1. Qualcosa di nuovo in Cardiologia Dott. Sergio Agosti Dirigente Medico SOC Cardiologia Ospedale Novi Ligure FA e NAO: dai trials alla pratica clinica? Seminario Arcivescovile di Vercelli, 26-27 Febbraio 2016

2. ➢ A new drug comes to the market. Compared to NAOs, the new drug has: - cheaper - antidote - requirement for monthly monitoring to adjust dose - many food and drug interactions - 25% increased relative risk of stroke/systemic embolism - nearly 50% increased relative risk of major bleeding - approx. 2.5 times the rate of ICH - 10% increased relative risk of mortality ➢ Would Warfarin be approved by regulatory authorities now? Assume that NAOs have been on the market for 5 year WOULD WARFARIN BE APPROVED TODAY?

3. Lancet, published online December 4, 2013

4. STROKE OR SYSTEMIC EMBOLISM Ruff CT, Lancet, December 4, 2013 NNT 173

5. MAJOR BLEEDING Ruff CT, Lancet, December 4, 2013

6. EFFICACY AD SAFETY SECONDARY ENDPOINTS ICH NNT 141 Ruff CT, Lancet, December 4, 2013

7. Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014 Haemorrhagic stroke 60% RRR

8. "The unthinkable has become conceivable” David Baltimore

9. Mackmann, Anesth Analg. 2009 May; 108(5):1447-52 The role of tissue factor and factor VIIa in hemostasis. Haemorrhagic stroke (TF receptor)

10. J Thromb Thrombolysis, 2013

11. Thrombin generation profiles: Plasma samples from patients on warfarin were pooled to yield an INR value of 2.6. the pooled plasma was then diluited with PNP to create plasma pools with a range of INR values.

12. Dabigatran was added to PNP. The thrombin generation profile for PNP is shown on each plot for comparison.

13. Circulation. 2015;132:517-525

14. OAC No Thp AT Circulation. 2015;132:517-525

15. Antidoto

16. Idarucizimab Circulation. 2015;132:2412-2422

17. In which patients  Elderly patients  Patients with renal insufficiency  Patients with valvular atrial fibrillation

18. NOA in Elderly Patients

25. NAO vs Warfarin nei pazienti > 75 anni MAJOR BLEEDING J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults: evidence from a meta-analysis of randomized trials. Sardar P, Lip G.

26. NAO vs Warfarin nei pazienti > 75 anni INTRACRANIAL BLEEDING La Brooy et al. Australian Journal of Pharmacy 2015, 96; 91-95

27. NAO vs Warfarin nei pazienti > 75 anni STROKE OR SE J. Am Geriatr. Soc. 2014 May; 62: 857-64. NAO in elderly adults: evidence from a meta-analysis of randomized trials. Sardar P, Lip G.

28. NOA in Patients with Renal Insufficiency

29. Chronic kindney disease is common among AF patients Kooiman et al. J Thromb Haemost 2011;9:1652–3

30. Chronic kindney disease increases the risk of stroke, bleeding, and all-cause death in AF patients Olesen et al. N Engl J Med 2012;367:625–35.

31. NOA are eliminated from the body via multiple routes

32. NAO vs Warfarin nei pazienti con IR moderata MAJOR BLEEDING Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials. Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.

33. NAO vs Warfarin nei pazienti con IR moderata STROKE OR SE Novel Oral Anticoagulants in Patients With Renal Insufficiency: A Meta-analysis of Randomized Trials. Partha Sardar et al, Can. J Cardiol. 2014; Aug, 30: 888-97.

34. Raccomandazioni dell’ESC nei pazienti con IR

35. Raccomandazioni dell’EHRA nei pazienti con IR (2015)

36. NOA in Patients with Valvular Atrial Fibrillation

37. Updated EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with NVAF: Heidbuchel, August 31, 2015 Definition of non valvular atrial fibrillation (NVAF)

38. NAO in numeri…. 180000 pz nei trials Oltre 18 milioni di pz trattati nel mondo 7000 articoli - studi clinici (PUBMED) Almeno 300000 pz nei registri

39. Real world data

40. Due importanti problemi nell’interpretazione dei dati provenienti dal mondo reale (registri e studi osservazionali) Selection bias Prescrizione inappropriata

42. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)www.fda.gov/Drugs/DrugSafety/ucm396470.htm Incidence rate per 1000 person- years Adjusted HR (95% CI) DabigatranWarfarin Ischaemic stroke11.313.90.80 (0.67-0.96) Intracranial haemorrhage3.39.60.34 (0.26-0.46) Major gastrointestinal bleeding 34.226.51.28 (1.14-1.44) Acute myocardial infarction15.716.90.92 (0.78-1.08) Mortality32.637.80.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Medicare analysis: results

43. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)www.fda.gov/Drugs/DrugSafety/ucm396470.htm Incidence rate per 1000 person- years Adjusted HR (95% CI) DabigatranWarfarin Ischaemic stroke11.313.90.80 (0.67-0.96) Intracranial haemorrhage3.39.60.34 (0.26-0.46) Major gastrointestinal bleeding 34.226.51.28 (1.14-1.44) Acute myocardial infarction15.716.90.92 (0.78-1.08) Mortality32.637.80.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Medicare analysis: results

44. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)www.fda.gov/Drugs/DrugSafety/ucm396470.htm Incidence rate per 1000 person- years Adjusted HR (95% CI) DabigatranWarfarin Ischaemic stroke11.313.90.80 (0.67-0.96) Intracranial haemorrhage3.39.60.34 (0.26-0.46) Major gastrointestinal bleeding 34.226.51.28 (1.14-1.44) Acute myocardial infarction15.716.90.92 (0.78-1.08) Mortality32.637.80.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Medicare analysis: results

45. Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Warfarin is the reference group. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; Available at: www.fda.gov/Drugs/DrugSafety/ucm396470.htm (accessed May 2014)www.fda.gov/Drugs/DrugSafety/ucm396470.htm Incidence rate per 1000 person- years Adjusted HR (95% CI) DabigatranWarfarin Ischaemic stroke11.313.90.80 (0.67-0.96) Intracranial haemorrhage3.39.60.34 (0.26-0.46) Major gastrointestinal bleeding 34.226.51.28 (1.14-1.44) Acute myocardial infarction15.716.90.92 (0.78-1.08) Mortality32.637.80.86 (0.77-0.96) Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin. Risk of MI was similar for dabigatran and warfarin. Medicare analysis: results

47. Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS 2 Prior stroke # ROCKET AF 1 3.555% XANTUS 2 2.019% # Includes p rior stroke, SE or TIA; *Events per 100 patient-years 1.Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

48. Conclusions The efficacy and major bleeding results of NOA vs warfarin were consistent NOA have benefits over warfarin that are maintained irrespective of age NOA real world data are consistent NOA have benefits over warfarin that are maintained irrespective of renal function

49. Karl Link 1941

50. GRAZIE PER L’ATTENZIONE