Laboratory Monitoring Measurement of the DOACs

Transcription

1 1 Laboratory Monitoring Measurement of the DOACs ACC Anticoagulation Consortium Roundtable Meeting October 24, 2015 Adam Cuker, MD, MS Perelman School of Medicine University of Pennsylvania

2 2 Full disclosures (last 12 months) Research support NIH FDA T2 Biosystems Consultant/Advisory Board Sanofi/Genzyme Bracco Amgen Patents Laboratory assays for HIT Off-label use Some assays are not FDA-approved for DOAC measurement

3 3 Outline Basic principles Variability in drug levels On-therapy vs. therapeutic range Why measure? Attributes of an ideal assay Dabigatran Factor Xa inhibitors Recommendations

4 4 Plasma drug levels Drug Dose Trough plasma level (ng/ml) Peak plasma level (ng/ml) Median 5 th -95 th percentile Median 5 th -95 th percentile Dabigatran 150 mg BID Rivaroxaban 20 mg daily Apixaban 5 mg BID Edoxaban 60 mg daily a a a Interquartile range Ezekowitz MD et al., Am J Cardiol 2007;100:1419; Mueck W et al., Clin Pharmacokinet 2014;53:1; Kowalski et al., J Pharmacokinet Pharmacodyn 2014;41(Supp 1):S19; Weitz JI et al., Thromb Haemost 2010;104:633

5 5 Variability in trough levels US adult male height: 5 th percentile: th percentile: 6 3 If variation in height was equivalent to variation in rivaroxaban trough levels U.S. Census Bureau, Statistical Abstract of the United States: 2012

6 6 Therapeutic On-therapy range Below ontherapy range On-therapy range Above ontherapy range 0 5 th percentile trough level DOAC level 95 th percentile peak level

7 7 Why measure? Treatment failure Preoperative state Non-compliance Obesity Renal hyperfunction GI malabsorption Drug interaction Trauma Emergent procedure Reversal agent Bleeding Overdose Renal dysfunction Low body weight Advanced age Drug interaction Below ontherapy range On-therapy range Above ontherapy range 0 Drug level

8 8 Attributes of an ideal assay Assay result Below On-therapy Above 1. Linear correlation between assay result and drug levels (r 2 > 0.9) 2. Across a broad range of drug levels 3. Sensitive 4. Specific 5. Available 24-7, short TAT Plasma drug concentration

9 9 Dabigatran

10 10 Dabigatran (TT) > Trough: 90 (31-225) Drug Peak: 184 (64-443) Problem: Too sensitive. Cannot be used to quantify drug. Use: Normal TT excludes clinically significant drug levels Hapgood et al., Thromb Haemost 2013;64:1128

11 11 Dabigatran (Dilute TT and ECT) Dilute TT r 2 = ECT r 2 = Use: Quantification across broad range of levels Problem: Limited availability Cuker et al., J Am Coll Cardiol 2014;64:1128; van Ryn et al., Thromb Haemost 2010;103:1116

12 12 Dabigatran (APTT) Trough: 90 (31-225) Peak: 184 (64-443) Problems: Curvilinear, insufficient sensitivity (normal APTT does not exclude clinically relevant drug levels), reagent variability Use: Normal APTT excludes above on-therapy levels van Ryn et al., Thromb Haemost 2010;110:308; Harenberg et al., Semin Thromb Hemost 2012;38:16

13 13 Dabigatran (PT/INR) Trough: 90 (31-225) Peak: 184 (64-443) Problem: Poor correlation, insufficient sensitivity, reagent variability Use: None Antovic et al., Eur J Clin Pharmacol 2013;69:1875; Helin et al., Clin Chem 2013;59:807

14 14 FXa inhibitors (Rivaroxaban, Apixaban, Edoxaban)

15 15 FXa-inhibitors (Anti-Xa activity) Rivaroxaban (r ) Apixaban (r ) Edoxaban (r ) Use: Quantification across broad range of levels Problem: Limited availability Cuker et al., J Am Coll Cardiol 2014;64:1128; Cuker et al., J Thromb Thrombolysis 2015;39:288 Douxfils et al., Thromb Haemost 2013;110:723; Becker et al., J Thromb Thrombolysis 2011;32:183; Zafar et al., Thromb Haemost 2007;98:883

16 16 FXa-inhibitors (PT/INR) Rivaroxaban Apixaban Edoxaban Trough: 26 (6-87) Peak: 270 ( ) Trough: 103 (41-230) Peak: 171 (91-321) Trough: 22 (10-40) Peak: 170 ( ) Use: Normal PT excludes above on-therapy levels of rivaroxaban and edoxaban (but not apixaban) Problem: Normal PT does not exclude clinically relevant levels, reagent variability Samama et al., Thromb Haemost 2010;103:815; Barrett et al., Thromb Haemost 2010;104:1263; Zafar et al., Thromb Haemost 2007;98:883

17 17 FXa-inhibitors (APTT) Rivaroxaban Apixaban Edoxaban Trough: 26 (6-87) Peak: 270 ( ) Trough: 103 (41-230) Peak: 171 (91-321) Trough: 22 (10-40) Peak: 170 ( ) Problem: Normal APTT does not exclude clinically relevant levels, reagent variability Use: None Dale et al., J Thromb Haemost 2014;12:1810; Zafar et al., Thromb Haemost 2007;98:883

18 18 Suggestions for DOAC measurement if specialized assays are available Exclude clinically relevant drug levels Dabigatran TT Normal TT excludes clinically relevant levels FXa inhibitors Anti-Xa Absent anti-xa activity likely excludes clinically relevant levels Measure ontherapy levels Dilute TT, ECT Determine whether above on-therapy levels are present - Dilute TT, ECT Anti-Xa Anti-Xa - - ECA, ecarin chromogenic assay; ECT, ecarin clotting time; TT, thrombin time Cuker et al., J Thromb Thrombolysis 2015; Epub ahead of print

19 19 Suggestions for dabigatran measurement if specialized assays are not available Exclude clinically relevant drug levels Dabigatran TT Normal TT excludes clinically relevant levels Determine whether above on-therapy levels are present APTT Prolonged APTT suggests that on-therapy or above on-therapy levels are present. Normal APTT likely excludes above on-therapy levels. Normal APTT may not exclude on-therapy levels. Cuker et al., J Thromb Thrombolysis 2015; Epub ahead of print

20 20 Suggestions for measurement of FXa inhibitors if specialized assays are not available Rivaroxaban Edoxaban Apixaban Exclude clinically relevant drug levels None Normal PT and APTT do not exclude clinically relevant levels None Normal PT and APTT do not exclude clinically relevant levels Determine whether above ontherapy levels are present PT Prolonged PT suggests that on-therapy or above ontherapy levels are present. Normal PT likely excludes above on-therapy levels. Normal PT may not exclude on-therapy levels. PT Prolonged PT suggests that on-therapy or above ontherapy levels are present. Normal PT may not exclude on-therapy or above ontherapy levels. Cuker et al., J Thromb Thrombolysis 2015; Epub ahead of print

21 21 Will we monitor DOACs in the future? Reilly PA et al., J Am Coll Cardiol 2014;63:321

22 22 Thrombin generation assay Time to peak Peak thrombin generation ETP Rate Lag time Hoffman et al., Anesthesiology 2015;122:353

23 23 Thromboelastography (TEG) R K Alpha angle MA Escolar et al., PLoS One 2013;8:e78696

24 24 Take-home points The DOACs have variable effects on coagulation assays Laboratory measurement may be desirable in special circumstances Selection of the optimal assay depends on the drug, indication for measurement, and assay availability Dabigatran Normal TT excludes clinically relevant levels Dilute TT and ECT can be used for quantification across a broad range of levels Normal APTT excludes excess levels FXa inhibitors Normal anti-xa excludes clinically relevant levels Anti-Xa can be used for quantification across a broad range of levels Normal PT excludes excess levels of rivaroxaban and edoxaban, but not apixaban