laboratory monitoring of Direct Oral Anticoagulant: who, when and how Dr. Malake Naboulsi Hôpital Albert Haykel Laboratoire d hématologie.

Transcription

1 laboratory monitoring of Direct Oral Anticoagulant: who, when and how Dr. Malake Naboulsi Hôpital Albert Haykel Laboratoire d hématologie.

2 Disclosures Malake Naboulsi declare to meeting attendees that there are no financial relationships with any for-profit companies that are directly or indirectly related to the subject of my presentation 27/12/2017 2

3 Anticoagulants: Essential and unavoidable medicines Authorized for the treatment and prevention of thromboembolic events Highly demonstrated efficiency But Medicines associated with a high hemorrhagic risk => Essential prevention of iatrogenic risk

4 Direct oral anticoagulants (DOACs) Traditional anticoagulants warfarin, heparin, and LMWH have been used for decades - Medical and laboratory personnel are familiar with when and how these should be monitored - Prior to 2010, warfarin was the only option for oral anticoagulation Now there are several new oral anticoagulants with a direct mechanism of action (DOACs)

5 What s in a name? New or Novel oral anticoagulants - NOACs Target specific oral anticoagulants TSOACs Non-vitamin K oral anticoagulants - NOACs Direct oral anticoagulants - DOACs

6 DOAC Direct oral anticoagulants (DOACs) Dabigatran (Pradaxa ) 75 mg, 110 mg et 150 mg. Mechanism of action Direct thrombin inhibitor (DTI) Date of first FDA approval Indications 2010 DOACs are variably approved to: Rivaroxaban (Xarelto ) 2,5 mg, 10 mg, 15 mg et 20 mg. Apixaban (Eliquis ) 2,5 mg et 5 mg. Direct factor Xa inhibitor 2011 Direct factor Xa inhibitor 2012 Prevent stroke and systemic embolism in non-valvular atrial fibrillation Treat and prevent VTE Edoxaban (Savaysa ) Direct factor Xa Inhibitor 2015 Treat and prevent PE Prevent VTE after major orthopedic surgery

7 Mecanisme of action XII Intrinsec pathway XII a Extrinsec pathway Tissue injury VIII XI II a XI a IX VIII a X II a V IX a V a Ca 2+ PLQ Ca 2+ PL Apixaban Rivaroxaban Edoxaban X a VII a HBPM Heparin + ATIII F. Tissues Ca 2+ Plalettes Thromboplastin XIII Ca 2+ VII Dabigatran AVK Prothrombine (II) Thrombin (II a ) XIII a Fibrinogene Fibrin Fibrin stable

8 Novel Oral Anticoagulants Pharmacological Properties Characteristic Dabigatran Rivaroxaban Apixaban (Pradaxa) (Xarelto) (Eliquis) Target Factor IIa Factor Xa Factor Xa Prodrug Yes No No Dosing BID OD BID Bioavailability, % 6.5% %* 50% Half-life h 5-13h 8-15 h Elimination Renal clearance:80% Bile : 20% 33% unchanged via the kidneys, 66% metabolized in the liver and eliminated through the kidneys or fecal route in a 50: 50 ratio 25% unchanged via the kidneys, 75% metabolized in the liver and eliminated through the fecal route Cmax 1-2 h 2-4 h 3-4 h Drug interactions P-gp inhibitors Strong inhibitors of both CYP3A4 and P-gp Strong inhibitors of both CYP3A4 and P-gp

9 DOACs - advantages Characteristic Warfarin DOACs Mechanism Indirect Direct Onset of action Slow Rapid Dosing Variable Fixed Food interaction Yes No Drug interaction Many Few Routine monitoring Yes No Offset Long Short

10 DOACs - disadvantages Characteristic Warfarin DOACs Dosing Frequency Once daily Once or twice daily, depending on drug and indication Renal Clearance None Variable: Dabigatran ~80% Xa Inhibitors ~30% or more depending on drug Specific antidote Yes Variable: Dabigatran - Idarucizumab (Praxbind) Xa Inhibitors none currently Cost Very low Higher

11 No need to measure plasma levels of DOACs? DOAC apixiban, dabigatran and rivaroxaban introduced with the intention of NO routine monitoring Fixed dosages for well-defined indications Wide therapeutic window Adapted dosage based on renal profile (Cockcroft-Gault) Adapted dosage based on some co-medications

12 But Clinical trials often exclude patients with impaired renal function, children, the very elderly, those with an increased bleeding risk and those at the extremes of body weight. The lack of monitoring needs demonstrated in the trials may therefore not be applicable to groups excluded from trial entry

13 Why test drug levels? 27/12/

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16 Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients. J Am Coll Cardiol 2014;63: The increased risk of major bleeding at higher plasma levels of dabigatran, especially in those 75 years of age, suggests an opportunity to prevent these events by adjusting the dose of dabigatran, though the optimal strategy for achieving this is uncertain. The flat curve for stroke/see versus drug concentration suggests that there is a wide therapeutic window for prevention of embolic events with dabigatran.

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18 1- DOAC are superior to warfarin in preventing stroke in patients with atrial fibrillation 2. DOAC have a decreased risk of intracranial hemorrhage compared to warfarin 3. There is no difference in GI bleeding risk between DOAC and warfarin. 27/12/

19 Drug interactions dabigatran, rivaroxaban and apixaban are all a substrates of the P- glycoprotein (P - gp) only anti-xa are substrates of cytochrome P450 (especially the isoforms CYP3A4/5). Thus, clinically significant drug interactions are possible between - anti-xa and - P-gp inhibitors (amiodaron) - CYP3A4 inhibitors (ketoconazole, ritonavir, erythromycin, clarithromycin) -Dabigatranand - P-gp inhibitor

20 Drug interactions 27/12/

21 No longer need of biological tests to adjust the dose, represents a significant simplification... However, these new drugs should be accompanied by tests not for monitoring but for the control of hypo or hypercoagulability in thromboembolic or especially hemorrhagic accidents

22 Quantifying DOAC levels: WHEN? CLEAR REASON FOR LABORATORY ASSESSMENT 1- Onset of thrombotic or hemorrhagic events whilst on therapy. 2- Pre-surgical screening in patient how have recently taken these drug. 3- Other reasons for necessity to reversal of anticoagulation. 4- Suspicion of overdosing and intoxication 5- Acute kidney failure (especially for dabigtran and edoxaban (~50 % renal metabolism) 6- acute liver failure (especially for apixaban rivaroxaban and edoxaban (>50 % liver metabolosme)

23 Quantifying DOAC levels: WHEN? POSSIBLE REASON FOR LABORATORY ASSESSMENT 1- Patient unknown to be on anticoagulant in select clinical situation (e. g., unconscious with acute bleeding; emergency stroke or cardiac admission?) 2- Patient requiring urgent surgery unknown to be on anticoagulant? 3- Patient of extreme of body weight. 4 - Children and very eldery? 5 - Other patient types excluded in clinical trials and known to be on anticoagulant. 6- assessment of adherence to therapy, 7- Concurrent administration of P-gp inducer or inhibitor 8- Concurrent administration of other drugs where effects on DOACSs unclear? 9- Chronic kidney failure (especially for dabigtran and edoxaban (~50 % renal metabolisme) 10- Chronic liver failure (especially for apixaban rivaroxaban and edoxaban (>50 % liver metabolosme) 11- gastrointestinal malabsorption 12- renal hyperfunction

24 Which test? The Ideal biological test for the monitoring of the DOACs must be - available in many laboratories, - easy and quick to perform in emergency, - be reproducible, sensitive, accurate, easy to standardize, - present a dose-dependent relationship linear, - benefit from well-defined pre-analytical conditions - be not expensive.

25 DOAC and the clinical laboratory Questions they ask us: - What do these drugs do to lab tests? - What do these results mean? Question we should be asking them : - What do you want to know? Question we ask ourselves: - How sensitive is my method?

26 Lab tests and DOAC Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is the gold standard for measuring DOAC concentrations Routine laboratory coagulation test results are influenced by the DOAC (PT, APTT, TT, Fib) - But results do not provide direct information on drug level - The prolongation of individual tests varies with different reagents and analyzers

27 Assay NOAC Anti-IIa NOAC Anti-Xa TCT Markedly No effect Clauss Fibrinogen No effect or falsely No effect APTT Mixing Study Incomplete correction Incomplete correction PT Mixing Study # Incomplete correction Incomplete correction Other coagulation test influenced by DOAC Bethesda assay Falsely present Not tested APTT- based factor assays, one stage (VIII, IX, XI, XII) Possibly Falsely Possibly Falsely PT- based factor assays, one stage # Possibly Falsely Possibly Falsely Chromogenic FVIII activity No effect Possibly Falsely AT Activity PC Activity a. FXa based a. No effect a. Falsely b. FIIa based b. Falsely b. No effect a. Clot based a. Falsely a. Falsely b. Chromogenic b. No effect b. No effect PS Activity a. Clot based a. Markedly a. Falsely b. ELISA or LIA based b. No effect b. No effect LA Tests Possible to misclassify as LA Possible to misclassify as LA APCR Falsely ratio Falsely ratio

28 Lab tests and DOAC To interpret coagulation tests meaningfully and ensure that the correct tests are done, an accurate information on drug history is needed by the lab

29 Baseline information to consider interpreting levels Age Which drug the patient is taking and dose regime.. The time the last dose was taken - Cmax. 2 4 h after drug administration anticoagulation status - Cmin. 12 h after drug administration overdosing The renal (e-gfr) and hepatic function of the patient If the patient is bleeding it is essential to consider other factors that could contribute to bleeding ie platelet count/use of anti-platelet drugs, DIC

30 Dabigatran and routine hemostasis test PT APTT Insensitive Qualitative use only normal aptt excludes above on-therapy levels; trough levels can have normal aptt; mild prolongation can represent significant amount of drug. Favaloro EJ, Semin Thromb Hemost Mar;41(2):208-

31 Thrombin time, s Dabigatran specific test: Thrombin Time TT Dabigatran level, ng/ml dtt Ultrasensitive to inhibitory effects of heparin or DTIs (dabigatran) on thrombin Widely available, Qualitative Not quantitative: Normal TT excludes significant amount of drug dtt quantitative across range of drug concentrations dtt not widely available Dager, et al Ann Pharmacotherapy 2012; 46:

32 Dabigatran specific test : Ecarin Clotting Time (ECT) or chromogenic assay (ECA) Ecarin- a snake venom that converts prothrombin to meizothrombin (Meizothrombin inhibited by dabigatran but not by heparin) Quantitative across range of drug concentrations Not widely available Fibrinogen Clotting time, s prothrombin meizothrombin LAB A ECT = x R2 = Ecarin Dabigatran Fibrin BI-MS Dabigatran, ng/ml

33 Anti-Xa and PT Neoplastin CI+ Prothrombin time ratio Recombiplastin 2G Innovin Apixaban, ng/ml -PT/INR is sensitive to rivaroxaban, inadequately sensitive to apixaban Normal PT suggests little anticoagulant effect Marked differences in sensitivity between PT reagents Favaloro EJ, Semin Thromb Hemost Mar;41(2):208-

34 Anti-Xa and aptt Insensitive aptt is less sensitive than PT/INR to direct factor Xa inhibitors and may be normal at typical on-therapy levels Favaloro EJ, Semin Thromb Hemost Mar;41(2):208-

35 Tests spécifiques de la cible (anti-xa) : tests chromogéniques anti-xa Easy, fast, and cheap Same kits as UFH/LMWH with specific calibrator and control Patient result is read from a calibration curve

36 Horizontal bars represent approximate range of detectability and vertical hatching corresponds with range of linearity.. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:

37 Measuring Recommendations Scientific and Standardization Subcommittee on the Control of Anticoagulation of the International Society for Thrombosis and Haemostasis (April 2013) recommendations: In emergent situations the use of an easily performed assay(s) that to provide semiquantitative results but these assays are not to be used to determine drug concentration PT, APTT, TT Assay(s) that provides quantitative results should be used to determine concentration of drug in serum or plasma drug calibrated methods (ecarin, dtt, anti-xa, LC-MS/MS) Baglin T, Hillarp A, Tripodi A, et al, J Thromb Haemost 2013;11:

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39 Summary The direct oral anticoagulants (DOACs) currently include one direct thrombin inhibitor (dabigatran) and three direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) which have various approvals for treatment and prevention of thromboembolic events DOACs do not require routine laboratory monitoring due to predictable pharmacodynamics, pharmacokinetics, and wide therapeutic windows DOACs have variable effects on routine coagulation tests, such as PT/INR and aptt, depending on the specific drug/concentration, patient/indication, and assay/reagent Quantitative tests for the new drugs exist but are not widely available and none are FDA approved 27/12/

40 Haemostasis = Love Everybody talks about it, nobody understands it. 27/12/