1. Γεώργιος Ντάιος Παθολογική Κλινική Πανεπιστημίου Θεσσαλίας Κλινικές περιπτώσεις με μη βαλβιδική κολπική μαρμαρυγή

2. Disclosures Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis. Honoraria: Medtronic; Quintiles; Boehringer-Ingelheim. Speaker fees/Advisory Boards: Sanofi; Boehringer-Ingelheim; Galenica; Elpen; Bayer; Winmedica; BMS/Pfizer; Amgen Research support: European Union (Horizon 2020); BMS/Pfizer (ERISTA)

3. Our patient ♂, 89yrs Arterial hypertension on amlodipine HbA1c: 7.9% on metformin eGFR: 44ml/min Diastolic heart failure Atrial fibrillation on vit-K antagonist Frequent INR monitoring Frequent dose adjustments Drug and drug interactions Food and drug interactions

4. “Too old for this? “ “Too old for this? “

5. Primary endpoint: Stroke/SE HR : 0.80 (0.63–1.02) 0 1 2 3 4 5 6 0 612 18 24 Months from randomization 2.85%/yr 2.29%/yr Estimated cumulative probability of stroke/SE (%) Warfarin ≥75 years Rivaroxaban ≥75 years

6. “Too old for this? “ “Too old for this? “ Age ≥75 years (%/year) RivaroxabanWarfarin Major bleeding4.864.40 ICH0.660.83

7. “What about my renal failure? “ “What about my renal failure? “

8. Primary endpoint: Stroke/SE 0 1 2 3 4 5 6 2.8%/yr 2.3%/yr HR: 0.84 (0.57–1.23) Cumulative event rate (%) 0 120 240480600720840360 Days from randomization Warfarin CrCl 30–49 mL/min Rivaroxaban CrCl 30–49 mL/min

9. “What about my renal failure? “ “What about my renal failure? “ Events (%/year) HR 0.55 (95% CI 0.30–1.00) HR 0.39 (95% CI 0.15–0.99) Warfarin Rivaroxaban 15 mg OD 0.8 0.7 0.9

10. “What about my diabetes? “ “What about my diabetes? “

11. HR: 0.74 (0.54–1.01) Days from randomization 0 120 0.05 840 Cumulative event rate 0.04 0.03 0.02 0.01 0 240360480600720 Primary endpoint: Stroke/SE 1.59%/yr 2.15%/yr Warfarin with DM Rivaroxaban with DM

12. “What about my diabetes? “ “What about my diabetes? “

13. “What about my heart failure? “ “What about my heart failure? “

14. Primary endpoint: Stroke/SE (ITT) HR: 0.91 (0.74–1.13) 0 0.01 0.02 0.03 0.04 0.05 0 840 120 360 600720 Rivaroxaban with HF Days from randomization Cumulative event rate (%) 240 480 2.10%/yr 1.90%/yr Warfarin with HF

15. “What about my heart failure? “ “What about my heart failure? “ With HF (%/year) Riva.Warf. Major/NMCR bleeding 14.2214.02 Haemorrhagic stroke 0.160.43 Intracranial haemorrhage 0.400.65

16. “OK, but too many co-morbidities…“ “OK, but too many co-morbidities…“ ≤123–6CHADS 2 score

17. “OK, but too many co-morbidities…“ “OK, but too many co-morbidities…“

20. “OK, but does it really work ?“ “OK, but does it really work ?“

21. CHADS 2 ROCKET AF3.5 XANTUS2.0 XANTUS vs. ROCKET AF

22. Bleeding events per CHADS 2 group Mean CHADS 2 score Major bleeding event rate/year Randomized clinical trial ROCKET AF 1* n=7111 3.6% 3.0% 2.9% 2.1% Prospective registry Dresden NOAC 2# n=1200 3.5 2.2 2.4 2.0 Retrospective database US DoD PMSS 3‡ n=27,467 Observational study XANTUS 4* n=6784

23. “OK, but which dose?“ “OK, but which dose?“

24. Switch from VKA to NOACs Heidbuchel et al. Europace 2015

26. Interventions in anticoagulated patients: not rare

27. Pre-operative discontinuations of NOACs Heidbuchel. European Heart Journal 2013

28. Postoperative resumption of NOACs Heidbuchel. European Heart Journal 2013

30. Acute endovascular treatment - thrombectomy

31. Andexanet: an antidote for Xa inhibitors

32. Last intake of Rivaroxaban <24 hours Within 4.5 hours after onset ? Mechanical thrombectomy Andexanet alpha / ciraparantag IV rt-PA Anti-Xa assays prolonged Within 6 hours after onset? Arterial occlusion accessible by mechanical thrombectomy in CTA ? Yes No No attempt for recanalization Yes Last intake of Rivaroxaban not known No Yes No

33. Anticoagulation after AF-stroke: how soon (or late?)

34. The 1-3-6-12 rule TIA  1 day Small infarct  3 days Moderate infarct  6 days Large infarct  12 days

35. NOACs could be the answer? Ruff et al. Lancet 2013

37. Restart OAC after AF/OAC-related ICH Nielsen et al. Circulation 2015

38. Restart OAC after AF/OAC-related ICH Nielsen et al. Circulation 2015

39. NOAC vs. VKA: Intracranial haemorrhage Ruff et al. Lancet 2013

40. Take-home messages Rivaroxaban has similar effect across subgroups Switch VKAs to NOACs Interruption of NOACs for elective procedures Andexanet alpha is around the corner Recanalization techniques in anticoagulated acute-stroke patients Anticoagulation after ischemic stroke: how soon? Anticoagulation after intracerebral haemorrhage