the direct oral anticoagulants (doacs) and major trauma dr tina biss consultant haematologist...
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The direct oral anticoagulants (DOACs)
and major traumaDr Tina Biss
Consultant HaematologistNewcastle Hospitals NHS Foundation Trust
NTN Annual Trauma Conference17th 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 hemi-
cranium)–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
BloodsTime (hrs) Dabigatran TT PT APTT Clauss Fib Platelets Cr eGFR
0 190 400 35 64 0.8 148 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)
Dabigatran TT PT APTT Clauss
Fib Platelets Cr eGFR
0 190 400 35 64 0.8 148 92 55.2
1 178 400 15 76 1.2 150 70 75.6
4 163 400 9 51 1.5 146
7 400 10 49 1.5 136 65 82.4
10 400 9 40 2.3 141 57 95.8
Outcome
• No improvement in GCS or clinical state
• Brain stem death confirmed
• Died on 4 day of admission
0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536373839404142434445464748490
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100
150
200
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300
DabigatranTTPTAPTTeGFR
Withdraw careOrgan donation
Beriplex & TA IV
Angiogram of aorta & embolisation
Central line & CVVH
0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536373839404142434445464748490
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100
150
200
250
300
DabigatranTTPTAPTTeGFR
Withdraw care
Beriplex & TA IV
Angiogram of aorta & embolisation
Central line & CVVH
0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536373839404142434445464748490
50
100
150
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250
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DabigatranTTPTAPTTeGFR
Withdraw care
Beriplex & TA IV
Angiogram of aorta & embolisation
Central line & CVVH
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
TF=tissue factorAdapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853.
FibrinFibrinogen
TFPI (tifacogin)
Indirect Xa inhibitors FondaparinuxIdraparinuxSSR-126517
Xa Inhibitors:RivaroxabanApixabanEdoxabanLY517717YM150PRT-054021
IIa InhibitorsXimelagatranDabigatran
ORAL PARENTERAL
Direct Xa InhibitorsDX-9065aOtamixaban
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
AT
APC (drotrecogin alfa)sTM (ART-123)
TTP889
Targets of Direct Anticoagulant Agents
TF=tissue factorAdapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853.
FibrinFibrinogen
TFPI (tifacogin)
Indirect Xa inhibitors FondaparinuxIdraparinuxSSR-126517
Xa Inhibitors:RivaroxabanApixabanEdoxabanLY517717YM150PRT-054021
IIa InhibitorsXimelagatranDabigatran
ORAL PARENTERAL
Direct Xa InhibitorsDX-9065aOtamixaban
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
AT
APC (drotrecogin alfa)sTM (ART-123)
TTP889
Predictable dose-response relationshipNo monitoring required
Few drug interactionsNo 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
GI Bleeding
ICH
1.25 (1.01 - 1.55)
0.48 (0.39 - 0.59)
Risk Ratio (95% CI)
p=0.043
p<0.0001
Favours NOAC Favours Warfarin
0.2 0.5 1 2
DOACs vs warfarin for AF:Intracranial and GI Bleeding
Dentali F et al Circulation. 2012;126:2381-2391.
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, 2567-2574Management 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 drugDocument timing of last dose, estimate elimination
half-lifeCheck FBC, coagulation screen, creatinine/eGFR, G+SCorrect haemodynamic compromiseDefer surgery if ableControl haemorrhage:
Mechanical compressionSurgical/radiological intervention
• Specific measures:Dabigatran
Oral activated charcoal if last dose <2 hoursConsider haemodialysis/haemofiltration
≈60% removed within 2 hoursguided by normalisation of APTTcaution re rebound increases in Dabigatran concentration
Rivaroxaban/Apixaban/EdoxabanOral activated charcoal if last dose <2 hours
DOACs: Management of bleeding or urgent surgery
• Pharmacological measures:Antifibrinolytics- Tranexamic acid, oral/IV/topicalHaemostatic agents-
PCC (Beriplex)rFVIIa (NovoSeven)aPCC (FEIBA)
???
DOACs: Management of bleeding or urgent surgery
Direct thrombin inhibitors(dabigatran)
FXa inhibitors (apixaban, rivaroxaban)
Non-major bleed
Direct thrombin inhibitors(dabigatran)
FXa inhibitors(apixaban, rivaroxaban)
Major bleed
Time since last oral dose + dosing regimenMeasure FBC, U+E, eGFR, PT, APTT
Consider oral charcoal (<2 hrs ingestion) Local haemostatic measures
Tranexamic acidDelay / Omit next anticoagulant dose
Time since last oral dose + dosing regimen, Concomitant medicationsMeasure FBC, U+E, eGFR, PT, aPTT
Hemoclot dilute TCT NOAC Anti-Xa assay
Maintain BP and urine output
Consider oral charcoal (<2 hrs ingestion) Local haemostatic measures
(mechanical compression, surgical / radiological intervention)
Tranexamic acid (1g i.v.)
Prothrombin complex concentrate (PCC)Activated PCC (FEIBA) rFVIIa (NovoSeven)
Dialysis
Blood product replacement therapy as per major haemorrhage protocol
Identify bleeding source (surgery, endoscopy, interventional radiology)
Limb / Life-threatening bleed
Emergency surgery
Discuss with surgeon feasibility of delaying surgeryDelay by >/= 12 hours: Omit dose
Delay by 4-12 hours: If dabigatran, consider dialysisImmediate surgery: PCC/rFVIIa/aPCC
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