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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

Laboratory Monitoring Measurement of the DOACs

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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

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

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

Plasma drug levels

Drug Dose Trough plasma level (ng/mL)

Peak plasma level (ng/mL)

Median 5th-95th percentile

Median 5th-95th percentile

Dabigatran 150 mg BID 90 31-225 184 64-443 Rivaroxaban 20 mg daily 26 6-87 270 189-419 Apixaban 5 mg BID 103 41-230 171 91-321 Edoxaban 60 mg daily 22 10-40a 170 120-250a

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

aInterquartile range

5

Variability in trough levels

US adult male height:

5th percentile: 5’4’’ 95th 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

DOAC level 0

Below on-therapy range

On-therapy range

Above on-therapy range

5th percentile trough level

95th percentile peak level

Therapeutic On-therapy range

7

Why measure?

Drug level 0

Below on-therapy range

On-therapy range

Above on-therapy range

Bleeding Overdose

Renal dysfunction Low body weight Advanced age

Drug interaction

Treatment failure Preoperative state Non-compliance

Obesity Renal hyperfunction

GI malabsorption Drug interaction

Trauma Emergent procedure

Reversal agent

8

Attributes of an ideal assay

Plasma drug concentration

Assa

y re

sult

1. Linear correlation between assay result and drug levels (r2 > 0.9)

2. Across a broad range of drug levels

3. Sensitive 4. Specific 5. Available 24-7,

short TAT Below On-therapy Above

9

Dabigatran

10

Dabigatran (TT)

Hapgood et al., Thromb Haemost 2013;64:1128

Use: Normal TT excludes clinically significant drug levels

Problem: Too sensitive. Cannot be used to quantify drug. Drug Drug Trough: 90 (31-225)

Peak: 184 (64-443)

>

11 Dabigatran (Dilute TT and ECT) Dilute TT ECT

r2 = 0.92-1.00 r2 = 0.92-0.99

Cuker et al., J Am Coll Cardiol 2014;64:1128; van Ryn et al., Thromb Haemost 2010;103:1116

Use: Quantification across broad range of levels Problem: Limited availability

12 Dabigatran (APTT)

van Ryn et al., Thromb Haemost 2010;110:308; Harenberg et al., Semin Thromb Hemost 2012;38:16

Problems: Curvilinear, insufficient sensitivity (normal APTT does not exclude clinically relevant drug levels), reagent variability

Use: Normal APTT excludes above on-therapy levels

Trough: 90 (31-225) Peak: 184 (64-443)

13 Dabigatran (PT/INR)

Antovic et al., Eur J Clin Pharmacol 2013;69:1875; Helin et al., Clin Chem 2013;59:807

Problem: Poor correlation, insufficient sensitivity, reagent variability Use: None

Trough: 90 (31-225) Peak: 184 (64-443)

14

FXa inhibitors (Rivaroxaban, Apixaban, Edoxaban)

15

FXa-inhibitors (Anti-Xa activity)

Rivaroxaban (r2 0.95-1.00)

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

Apixaban (r2 0.89-0.95) Edoxaban (r2 0.96-0.99)

Use: Quantification across broad range of levels Problem: Limited availability

16

FXa-inhibitors (PT/INR) Edoxaban

Samama et al., Thromb Haemost 2010;103:815; Barrett et al., Thromb Haemost 2010;104:1263; Zafar et al., Thromb Haemost 2007;98:883

Rivaroxaban Apixaban

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

Trough: 26 (6-87) Peak: 270 (189-419)

Trough: 103 (41-230) Peak: 171 (91-321) Trough: 22 (10-40)

Peak: 170 (120-250)

17

FXa-inhibitors (APTT)

Rivaroxaban

Dale et al., J Thromb Haemost 2014;12:1810; Zafar et al., Thromb Haemost 2007;98:883

Apixaban Edoxaban

Problem: Normal APTT does not exclude clinically relevant levels, reagent variability Use: None

Trough: 26 (6-87) Peak: 270 (189-419)

Trough: 103 (41-230) Peak: 171 (91-321)

Trough: 22 (10-40) Peak: 170 (120-250)

18 Suggestions for DOAC measurement if specialized assays are available

Exclude clinically relevant drug levels

Measure on-therapy levels

Determine whether above on-therapy levels are present

Dabigatran TT Normal TT excludes clinically relevant levels

Dilute TT, ECT

- Dilute TT, ECT

-

FXa inhibitors

Anti-Xa Absent anti-Xa activity likely excludes clinically relevant levels

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

Exclude clinically relevant drug

levels

Determine whether above on-therapy levels are present

Dabigatran TT Normal TT excludes clinically relevant levels

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.

Suggestions for dabigatran measurement if specialized assays are not available

Cuker et al., J Thromb Thrombolysis 2015; Epub ahead of print

20

Exclude clinically relevant drug levels

Determine whether above on-therapy levels are present

Rivaroxaban Edoxaban

None Normal PT and APTT do not exclude clinically relevant levels

PT • Prolonged PT suggests that on-therapy or above on-therapy levels are present.

• Normal PT likely excludes above on-therapy levels.

• Normal PT may not exclude on-therapy levels.

Apixaban None Normal PT and APTT do not exclude clinically relevant levels

PT • Prolonged PT suggests that on-therapy or above on-therapy levels are present.

• Normal PT may not exclude on-therapy or above on-therapy levels.

Suggestions for measurement of FXa inhibitors if specialized assays are not available

Cuker et al., J Thromb Thrombolysis 2015; Epub ahead of print

21 Will we monitor DOACs in the future?

Reilly PA et al., J Am Coll Cardiol 2014;63:321

22 Thrombin generation assay

Hoffman et al., Anesthesiology 2015;122:353

Peak thrombin

generation

Rate

ETP

Time to peak

Lag time

23 Thromboelastography (TEG)

Escolar et al., PLoS One 2013;8:e78696

R

MA

Alpha angle

K

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