rivaroxaban concentration to guide acute treatment decisions is warranted.
Seiffge DJ, et al. J Thromb Thrombolysis 2016

31. How to measure DOACs: summary of systematic reviews and recommendations
Focaliser sur dabigatran avec un cadre?
Cuker A., et al. J Am Coll Cardiol. 2014
Lippi G. Clin Chem Lab Med. 2015
Samuelson BT, Cuker A. Blood Rev 2016

32. Mass spectrometry : advantages and limitations of the gold standard method
specificity
labour-intensive preparation
sensitivity
LOD around 1 ng/mL
LOQ around 3 ng/mL
complexity of the technique
selectivity
compared to coagulation-based assay
cost >< availability
reproducibility
intra-assay precision < 6%
inter-assay precision < 10%
Lack of standardization: in-house validation
matrix effect
interference with plasma phospholipids
presence of other compounds
removal of proteins
interference by drug metabolites (either active or not)
accuracy
external quality control
turn-around time
Douxfils J., et al. Trends in Analytical Chemistry. 2016

33. Standard laboratory assays (PT/APTT) for DOACs
Poor comparability of APTT/PT with specific assays 33
Testa S. et al, J Thromb Haemost 2016

34. Dabigatran: aPTT APTT is not reliable:
not sensitive enough to dabigatran
not possible to estimate dabigatran concentration
normal aPTT cannot exclude the presence of dabigatran
multiple other biological variable interfering with aPTT
Do not calibrate with commercial standards
Douxfils J,, Mullier F et al. Thromb Haemost. 2012
Douxfils J,, et al. Thromb Haemost. 2013
Hawes E. M., et al. JTH. 2013
Baglin T., et al. JTH. 2013
Van Blerk M., et al. Thromb Haemost. 2015
Samuelson BT, et al. Chest 2016

35. TT may be useful for low concentrations
Often used in clinical practice even if it is not recommended
Normal TT excludes clinical relevant dabigatran level
A prolonged TT is not always associated with a concentration higher than 30 ng/ml  some anesthesiologists/surgeons may uselessly delay an invasive procedure
Lack of standardisation and specificity (heparin bridging, inflammatory syndrome, fibrin degradation products…)
Several biological and analytical variables:
Thrombin origin
Concentration of thrombin
Lot to lot reagent differences
Instrumentation/Storage
Lessire S, Douxfils J et al. Thromb Res 2015; Douxfils J, Lessire S et al. Thromb Haemost. 2015; Chin et al. Br J Clin Pharmacol 2014. 35

36. Dabigatran: Dilute Thrombin Time and Ecarin Chromogenic Assay
Hemoclot® Thrombin Inhibitors (HTI) and Ecarin Chromogenic assay (ECA) and STA®-ECA II (ECA II)
useful for normal and high dabigatran concentrations
but lower limits of quantitation between 30 and 50 ng/mL.
Stangier J and coll. Blood Coagul Fibrin 2012
Lange U and coll. Pathophysiology of Haemostasis and Thrombosis 2003
Gosselin RC and coll. Ann Pharmacother 2013
Douxfils J and coll. Thromb Haemost 2013
Hawes EM and coll. J Thromb Haemost 2013
Antovic JP and coll. Eur J Clin Pharmacol 2013
Douxfils J, Mullier F and coll. Thromb Haemost 2012
van Ryn J and coll. Thromb Haemost 2010
Skeppholm M. and coll. Thromb Res 2014

37. Dabigatran and dedicated coagulation assays : External UKNEQAS survey

38. Dabigatran and dedicated coagulation assays : External UKNEQAS survey
High CVs were observed for the two samples with lower levels of dabigatran.
Between center agreement was better for sample S14:13 (median concentration 158.5ng/ml, CV 19.1%).

39. Dabigatran and dedicated coagulation assays : External UKNEQAS survey
Only 3 CE marked assays
Most of the assays are useful for normal and high concentrations but have lower limits of quantitation between 30 and 50 ng/mL
Stangier J et al. Blood Coagul Fibrin 2012; Lange U et al. Pathophysiology of Haemostasis and Thrombosis 2003; Gosselin RC et al. Ann Pharmacother 2013; Douxfils J et al. Thromb Haemost 2013, Hawes EM et al. J Thromb Haemost 2013; Antovic JP et al. Eur J Clin Pharmacol 2013; Douxfils J, Mullier F et al. Thromb Haemost 2012; van Ryn J et al. Thromb Haemost 2010; Skeppholm M. et al. Thromb Res 2014

40. Dabigatran and dedicated coagulation assays : Other international surveys
UKNEQAS 2015
Sample 15:01(n=56) : median 92ng/ml: overall CV: 15.1%
Sample 15:02 (n=55): median 154 ng/ml, overall CV: 16.7%
ECAT 2015
Sample 15:88 (n=111): median 131 ng/ml, overall CV: 15.4%
Sample 15:89 (n=112): median 235 ng/ml, overall CV: 11.6%

41. New specific tests are available for low dabigatran concentrations
Good accuracy in the low concentration range
HemosIL Direct Thrombin Inhibitor also accurate (UKNEQAS 2014)
Douxfils J,, et al. Thromb Haemost

42. Comparison of specific assays for dabigatran
Importance to use specific assays to make decisions in the perioperative management of patients
Lessire et al. Submitted - Blood coagulation & fibrinolysis

43. Assays sensitive to low plasma concentrations of dabigatran are required to assess the reversal by idarucizumab
RE-VERSE AD interim results: primary endpoint by dTT reversal
Assay upper limit of normal
Idarucizumab
2x 2.5 g
dTT (s)
130
110 70 60 50 40 30 20
120
100 90 80 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min
Time post idarucizumab
Uncontrolled bleeding
Emergency surgery or procedure
Idarucizumab
2x 2.5 g
dTT (s)
130
110 70 60 50 40 30 20
120
100 90 80 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min
Time post idarucizumab
Interim analysis includes data for the first 90 patients.
Pollack CV et al. N Engl J Med 2015:373:511–20
Lower limit of quantitation: 30-50ng/ml!

44. Heparin-calibrated chromogenic anti-Xa assays
Correlation only between low anti-Xa inhibitors conc. and heparin anti-Xa activity
High inter-assay variability: no relationship between anti-Xa inhibitor concentration and heparin anti-Xa U/mL
Given the availability of heparin calibrated anti-xa assays, the performance of these assays to mesure direct anti-Xa inhibitors have been tested.
Direct anti-Xa inhibitors yield high heparin anti-Xa activity
Correlation between drug conc. and heparin anti-Xa U/mL only over calibration ranges: low drug concentrations
Variabiliy between commercial kits and calibrators: no relationship between drug conc. and heparin anti-Xa U/mL
Suitable for ruling out presence of direct anti-Xa
Should not be used to quantify direct anti-Xa
Gosselin R, Ann Pharmacother 2015
Gosselin R, J Thromb Haemost 2016
Samama MM, Thromb Haemost 2010 44

45. Specific tests for direct anti-Xa concentration measurement: chromogenic anti-Xa assays
Advantages
Drawbacks
Same reagents for measurement of UFH, LMWH anti-Xa activity and direct anti-Xa inhibitors
Ready-to-use reagents
Not affected by pre-analytical variables and alterations of clotting factor levels
Measurement in plasma/serum
High correlation with LCMSMS
Specific calibrators and controls for each anti-Xa inhibitor:
Rivaroxaban: available
Apixaban: available
Edoxaban: coming soon
Lack of standardization: a reference international calibrator is required
Each laboratory should establish, riva, api and edoxaban-specific standard curves
Harenberg J, Clin Chem Lab Med 2016
Cuker A, J Thromb Thrombolysis 2016
Douxfils J, Bio Med Res Int 2015
Dale BJ, Br J Haematol 2015
Gosselin RC, Arch Pathol Lab Med 2014
Cuker A, JACC 2014 45

46. Intra-assay CV %: < 5% Inter-assay CV%: < 10%
Specific chromogenic anti-Xa assays for rivaroxaban and apixaban measurement
Reagents: one- or two-stage assay, different buffers, dilution factors, concentrations of Xa, types of chromogenic substrate
Methods with exogenous antithrombin: over estimation of rivaroxaban
Mani H, Thromb Haemost 2012 ; Helin TA, Clin Chem 2013 ; Asmis IM, Thromb Res 2012, Gosselin R Arch Pathol Lab Med 2014
Calibrators: 4 to 5 levels from 0 to 500 ng/mL (Stago, Hyphen, Technoclone)
Lower limit of detection/quantification: ~ ng/mL (sometimes lower Mani H, Thromb Haemost 2012 , Lessire S. CATH 2016 Accepted)
Upper limit of quantification: ~ ng/mL (if higher: dilution in buffer/plasma)
Chromogenic anti-Xa assays are available from many commercial diagnostic companies. They differ in the type of methods,
Biophen DiXa: specific for direct anti-Xa; Insensitive to the presence of heparin-like anti-Xa
Berichrom contains AT
Intra-assay CV %: < 5%
Inter-assay CV%: < 10%
Samama MM, Thromb Haemost 2010 ; Becker RC, J thromb Thrombolysis 2011 ; Douxfils J, Thromb Res 2012 ; Mani H, Thromb Haemost 2012 Douxfils J, Thromb Haemost 2013 ; Barrett YC, Thromb Haemost 2013 ; Francard S, Thromb Haemost 2014
Package inserts from diagnostic companies 46

47. Interference of heparin on DOAC specific assays
Lessire S. et al. Clin App Thromb Hemost Accepted

48. Are the tests limited to specialized laboratories?
NO!

49. Are the tests limited to specialized laboratories?
NO!
Weitz J, Eikelboom J. Circulation 2016

50. Interference of DOACs on various coagulation tests

51. Take home messages (1/4)
2 key opinion leaders says: Registration by regulatory agencies and their widespread implementation in clinical laboratories are “urgently” needed
Dabigatran versus warfarin in patients with atrial fibrillation.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators.
N Engl J Med Sep 17;361(12):
Idarucizumab for Dabigatran Reversal.
Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI.
N Engl J Med Aug 6;373(6): 51

52. Take home messages (2/4)
DOACs are now cornerstones in the treatment of various thromboembolic diseases
Although routine assessment of the intensity of anticoagulation is not required with these drugs, several situations may require the use of coagulation testing 52

53. Take home messages (3/4)
aPTT should not be used except for screening a bleeding patient on dabigatran etexilate
Normal APTT and/or PT don’t exclude presence of therapeutic levels
Normal TT excludes clinical relevant drug level of dabigatran
dTT and ECA should be preferred for normal and high concentrations (ECT is not recommended)
Adaptations of the assays are required for low concentrations (perioperative management, reversal by idarizucimab)
Importance of delay between last administration and sampling 53

54. Take home messages (4/4)
How to interpret DOACs assays in urgent situations?
3 cut-offs: 30 – 50 – 200 ng/mL
Use the appropriate assay
(Laboratories): limit of quantitation, linearity ad interferences

55. Perspectives Development of point of care devices
Development of a reference international calibrator
Collect data about sample stability are lacking
To validate low methodologies for apixaban and edoxaban in a perioperative setting
To optimize the specificity of chromogenic assays for low DOACs plasma concentrations
To reduce the turn-around time (TAT) of urgent DOAC level estimation
To analyze the value of DOAC measurements in patients in emergency setting

56. Thank you for your attention

57. Acknowledgments Dr. Jonathan Douxfils Dr. Sarah Lessire
Dr. Anne-Sophie Dincq
Ph. Anne-Sophie Larock
Ph. Anne-Laure Sennesael
Dr. Bérangère Devalet
Dr. Valérie Mathieux
Pr. Bernard Chatelain
Pr. Christian Chatelain
Mrs. Justine Baudar
Mrs. Maité Guldenpfennig
Pr. Paul Hjemdahl
Pr. Pierre Wallemacq
Pr. Jean-Michel Dogné
Dr Anne Godier
Dr Isabelle Gouin-Thibault