DOACs: When and how to measure their anticoagulant effect

Transcription

1 DOACs: When and how to measure their anticoagulant effect Stavroula Tsiara MD, PhD, FRCP Associate Professor of Internal Medicine University of Ioannina, Greece

2 NOACs NOACs, TSOACs, DOACs (ISTH)

3 Target specific anticoagulants, competitive antagonists of activated coagulation factors Inhibit both free and bound activated serine proteases Activated coagulation factors are more efficient Thus the anticoagulant effect of DOACs is more robust than that of VKAs and heparin DOACs characteristics

4 As effective as VKAs Reduced incidence of intracranial hemorrhage Lower bleeding rates relatively to standard therapy Stroke prevention in NVAF patients VTE thromboprophylaxis and treatment Fixed dose Rapid acting Predictable pharmakokinetics and pharmakodymanics Routine monitoring is not required Dose adjustment on the basis of clinical criteria (renal failure) DOACs advantages

5 Mode of Action

6 Routine coagulation monitoring was considered unnecessary because of pharmacodynamic and pharmacokinetic predictability, absorption metabolism and elimination Coagulation monitoring Samama MM, Thromb Haemost 2010

7 Exponential growth of usage Stable anticoagulant effect under controlled conditions Adherence (chronic disease) Children and pregnancy Dehydration Elderly Safe anticoagulation (dose-range) Dose personalization Bleeding or thrombosis while on therapy Urgent reversal in case of emergency situations (surgery, hemorrhage) Variability in the absorption (P-gp) Liver and renal disorders Concerns about DOACs use

8 Routine therapeutic monitoring Urgent therapeutic monitoring

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12 Emergency lab assessment Prior to the initiation of anticoagulation therapy Thrombotic or hemorrhagic events in critical organs Pre-surgical treatment Trauma Immediate reversal Emergency surgery Overdosing Intoxication Renal failure Liver failure Interactions Probably needed monitoring Chronic anticoagulation (1-2 wks) after initiation Any Hospitalization Patients with extreme body weight Pregnancy Assess compliance Improve adherence and persistence P-gp co-administration Crowther MA, JTH 2009 Reilly et al, JACC 2014

13 Methods of lab testing

14 There is not a specific test for each one of the drugs However Few tests are recommended for the interpretation of their anticoagulant effect Laboratory tests

15 Direct assessment of serum or plasma concentrations Liquid chromatography Substantial problems for routine clinical laboratories Specialized personnel, instruments Useless in the everyday clinical practice Depends on the dosage and time after administration G Lippi, Clin Chem Lab Med 2015

16 Routine coagulation screening tests PT aptt Thrombin time Widely available In most laboratories Emergency basis These are not reliable measure of the anticoagulant effect of DOACs Non-linear dose response Reagents

17 dtt ECT Sensitive to measure therapeutic concentrations Linear relation to the dosage Detect overdosage Chromogenic anti-xa Effective plasma concentrations Always Consider the time elapsing from drug administration

18 Dabigatran Inhibits the activity of soluble and bound thrombin Limits thrombus propagation Rapid onset of action Maximal anticoagulant effect within 2 h after ingestion Dabigatran has h half-life time and is mainly excreted by the kidneys GFR<30 and age are associated with high bleeding risk Dabigatran acts to thrombin and affects all coagulation assays van Ryn Thromb Haemost 2010

19 How several tests are affected

20 van Ryn Thromb Haemost 2010

21 aptt Reflects the intrinsic pathway of the coagulation cascade Prolongation occurs with increasing dabigatran plasma concentrations In patients receiving 150 mg bid median aptt is 2-fold that of control Coagulometer Reagents Qualitative indication of D activity

22 Represents the clotting time in the extrinsic coagulation pathway D has little effect on INR in high plasma concentrations Therapeutic concentrations of D result in modest elevation of INR PT -INR J van Ryn Thromb Haemost 2010

23 Thrombin clotting time Directly assess thrombin activity Direct measure of DTIs activity Linear dose response In high concentrations results exceed maximum measurements Determining if any D is present van Ryn Thromb Haemost 2010

24 Activated clotting time This test resembles to aptt but clotting occurs in whole blood samples It is commonly used to detect the anticoagulant effect of heparin in patients undergoing CABG or PTCA Flat dose response van Ryn Thromb Haemost 2010

25 Specific assay for thrombin generation D inhibits the thrombinlike activity of meizothrombin Direct measure of D activity linear correlation between plasma concentrations and ECT prolongation Sensitive test Superior over aptt Needs improvement Currently is used as a research tool Ecarin clotting time

26 Hemoclot (HTI, Hyphen BioMed) Sensitive assay Quantitative DTI activity measurement in plasma Inhibition of a constantdefined thrombin concentration Test plasma is mixed with normal plasma Clotting initiated by adding thrombin Direct linear relationship van Ryn Thromb Haemost 2010

27 aptt urgent detection of dabigatran screening test in bleeding patients HTI, ECT Second line tests, accurate estimation of the anticoagulant effect of dabigatran

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29 Drugs with anti-fxa action Direct target: FXa Rivaroxaban, apixaban and edoxaban inhibit both free and prothrombinase bound FXa Block thrombin generation MM Samama Thromb Haemost 2010

30 Rivaroxaban plasma concentrations variability according several factors 10 mg 20 mg Age, body weight, CrCl MM Samama Thromb Haemost 2010

31 Influence on coagulation assays PT Rivaroxaban prolongs PT in a linear way (weak in higher concentrations) Depends on the kind of thromboplastin used and coagulometer Exhibits optimal reproducibility Dilute PT test Neoplastin Douxfils J, Thromb Res 2012

32 Neoplastin Minimal time variation

33 Dilute PT ratio

34 Normal PT in sec or PT ratio indicates normal haemostatic function and may be used for urgent measurements of rivaroxaban in bleeding patients Is available to all hospital labs and is prone to standardization It is not expensive INR is not suitable for assessment of rivaroxaban coagulation activity Tripodi A JTH 2013 Sammama Thr Haemost 2013

35 aptt Curvilinear response to rivaroxaban Patients receiving 20 mg have times that of control Reagents and coagulometers influence results

36 TEG Citrated whole blood Speed and strength of clot Prolongation of the R and K parameters is concentration dependant

37 HepTest Inhibition of exogenous FXa by plasma PP Plasma test Paradoxically low concentration produce short clotting time

38 drvvt Good linearity and response It is commonly used to detect circulating coagulation inhibitors Needs standardization Purification of the viper venom

39 Chromogenic Anti Xa activity Test of choice for xabans It is not readily available in emergency situations There is experience from its use to monitor LMWH activity There is need for rivaroxaban calibrators and controls Standardized kits are commercially available Close relationship between rivaroxaban plasma levels and FXa inhibition Range rivaroxaban plasma concentrations μgr/l

40 Interpretation of measured plasma levels Time of blood sampling Administered dose Does not assess anticoagulant activity or intensity of anticoagulation A higher plasma level does not always reflects increased risk of bleeding

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42 Apixaban PT, PiCT, Anti-FXa Edoxaban Anti-FXa ISTH 2014 Apixaban and edoxaban

43 Siegal D Eur Heart J 2012

44 Assessment of drug effect in emergency situations G Lippi, Clin Chem Lab Med 2015

45 Which test for which drug? G Lippi, Clin Chem Lab Med 2015

46 G Lippi, Clin Chem Lab Med 2015

47 Conclusions Normal aptt essentially excludes dabigatran as the cause of bleeding Hemoclot if it is available is the test of choice for the assessment of dabigatran activity PT within normal values exclude anti-xa drugs as the cause of bleeding Chromogenic anti-fxa assay, if it is available, is the test of choice for the assessment of rivaroxaban activity Influence on coagulation assays depends on the drug Time of the administration Reagent used