EHRA Practical Guide on the Use of New Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation

1. EHRA practical guide on the use of new oral anticoagulants in patients with non- valvular atrial fibrillation Hein Heidbuchel 1 , M.D., Ph.D., Peter Verhamme 1 , M.D., Ph.D., Marco Alings 2 , M.D., Ph.D., Matthias Antz 3 , M.D., Werner Hacke 4 , M.D., Jonas Oldgren 5 , M.D., Ph.D., Peter Sinnaeve 1 , M.D., Ph.D., A. John Camm 6 , M.D., Paulus Kirchhof 7 , M.D., Ph.D. 1. Department of Cardiovascular Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; 2. Department of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; 3. Department of Cardiology, Klinikum Oldenburg, Oldenburg, Germany; 4. Department of Neurology, Ruprecht Karls Universitt, Heidelberg, Germany; 5. Uppsala Clinical Research Center and Dept of Medical Sciences, Uppsala University, Uppsala, Sweden; 6. Clinical Cardiology, St Georges University, London, United Kingdom; 7. University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK, and Department of Cardiology and Angiology, University of Mnster, Germany

2. www.escardio.org/EHRA Special Thanks to Distributed through an educational grant from Bayer

3. EHRA Practical Guide on the use of new oral anticoagulants (NOAC) in patients with non-valvular atrial fibrillation This slide set is based on the following full text paper: European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvularatrial fibrillation. H. Heidbuchel; P. Verhamme; M. Alings; M. Antz; W. Hacke; J. Oldgren; P. Sinnaeve; A.J. Camm; P. Kirchhof. EP Europace 15: 625-651 (2013) Published by Oxford University Press, May 15, 2013. doi: 10.1093/europace/eut083 http://www.ncbi.nlm.nih.gov/pubmed/23625942 An executive summary was published in: European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Executive Summary. H. Heidbuchel; P. Verhamme; M. Alings; M. Antz; W. Hacke; J. Oldgren; P. Sinnaeve; A.J. Camm; P. Kirchhof. European Heart Journal 34: 2094-106 (2013 ) Published by Oxford University Press, April 26, 2013 http://www.ncbi.nlm.nih.gov/pubmed/23625209 Updated information, downloadable anticoagulation cards, and possibility for feedback are available via : www.NOACforAF.eu

4. The articles and related educational material (slide set, Web page, Key Message booklet, ) were produced by and under the sole responsibility of the European Heart Rhythm Association, EHRA. The project was funded by unrestricted educational grants from the Alliance Bristol-Myers Squibb / Pfizer, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, and Daiichi Sankyo Europe GmbH. The EHRA writing committee collaborated with medical experts from the different companies to assure data accuracy and completeness. www.escardio.org/EHRA

5. Advantages of new oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for thromboembolic prevention in patients with non-valvular AF predictable effect without need for monitoring fewer food and drug interactions more predictable half-life/elimination improved efficacy/safety ratio 1 www.escardio.org/EHRA

6. Need for a practical guide 2010 ESC Guidelines (and the 2012 Update) do not detail the NOAC in specific clinical situations. 1,2 Multiple physician tools supplied with each drug may be confusing. EHRA has now produced a practical guide to supplement AF guidelines. 2 www.escardio.org/EHRA 1. Camm et al, Europace 2010;12:1360-420 2. Camm et al, Eur Heart J 2012; 33:2719-47

7. NOACs approved or under evaluation for prevention of systemic embolism or stroke in patients with non-valvular AF Dabigatran Apixaban Edoxaban * Rivaroxaban Action Direct thrombin inhibitor Activated factor Xa (FXa) inhibitor Activated factor Xa (FXa) inhibitor Activated factor Xa (FXa) inhibitor Dose 150 mg BID 110 mg BID 5 mg BID 2.5 mg BID 60 mg QD 30 mg QD 15 mg QD 20 mg QD 15 mg QD Phase III clinical trial RE-LY 1 ARISTOTLE 2 AVERROES 3 ENGAGE-AF 4 ROCKET-AF 5 3 www.escardio.org/EHRA 1. Connolly et al, N Engl J Med 2009; 361:1139-51 4. Ruff et al, Am Heart J 2010; 160:635-41 2. Granger et al, N Engl J Med 2011; 365:981-92 5. Patel et al, N Engl J Med 2011;365:883-91 3. Connolly et al , N Engl J Med 2011; 364:806-17 * not yet approved by EMA

8. 1. Practical start-up and follow-up scheme for patients on NOACs Risk/benefit analysis: is a NOAC indicated? When choosing a NOAC, consider co-medications taken by patient. Consider co-medications such as PPI to reduce risk for gastro-intestinal bleeding. Carry information card: generic card could serve for all NOACs. Need to educate patient on importance of strict adherence to regimen discontinuation is dangerous. 4 www.escardio.org/EHRA

9. EHRA proposal for a universal NOAC anticoagulation card 5 www.escardio.org/EHRA Card can be downloaded in a printer-ready form or in a ppt format that can be configured to the local language from www.NOACforAF.eu

10. Need for structured follow-up All NOACs are anticoagulants and hence can cause serious bleeding. All NOACs have some drug-drug interactions (DDIs). AF population is a fragile patient population. Patients should return for ongoing review according to a predetermined schedule. Follow-up can be undertaken by specialist or GP with experience in the field and/or appropriate secondary care physicians. Nurse co-ordinated AF clinics may be used. 1 1. Berti et al, Eur Heart J, 2013 (Epub ahead of print) 6 www.escardio.org/EHRA

11. Suggested structured follow-up 7 www.escardio.org/EHRA

12. Checklist during follow-up of AF patients on NOACs Interval Comments Compliance Each visit Inspect remaining medication Stress importance of compliance Inform about compliance aids Thrombo-embolism Each visit Cerebral, systemic and pulmonary circulation Bleeding Each visit Nuisance bleeding prevention possible? Bleeding with risk or impact on QoL prevention possible? Need to revise dose? Side effects Each visit Continuation? Temporary cessation with bridging? Change of anticoagulant drug? Co-medications Each visit Prescription or over-the counter drugs? Even temporary use can be risky Blood sampling Yearly 6-monthly 3-monthly on indication Haemoglobin, renal, liver function Renal function if CrCl 30-60 ml/min or if on dabigatran and aged >75 years or fragile If CrCl 15-30 ml/min If intercurring condition may impact renal or hepatic function. 8 www.escardio.org/EHRA

13. Follow-up: considerations Renal function: impaired renal function increases plasma levels and hence anticoagulant effect of all NOACs, especially dabigatran. Dose reduction may be indicated. Minor bleeding: most is temporary and classified as nuisance. Discontinuation or dose reduction should not be considered unless frequent and impacting on patients QoL. 9 www.escardio.org/EHRA

14. 2. How to measure the anticoagulant effect of NOACs Routine monitoring of coagulation not required, but quantitative assessment of drug exposure may be needed in emergency situations: serious bleeding and thrombotic events urgent surgery renal or hepatic insufficiency potential DDI suspected overdosing 10 www.escardio.org/EHRA

15. Measuring the anticoagulant effect of NOACs Important to know exactly when NOAC was administered relative to time of blood sampling. Maximum effect at maximum plasma concentration (~3h after administration). Activated thromboplastin time (aPTT): qualitative assessment of dabigatran, but sensitivity varies. Diluted thrombin time (DTT): Hemoclot suitable for quantitative assessment of dabigatran but no data on cut off below which surgery is safe. Anti-FXa chromogenic assays: commercially available for quantitative assessment, but no data to associate level with bleeding or thrombo- embolism risk. 11 www.escardio.org/EHRA

16. Measuring the anticoagulant effect of NOACs Dabigatran Apixaban Edoxaban Rivaroxaban Plasma peak 2h after ingestion 1-4h post ingestion 1-2h after ingestion 2-4h after ingestion Plasma trough 12-24h after ingestion 12-24h after ingestion 12-24h after ingestion 16-24h after ingestion PT cannot be used cannot be used prolonged but no known relation with bleeding risk prolonged: may indicate excess bleeding risk but local calibration required INR cannot be used cannot be used cannot be used cannot be used aPTT at trough >2x ULN suggests excess bleeding risk cannot be used prolonged but no known relation with bleeding risk cannot be used dTT At trough >200ng/ml 65s: excess bleeding risk cannot be used cannot be used cannot be used Anti-FXa assays n/a no data yet quantitative; no data on threshold values for bleeding or thrombosis quantitative; no data on threshold values for bleeding or thrombosis Ecarin clotting time at trough >2x ULN: excess bleeding risk not affected; cannot be used not affected; cannot be used not affected; cannot be used 12 www.escardio.org/EHRA

17. Curvilinear relationship between aPTT and dabigatran plasma levels 13 www.escardio.org/EHRA Van Ryn et al Thrombosis and haemostats 2010;103:1126-7

18. Relation between PT and FXa inhibitor (rivaroxaban) plasma levels 14 www.escardio.org/EHRA Douxfils et al Thromb Res. 2012;130:956-66

19. 3. Drug-drug interactions and pharmacokinetics of NOACs Absorption and metabolism of NOACs 15 www.escardio.org/EHRA

20. Absorption and metabolism of NOAC Dabigatran Apixaban Edoxaban * Rivaroxaban Bioavailability 3-7% 50% 62% 66% (w/o food) ~100% with food Prodrug yes no no no Clearance: non-renal/renal of adsorbed dose if normal renal function 20%/80% 73%/27% 50%/50% 65%/35% Liver metabolism: CYP3A4 no yes (elimination; minor CYP3A4) minimal (<4% of elimination) yes (elimination) Absorption with food no effect no effect 6-22% more +39% Intake with food? no no no official recommendation yet mandatory Absorption with H2B/PPI plasma level -12 to -30% no effect no effect no effect Asian ethnicity plasma level +25% no effect no effect no effect GI tolerability dyspepsia 5-10% no problem no problem no problem Elimination half-life 12-17h 12h 9-11h 5-9h (young)/11-13h (elderly) 16 www.escardio.org/EHRA * not approved yet

21. Mechanisms underlying DDIs in NOACs P-glycoprotein transporter involved in absorption and renal clearance plasma levels may be affected by P-gp inducers or inhibitors 1 Cytochrome P450 CYP3A4 involved in hepatic clearance of rivaroxaban and apixaban plasma levels may be affected by CYP3A4 inducers of inhibitors 2 17 www.escardio.org/EHRA 1. Gnoth et al, J Pharmacol Exp Ther 2011;338:372-80 2. Mueck et al, Br J Clin Pharmacol 2013

22. Action to be taken in case of DDIs Three levels of alert: Red contraindicated/not recommended for use Orange adapt NOAC dose dabigatran: 150 mg to 110 mg BID rivaroxaban: 20 mg to 15 mg QD apixaban: 5 mg to 2.5 mg BID Yellow consider dose reduction if two concomitant yellow interactions Where no data available, NOACs not recommended yet 18 www.escardio.org/EHRA

23. Possible drug-drug interactions Effect on NOAC plasma levels part 1 Dabigatran Apixaban Edoxaban Rivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect Digoxin P-gp no effect no data yet no effect no effect Verapamil P-gp/ wk CYP3A4 +12180% no data yet + 53% (slow release) minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect Quinidine P-gp +50% no data yet +80% +50% Amiodarone P-gp +1260% no data yet no effect minor effect Dronedarone P-gp/CYP3A4 +70100% no data yet +85% no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 +140150% +100% no data yet up to +160% 19 www.escardio.org/EHRA Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

24. Possible drug-drug interactions Effect on NOAC plasma levels part 2 Interaction Dabigatran Apixaban Edoxaban Rivaroxaban Fluconazole CYP3A4 no data no data no data +42% Cyclosporin; tacrolimus P-gp no data no data no data +50% Clarithromycin; erythromycin P-gp/ CYP3A4 +1520% no data no data +3054% HIV protease inhibitors P-gp and BCRP/ CYP3A4 no data strong increase no data up to +153% Rifampicin; St Johns wort; carbamezepine; phenytoin; phenobarbital P-gp and BCRP/ CYP3A4/CYP2J2 -66% -54% -35% up to -50% Antacids GI absorption -12-30% no data no effect no effect 20 www.escardio.org/EHRA Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

25. Factors associated with raised plasma levels of NOACs part 3 Dabigatran Apixaban Edoxaban Rivaroxaban Aged 80 years Increased plasma level no data Aged 75 years Increased plasma level no data Weight 60 kg Increased plasma level Renal function Increased plasma level 21 www.escardio.org/EHRA Other increased bleeding risk Pharmacodynamic interactions antiplatelet drugs, NSAIDs Systemic steroid therapy Other anticoagulants Recent surgery on critical organ (brain, eye) Thrombocytopenia (e.g. chemotherapy) HAS-BLED 3 Orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

26. 4. Switching between anticoagulant regimens VKA to NOAC INR <2.0: immediate INR 2.02.5: immediate or next day INR >2.5: use INR and VKA half-life to estimate time to INR <2.5 Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) Low molecular weight heparin (LMWH) Start once UFH discontinued (t =2h). May be longer in patients with renal impairment Start when next dose would have been given NOAC to VKA Administer concomitantly until INR in appropriate range Measure INR just before next intake of NOAC Re-test 24h after last dose of NOAC Monitor INR in first month until stable values (2.03.0) achieved NOAC to parenteral anticoagulant Initiate when next dose of NOAC is due NOAC to NOAC Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Aspirin or clodiprogel to NOAC Switch immediately, unless combination therapy needed 22 www.escardio.org/EHRA

27. 5. Ensuring compliance with NOAC intake Important anticoagulant effect drops rapidly after 12-24 h QD better adherence than BID for cardiovascular drugs in general, but no data on superior dosing scheme for NOAC in clinical practice. Patient education crucial: leaflets and instruction at initiation, patient safety card, group sessions. Involve family members. 23 www.escardio.org/EHRA

28. Ensuring compliance with NOAC intake Nurse-co-ordinated AF centres to focus on compliance? Technological aids medication boxes, smartphone apps. INR monitoring not needed/not useful. Involve pharmacy? If low compliance despite these, consider VKAs. 24 www.escardio.org/EHRA

29. 6. How to deal with dosing errors Missed dose: BID: take missed dose up to 6 h after scheduled intake. If not possible skip dose and take next scheduled dose. QD: take missed dose up to 12 h after scheduled intake. If not possible skip dose and take next scheduled dose. Double dose: BID: skip next planned dose and restart BID after 24 h. QD: continue normal regimen. Uncertainty about intake: BID: continue normal regimen. QD: take another dose then continue normal regimen. Overdose: Hospitalization advised. 25 www.escardio.org/EHRA

30. 7. Patients with chronic kidney disease Dabigatran Apixaban Edoxaban Rivaroxaban CrCl 60 ml/min CKD Stage I & II ~ 14 h 1 no data ~ 8.6 h 2 ~ 8.5 h 3 (+44%) CrCl 3060 ml/min CKD Stage III ~ 18 h 1 no data ~ 9.4 h 2 ~ 9 h 3 (+52%) CrCl 1530 ml/min CKD Stage IV ~ 28 h 1 no data ~ 16.9 h 2 ~ 9.5 h 3 (+64%) CrCl 15 ml/min CKD Stage V no data no data no data no data 26 www.escardio.org/EHRA Estimated t and AUC NOAC plasma concentrations compared to healthy controls 1. Stangier et al, Clinical pharmacokinetics 2010;49:259-68 2. Ridout et al, J Clin Pharmacol 2009:49:1124 3. Kubitza et al, Br J Clin Pharmacol 2010:70:703-2

31. NOACs in renal dysfunction Approved European labels Dabigatran Apixaban Edoxaban Rivaroxaban % of absorbed dose renally excreted 80% 27% 50% 1 35% Bio-availability 3-7% 50% 62% 2 66% without food ~ 100% with food % of administered dose renally excreted 4% 14% 37% 33% Approved for CrCl 30 ml/min 15 ml/min not available 15 ml/min Label dosing recommendation CrCl 15 ml/min, no adjustment (i.e. 150 mg BID) Serum creatinine 1.5 ml/dl, no adjustment (i.e. 5 mg BID) CrCl 50 ml/min, no adjustment (i.e. 20 mg QD) 27 www.escardio.org/EHRA 1. Ogata et al J Clin Pharmacol 2010;50:743-53 2. Matsushima et al The AAPS Journal 2011;13:S2

32. NOACs in renal dysfunction Practical recommendations for dosing in chronic kidney disease Dabigatran Apixaban Edoxaban * Rivaroxaban When CrCl 30-49 ml/min, 150 mg BID is possible (SmPC) but 110 mg BID if high risk of bleeding (SmPC) or recommended (GL update) 1 Note: 75 mg BID approved in US only ** - if CrCl 15-30 ml/min - if CrCl 30-49 ml/min - and other orange factor (e.g. verapamil) CrCl 15-29 ml/min: 2.5 mg BID is possible Serum creatinine 1.5 mg/dl in combination with age 80 years or weight 60 kg (SmPC) or with other yellow factor: 2.5 mg BID not available 15 mg OD when CrCl 15-49 ml/min 28 www.escardio.org/EHRA 1. Camm et al, Eur Heart J 2012;33:2719-47 * No EMA approval yet. Needs update after finalisation of SmPC ** No EMA indication. FDA recommendation based on pharmacokinetics. Carefully consider benefits and risks of this approach Note that 75 mg capsules are not available in Europe for AF indication.

33. NOACs in chronic kidney disease Clinical evidence CKD a risk factor for both thrombo-embolic events and bleeding 1,2 CrCl <60 ml/min may predict increased stroke and systemic embolism 3 In Phase III trials, similar AUCs for reduced doses in patients with decreased renal function as for higher dose in patients with normal renal function 4 Rivaroxaban approved for people with CKD stage IV, with lower dose regimen, but should be used with caution: no trial data available in patients with CrCl 15-30 ml/min Low dose dabigatran (75 mg BID) approved by FDA but not EMA for patients with severe renal insufficiency 29 www.escardio.org/EHRA 1. Olesen et al, N Engl J Med 2012;367:625-35 3. Piccini et al, Circulation 2013;127:169-71 2. Hohnloser et al, Eur Heart J 2012;33:2821-30 4. Mueck et al Clin Pharmacol 2011;50:675-86

34. NOACs in chronic kidney disease Practical suggestions CKD should be considered an additional risk factor for stroke in AF but CKD also increases bleeding risk NOACs are a reasonable choice for anticoagulant therapy in AF patients with mild or moderate CKD NOACs similar benefit/risk ratio to VKAs with rivaroxaban (15 mg QD) in renal impairment (CrCl <50 ml/min). 1 With apixaban, there may be a lower relative bleeding risk 2 30 www.escardio.org/EHRA 1. Fox et al, Eur Heart J 2011;32:2387-94 2. Hohnloser et al, Eur Heart J 2012;33:2821-30

35. NOACs in chronic kidney disease Practical suggestions Dabigatran may not be first choice as primarily cleared renally but may be used in stable patients. FXa inhibitors have 25-50% renal clearance therefore may be preferred Consider dose reductions in patients with CrCl <50 ml/min: apixaban 2.5 mg BID, 1 rivaroxaban 15 mg/day 2 Avoid NOACs in AF patients on haemodialysis: consider VKAs 31 www.escardio.org/EHRA 1. Fox et al, Eur Heart J 2011;32:2387-94 2. Connolly et al N Engl J Med 2011; 364:806-17

36. NOACs in chronic kidney disease Practical suggestions Monitor renal function regularly and adapt the dose accordingly Monitor renal function at the following intervals: 32 www.escardio.org/EHRA yearly stage I-II (CrCl 60 ml/min) 6-monthly stage III, elderly (>75 yrs) or frail patients on dabigatran (CrCl 3060 ml/min) 3-monthly stage IV (CrCl 30 ml/min)

37. 8. What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding Acute recent ingestion of overdose: activated charcoal to reduce absorption (standard dosing scheme for adults of 30 to 50 g). Consider coagulation tests to assess possible bleeding risk. In absence of bleeding, wait-and see approach. 33 www.escardio.org/EHRA

38. 9. Management of bleeding complications Possible measures to take in case of bleeding part 1 Dabigatran FXa inhibitors Inquire last intake + dosing regimen Estimate normalization of haemostasis Normal renal function: 24h CrCl 50-80 ml/min: 24-36h CrCl 30-50 ml/min: 36-48h CrCl <30 ml/min: 48h Maintain diuresis Local haemostatic measures Fluid replacement (colloids if needed) Inquire last intake + dosing regimen Normalisation of haemostasis: 24h Local haemostatic measures Fluid replacement (colloids if needed) 34 www.escardio.org/EHRA Non life-threatening

39. Possible measures to take in case of bleeding part 2 Dabigatran FXa inhibitors RBC substitution if necessary Platelet substitution (in case of thrombocytopenia 60 x 10 9 /L or thrombopathy) Fresh frozen plasma as plasma expander (not as reversal agent) Tranexamic acid can be considered as adjuvans Desmopressin can be considered in special cases (coagulopathy or thrombopathy) Consider dialysis (primary evidence: - 65% after 4h) Charcoal haemoperfusion not recommended (no data) RBC substitution if necessary Platelet substitution (in case of thrombocytopenia 60 x 10 9 /L or thrombopathy) Fresh frozen plasma as plasma expander (not as reversal agent) Tranexamic acid can be considered as adjuvans Desmopressin can be considered in special cases (coagulopathy or thrombopathy) 35 www.escardio.org/EHRA Non life-threatening

40. Possible measures to take in case of bleeding part 3 Dabigatran FXa inhibitors All of the above Prothrombin complex concentrate (PCC) 25 U/g (may be repeated once or twice but no clinical evidence) Activated PCC 50IE/kg; max 200 IE/day: no strong data about additional benefit over PCC. Can be considered before PCC if available Activated factor VII (rFVIIa; 90 g/kg); no data about additional benefit + expensive (only animal evidence) All of the above Prothrombin complex concentrate 25 U/kg (may be repeated once or twice but no clinical evidence) Activated PCC 50IE/kg; max 200 IE/day: no strong data about additional benefit over PCC. Can be considered before PCC if available Activated factor VII (rFVIIa; 90 g/kg); no data about additional benefit + expensive (only animal evidence) 36 www.escardio.org/EHRA Life-threatening

41. Possible measures to take in case of bleeding 37 www.escardio.org/EHRA Van Ryn et al Am J Med 2012;125:417

42. 10. Patients undergoing a planned surgical intervention or ablation Classification of surgical interventions according to bleeding risk Interventions not necessarily requiring discontinuation of anticoagulant Perform procedures at through levels of NOAC. Consider scheduling intervention 18-24 h after last intake and then restart 6 h later (i.e. skipping 1 dose with BID NOAC) Dental interventions Extraction of 1 to 3 teeth Paradontal surgery Incision of abscess Implant positioning Ophthalmology Cataract or glaucoma intervention Endoscopy without surgery Superficial surgery (e.g. abscess incision, small dermatological excision) 38 www.escardio.org/EHRA

43. Classification of surgical interventions according to bleeding risk Low risk Endoscopy with biopsy Prostate or bladder biopsy Electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia (including left sided ablation via single transseptal puncture) Angiography Pacemaker or ICD implantation (unless complex anatomical setting e.g. congenital heart disease) High risk Complex left-sided ablation: pulmonary vein isolation, VT ablation Spinal or epidural anaesthesia; lumbar diagnostic puncture Thoracic surgery Abdominal surgery Major orthopedic surgery Liver biopsy Transurethral prostate resection Kidney biopsy 39 www.escardio.org/EHRA

44. When to stop NOACs before a planned surgical intervention Dabigatran Apixaban Edoxaban * Rivaroxaban No important bleeding risk and/or local haemostasis possible: perform at trough level (i.e. 12h or 24h after last intake) Low risk High risk Low risk High risk Low risk High risk Low risk High risk CrCl 80 ml/min 24h 48h 24h 48h no data yet no data yet 24h 48h CrCl 5080 ml/min 36h 72h 24h 48h no data yet no data yet 24h 48h CrCl 3050 ml/min 48h 96h 24h 48h no data yet no data yet 24h 48h CrCl 1530 ml/min not indicated not indicated 36h 48h no data yet no data yet 36h 48h CrCl <15 ml/min no official indication for use 40 www.escardio.org/EHRA Last intake of drug before elective surgical intervention *no EMA approval yet.; Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding many of these patients may be on the lower dose of dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d).

45. When to restart NOACs after a planned surgical intervention Procedures with immediate and complete haemostasis: Atraumatic spinal/epidural anethesia Clean lumbar puncture Resume 68 h after surgery Procedures associated with immobilization: Procedures with post-operative risk of bleeding: Initiate reduced venous or intermediate dose of LMWH 68 h after surgery if haemostasis achieved. Restart NOACs 4872h after surgery upon complete haemostasis Thromboprophylaxis (e.g. with LMWH) can be initiated 6-8 h after surgery 41 www.escardio.org/EHRA

46. Recommendations for stopping and starting NOACs after AF ablation procedures Limited available data. 1-5 Recommend strategy of bridging (with well-timed preoperative discontinuation, as above: slide 40) and restarting of NOACs. A too aggressively shortened periprocedural cessation of NOACs and/or no bridging may be less safe when compared to continued VKA administration and ablation under an INR between 2.0 and 3.0, both concerning bleeding and cardioembolic complications. 42 www.escardio.org/EHRA 1. Kakkireddy et al, J Am Coll Cardiol 2012; 59:1168-74 4. Winkle et al J Card Electrophysiol 2012; 23:264-8 2. Kaseno et al, Circ J 2012; 76:2337-42 5. Kim et al, Heart Rhythm, 2013 (ePub ahead of print) 3. Snipelisky et al, J Interv Card Electrophysiol 2012; 35:29-33

47. 11. Patients undergoing an urgent surgical intervention Discontinue NOAC. Try to defer surgery at least 12 h and ideally 24 h after last dose. Urgent surgery associated with much higher rates of bleeding than elective procedures, but lower than VKA-treated patients. 1 Coagulation tests can be considered (classical test or specific tests) but strategy based on these results has never been evaluated. Therefore such strategy cannot be recommended and should not be used routinely. 43 www.escardio.org/EHRA 1. Healey et al, Circulation 2012:126;343-8

48. 12. Patients with AF and coronary heart disease Clinical evidence part 1 AF with ST-elevation (STE) or non ST-elevation (NSTE) ACS is associated with higher mortality rates. 1 Thrombotic vs bleeding risk in published trials and cohorts influenced by comorbidities and local practice. Triple therapy with VKA doubles risk of bleeding complications compared with clopidogrel +VKA. 2,3 Triple therapy with double antiplatelet drug therapy (DAPT) and NOACs at least doubles bleeding risk after ACS. 4 Data from RE-LY trial suggests that the advantages of NOAC over VKA in dual or triple therapy are preserved, but no comparative trial data to recommend one over the other. 5 44 www.escardio.org/EHRA 1. Lopes et al Eur Heart J 2009;30:2019-28 2. Sorensen et al, Lancet 2009; 374:1967-74 3. Lamberts et al Circulation 2012:126:1185-93 4. Mega et al, N Engl J Med 2012;366:9-19 5. Dans et al Circulation 2013;127:634-40

49. Patients with AF and coronary heart disease Clinical evidence part 2 No Phase III trial data available for evaluation of NOACs in patients with recent ACS. In a meta-analysis of dabigatran trials, small but significant increased rate of MIs with dabigatran vs VKA (OR 1.33, 95% CI 1.031.71, p=0.03) but without impact on overall net clinical survival benefit 1,2 No excess MI observed in AF trials assessing FXa inhibitors. After ACS, DAPT with apixaban increases major bleeding risk. 3 Low-dose rivaroxaban with DAPT improves ischemic outcome after ACS but increased major bleeding risk. 45 www.escardio.org/EHRA 1. Uchino et al, Arch Intern Med 2012;172:397-402 3. Alexander et al, N Engl J Med 2011;365:699-7082 2. Hohnloser et al Circulation 2012;125:669-76

50. Scenario 1. Recommendations concerning management of AF patients on NOACs who present with an acute coronary syndrome (ACS) part 1 Temporarily discontinue NOACs upon presentation Initiate DAPT therapy unless frail with high bleeding risk Administer low-dose aspirin (150300 mg loading; 75100 mg later) on admission, preferably combined with ADP receptor inhibitor (ticagrelor or prasugrel preferred over clopidogrel) Initiate paraenteral anticoagulation (fondaparinux preferred) 46 www.escardio.org/EHRA

51. Scenario 1. Recommendations concerning management of AF patients on NOACs who present with an acute coronary syndrome (ACS) part 2 In case of STEMI: use primary PCI (radial approach) over fibrinolysis avoid UFH or enoxaparin until NOAC effect disappeared In case of NSTE-ACS: if not urgent, delay coronary angiography until waning of NOAC effect peri-procedural anticoagulation (UFH or bivalirudin preferred) 47 www.escardio.org/EHRA 1. Uchino et al, Arch Intern Med 2012;172:397-402; 2. Alexander et al, N Engl J Med 2011;365:699-708

52. Scenario 1. Recommendations concerning management of AF patients on NOACs who present with an acute coronary syndrome (ACS) part 3 In case of PCI: use radial approach if indicated, balloon angioplasty without stenting use bare metal stents use additional paraenteral anticoagulation periprocedural bivalirudin preferred. Discontinue immediately after PCI avoid glycoprotein IIb/IIIa inhibitors unless bail-out situations 48 www.escardio.org/EHRA

53. Scenario 1. Recommendations concerning management of AF patients on NOACs who present with an acute coronary syndrome (ACS) part 4 In patients requiring revascularization, bypass surgery may be preferred in selected patients. When restarting NOAC consider dose reduction according risk and aim for shortest necessary duration of dual/triple therapy. Newer platelet inhibitors prasugrel and ticagrelor have not been evaluated for NOACs. Recommend awaiting further data before combining these with NOACs. 49 www.escardio.org/EHRA

54. Scenario 2. Recommendations concerning new onset AF in patients with a recent (<1y) ACS part 1 In patients with low atherothrombotic risk, consider VKAs in monotherapy after 1-3 months (6 months in case of recent DES), especially where bleeding risk elevated (HAS-BLED 3). In patients with high GRACE score (> 118), use additional single antiplatelet therapy (clopidogrel preferred) in the first 6 to 12 months after the acute event. 50 www.escardio.org/EHRA

55. Scenario 2. Recommendations concerning new onset AF in patients with a recent (<1y) ACS part 2 If NOAC indicated, consider FXa inhibitor (small and insignificant increased risk of MI for dabigatran, but weigh against clinical benefit). If dabigatran indicated, consider low dose (110 mg BID), in combination with low-dose aspirin or with clopidogrel. Ultra-low dose rivaroxaban in combination with DAPT has not been evaluated in this setting and is not currently recommended. 51 www.escardio.org/EHRA

56. Scenario 3. Recommendations concerning new onset AF in patients with a remote(>1 year ACS) Anticoagulation without additional antiplatelet agents is sufficient for most AF patients with stable CAD. Advantages of NOACs over VKAs likely to be preserved: NOACs may be safe and effective alternatives to VKAs. 1 No preference given to any of NOACs. If using dabigatran, consider lower dose (110 mg BID) plus low-dose aspirin (clopidogrel in case of allergy to aspirin). 2 52 www.escardio.org/EHRA 1. Hohnloser et al, Circulation 2012;125:669-675; 2. Dans et al Circulation 2013;127:634-40

57. 13. Cardioversion in a NOAC treated patient In patients with AF >48h duration undergoing cardioversion, oral anticoagulants should have been given for at least 3 weeks before cardioversion. Continuous oral anticoagulation is mandatory for 4 weeks following cardioversion. Clinical trial data show no significant additional risk in patients treated with NOACs vs. VKAs. 1 If NOAC compliance can be reliably confirmed, cardioversion should be safe. If doubt about compliance, consider prior TEE. 2 53 www.escardio.org/EHRA 1. Nagarakanti et al Circulation 2011;123:131-6; 2. Piccini et al Circulation 2012;126:A19281

58. 14. Patients presenting with acute stroke while on NOACs Acute haemorrhagic stroke Discontinue NOACs. Limited data to support use of aspecific procoagulants e.g. PCC, aPCC and aFVII. Use PCC or fresh frozen plasma as discussed in slides about measures in case of major bleeding. Same poor prognosis as for warfarin. 1 54 www.escardio.org/EHRA 1. Hart et al. Stroke 2012;43:1511-7

59. Patients presenting with acute stroke while on NOACs Acute ischaemic stroke Assess the time window since last intake of NOAC: thrombolytic therapy is associated with increased bleeding risk within 48h of last NOAC dose. In case of uncertainty regarding last dose, prolonged aPTT (dabigatran) or PT (FXa inhibitors) indicates that thrombolysis should not be given. If NOACs have been given within 48h and coagulation tests not available or abnormal, consider recanalization of occluded vessels. 55 www.escardio.org/EHRA

60. Stroke patients Management of post-acute phase Haemorrhagic stroke If cardioembolic risk high and risk of new haemorrhage low, restart NOACs 10-14 days after intracerebral haemorrhage. For patients with low cardioembolic risk and high bleeding risk, carefully consider reinintiation of NOACs: contraindicated unless bleeding risk has been reversed. Consider non pharmacological strategies instead of NOACs (e.g. ablation or occlusion of the atrial appendage). Mechanical thrombectomy without thrombolysis: no restrictions. 56 www.escardio.org/EHRA

61. Stroke patients Management of post-acute phase Ischaemic stroke If infarct size not expected to increase risk of secondary intracerebral bleeding, re-initiate: - in patients with TIA after 1 day - small, non-disabling infarct after 3 days - large infarcts not before 2 weeks TIA of cardioembolic origin (Re)start NOACs as soon as possible. Bridging with LMWH not required. In AF patients not suitable for VKAs, apixaban is superior to aspirin in stroke prevention. 1 57 www.escardio.org/EHRA 1. Connolly et al, N Engl J Med 2011;364:808-17

62. Stroke patients Management of post-acute phase Ischemic stroke of cardioembolic origin Initiation of NAOCs depends on infarct size and risk of new embolic stroke. Bridging with LMHW not required. Aspirin is not useful in secondary stroke prevention. Patients with AF and significant carotid stenosis Carotid endarterectomy and not stenting recommended to avoid triple therapy. 58 www.escardio.org/EHRA

63. 15. NOACs vs VKAs in AF patients with a malignancy Patients with malignancies are at increased risk for thromboembolic events: tumours may secrete prothrombotic factors or induce inflammatory responses. Cancer therapy inflicts bleeding risks through surgery, tissue damage (irradiation) or myelosuppression. Many malignancies are associated with increased risk of mucosal bleeding. Chemotherapy causes myelosuppression (leucopenia/ reduced platelet count). This also reduces red blood cells and therefore reduces safety margin in a bleeding event. 59 www.escardio.org/EHRA

64. NOACs in patients with cancer Practical suggestions part 1 Multidisciplinary care by cardiologist and oncologist. When new anticoagulant initiation is needed, consider VKA over NOACs: more clinical experience and reversal options, although INR is difficult to manage. Malignancy in patients with AF increases stroke risk. If already on stable NOAC treatment: continue unless contraindications, i.e. switch to VKA not mandatory. 60 www.escardio.org/EHRA

65. NOACs in patients with cancer Practical suggestions part 2 No additional anticoagulant therapy (e.g. LMHW) is needed if NOACs are used. In patients receiving moderately myelosuppressive therapies, NOACs may be continued. In patients undergoing tumour surgery, same principles apply as in elective surgery. Consider therapy-induced changes in organ function and adapt dose if indicated. 61 www.escardio.org/EHRA

66. NOACs in patients with cancer Practical suggestions part 3 In patients undergoing myelosuppressive chemotherapy or radiation therapy, consider temporary dose reduction or cessation of NOACs. Monitor blood counts, bleeding signs and liver and renal function. Consider gastric protection with PPI or H2 blockers in all patients treated with NOACs. Patients on NOACs should be instructed to monitor signs of bleeding (petechiae, haemoptysis, black stools) and to contact therapy centre if these develop. 62 www.escardio.org/EHRA

67. Special thanks to: the Alliance Bristol-Myers Squibb / Pfizer Bayer HealthCare Pharmaceuticals Boehringer Ingelheim Daiichi Sankyo Europe GmbH Special thanks to: AER (Arrhythmia & Electrophysiology Review) a Journal produced by Radcliffe Cardiology ( Lifelong Learning for Cardiovascular Professionals) for their contribution to the creation of this slide set www.escardio.org/EHRA