seminaires iris Mon patient prend un NACO, comment évaluer sa coagulation au Service des Urgences?

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1 Mon patient prend un NACO, comment évaluer sa coagulation au Service des Urgences? Jonathan DOUXFILS, Department of pharmacy Faculty of Medicine University of Namur Séminaire IRIS

2 Content Introduction Monitoring: Why to measure? When to measure? How to measure? Impact on coagulation tests Conclusions 2

3 MONITORING? WHY? 3

4 Content Introduction Monitoring: Why to measure? When to measure? How to measure? Impact on coagulation tests Conclusions 4

5 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):

6 PK and PD rivaroxaban apixaban edoxaban dabigatran 6

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

8 Brief reminder dabigatran etexilate (PRADAXA ) rivaroxaban (XARELTO ) apixaban (ELIQUIS ) edoxaban (LIXIANA ) T MAX (hours) T TROUGH (hours)

9 Content Introduction Monitoring: Why to measure? When to measure? How to measure? Impact on coagulation tests Conclusions 9

10 Drug interactions dabigatran etexilate (PRADAXA ) rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp Anti-H 2 /proton pump inhibitors 30% reduction of the AUC No impact on efficacy in RCT No impact No impact No impact edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism Eu-SmPC Pradaxa Xarelto Eliquis Lixiana 10

11 Drug interactions P-glycoprotein Substrates antimalignants immunosuppressive drugs (ciclosporine, tacrolimus) Loperamide Colchicin Saquinavir Digoxin Inducers Rifampicin St John s wort Ritonavir, tripanavir Inhibitors Diltiazem, verapamil Amiodarone, quinidine, propafenone Atorvastatin Dipyridamole Clarithro-, azithro-mycin Itraconazole, kétoconazole Ciclosporine Tacrolimus 11

12 Drug interactions dabigatran etexilate Strong P-gp inhibitors Contraindicated Ketoconazole Itraconazole Dronédarone Ciclosporine Tacrolimus dabigatran etexilate (PRADAXA ) Moderated P-gp inhibitors Caution! Amiodarone Verapamil Quinidine Clarithromycin rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism Strong P-gp inducers Caution! Rifampicin St John s wort Carbamazepine Phenytoin apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp Dose tailoring: - VTE prevention post TKR/THR: max 150 mg/day (2 caps of 75 mg od) - SPAF: max 220 mg/day (1 caps 110 mg bid) + PD interactions ASA Clopidogrel NSAIDs SSRI and SNERI Concomitant treatment with other anticoagulant edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism CI Eu-SmPC Pradaxa 12

13 Drug interactions rivaroxaban Strong P-gp and CYP3A4 inhibitors Not-recommended Ketoconazole Itraconazole Voriconazole Posaconazole Protease inhibitors (ritonavir, ) dabigatran etexilate (PRADAXA ) Moderated P-gp inhibitors Caution! Clarithromycin Erythromycin rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism Strong P-gp inducers Caution! Rifampicin St John s wort Carbamazepine Phenytoin Phenobarbital apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp + PD interactions ASA Clopidogrel NSAIDs SSRI and SNERI Concomitant treatment with other anticoagulant No dose adjustment edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism CI Eu-SmPC Xarelto 13

14 Drug interactions apixaban Strong P-gp and CYP3A4 inhibitors Not-recommended Ketoconazole Itraconazole Voriconazole Posaconazole Protease inhibitors (ritonavir, ) dabigatran etexilate (PRADAXA ) Moderated P-gp inhibitors Caution! rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism Strong P-gp inducers Caution! / Rifampicin St John s wort Carbamazepine Phenytoin Phenobarbital apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp + PD interactions ASA Clopidogrel NSAIDs SSRI and SNERI Concomitant treatment with other anticoagulant No dose adjustment edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism CI Eu-SmPC Eliquis 14

15 Drug interactions edoxaban P-gp and CYP3A4 inhibitors Dose reduction Cyclosporine Dronedarone Erythromycin Ketoconazole dabigatran etexilate (PRADAXA ) Other P-gp and CYP3A4 inhibitors Caution! Amiodarone Verapamil Quinidine rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism Strong P-gp inducers Caution! Rifampicin St John s wort Carbamazepine Phenytoin Phenobarbital apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp SPAF and DVT/PE: - edoxaban 30 mg od + PD interactions ASA Clopidogrel NSAIDs SSRI and SNERI Concomitant treatment with other anticoagulant No dose adjustment edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism CI Eu-SmPC Lixiana 15

16 Drug interactions unknown drug interactions Strong P-gp and CYP3A4 inhibitors Not recommended if requested: Clinical monitoring Biological tests? dabigatran etexilate (PRADAXA ) Moderated P-gp and CYP3A4 inhibitors Caution Clinical monitoring rivaroxaban (XARELTO ) CYP substrate 3A4, 2J2 + cypindependent mechanism Strong P-gp and CYP3A4 inducers Caution Risk of underdosing apixaban (ELIQUIS ) 3A4/5, 1A2, 2J2 + cypindependent mechanism Transport substrate P-gp P-gp P-gp P-gp + PD interactions ASA Clopidogrel dypiridamol,etc Concomitant treatment with other anticoagulant Following regional availability, a consultation with a coagulation specialist has to be envisaged in case of bleeding or recurrence of thrombosis edoxaban (LIXIANA ) 3A4/5 + cypindependent mechanism Assessment of the B/R balance CI 16

17 Renal impairment Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment with DOACs Several dosing recommendations based on CrCl Algorythm for the monitoring of the renal function has been proposed* 60 ml/min should be assessed every 6 months 50 ml/min should be assessed every 5 months 40 ml/min every 4 months etc CrCl divided by 10 if CrCl is below 60 ml/min * There are several proposals for the monitoring of the kidney function, but in any case, yearly monitoring is probably not sufficient in patients with impaired renal function. Heidbuchel H, et al. Europace: Eu-SmPC Pradaxa Xarelto Eliquis and Lixiana 17

18 Hepatic impairment Hepatic disease associated with coagulopathy dabigatran etexilate (PRADAXA ) Recommendation: rivaroxaban (XARELTO ) CONTRINDICATED apixaban (ELIQUIS ) Prior to initiating DOACs, liver function testing should be performed. edoxaban (LIXIANA ) Heidbuchel H, et al. Europace: Eu-SmPC Pradaxa Xarelto Eliquis Lixiana 18

19 Extreme body weight Low body weight (<50-60 kg) High body weight (>120 kg) dabigatran etexilate (PRADAXA ) No dose adjustment required Limited clinical data are available for patients <50 kg No dose adjustment required Trough dabigatran concentrations were 20% lower in patients >100 kg compared to the kg group rivaroxaban (XARELTO ) No dose adjustment required Variation of less than 25% of the exposure No dose adjustement required Variation of less than 25% of the exposure apixaban (ELIQUIS ) Dose reduction: 2.5 mg bid if at least 2 of the following: 80 years 60 kg serum creat. 1,5 mg/dl or if CrCl ml/min 30 % increase of the exposure No dose adjustement required 30% reduction of the exposure edoxaban (LIXIANA ) Dose reduction: 30 mg od C MAX and AUC increased by 40% and 13%, respectively No information Eu-SmPC Pradaxa Xarelto Eliquis Lixiana 19

20 Extreme body weight Guidance from the SSC of the ISTH i. We recommend appropriate standard dosing of the DOACs in patients with a BMI less than or equal to 40 kg/m 2 and weight less than or equal to 120 kg ii. iii. We suggest that DOACs should not be used in patients with a BMI of > 40 kg/m 2 or a weight of > 120 kg, because there are limited clinical data available for patients at the extreme of weight, and the available PK/PD evidence suggests that decreased drug exposures, reduced peak concentrations and shorter half-lives occur with increasing weight, which raises concerns about underdosing in the population at the extreme of weight. If DOACs are used in a patient with a BMI of > 40 kg/m 2 or a weight of > 120 kg, we suggest checking a drug-specific peak and trough level. Martin et al. Journal of Thrombosis and Haemostasis

21 Other special populations Elderly Ethnic origin and race dabigatran etexilate (PRADAXA ) Patients aged 80 years or above should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily due to the increased risk of bleeding in this population. No clinically relevant ethnic differences. However, 32.8% of the white European participants of the RE- LY study presented a particular SNP that decreased trough concentrations to the rate of the 110mg BID dose rivaroxaban (XARELTO ) Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary. No clinically relevant interethnic differences apixaban (ELIQUIS ) Dose reduction: 2.5 mg bid if at least 2 of the following: 80 years 60 kg serum creat. 1,5 mg/dl or if CrCl ml/min Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in C MAX. No clinically relevant interethnic differences edoxaban (LIXIANA ) After taking renal function and body weight into account, age had no additionnal clinically significant effect on edoxaban pharmacokinetics No clinically relevant interethnic differences. 21

22 Pro or cons monitoring? Cons: PK-PD studies: preditable response All RCT were performed without monitoring Large therapeutic range Bounameaux H, Reber G. JTH

23 Pro or cons monitoring? Pro: dabigatran etexilate Correlation between clinical events and plasmatic dabigatran concentrations Possible improvement of the B/R balance Reilly PA et al., JACC. 2013; Ruff et al., The Lancet. 2015; Douxfils et al., Exp. Op. Drug Saf

24 Pro or cons monitoring? Pro: rivaroxaban and apixaban Lack of data in the literature FDA level: 50% increase of major bleeding by 200% increase of C MAX Apixaban: similar approach (based on the AUC) FDA 2013 Clinical Pharmacology and Biopharmaceutical review 24

25 Pro or cons monitoring? Pro: edoxaban a similar association between plasma concentrations and clinical outcomes has been identified with edoxaban Ruff et al. The Lancet

26 Patients or situations requiring an assessment of the response Bleeding or recurrence of thrombosis Before an invasive procedure (elective or urgent surgery) In patients with potential drug interactions that affect the pharmacokinetics of DOACs In patients with extreme body weight (< 50 or > 100 kg) In elderly patients (> 75 years of age) In patients with genetic mutations (i.e., rs minor allele carriers for dabigatran etexilate) In case of accumulating interfering factors Douxfils et al. Exp. Op. Drug. Saf

27 Why is the need for these tests so urgent? (1/3) Quantification of plasma concentration is critical when: i. Assessing the contribution of DOACs to serious bleeding ii. iii. Making decision about the timing of urgent surgery of interventions Determining whether patients with acute ischemic stroke can safely be given thrombolytic Weitz et al. Circulation 2016

28 Why is the need for these tests so urgent? (2/3) Patients with elevated drug levels in emergent situations: i. May benefit from the administration of reversal agent >< those with little or no circulating drug ii. iii. How do we identify those requiring reversion? How do we monitor the extent of reversal achieved? Weitz et al. Circulation 2016

29 Why is the need for these tests so urgent? (3/3) For andexanet administration: i. 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 et al. Circulation 2016

30 Guidance of the SSC of the ISTH (1/2) For the administration of reversal agents: i. Delaying antidote administration until coagulation test results are available may be detrimental in DOAC-treated patients with life-threatening bleeding, such as intracranial bleeding, or in those requiring emergency surgery for lifethreatening conditions such as a ruptured aortic aneurysm. ii. The decision as to whether an antidote is indicated can be guided by the time since the last intake of the DOAC, determination of the creatinine clearance, which influences the half-lives of the DOACs, and the results of laboratory tests, which measure the anticoagulant effects of the DOACs or the plasma drug concentrations Levy et al. Journal of Thrombosis and Hemostasis 2016

31 Guidance of the SSC of the ISTH (2/2) For the administration of reversal agents: iii. 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. Journal of Thrombosis and Hemostasis 2016

32 Assays available to measure plasma levels of the DOACs Weitz et al. Circulation 2016

33 The questions in emergent situations Is a DOAC present? Two possible scenarios: i. Patients known taking a DOAC and requiring an emergent intervention ii. Patients with unknown medical or treatment history also requiring urgent intervention And how much is it? Gosselin et al. Journal of Thrombosis and Haemostasis

34 The questions in emergent situations In any case, clinical laboratory scientist should be PROACTIVE and determine WHAT information the clinician needs Gosselin et al. Journal of Thrombosis and Haemostasis

35 The questions in emergent situations Is a DOAC present? Two possible scenarios: i. Patients known taking a DOAC and requiring an emergent intervention ii. Patients with unknown medical or treatment history also requiring urgent intervention And how much is it? Gosselin et al. Journal of Thrombosis and Haemostasis

36 Known dabigatran treatment Normal TT virtually excludes the presence of dabigatran i. If TT is elevated, TT mixing studies or reptilase test may help to discriminate between fibrinogen abnormalities and dabigatran effect ii. TT mixing studies not corrected dabigatran iii. TT with protamine sulfate corrected heparin iv. Abnormal TT, normal fibrinogen and reptilase dabigatran v. Abnormal TT, fibrinogen and reptilase hypo-/dysfibrinogenemia Gosselin et al. Journal of Thrombosis and Haemostasis

37 Known anti-fxa DOAC treatment If acutely needed for patients with known FXa DOAC use, a chromogenic anti-fxa assay (calibrated with unfractionated heparin [UFH] or low molecular weight heparin [LMWH]) that yields a value at or below the LOQ may virtually exclude the presence of an anti-fxa DOAC. Gosselin et al. Journal of Thrombosis and Haemostasis. 2015; Douxfils et al. TrAC

38 Unknown medication history If acutely needed for patients with an unknown medication history, a traditional TT and the use of heparin calibrated anti-fxa tests can guide clinicians to the presence of anti-fiia or anti-fxa DOACs. i. A normal TT excludes the presence of dabigatran. ii. Anti-FXa below the LOQ may rule out the presence of an FXa DOAC Note: Use these data in conjunction with PT, APTT and fibrinogen to assess other causes of coagulopathy in a bleeding patient Note: Chromogenic anti-fxa assays cannot discriminate between heparin and anti-fxa DOACs. Gosselin et al. Journal of Thrombosis and Haemostasis. 2015; Douxfils et al. TrAC

39 Results from the REVERSE-AD study More sensitive tests than aptt are needed i. At baseline, 25/90 patients had normal aptt whereas only 9/90 had normal ECT Weitz et al. Circulation 2016; Pollack et al. NEJM 2016

40 Results from the ANNEXA-4 study Chromogenic anti-xa assays were used to assess the reversal i. No mention of PT and or aptt ii. DOAC calibrated chromogenic anti-xa assay Weitz et al. Circulation 2016; Connolly et al. NEJM 2016

41 Implementation in routine care setting PT and APTT are not adequate methods to detect low levels of DOAC Most automated coagulation instruments can perform TT, dtt, ecarin-based assays and chromogenic anti-xa assays Gosselin et al. Journal of Thrombosis and Haemostasis. 2015; Douxfils et al. TrAC. 2016

42 The questions in emergent situations Is a DOAC present? Two possible scenarios: i. Patients known taking a DOAC and requiring an emergent intervention ii. Patients with unknown medical or treatment history also requiring urgent intervention And how much is it? Gosselin et al. Journal of Thrombosis and Haemostasis

43 Which tests? ng/ml TT DABIGATRAN dtt - ECA RIVAROXABAN aptt PT Calibrated chromogenic anti-xa assays PT aptt NVAF C TROUGH : 91 ( ng/ml) mean (25 th 75 th percentile) NVAF C MAX :175 ( ng/ml) - mean (25 th 75 th percentile) VTE C TROUGH : 91 ( ng/ml) - mean (25 th 75 th percentile) VTE C MAX : 175 ( ng/ml) - mean (25 th 75 th percentile) NVAF C TROUGH : 44 ( ng/ml) - mean (5 th 95 th percentile) NVAF C MAX : 249 ( ng/ml) - mean (5 th 95 th percentile) VTE C TROUGH : 26 (6 87 ng/ml) - mean (5 th 95 th percentile) VTE C MAX : 270 ( ng/ml) - mean (5 th 95 th percentile) APIXABAN Note: adapted methodology may be required for specific tests due to the LOQ Douxfils et al. Eur Heart J. Submitted NVAF C TROUGH : 103 ( ng/ml) - median (5 th 95 th percentile) NVAF C MAX : 171 ( ng/ml) - median (5 th 95 th percentile) VTE C TROUGH : 63 ( ng/ml) median (5 th 95 th percentile) VTE C MAX : 132 (59 302ng/ml) median (5 th 95 th percentile) 43

44 aptt PT Which tests? RIVAROXABAN Calibrated chromogenic anti-xa assays aptt ng/ml TT DABIGATRAN APIXABAN PT Calibrated chromogenic anti-xa assays dtt - ECA EDOXABAN RIVAROXABAN aptt PT PT aptt Calibrated chromogenic anti-xa assays Calibrated chromogenic anti-xa aptt assays PT PT aptt NVAF C TROUGH : 44 ( ng/ml) - mean (5 th 95 th percentile) NVAF C MAX : 249 ( ng/ml) - mean (5 th 95 th percentile) VTE C TROUGH : 26 (6 87 ng/ml) - mean (5 th 95 th percentile) VTE C MAX : 270 ( ng/ml) - mean (5 th 95 th percentile) NVAF NVAF C TROUGH TROUGH : (61 ( ng/ml) ng/ml) - mean median (25 (5 th th th th percentile) percentile) NVAF C NVAF MAX :175 ( ng/ml) - mean (25 MAX : 171 ( ng/ml) median (5 th th th th percentile) percentile) VTE C VTE TROUGH : 91 ( ng/ml) - mean (25 TROUGH 63 ( ng/ml) median (5 th th th th percentile) percentile) VTE VTE C MAX MAX : (59 ( ng/ml) 275 ng/ml) median - mean (25 (5 th th th th percentile) percentile) NVAF C TROUGH : 36 (19 62ng/ml) - median (1.5 x IQR) NVAF C MAX : 170 ( ng/ml) median (1.5 x IQR) NVAF C TROUGH : 44 ( ng/ml) - mean (5 th 95 th percentile) NVAF C MAX : 249 ( ng/ml) - mean (5 th 95 th percentile) VTE C TROUGH : 26 (6 87 ng/ml) - mean (5 th 95 th percentile) VTE C MAX : 270 ( ng/ml) - mean (5 th 95 th percentile) Douxfils et al. Eur Heart J. Submitted APIXABAN Note: adapted methodology may be required for specific tests due to the LOQ NVAF C TROUGH : 103 ( ng/ml) - median (5 th 95 th percentile) NVAF C MAX : 171 ( ng/ml) - median (5 th 95 th percentile) VTE C TROUGH : 63 ( ng/ml) median (5 th 95 th percentile) VTE C MAX : 132 (59 302ng/ml) median (5 th 95 th percentile) 44

45 How much is it? Routine test Specific test Which test(s) could/should be used? dabigatran etexilate (PRADAXA ) aptt cut-off: THR/TKR: ratio >1.3 SPAF: ratio >2.0 (TT) Calibrated dtt cut-off: THR/TKR: 67 ng/ml SPAF: 200 ng/ml Ecarin-based tests rivaroxaban (XARELTO ) apixaban (ELIQUIS ) PT / PT Calibrated chromogenic anti-xa assays Calibrated chromogenic anti-xa assays edoxaban (LIXIANA ) Calibrated chromogenic anti-xa assays Note: i. other specific testing are under development (drvvt) which could be used for all DOACs but needs further validation ii. INR is not valid for DOACs iii. Cut-off at 30 and 50 ng/ml require adapted methodology due to the LOQ of the specific tests Douxfils et al. BioMed Res. Int. 2015; Douxfils et al. Thromb Haemost. 2016; Douxfils et al. Thromb Res. 2016; Sennesael et 45 al. Thromb Haemost. Submitted; Eu-SmPC Pradaxa Xarelto Eliquis and Lixiana

46 Management of bleeding patients in emergent situations - GIHP Dabigatran (1/2) Plasma concentrations Specific test to use or (non optimal option) global coagulation test interpretation and action 30 ng/ml Specific tests Operate STA -ECA II dtt using dedicated procedure (i.e. Hemoclot Thrombin Inhibitor (HTI) LOW or HemosIL DTI) Global coagulation tests (not the optimal option) TT (normal: excludes concentration higher than 30ng/ml) 30 ng/ml < [dabigatran] < 200 ng/ml Specific tests Wait until 12h and obtain specific dosage or new APTT/PT STA -ECA-II and TT or (If not compatible with the emergency) operate dtt using normal procedure (i.e. HTI or HemosIL DTI) and if abnormal bleeding: antagonize Global coagulation tests (not the optimal option) Note: Idarucizumab (Praxbind ) should not be given in APTT (if 1.2 < APTT ratio < 1.8 and 1.0 < PT ratio < 1.2 it is likely that the plasma concentration is in this range in < 50 ng/ml (or if specific dosage not available, if the TT < absence of other interfering factors) 120 s). In those requiring urgent intervention associated TT (if results <120 s, it is likely that the plasma concentration with high bleeding risk, antidote administration should be is below 50 ng/ml) patients with serious bleeding and plasma concentrations considered if plasma concentration > 30 ng/ml. *Algorithm adapted and updated from the proposal of the French Working Group on Perioperative Haemostasis (GIHP). Pernod et al. Arch Cardiovasc Dis. 2013; Douxfils et al. Eur Heart J. Submitted

47 Management of bleeding patients in emergent situations - GIHP Dabigatran (2/2) Plasma concentrations Specific test to use or (non optimal option) global coagulation test interpretation and action 200 ng/ml < [dabigatran] < 400 ng/ml Specific tests Wait until 12h-24h and obtain specific dosage or new [dabigatran] > 400 ng/ml STA -ECA-II dtt using normal procedure (i.e. HTI or HemosIL DTI) APTT/PT Maximum delay surgery and (If not compatible with the Global coagulation tests (not the optimal option) emergency) operate and if abnormal bleeding: antagonize APTT and PT (if 1.8 < APTT ratio 2.2 and 1.2 < PT ratio < 1.5 it is likely that the plasma concentrations is in this range in absence of other interfering factors) Request CrCl assessment: if < 50 ml/min obtain specific dosage (dtt using normal procedure or STA -ECA-II) Note: Idarucizumab (Praxbind ) should not be given in patients with serious bleeding and plasma concentrations < 50 ng/ml (or if specific dosage not available, if the TT < 120 s). In those requiring urgent intervention associated with high bleeding risk, antidote administration should be considered if plasma concentration > 30 ng/ml. Specific tests STA -ECA-II dtt using normal procedure (i.e. HTI or HemosIL DTI) Global coagulation tests (not the optimal option) APTT and PT (if APTT ratio > 2.2 and PT ratio > 1.5 it is likely that the plasma concentrations is in this range in absence of other interfering factors) Overdose major haemorrhagic risk: antagonize

48 Management of bleeding patients in emergent situations - GIHP Rivaroxaban (1/2) Plasma concentrations Specific test to use or (non optimal option) global coagulation test interpretation and action 30 ng/ml Specific tests Operate Rivaroxaban calibrated chromogenic anti-xa assays Other coagulation tests (not the optimal option) Heparin calibrated chromogenic anti-xa assays (if anti-xa units < 0.1 IU/ml, this can virtually exclude the presence of rivaroxaban) 30 ng/ml < [rivaroxaban] < 200 ng/ml Specific tests Wait until 12h and obtain specific dosage or new anti-xa or Rivaroxaban calibrated chromogenic anti-xa assays PT or (If not compatible with the emergency) operate and if Global coagulation tests (not the optimal option) abnormal bleeding: antagonize Heparin calibrated chromogenic anti-xa assays (if anti-xa units < 0.1IU/ml, this can virtually exclude the presence of rivaroxaban) Note: recommendation on PT and aptt cannot be given for rivaroxaban due to the very high reagent-dependent variability. Cut-off should be elaborated locally with plasma enriched with rivaroxaban *Algorithm adapted and updated from the proposal of the French Working Group on Perioperative Haemostasis (GIHP). Pernod et al. Arch Cardiovasc Dis. 2013; Douxfils et al. Eur Heart J. Submitted

49 Management of bleeding patients in emergent situations - GIHP Rivaroxaban (2/2) Plasma concentrations 200 ng/ml < [rivaroxaban] < 400 ng/ml [rivaroxaban] > 400 ng/ml Specific test to use or (non optimal option) global coagulation test Specific tests Rivaroxaban calibrated chromogenic anti-xa assays Global coagulation tests (not the optimal option) Specific tests Note: recommendation on PT and aptt cannot be given for rivaroxaban due to the very high reagent-dependent variability. Cut-off should be elaborated locally with plasma enriched with rivaroxaban Rivaroxaban calibrated chromogenic anti-xa assays Global coagulation tests (not the optimal option) Note: recommendation on PT and aptt cannot be given for rivaroxaban due to the very high reagent-dependent variability. Cut-off should be elaborated locally with plasma enriched with rivaroxaban interpretation and action *Algorithm adapted and updated from the proposal of the French Working Group on Perioperative Haemostasis (GIHP). Pernod et al. Arch Cardiovasc Dis. 2013; Douxfils et al. Eur Heart J. Submitted Wait until 12h-24h and obtain specific dosage or new PT Maximum delay surgery and (If not compatible with the emergency) operate and if abnormal bleeding: antagonize Request CrCl assessment: if < 50 ml/min obtain specific dosage (with rivaroxaban calibrated chromogenic anti-xa assays) Note: This algorithm needs to be validated prospectively Overdose major haemorrhagic risk: antagonize

50 Perioperative DOAC management and estimation of drug concentrations Clinical trials on perioperative DOAC management with estimation of their plasmatic concentrations has been published: 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 Schulman et al. Circulation 2015 Godier et al. Thromb Res 2015

51 Content Introduction Monitoring: Why to measure? When to measure? How to measure? Impact on coagulation tests Conclusions 51

52 Interference of DOACs on various coagulation tests Test Dabigatran Rivaroxaban Apixaban Edoxaban Notes Clotting factors based on PT Clotting factors based on aptt / / All factors affected Most sensitive to rivaroxaban / / All factors affected Most sensitive to dabigatran Lupus anticoagulant / / -/ / False positive due to high screen/confirmation assay ratios APCR aptt-based assays are mostly affected No interference of rivaroxaban with Pefakit APCR Factor V Leiden Protein C activity - / - / - / - Chromogenic assays: unaffected Antigen-based assays: unaffected Clot-based assays: affected (not yet tested for edoxaban) Protein S activity - / - / - / Antigen-based assay: unaffected (not yet tested for edoxaban) Clot-based: affected Antithrombin activity - / - / - / - / Anti-thrombin-based assays are affected by dabigatran Anti-Factor Xa-based assays are affected by the Factor Xa inhibitors

53 Content Introduction Monitoring: Why to measure? When to measure? How to measure? Impact on coagulation tests Conclusions 53

54 Take home messages 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):

55 Take home messages 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 55

56 Take home messages How to interpret DOACs assays in urgent situations? i. 3 cut-offs: ng/ml ii. iii. Use the appropriate assay (Laboratories): limit of quantitation, linearity ad interferences

57 Conclusions - perspectives 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 Specific tests are more suitable but still not easy to implement i. Mainly due to position of regulatory bodies and cost ii. On a technical point of view, they can be implemented in routine 57

58 Conclusions - perspectives Determination of plasma concentration is feasible but safe threshold have to be clearly established for all DOAC i. NEED: Correlate the results of these assays with clinical decisions and/or strategies Benefit/risk balance and the safety of DOAC could be improved by assessing the response at the individual level taking into account the clinical situation 58

59 Acknowledgments Prof. Jean-Michel Dogné Prof. François Mullier Prof. Bernard Chatelain Technical teams of the CHU UCL Namur and the University of Namur

60 THANK YOU FOR YOUR ATTENTION