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

50

100

150

200

250

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

50

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

200

250

300

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