1. Use of direct oral anticoagulants (DOACs) in primary care Julia Anderson Consultant Haematologist Royal Infirmary of Edinburgh

2. The ideal anticoagulant PREDICTABLE PHARMACOKINETICS and ANTICOAGULANT PROFILE FEW DRUG AND FOOD INTERACTIONS ORAL ADMINISTRATION NO NEED FOR MONITORING SIMPLE DOSING SHORT HALF-LIFE ANTIDOTE

3. New Direct Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Idrabiotaparinux Rivaroxaban Apixaban Edoxaban LY517717 YM150 DU-176b TAK 442 Betrixaban Dabigatran ORAL “DOACS” PARENTERAL DX-9065a Otamixaban Xa thrombin TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2007 TTP889

4. S DrugDabigatranRivaroxabanApixabanEdoxabanWarfarin Time to maximum effect 1.5-2h2h3-4h1-2h5 days Half-life 12-17h5-9h8-15h9-10h36-48h Plasma protein binding 35%92-95%87%40-59%99% Renal elimination 80%33%25%35-39%0% Interactions P-gpP-gp, CYP3A4 CYP2C9 (S) CYP1A2 (R) Food effect Absorption delayed Required for absorption No Dark green vegetables etc CHARACTERISTICS OF THE DIRECT ORAL ANTICOAGULANTS Adapted from Schulman J Int Med 2014; 275 1-11 The direct oral anticoagulants exert effect almost immediately - rivaroxaban and apixaban do not need initial overlap with heparin or LMWH No need for bridging anticoagulation with heparin pre-operatively in view of half-life - Stop 1-2 days before elective surgery if renal function is normal

5. Lothian Adult Formulary: approved indications for apixaban Non-valvular Atrial Fibrillation: Prophylaxis of stroke and systemic embolism when warfarin is not appropriate Deep vein thrombosis (DVT) and Pulmonary Embolism (PE): Acute Treatment of DVT and PE Prevention of recurrent DVT and PE Patients undergoing Cardioversion and RF ablation requiring anticoagulant cover where continuing warfarin is not appropriate

6. DOACs should NOT be prescribed for: Mechanical heart valves – lack of efficacy Antiphospholipid antibody syndrome- unclear efficacy in pts with VTE, and NOT for patients with arterial thrombosis Thrombosis in unusual sites – including axillary vein thrombosis, splanchnic vein thrombosis and cerebral vein thrombosis and in hereditary thrombophilias – efficacy uncertain Acute PE/DVT with large bulk thrombus (e.g. saddle PE, phlegmasia caerulea dolens: use IV UFH) Thrombosis in cancer patients – use LMWH

7. Commencing apixaban therapy: check Is the indication approved by NHS Lothian Does the benefit of anticoagulation outweigh the bleed? Does the patient have hepatic disease with coagulopathy? Does the patient have impaired renal function? Is the patient prescribed concomitant interacting medicines? eg CYP3A4 inhibitors or inducers triazole and imidazole antifungals [except fluconazole], protease inhibitors (HIV antiviral drugs); rifampicin, phenytoin, carbamazepine, St John’s Wort Is the patient prescribed concomitant antiplatelets / anticoagulants / NSAIDs – usually need d/c but if ACS or PCI must check with cardiology

8. Apixaban Dosing Guidance Non-valvular AF ∙ 5mg twice daily if eGFR ≥ 30ml/min ∙ Reduce to 2.5mg twice daily if 2 or more of: - Patient ≥ 80 yrs - Body weight ≤ 60 Kg - Creatinine ≥ 133 micromol/L ∙ Reduce to 2.5mg twice daily if eGFR is 15-29 ml/min ∙ Apixaban is not recommended if eGFR < 15ml/min or dialysed patients

9. Apixaban Dosing Guidance DVT/PE Initial dosing 10mg twice daily for 7 days Then 5mg twice daily (maximum 6 months at this dose) Ongoing therapy after 6 months 2.5mg twice daily Apixaban is not recommended if eGFR <30ml/min or dialysed patients (No dose reduction for weight or age)

10. Patient Education/Counselling Counselling sheet for NHS Lothian proposed, with tick boxes to indicate information has been given to patient/guardian Signed and dated by counsellor and patient Explain indication for therapy Explain expected duration of therapy Explain dose

11. Administration: - Swallow whole with water (with or without food) - Take roughly at the same time each day - Advise that a missed dose will increase the risk of further blood clots and that strict compliance is essential Missed dose: - Up to 6 hrs later than scheduled dose - Take as soon as remembered then continue with the twice daily dose - More than 6hrs later than scheduled dose - Wait and take the next scheduled dose

12. Advise of potential drug interactions Check with pharmacist before buying Over-The-Counter medicines, alternative medicines, herbal remedies Always tell the doctor, dentist or pharmacist that you take apixaban Bleeding risk: - Advise patient of bleeding risk and lack of reversal - Seek immediate medical attention if significant bleeding or head injury - Avoid risks from falls/injury ; need to take care with hobbies/leisure activities and avoid contact sports - Advise on the dangers of excess alcohol (increased risk of fall and bleed)

13. Pregnancy and breastfeeding Apixaban must not be prescribed There is a lack of safety evidence for apixaban during pregnancy / breastfeeding If patient becomes pregnant while taking apixaban immediately contact haematology consultant at RIE or SJH to arrange switch to LMWH and further obstetric advice (RefHelp guide) Reliable contraception required: referral pathway to Chalmers clinic being developed

14. Patient Information Sheets & Alert Cards Supply appropriate patient information leaflet and alert card (in Apixaban tablet box) https://www.eliquis.co.uk/resourcesforyourpatients/patientinformation/

15. Switching anticoagulants Switch from LMWH to apixaban Start apixaban when next dose of LMWH would have been due Switch from warfarin to apixaban Check INR When INR < 2.0 start apixaban

16. Peri-operative Management Timing for last dose of anticoagulant Xa inhibitorsHigh risk and/or renal Low risk DabigatranHigh risk and renal Creat cl 30-49ml/min High risk or renalLow risk and no renal 96hrs48hrs24hrs

17. Minor Procedures: NHS Lothian policies Endoscopy: protocol in place, follows BSG guidance: withhold DOAC 24 hours in advance of procedure Dental procedures: SDCEP guidance Working Group to advise on implementation in NHS Lothian Advocates no discontinuation of DOACs

18. Reversal Antidote to factor Xa inhibitors (Andexanet alfa) under evaluation in clinical trials (modified recombinant human fXa “decoy” molecule, Portola Pharmaceuticals) Currently no way to reverse anti-Xa effect, but short lived effect; standard resuscitation measures, compression of bleeding point and correction of acquired coagulopathy Antidote to Dabigatran evaluated in REVERSE-AD trial, and approved by FDA and being considered for approval by EMA: Idarucizumab (Praxbind®)

19. SUMMARY 2 exciting new classes of oral anticoagulants Clear Advantages yet there are Limitations Challenges :- – the education of medical and nursing staff to avoid pitfalls – the education of patients regarding compliance – the development of protocols regarding anticoagulant switches – introduction of systems to inform lab staff if a patient is taking a DOAC – the development of protocols for peri-operative management and management of bleeding – understanding bleeding risk in specific patient populations outwith trials