Download 2.3 NOAC in major trauma

The direct oral
anticoagulants (DOACs)
and major trauma
Dr Tina Biss
Consultant Haematologist
Newcastle Hospitals NHS Foundation Trust
NTN Annual Trauma Conference
17th April 2015
Case history
•
•
•
•
•
73 year old female
Anticoagulated for stroke prevention in AF
Dabigatran 150mg bd
PMH: Age related macular degeneration
Baseline eGFR >60
Presentation
• Nov 2013: Brought in to A+E department
• Found by a family member at the bottom of the stairs at
04:20, presumed she had fallen down the stairs
• Unclear how long she had been there
• No previous falls history
• Unable to ascertain the timing of the last dose but presumed
to be within 12 hours of presentation
Initial Assessment
• GCS 10/15, haemodynamic instability
• CT head + 10mins
–Acute subarachnoid haemorrhage (primarily in left hemicranium)
–Small extra-dural bleed over left parietal region
–Right base of skull and sphenoid fracture
–Fracture through body of C8
• CT thorax/abdomen/pelvis
–Right flail chest with underlying pneumo and haemothorax
–Possible areas of active bleeding in chest
–Large right para-lumbar haematoma
–Fracture of right clavicle and T11
Bloods
Time
(hrs)
0
Dabigatran
TT
PT
APTT
190
400
35
64
Clauss Fib Platelets
0.8
148
Cr
eGFR
92
55.2
Initial management
• 4 units FFP given
• CT head + 2 hrs
–Marked progression of subarachnoid haemorrhage
–Increasing extra-dural haemorrhage
–Midline shift to the right
–Developing hydrocephalus and raised intra-cranial pressure
Further management
• Medical management + 2 hrs
– 30 U/kg Prothrombin Complex Concentrate (Beriplex)
– 1.5g IV Tranexamic acid
• Angiography of aorta + 3 hrs
– Embolisation of right lumbar and right intercostal artery
– 90 mcg/kg recombinant factor VIIa (NovoSeven)
• Commenced CVVH + 8 hrs
• CT head + 12 hrs
– New acute subdural haematoma
– Extensive subarachnoid haemorrhage, tentorial subdural haematoma
and intra-ventricular haemorrhage
Bloods

Time
(hrs)
0
Dabigatr
an
190
TT
PT
APTT
Clauss
Platelets
Fib
0.8
148
400
35
64
1
178
400
15
76
1.2
150
4
163
400
9
51
1.5
146
7
400
10
49
1.5
10
400
9
40
2.3
Cr
eGFR
92
55.2
70
75.6
136
65
82.4
141
57
95.8
Outcome
• No improvement in GCS or clinical state
• Brain stem death confirmed
• Died on 4 day of admission
300
250
200
Beriplex & TA IV
Angiogram of aorta
& embolisation
Central line & CVVH
150
Dabigatran
Withdraw care
Organ donation
TT
PT
APTT
eGFR
100
50
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
300
250
200
Beriplex & TA IV
Angiogram of aorta
& embolisation
Dabigatran
Central line & CVVH
150
Withdraw care
TT
PT
APTT
eGFR
100
50
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
300
250
200
Beriplex & TA IV
Angiogram of aorta
& embolisation
Dabigatran
Central line & CVVH
150
Withdraw care
TT
PT
APTT
eGFR
100
50
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
Points to Consider
• In view of the extent of her injuries:
– would the outcome have been different if she had not
been anticoagulated?
– would the outcome have been different if she had been
anticoagulated with warfarin rather than a DOAC?
Targets of Direct Anticoagulant Agents
PARENTERAL
ORAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Xa Inhibitors:
Rivaroxaban
Apixaban
Edoxaban
LY517717
YM150
PRT-054021
IX
IXa
VIIIa
APC (drotrecogin alfa)
sTM (ART-123)
Va
AT
Xa
II
IIa Inhibitors
Ximelagatran
Dabigatran
Direct Xa Inhibitors
DX-9065a
Otamixaban
IIa
Fibrinogen
TF=tissue factor
Adapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853.
Indirect Xa inhibitors
Fondaparinux
Idraparinux
SSR-126517
Fibrin
Targets of Direct Anticoagulant Agents
PARENTERAL
ORAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Xa Inhibitors:
Rivaroxaban
Apixaban
Edoxaban
LY517717
YM150
PRT-054021
IX
IXa
VIIIa
APC (drotrecogin alfa)
sTM (ART-123)
Va
AT
Xa
II
IIa Inhibitors
Ximelagatran
Dabigatran
Direct Xa Inhibitors
DX-9065a
Otamixaban
IIa
Fibrinogen
TF=tissue factor
Adapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853.
Indirect Xa inhibitors
Fondaparinux
Idraparinux
SSR-126517
Fibrin


Predictable dose-response relationship
No monitoring required
Few drug interactions
No dietary interactions
Current licensed indications for DOACs
Stroke
prevention
in AF
VTE
prevention
(THR/TKR)
VTE treatment
(DVT/PE)
Dabigatran
✔
✔
✔
Rivaroxaban
✔
✔
✔
Apixaban
✔
✔
✔
Non-inferiority confirmed in clinical trials
when compared with warfarin
DOACs vs warfarin for AF:
Intracranial and GI Bleeding
Risk Ratio (95% CI)
0.48 (0.39 - 0.59)
ICH
p<0.0001
1.25 (1.01 - 1.55)
GI Bleeding
p=0.043
0.2
0.5
Favours NOAC
Dentali F et al Circulation. 2012;126:2381-2391.
1
2
Favours Warfarin
Anticoagulant-associated ICH: Is reversibility
important?
Features of anticoagulant-associated ICH
• Rapid deterioration with first 24-48 hours, increasing ICH
volume
• Poor outcome associated with:
– ICH volume
– Intraventricular extension of bleeding
• Majority of warfarin-related ICH occurs with INR 2-3.5
• Rapid reversal of anticoagulant effect essential:
– To prevent haematoma expansion
– To facilitate appropriate surgical intervention
Sjoblom et al. Stroke (2001), 32, 2567-2574
Management and prognostic features of ICH during anticoagulant therapy: A
Swedish Multicenter Study
Options for warfarin reversal

Rapid
10 mins
PCC (Beriplex)
Fast (Partial)
1-2 hrs
FFP
Prompt
4-6 hrs
IV vitamin K
Slow
24 hrs
Oral vitamin K
Ultra-slow
2-4 days
Omit warfarin
DOACs: Management of bleeding or urgent surgery
• General measures:
Stop the drug
Document timing of last dose, estimate elimination
half-life
Check FBC, coagulation screen, creatinine/eGFR, G+S
Correct haemodynamic compromise
Defer surgery if able
Control haemorrhage:
Mechanical compression
Surgical/radiological intervention
DOACs: Management of bleeding or urgent surgery
• Specific measures:
Dabigatran
Oral activated charcoal if last dose <2 hours
Consider haemodialysis/haemofiltration
≈60% removed within 2 hours
guided by normalisation of APTT
caution re rebound increases in Dabigatran concentration
Rivaroxaban/Apixaban/Edoxaban
Oral activated charcoal if last dose <2 hours
DOACs: Management of bleeding or urgent surgery
• Pharmacological measures:
Antifibrinolytics- Tranexamic acid, oral/IV/topical
Haemostatic agentsPCC (Beriplex)
rFVIIa (NovoSeven)
aPCC (FEIBA)
???
Non-major bleed
Direct thrombin inhibitors
(dabigatran)
FXa inhibitors
(apixaban, rivaroxaban)
Major bleed
Direct thrombin inhibitors
(dabigatran)
FXa inhibitors
(apixaban, rivaroxaban)
Time+since
lastregimen
oral dose + dosing regimen, Concomitant medications
Time since last oral dose
dosing
Measure FBC, U+E, eGFR, PT, APTTMeasure FBC, U+E, eGFR, PT, aPTT
Hemoclot dilute TCT
Consider oral charcoal (<2 hrs ingestion)
Local haemostatic measures
NOAC Anti-Xa assay
Maintain BP and urine output
Tranexamic acid
Consider oral charcoal (<2 hrs ingestion)
Local haemostatic measures
Delay / Omit next anticoagulant dose
(mechanical compression, surgical / radiological intervention)
Tranexamic acid (1g i.v.)
Blood product replacement therapy as per major
haemorrhage protocol
Emergency surgery
Identify bleeding source
(surgery, endoscopy, interventional radiology)
Discuss with surgeon feasibility of delaying surgery
Delay by >/= 12 hours: Omit dose
Limb / Life-threatening bleed
Delay by 4-12 hours: If dabigatran, consider dialysis
Immediate surgery: PCC/rFVIIa/aPCC
Prothrombin complex concentrate (PCC)
Activated PCC (FEIBA)
Dialysis
rFVIIa (NovoSeven)
General concerns
•
Lack of knowledge of patient and physician about the DOACs
•
Effect of the DOACs on the basic coagulation tests
•
Interpretation of drug assays