Peri-operative Management of
the Novel/Direct Oral
Anticoagulants (NOAC/DOAC)
Art Szkotak, MD, PhD, FRCPC
artur.szkotak@albertahealthservices.ca
Laboratory Services
University of Alberta Hospital
Disclosures
Outline
• Introduction to DOACs
• Management of DOACs peri-operatively.
• Limitations of the INR/aPTT in DOAC
assessment.
• How to assess for the presence of DOACs
using tests available today.
DOACs
• Direct Thrombin Inhibitors (DTI):
– Ximelagatran (liver toxicity – failed approval
process)
– Dabigatran (Pradaxa®)
• Direct Factor Xa Inhibitors (DXI):
– Rivaroxaban (Xarelto®)
– Apixaban (Eliquis®)
“Direct” in that no plasma cofactor is needed
Heparin is “Indirect” requiring Antithrombin III
Current Licensed Indications
• Venous Thromboembolism prophylaxis
Post-Orthopedic surgery
– First approved: Dabigatran in June 2008
• Non-Valvular Atrial Fibrillation
– First approved: Dabigatran in Oct. 2010
• Treatment of DVT and/or Pulmonary
Embolism
– First approved: Rivaroxaban in Feb. 2012
Advantages over Warfarin
• Reproducible dosing
• No need for routine coagulation monitoring
– Creatinine monitoring still needed
•
•
•
•
No lag in onset of effect
Faster off-set of effect
Far fewer interactions with foods/drugs
Decreased rates of intracranial bleeding
Outpatient INRs in Edmonton
(DynaLife Data) are decreasing…
Dabigatran
Licensed for A.Fib.
(Oct. 2010)
Annual INRs (total)
300,000
280,000
260,000
240,000
220,000
200,000
2005
2006
2007
2008
2009
2010
2011
2012
Year (ending in September)
2013
2014
…but this is only the tip of the
iceberg.
Annual INRs (total)
300,000
250,000
Dabigatran
Licensed for A.Fib.
(Oct. 2010)
200,000
150,000
100,000
50,000
0
2005
2006
2007
2008
2009
2010
2011
2012
Year (ending in September)
2013
2014
Disadvantages compared to
Warfarin
• Specific assays for DOACs are not widely
available.
• No “reversal” agents for DOACs currently
available.
• Cost (without dispensing fees):
– Warfarin = $0.10/d = $36.50/yr ($11/yr with
Coverage)
– Dabigatran (150 mg bid) = $3.52/d = $1,284.80/yr
– Rivaroxaban (20 mg qd) = $3.12/d = $1,138.80/yr
– Apixaban (5 mg bid) = $2.29/d = $835.85/yr
Outline
• Introduction to DOACs
• Management of DOACs peri-operatively.
• Limitations of the INR/aPTT in DOAC
assessment.
• How to assess for the presence of DOACs
using tests available today.
Provincial Guidelines
(Boehringer Ingelheim) Sponsored
Peri-operative Management:
• Based on:
– Timing of last dose
– Renal function
• Must use weight based GFR calculation (eg. Cockroft-Gault)
• Lab provided MDRD or CKD-EPI GFR calculation is inadequate.
– Bleeding risk
• Using the above, routine coagulation testing
is not strictly necessary Pre-op (N.Engl.J.Med. 2009,
361: 1139-1151; Can.J.Cardiol. 2013; 29: S54-S59).
• Patients at high risk of thrombosis may
require heparin bridging if discontinued >48
hours before surgery.
When to Stop Pre-Op
No need for bridging therapy if:
• Discontinued within 48 hours of surgery
• Patient is low risk of thrombosis
Fewer patients should need bridging than with warfarin!
When to Re-Start Post-Op
Pre-op coagulation testing may still
be needed in some circumstances.
• To assess for clearance (common):
– Timing of last dose unknown.
– Emergency procedures.
– Compliance.
• To assess for supratherapeutic levels (uncommon):
– Patients at extremes of weight (esp. <50 kg).
– Suspected overdose.
– Severe renal dysfunction.
Outline
• Introduction to DOACs
• Management of DOACs peri-operatively.
• Limitations of the INR/aPTT in DOAC
assessment.
• How to assess for the presence of DOACs
using tests available today.
The Debate
PT-INR and aPTT don’t tell the
whole story.
Young et al. Blood, 2013; 121(11): 1944-1950
NEG – negative charge eg. silica, kaolin
PL = Phospholipid
TF = Tissue Factor
XIIa
XI
PT-INR
TF + PL + Ca2+
XIa
IX
VIII
IXa
TF + VIIa
VII
VIIIa
X
Extrinsic
XII
Xa
V
Va
II
Fibrinogen
IIa (Thrombin)
Fibrin
Common
Intrinsic
aPTT
NEG + PL + Ca2+
Coagulation Cascade
aPTT
PT-INR
NEG + PL + Ca2+
TF + PL + Ca2+
FXII
FVII
FII (Thrombin)
FX
FXI
FV
FIX
FII (Thrombin)
FVIII
Fibrinogen
FX
FV
FII (Thrombin)
Fibrinogen
Reagent
Patient
Plasma
Coagulation Cascade
Warfarin
aPTT
PT-INR
NEG + PL + Ca2+
TF + PL + Ca2+
FXII
FVII
FII (Thrombin)
FX
FXI
FV
FIX
FII (Thrombin)
FVIII
Fibrinogen
FX
FV
FII (Thrombin)
Fibrinogen
Coagulation Cascade
Unfract. Heparin
aPTT
PT-INR
NEG + PL + Ca2+
TF + PL + Ca2+
FXII
FVII
FII (Thrombin)
FX
FXI
FV
FIX
FII (Thrombin)
FVIII
Fibrinogen
FX
FV
FII (Thrombin)
Fibrinogen
Coagulation Cascade
LMWH
aPTT
PT-INR
NEG + PL + Ca2+
TF + PL + Ca2+
FXII
FVII
FII (Thrombin)
FX
FXI
FV
FIX
FII (Thrombin)
FVIII
Fibrinogen
FX
FV
FII (Thrombin)
Fibrinogen
aPTT
PT-INR
DXI (Riva/Apix)
NEG + PL + Ca2+
TF + PL + Ca2+
FXII
FVII
FII (Thrombin)
FX
FXI
FV
FIX
FII (Thrombin)
FVIII
Fibrinogen
Coagulation Cascade
DTI (Dabi)
FX
FV
FII (Thrombin)
Fibrinogen
All characterized by Peak and
Trough Pharmacokinetics
J van Ryn et al. Thromb.Haemost., 2010; 103: 1116–1127
Derived “Therapeutic Range”
(Caution: ranges NOT for dose adjustment)
Trough
Concentration
5th-95th percentile
of patients
(ng/ml)
Peak
Concentration
5th-95th percentile
of patients
(ng/ml)
Derived
“Therapeutic
Range”
Dabigatran1
31-225
64-443
31-443 ng/ml
Rivaroxaban2
5-155
177-409
5-409 ng/ml
Apixaban3
29-211
77-299
29-299 ng/ml
1Thromb.Haemost.
2Thromb.Res.
3Thromb.Haemost.,
2010, 103: 1116–1127
2012; 130: 956–966
2010; 104: 1263-1271, and Eliquis product monograph.
Dabigatran Example with one type
of aPTT and PT-INR reagent
31
443
31
443
Dabigatran “therapeutic range” = 31 – 443 ng/ml
J van Ryn et al. Thromb.Haemost., 2010; 103: 1116–1127
Unfortunately, variation in reagent
brand also profoundly affects results
29 299
Apixaban “Therapeutic Range” = 29 – 299 ng/ml
Barrett YC et al. Thromb.Haemost. 2010; 104: 1263-71.
Outline
• Introduction to DOACs
• Management of DOACs peri-operatively.
• Limitations of the INR/aPTT in DOAC
assessment.
• How to assess for the presence of DOACs
using tests available today.
Thrombin Time (TT)
aPTT
XII
XIIa
XI
XIa
IX
VIII
PT-INR
IXa
TF + VIIa
VII
VIIIa
X
Xa
V
TT
Va
II
Fibrinogen
IIa (Thrombin)
Fibrin
Exogenous
Thrombin
Fibrinogen
Heparin Level
(aka Anti-Xa Assay)
Exogenous FXa
OD/min @
405 nm
CBS 52.44

pNA
Report
LMWH
Level
(U/ml)
OD/min
Plasma
Plasma
ATIII &
Rivaroxaban/
Heparin
Apixaban
LMWH (U/ml)
aPTT
PT-INR
TT
Anti-Xa
NEG + PL + Ca2+
TF + PL + Ca2+
FIIa (Thrombin)
+ Ca2+
FXa + Ca2+
FXII
FVII
Fibrinogen
FII (Prothrombin)
FX
FXI
FV
FIX
FII (Prothrombin)
FVIII
Fibrinogen
FX
FV
FII (Prothrombin)
Fibrinogen
Warfarin
aPTT
PT-INR
TT
Anti-Xa
NEG + PL + Ca2+
TF + PL + Ca2+
FIIa (Thrombin)
+ Ca2+
FXa + Ca2+
FXII
FVII
Fibrinogen
FII (Prothrombin)
FX
FXI
FV
FIX
FII (Prothrombin)
FVIII
Fibrinogen
FX
FV
FII (Prothrombin)
Fibrinogen
Unfract. Heparin
aPTT
PT-INR
TT
Anti-Xa
NEG + PL + Ca2+
TF + PL + Ca2+
FIIa (Thrombin)
+ Ca2+
FXa + Ca2+
FXII
FVII
Fibrinogen
FII (Prothrombin)
FX
FXI
FV
FIX
FII (Prothrombin)
FVIII
Fibrinogen
FX
FV
FII (Prothrombin)
Fibrinogen
LMWH
aPTT
PT-INR
TT
Anti-Xa
NEG + PL + Ca2+
TF + PL + Ca2+
FIIa (Thrombin)
+ Ca2+
FXa + Ca2+
FXII
FVII
Fibrinogen
FII (Prothrombin)
FX
FXI
FV
FIX
FII (Prothrombin)
FVIII
Fibrinogen
FX
FV
FII (Prothrombin)
Fibrinogen
DTI (Dabi)
DXI (Riva/Apix)
aPTT
PT-INR
TT
Anti-Xa
NEG + PL + Ca2+
TF + PL + Ca2+
FIIa (Thrombin)
+ Ca2+
FXa + Ca2+
FXII
FVII
Fibrinogen
FII (Prothrombin)
FX
FXI
FV
FIX
FII (Prothrombin)
FVIII
Fibrinogen
FX
FV
FII (Prothrombin)
Fibrinogen
TT is extremely sensitive to
Dabigatran
31
443
…
Dabigatran “therapeutic range” = 31 – 443 ng/ml
Heparin Level
(aka Anti-Xa Assay)
29
299
Measurement
range of
UAH/RAH
Anti-Xa assay
0.1-2.0 U/ml
Apixaban “therapeutic range” = 29 – 299 ng/ml
Barrett YC et al. Thromb.Haemost. 2010; 104: 1263-71.
Recommendations
• Evidence indicates peri-op management should be
based on timing of last dose, renal function, and
bleeding risk.
• Coagulation testing is not routinely necessary for perioperative management of DOACs.
• If testing is needed for clearance use a sensitive assay:
– A normal Thrombin Time excludes the presence of Dabigatran.
– A normal/negative Anti-Xa assay (aka Heparin level) excludes
the presence of Rivaroxaban/Apixaban.
– INR and aPTT show poor sensitivity to DOACs
• INR/PTT assessment may be useful in overdose
situations.
• We’re working on test availability…
Test Availability in 780 Area
• INR/aPTT are already available STAT in most
laboratories.
• Thrombin Time:
– Prior to 2012 only available at UAH
– Since 2012, available at all Edmonton Zone hospital labs
STAT.
– Working on deployment to smaller/rural centers.
– Working on reporting a result that indicates negligible
Dabigatran concentration.
• Heparin Level (Anti-Xa level):
– Available at UAH and RAH STAT only.
– Deployment across Alberta will be much slower. Grande
Prairie to act as pilot site.