Laboratory Monitoring Measurement of the DOACs

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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

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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

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Outline

• Basic principles • Variability in drug levels • On-therapy vs. therapeutic range • Why measure?

• Attributes of an ideal assay • Dabigatran • Factor Xa inhibitors • Recommendations

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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

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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

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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

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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

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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

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Dabigatran

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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)

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FXa inhibitors (Rivaroxaban, Apixaban, Edoxaban)

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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

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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)

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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

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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

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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