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
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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)
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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
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
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