1. The direct oral anticoagulants (DOACs) and major trauma Dr Tina Biss Consultant Haematologist Newcastle Hospitals NHS Foundation Trust NTN Annual Trauma Conference 17 th April 2015

2. Case history 73 year old female Anticoagulated for stroke prevention in AF Dabigatran 150mg bd PMH: Age related macular degeneration Baseline eGFR >60

3. 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

4. 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

6. Bloods Time (hrs) DabigatranTTPTAPTTClauss FibPlateletsCreGFR 019040035640.81489255.2

7. 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

9. 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

11. Bloods Time (hrs) Dabigatr an TTPTAPTT Clauss Fib PlateletsCreGFR 019040035640.81489255.2 117840015761.21507075.6 41634009511.5146 740010491.51366582.4 104009402.31415795.8 

12. Outcome No improvement in GCS or clinical state Brain stem death confirmed Died on 4 day of admission

16. Points to Consider In view of the extent of her injuries: – would the outcome have been different if she had not been anticoagulated? – w ould the outcome have been different if she had been anticoagulated with warfarin rather than a DOAC?

17. Targets of Direct Anticoagulant Agents TF=tissue factor Adapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853. FibrinFibrinogen TFPI (tifacogin) Indirect Xa inhibitors Fondaparinux Idraparinux SSR-126517 Xa Inhibitors: Rivaroxaban Apixaban Edoxaban LY517717 YM150 PRT-054021 IIa Inhibitors Ximelagatran Dabigatran ORAL PARENTERAL Direct Xa Inhibitors DX-9065a Otamixaban Xa IIa TF/VIIa XIX IXa VIIIa Va II AT APC (drotrecogin alfa) sTM (ART-123) TTP889

18. Targets of Direct Anticoagulant Agents TF=tissue factor Adapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853. FibrinFibrinogen TFPI (tifacogin) Indirect Xa inhibitors Fondaparinux Idraparinux SSR-126517 Xa Inhibitors: Rivaroxaban Apixaban Edoxaban LY517717 YM150 PRT-054021 IIa Inhibitors Ximelagatran Dabigatran ORAL PARENTERAL Direct Xa Inhibitors DX-9065a Otamixaban Xa IIa TF/VIIa XIX IXa VIIIa Va II AT APC (drotrecogin alfa) sTM (ART-123) TTP889

21.  

22. Predictable dose-response relationship  No monitoring required Few drug interactions No dietary interactions

24. 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

25. 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.

26. Anticoagulant-associated ICH: Is reversibility important?

28. 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

29. Options for warfarin reversal Rapid10 minsPCC (Beriplex) Fast (Partial)1-2 hrsFFP Prompt4-6 hrsIV vitamin K Slow24 hrsOral vitamin K Ultra-slow2-4 daysOmit warfarin 

30. 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

31. 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

32. Pharmacological measures:  Antifibrinolytics- Tranexamic acid, oral/IV/topical  Haemostatic agents-  PCC (Beriplex)  rFVIIa (NovoSeven)  aPCC (FEIBA)  ??? DOACs: Management of bleeding or urgent surgery

33. Direct thrombin inhibitors (dabigatran) FXa inhibitors (apixaban, rivaroxaban) Non-major bleed Direct thrombin inhibitors (dabigatran) Direct thrombin inhibitors (dabigatran) FXa inhibitors (apixaban, rivaroxaban) FXa inhibitors (apixaban, rivaroxaban) Major bleed Time since last oral dose + dosing regimen Measure FBC, U+E, eGFR, PT, APTT Time since last oral dose + dosing regimen Measure FBC, U+E, eGFR, PT, APTT Consider oral charcoal (<2 hrs ingestion) Local haemostatic measures Tranexamic acid Delay / Omit next anticoagulant dose Consider oral charcoal (<2 hrs ingestion) Local haemostatic measures Tranexamic acid Delay / Omit next anticoagulant dose Time since last oral dose + dosing regimen, Concomitant medications Measure FBC, U+E, eGFR, PT, aPTT Time since last oral dose + dosing regimen, Concomitant medications Measure 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.) 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) 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) 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 surgery Delay by >/= 12 hours: Omit dose Delay by 4-12 hours: If dabigatran, consider dialysis Immediate surgery: PCC/rFVIIa/aPCC Discuss with surgeon feasibility of delaying surgery Delay by >/= 12 hours: Omit dose Delay by 4-12 hours: If dabigatran, consider dialysis Immediate surgery: PCC/rFVIIa/aPCC

34. 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