Atrial fibrillation and anticoagulation JIR-PING BOEY, DEPARTMENT OF HAEMATOLOGY, FLINDERS MEDICAL CENTRE FEBRUARY 2016

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1 1 Atrial fibrillation and anticoagulation JIR-PING BOEY, DEPARTMENT OF HAEMATOLOGY, FLINDERS MEDICAL CENTRE FEBRUARY 2016

2 Disclosures 2 No conflicts of interest

3 Some questions 3 Should my patient with AF receive an anticoagulant? Which anticoagulant? What s the evidence for NOACs? What are the bleeding risks? How to manage patients on anticoagulants who need a procedure?

4 Today s talk 4 Topics No. of slides Stroke risk and CHADS2 score 4 Warfarin and aspirin in AF 4 NOACs in AF 9 Renal impairment and the elderly 5 Starting anticoagulation warfarin or NOACs? 7 Procedures and bleeding 5 Summary of ACC 2014 guidelines 2

5 Stroke risk in AF increases with age 5 Courtesy A Gallus

6 Risk scores CHA2DS2-VASc 6 Score CHADS2 Score Cardiac failure 1 Hypertension 1 Cardiac failure 1 Hypertension 1 Age 75 1 Diabetes 1 Stroke/TIA 2 Gage Circulation 2004 Age 75 2 Diabetes 1 Stroke/TIA 2 Vascular disease 1 Age Female 1 Lip Chest 2010

7 CHADS2 predict strokes even in people without AF (N=20,970) 7 Mitchell Heart 2014

8 Ischaemic stroke risk in patients with AF CHADS2 Ischaemic stroke rate % % % % % % % CHA2DS2-VASc Ischaemic stroke rate % % % % % 5 7.2% % % % % 8 Friberg Eur Heart J 2012

9 Effect of warfarin on ischaemic stroke risk: The higher the CHADS2 score the greater the benefit 9 CHADS2 score Events per 100-person years Warfarin No warfarin NNT or Go JAMA 2003

10 10 Warfarin (n=488)* Aspirin (n=485)* p All strokes 1.6% 3.4% Fatal 1.0% 1.6% NS Ischaemic 0.8% 2.5% Haemorrhagic 0.5% 0.4% NS Other IC bleed 0.2% 0.1% NS *risk per annum

11 Effect of warfarin vs aspirin on stroke risk 11 Drug Absolute risk reduction, per year Primary prevention Secondary prevention Relative risk reduction Warfarin versus nil 2.7% 8.4% (NNT=12) 64% Aspirin versus nil % 2.5% 19-22% Warfarin versus aspirin 0.7% 7.0% 38% Hart Ann Intern Med 2007

12 Anticoagulation benefits patients with the highest CHADS2 and bleeding scores most 12 NCB: Absolute reduction in ischaemic stroke rate 1.5 (absolute increase in ICB rate) Olesen Thromb Haemost 2011

13 13 NOACs (Non-VKA Oral Anti-Coagulants)

14 14 Courtesy Gallus

15 NOAC basic pharmacology: Quick onset and offset of action 15 Dabigatran Rivaroxaban Apixaban t max h 2 4 h 3 4 h t ½ h 5 13 h 12 h Dosing BD OD BD Renal clearance 85% 33% 25% NOAC SPC

16 NOACs vs warfarin in stroke prevention in nonvalvular AF Study RE-LY ROCKET-AF ARISTOTLE 16 Drug Dabigatran 110 mg or 150 mg BD Rivaroxaban 20 mg OD Apixaban 5 mg BD Patients N = 18,113 CHADS 2 1 N = 14,264 CHADS 2 2 N = 18,201 CHADS 2 1 Age CHADS Previous stroke 20% 55% 19% Connolly NEJM 2009, Patel NEJM 2011, Granger NEJM 2011

17 17 Ruff Lancet 2014 Less strokes and less bleeding with NOACs In meta-analysis of RCTs

18 18 Trend towards less major bleeding with NOACs Especially if TTR < 65% Gomez-Outes Thrombosis 2013

19 19 Definitely less intracranial bleeding with NOACs Even if TTR > 65% Gomez-Outes Thrombosis 2013

20 5 fatal 20 1 fatal More GI bleeds with some NOACs Gomez-Outes Thrombosis 2013

21 Less fatal bleeding with NOACs Chatree Chai-Adisaksopha et al. Blood 2014;124: by American Society of Hematology

22 Absolute per annum event rates in NOAC trials OAC Stroke or Embolism Intracranial bleed Major Bleed 22 Death Warfarin Dabigatran Dabigatran Warfarin Apixaban Warfarin Rivaroxaban Rivaroxaban (real-world data, N = 6784) Connolly NEJM 2009, Patel NEJM 2011, Granger NEJM 2011, Camm Eur Heart J 2015

23 23 Renal Impairment and the Elderly

24 24 Same bleeding risk: NOACs and warfarin in moderate renal failure Sardar Can J Cardiol 2014

25 25 as Elderly patients have similar bleeding rate with NOACS and warfarin Sardar J Am Geriat Soc 2014

26 26 Less strokes with NOACs in moderate renal failure Sardar Can J Cardiol 2014

27 27 Elderly patients have less strokes on NOACs compared with warfarin Sardar J Am Geriat Soc 2014

28 Renal impairment: Check baseline and monitor 28 Severe renal impairment is a contraindication for NOACs CrCl < 30 ml/min: dabigatran and rivaroxaban CrCl < 25 ml/min: apixaban Patients with moderate renal impairment can go on a NOAC: Monitor renal function 6 monthly, and if unwell Dabigatran Apixaban Edoxaban Rivaroxaban t 1/2 / change in trough level Change in AUC Change in AUC Change in AUC CrCl 30-50: 18h / 1.8x CrCl 40: 29% CrCl 50 80: 32% CrCl< 50: 1.5-2x CrCl < 30: 27h / 3.6x CrCl 25: 38% CrCl 30-50: 74% NOAC SPC

29 29 Anticoagulation: Balancing Risks and Benefits

30 Informed decision to anticoagulate 30 Clinician and patient need to agree on NET CLINICAL BENEFIT before starting anticoagulation Start warfarin or NOACs if CHADS2 or CHADSVA2Sc score > 1 The higher the score the larger the net clinical benefit

31 Bleeding risk assessment: Use as reminder to modify risk factors 31 Feature Hypertension BP > 160 Abnormal renal / liver function Stroke, history of Bleeding tendency Labile INR Elderly > 65 years Modifiable Yes Maybe not No Maybe not Yes No Score Major bleeding rate 0 1.2% 1 2.8% 2 3.6% 3 6.0% 4 9.5% 5 7.4% Drug (antiplatelet/nsaid or alcohol) Yes Lip J Am Coll Cardiol 2011 Pisters Chest 2010

32 Warfarin or NOACs? 32 Patient preference. Dosing schedule: Fixed vs variable INR monitoring for warfarin Drug and food interactions

33 NOAC drug interactions Less common than warfarin, but not to forget 33 Anticoagulant effect * Amiodarone Azole-antifungals** (except fluconazole) Verapamil, Diltiazem Anticoagulant effect Carbamazepine Rifampicin Phenytoin HIV proteasome inhibitors** Macrolides antibiotics Ciclosporin *More pronounced in elderly / renally impaired. **Absolute contraindication to NOACs NOAC SPC

34 Warfarin or NOACs? 34 Strongly recommend switch to NOACS for patients on warfarin, compliant to treatment, if labile INR Poor adherence to therapy not an indication to switch

35 Good INR level paramount 35 Out-of-range INRs associated with adverse events Australian INR control in clinical trials one of the best Singer Circ Cardiovasc Qual Outcomes 2009 Wallentin Lancet 2010

36 No monitoring needed for NOACs* 36 Drug assays and on-therapy ranges available: Preferred over routine coags (which should not be performed routinely) Correlation with outcomes uncertain Coagulation test Dabigatran Rivaroxaban Apixaban APTT Fairly sensitive Insensitive PT Insensitive Fairly sensitive Insensitive *Patient selection is key NOAC SPC

37 37 Peri-procedural anticoagulation and Bleeding

38 38 Bridging increases bleeding without reducing strokes Note: Only 3% of patients CHADS2 score 5 6

39 Perioperative management 39 NOACs: no need to bridge Warfarin: bridging may be needed in: Mechanical heart valves CHADS2 score 5 6 Recent stroke or VTE (past 3 months)

40 Perioperative bridging warfarin 40 Before surgery Post-operative Majority of patients Patients with high thrombotic risk Cease 5 days pre-op Start Clexane 3 days pre-op, last dose 24 h pre-op Restart warfarin h post-op Start Clexane h post-op Douketis Chest 2012

41 Pre-operative cessation of NOACs 41 Renal function Surgical bleeding risk Apixaban and rivaroxaban Dabigatran Normal / mild impairment Low 1 d Normal / mild impairment High 2 3 d Moderate impairment* Low 2 d 2 3 d Moderate impairment* High 3 d 4 d *CrCl < 50 ml/min Tran Intern Med J 2014

42 Bleeding management 42 Stop the drug and refer to hospital if more than minor bleed. Supportive care, local measures and time Prothrombinex often given: efficacy uncertain Dabigatran dialysable Dabigatran antidote (idarucizumab) now available Antidote for factor Xa inhibitors in development

43 AHA/ACC/HRS 2014 guidelines 43 Shared decision making, discussion of risks, patient s preference CHA2DS2-VASc 0: no antithrombotics CHA2DS2-VASc 1: no antithrombotics or OAC or aspirin CHA2DS2-VASc 2: warfarin or NOACs CHA2DS2-VASc 2 and end-stage CKD: warfarin January J Am Coll Cardiol 2014

44 AHA/ACC/HRS 2014 guidelines 44 Evaluate renal function before starting NOACs and reevaluate when clinically indicated and at least annually NOACs if unable to maintain therapeutic INR Mechanical heart valves: warfarin OAC + clopidogrel (but not aspirin) after PCI Re-evaluate need for anticoagulation periodically January J Am Coll Cardiol 2014