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Haemostasis and Thrombosis DOACs Bleeding Perioperative management

Haemostasis and Thrombosis DOACs Bleeding Perioperative management. Dr Vanessa Manitta Clinical and Laboratory Haematologist Northern Hospital. Case Study 1: Mr A. P. 64-year-old man; pain in his Right lower leg

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Haemostasis and Thrombosis DOACs Bleeding Perioperative management

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  1. Haemostasis and ThrombosisDOACs BleedingPerioperative management Dr Vanessa Manitta Clinical and Laboratory Haematologist Northern Hospital

  2. Case Study 1: Mr A. P • 64-year-old man; pain in his Right lower leg • Noticed pain 3 days after arriving home 2 weeks ago from an overseas trip for work • Flight was long-haul and journey lasted 21 hours • Participated in 10-km fun run with colleagues 2 days before his return flight • Initially ignored pain; worsened in the last 3 days Differential Diagnosis? 2

  3. Case Study 1: Medical history • Personal • Nothing significant • No history of VTE; never taken anticoagulant therapy • Family history is unremarkable with no history of VTE • Comorbidities • None • Medications • None • System review • No focal symptoms of concern • No chest pain or palpitations 3

  4. Case Study 1 : Physical examination • General • Comfortable and well looking; physically active • BMI 24.5 kg/m2 • BP 125/75 mm Hg ; Pulse 70 bpm • Chest clear • No obvious abnormal findings • Lower extremities • Right calf swollen • No obvious venous distension • Mild erythema Right leg Investigations? 4

  5. Case Study 1 : Investigation • Doppler U/S of Right leg • Occlusive thrombus within femoral vein, 8 cm long Diagnosis Above knee DVT 5

  6. Case Study 1: Discussion What else do you need to know before proceeding with anticoagulation therapy? 6

  7. Need to know… • Full blood count • Baseline coagulation • Renal Function • Liver function • Important for establishing baseline values • Detect and monitor any complications during anticoagulant therapy 7

  8. Renal function: CrCl (Not eGFR) • Unfractionated heparin1 and warfarin2 not affected by renal function • Low molecular weight heparin (LMWH) is excreted renally1 • Requires dose adjustment and assessment of plasma concentration • 33% of rivaroxabanrenally excreted as unchanged active substance in the urine3 • Contraindicated if CrCl is <30 mL/min3 • ~27% of apixabanis excreted renally4 • Contraindicated if CrCl is <25 mL/min4 • Dabigatran85% renally excreted • Contraindicated if CrCl is <30 mL/min CrCl, creatinne clearance. 1Garcia et al Chest 2012;141(Suppl):e24S–43S; 2Brighton Aust Prescr 2010;33:38–41; 3Xarelto Product Information, 15 January 2015; 4Eliquis Product Information, 20 May 2015. 8

  9. Case study 1 • Laboratory test findings were normal APTT, activated partial thromboplastin time; CrCl, creatinine clearance; Hb, haemoglobin; INR, International Normalised Ratio; WCC, white cell count. 9

  10. Case Study 1 What are the anticoagulation options? • Warfarin with clexane bridging • NOAC/DOAC 10

  11. NOACs approved for VTE treatment in Australia • Rivaroxaban and apixaban are approved for the treatment of VTE (DVT and/or PE) and for the prevention of recurrent VTE1,2 • EINSTEIN clinical program: rivaroxaban was as effective as enoxaparin + VKA • AMPLIFY clinical program: apixaban was as effective as enoxaparin + VKA • Rivaroxaban and apixaban offer a simplified oral treatment strategy compared with enoxaparin + VKA1,2 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 May 2015. 11

  12. Coagulation cascade inhibition by Factor Xa inhibitors1 X TF VIIa Va Xa Rivaroxaban,Apixaban II Prothrombinase complex Legend Prothrombin Inactive Factor Active Factor IIa Transformation Thrombin Catalysis Fibrinogen Fibrin 12 1De Caterina et al Thromb Haemost 2013;109:569–79.

  13. Coagulation cascade inhibition by thrombin inhibitors1 X TF VIIa Va Xa II Prothrombinase complex Legend Prothrombin Inactive Factor Active Factor Dabigatran etexilate IIa Transformation Thrombin Catalysis Fibrinogen Fibrin 13 1De Caterina et al Thromb Haemost 2013;109:569–79.

  14. Approved indications for DOACs in Australia 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 May 2015; 3Pradaxa Product Information, 28 April 2015. 14

  15. DOACs • Absolute Contraindications • Mechanical valves • CrCl <25ml/min (Apixaban)/ CrCl <30ml/min (Rivaroxaban/Dabigatran) • LFT 3x ULN and/or known history of CLD • Pregnancy and Breastfeeding • Concomitant treatment with strong inhibitors of both CYP3A4 and P-gp e.g. azole-antimycotics or HIV proteases • Relative contraindications • Age ≥ 75 years and < 18 years • Extremes of body weight (<50kg and >120kg) • Consider alternative in frail patients and/or high falls risk • avoid in patients with poor compliance to medications due to short half-life.

  16. DOACs • There is little published evidence in • Antiphospholipid syndrome • Malignancy • Consult Haematology Unit

  17. Apixaban: Dosing

  18. Rivaroxaban Dosage

  19. Conversion of Anticoagulants

  20. Conversion of anticoagulants

  21. DOAC benefit: Simplified dosing regimen DOACs Heparin Warfarin • Oral tailored dose because of unpredictable pharmacokinetics and pharmacodynamics5,6 • Oral fixed dose according to clinical indication • Rivaroxaban once daily with food for stroke prevention in atrial fibrillation and the prevention of recurrent VTE*1 • Apixaban and dabigatranetexilate twice daily2,3 • Must be administered parenterally4 • Long-term use can be problematic and resource intensive *Rivaroxaban is dosed twice daily with food for 21 days for the treatment of VTE, then once daily thereafter.1 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 May 2015;3Pradaxa Product Information, 28 April 2015; 4Kubitza & Haas Expert Opin Investig Drugs 2006;15:843–55; 5Brighton Aust Prescr 2010;33:38–41; 6Ageno et al Chest 2012;15:843–55. 21

  22. DOAC benefit: Rapid onset and offset of action DOACs Warfarin • Onset of action within 30 min of intake • Time to maximum concentration 0.5–4 hr1-3 • Shorter elimination half-life • Rivaroxaban 5–9 hr (11–13 hr in elderly)1, apixaban 9–14 hr2, dabigatran etexilate 12–17 hr3 • No reversal agents for apixaban/rivaroxaban (Idaruciziumab for Dabigatran now available) • Onset of action 36–72 hr4 • Slow onset means bridging therapy required • Longer elimination half-life (20–60 hr) slows removal of anticoagulant effect after stopping • Reversal agents available4 • Plasma or factor concentrate for immediate reversal • Vitamin K for reversal within hours 1Xarelto Product Information, 15 January 2015;2Eliquis Product Information, 20 May 2015; 3Pradaxa Product Information, 28 April 2015; 4Brighton Aust Prescr 2010;33:38–41; 5Eriksson et al Ann Rev Med 2011;62:41–57. 22

  23. DOAC benefit: Routine monitoring not required DOACs1 • Do not require routine INR monitoring Heparin2 Warfarin3 • UFH requires regular monitoring • LMWH does not require routine INR monitoring • Seek specialist advice for very obese (BMI ≥30) or significant renal failure (CrCl <30 mL/min) • Requires routine INR monitoring to ensure patient is within therapeutic window (INR 2–3) BMI, body mass index; CrCl, creatinine clearance rate; INR, International Normalised Ratio; LMWH, low molecular weight heparin; UFH, unfractionated heparin. 1Brighton Aust Prescr 2010;33:38–41; 2Garcia et al Chest 2012;141(Suppl):e24S–43S; 3Eriksson et al Ann Rev Med 2011;62:41–57. 23

  24. DOAC benefit: Few drug interactions DOACs • Rivaroxaban and apixaban1,2 • Cytochrome P450 3A4 and P-glycoprotein inhibitors (ketoconazole, ritonavir) are contraindicated • Dabigatran etexilate3 • Proton pump inhibitors reduce absorption • Possible interactions with P-glycoprotein inhibitors and inducers Warfarin • Many clinically significant interactions5 • Care needed when modifying concomitant drug therapy6 Heparin • Low drug interaction potential4 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 May 2015; 3Pradaxa Product Information, 28 April 2015; 4Fragmin Product Information, 4 March 2013; 5Brighton Aust Prescr 2010;33:38–41; 6Eriksson et al Ann Rev Med 2011;62:41–57. 24

  25. VTE treatment: DOACs1 Phases of disease Acute Intermediate Long term Rivaroxaban1 • 15 mgtwice daily with food • Initial, therapeutic dose • 3 weeks • 20 mg once daily with food • Early maintenance • At least 3 months • 20 mg once daily with food • Long-term maintenance* Apixaban2 • 10 mgtwice daily ± food • Initial, therapeutic dose • 7 days • 5 mg twice daily ± food • Early maintenance • At least 6 months • 2.5 mg twice daily ± food • Long-term maintenance* *With re-assessment of the individual benefit–risk at periodic intervals 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 May 2015. 25

  26. DOACS for VTE management What are the clinical scenarios that would dictate choice of anticoagulant therapy? 26

  27. Clinical scenarios that dictate choice of NOAC vs warfarin * Note that warfarin must be taken with heparin during the acute phase of disease treatment. † Note that rivaroxaban 10 mg once daily may be prescribed for VTE prevention in patients with CrCl 15-29 mL/min undergoing total hip and knee replacement . 27 1Keeling & Alikhan Br J Haematol 2013;161:755–63; 2Xarelto Product Information, 15 January 2015; 3Eliquis Product Information, 20 May 2015.

  28. Case Study 1 Mr A.P • Pt prefers daily dosing of xarelto • Commence him on 15mg bd for 3 weeks, then 20mg daily • 2 months into treatment he presents to ED hypotensive and tachycardic • Examination • PR Malaena • Investigation • Hb 60g/L plat 300 • APTT and INR normal, Fibrinogen 1.0

  29. Case study 1 • How would you manage his condition?

  30. Case Study 1 • Non-life-threatening bleeding • Determine time of last dose and dosing regimen • Normalisation of haemostasis takes 12–24 hr (longer for patients with renal impairment taking dabigatran) • Local haemostatic measures • Fluid replacement (colloids if needed) • RBC and/or platelet substitution, if needed • Fresh frozen plasma as volume expander (not as reversal agent) • Life Threatening bleeding • As above but Consider Prothrombin X, Transexamic acid, Novoseven (off label) • For dabigatran - Idarucizumab

  31. Case study 2: Mr C J • A 78-year-old man attends a follow-up appointment after being diagnosed with nonvalvular AF • Has hypertension diagnosed 12 years ago • Well controlled on ACE inhibitor and calcium channel blocker • Examination • Clinically well, weighs 78 kg • BP 140/80 mm Hg, irregular pulse 32

  32. 1Lip et al Chest 2010;137:263–72; 2Lip et al Stroke 2010;41:2731–8; 3Hart et al J Am Coll Cardiol 2000;35:183–7. What is this patient’s risk of stroke according to CHA2DS2-VASc? 33

  33. Is this patient a candidate for anticoagulation therapy? Nonvalvular AF <65 years and lone AF (irrespective of gender) Yes No CHA2DS2-VASc score 0 1 ≥2 • Oral anticoagulation therapy* • ? NOAC • ? vitamin K antagonist No antithrombotic therapy *Assess HAS-BLED score and consider patient values and preferences 1Adapted from Camm et al Eur Heart J 2012;33:2719-47. 34

  34. What else do you need to consider before prescribing anticoagulants? • Risk of bleeding • Patient has no history of bleeding or other co-morbidities • Assess using HAS-BLED 35

  35. INR, international normalised ratio. 1Pisters et al Chest 2010;138:1093–100. What is this patient’s risk of bleeding according to HAS-BLED1? *Antiplatelets and NSAIDs • Bleeding risk is low, especially as hypertension is well controlled *P value for trend = 0.007 36

  36. What else do you need to assess before prescribing anticoagulants? • FBE • Renal function test results • Urea 14.8 mmol/L (ref range: 2.5–8.0 mmol/L) • Creatinine 170 µmol/L (ref range: 70–110 µmol/L) • Creatinine clearance (CrCl) = 35 mL/min (calculated by Cockroft-Gault equation) • LFTs • Coags • Other blood tests normal CrCl, creatinine clearance rate. 1Heidbuchel et al. Europace 2013;15:625–51; 2Xarelto Product Information, 15 January 2015; 3Pradaxa Product Information, 28 April 2015. 37

  37. Can this patient be prescribed a DOAC? • Rivaroxaban: 20 mg once daily1 • Apixaban: 5 / 2.5 mg twice daily*,2 • Dabigatranetexilate: 150 / 110 mg twice daily*,3 >50 mL/min • Rivaroxaban: 15 mg once daily1 • Apixaban: 5 / 2.5 mg twice daily*†,2 • Dabigatran etexilate: 110 mg twice daily3 Estimate CrCl 30–49 mL/min All approved NOACs contraindicated1-3 <30 mL/min *Refer to Product Information; †CrCl ≥25 mL/min 1Xarelto Product Information, 15 January 2015; 2Eliquis Product Information, 20 March 2015; 3Pradaxa Product Information, 28 April 2015. 38

  38. Dabigatran

  39. Conversion of Dabigatran

  40. Case Study 3 Mrs RG • A 76-year-old female with chronic nonvalvular AF (CHA2DS2-VASc score = 4) • History of ischaemic stroke, good recovery • Overweight (height 1.88 m, weight 95 kg) • Treated with rivaroxaban 20 mg once daily with no issues • Renal function was normal when last checked about 1 year ago • Recent blood test results: serum creatinine 110 µmol/L • Scheduled to have hip replacement surgery

  41. Perioperative anticoagulation • What patient characteristics influence timing of stopping anticoagulation therapy? • Renal function – determines half life • Risk of thrombosis • Risk of bleeding • PROMPT Guidelines – DOAC administration

  42. DOACs – an Approach to Interruption

  43. The Perioperative Timeline Dynamic Model of Bleeding vs Thrombosis Surgery Bleeding Risk Highest Thrombosis Risk Continually Increases Over Time Assess Thrombosis Risk Assess Bleeding Risk -10 1 -14 -5 -3 0 2 3 14 -7 -4 -2 -1 7 35 PREDICTABLE Risks Physician decides UNPREDICTABLE Risks Surgeon decides EXPECTED and EMERGENT Risks Collaborative approach Post surgery risks may change from predicted

  44. Perioperative anticoagulation: Minimal bleeding Risk • No clinically important bleeding risk • Minor dental surgery • Cataract or glaucoma intervention • Superficial surgery • May not require stopping • Perform surgery at trough concentration • 12 hr after last dose if twice daily • 24 hr after last dose if once daily • Or perform surgery 24 hr after last dose

  45. Perioperative Anticoagulation: Low to High bleeding risk • Low bleeding risk • Endoscopy with biopsy • Some biopsies • Angiography • Pacemaker insertion • High bleeding risk • Major surgery • Transurethral resection of the prostate • Kidney biopsy • Liver biopsy Stop NOAC therapy before surgery

  46. When to stop apixaban?

  47. When to stop Rivaroxaban?

  48. When to stop Dabigatran?

  49. Case Study 3: How would you manage this pt? • Thrombosis risk? • High • ? need for “bridging” • Not required for DOACs due to short half life • Renal function? • Creatinine clearance (CrCl) = 68 mL/min (calculated by Cockroft-Gault equation) • Bleeding Risk ? • High

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