H Θέση της απιξαμπάνης στην διαχείριση του θρομβοεμβολικού κινδύνου ασθενών με Μη Βαλβιδική Κολπική Μαρμαρυγή Η πλευρά του Κλινικού Καρδιολόγου

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1 H Θέση της απιξαμπάνης στην διαχείριση του θρομβοεμβολικού κινδύνου ασθενών με Μη Βαλβιδική Κολπική Μαρμαρυγή Η πλευρά του Κλινικού Καρδιολόγου Xάρης Γράσσος ΜD,FESC,PhD, EHS Διευθυντής Καρδιολόγος Γ.Ν.Α ΚΑΤ Yπεύθυνος Τμήματος Προληπτικής Καρδιολογίας O.E EKE 2018

2 Declaration of Interest I have receveid travel expenses or Research Grant or honoraria from the following : Elpen, Menarini, Novartis, Bayer, Pfizer, Amgen

3 THE NAME GAME!!!! NOAC TSOAC NOVEL ORAL ANTICOAGULANT NON-VITAMIN K ORAL ANTICOAGULANT TARGET SPECIFIC ORAL ANTICOAGULANT DOAC DIRECT ORAL ANTICOAGULANT

4 Timeline of Oral Anticoagulant Development FDA approval of warfarin Rivaroxaban approved for NVAF Dabigatran and rivaroxaban approved for DVT/PE Dabigatran approved for NVAF Apixaban approved for NVAF and DVT/PE & rivaroxaban approved for DVT/PE Edoxaban approved for NVAF, DVT/PE Silva, R. NOACs in NVAF. Cardiovascular and Hematological Agents in Medicinal Chemistry Accessed March 1, 2017

5 Trends in Oral Anticoagulant Use Barnes, et al. National Trends in Ambulatory Oral Anticoagulant Use. Am J Med. 2015:128,

6 Guideline Guidelines Support Using DOACs American College of Chest Physicians Guideline and Expert Panel Report: Antithrombotic Therapy for VTE Disease 2016 European Society of Cardiology Guidelines for the management of atrial fibrillation Recommendations In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC (apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in preference to a Vitamin K antagonist (Class IA). Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report. CHEST. 2016; 149(2): ESC Guidelines for the Management of Atrial Fibrillation. Eur Heart J

7 D(N)OACs vs. Warfarin Imagine if the NOACS had been established therapy FDA for some 6 decades and a new drug appeared that: Was unpredictable in terms of patient therapeutic response Had slow therapeutic onset and offset Had a narrow therapeutic window Required close monitoring via frequent blood tests Required frequent dose adjustment Had numerous drug-drug and drug-food interactions Was associated with more intracranial haemorrhage Resulted in a 10% increase in mortality

8 Without preventive treatment, each year approximately 1 in 20 patients (5%) with AF will have a stroke AF related strokes are more severe

9 IDEAL (N)DOAC θρομβωτικός κίνδυνος αιμορραγικός κίνδυνος Ισορροπώντας το θρομβωτικό με τον αιμορραγικό κίνδυνο στον ασθενή με μη βαλβιδική κολπική μαρμαρυγή

10 Τα NOACs είναι πιο αποτελεσματικά Ruff CT, et al. Lancet 2014;383:955 62

11 Aλλά υπάρχει και Ασφάλεια!!!! Ruff CT, et al. Lancet 2014;383:955 62

12 Granger C et al., N Engl J Med 2011;365:981-92

13 Το Apixaban υπερέχει έναντι της βαρφαρίνης και στις 3 ακόλουθες εκβάσεις. Ποσοστό Συμβαμάτων (% / έτος) Ανώτερη πρόληψη ΑΕΕ/ ΣΕ 21% RRR p=0.01 Ανώτερο προφίλ ασφαλείας στη μείωση του κινδύνου μείζονος αιμορραγίας 31% RRR p<0.001 Ανώτερη στη μείωση της θνησιμότητας από οποιοδήποτε αίτιο 11% RRR p= % 265/ % 212/ % 462/ % 327/ % 669/ % 603/9120 Πρωτεύον τελικό σημείο αποτελεσματικότητας Πρωτεύον τελικό σημείο ασφάλειας Βασικό δευτερεύον τελικό σημείο Διάμεση διάρκεια παρακολούθησης 1.8 έτη Γράφημα βάσει δεδομένων από Granger et al. N Engl J Med 2011;365: Apixaban Βαρφαρίνη (στόχος INR ) EU API315

14 Clinical special settings High Stroke risc High bleeding risk Elderly Hypertensive pts Quality of Life EU API315

15 EU API315 High Stroke Risk Patients

16 ARISTOTLE in previous stroke/tia pts EU API315 Granger C, et al. NEJM 2011

17 EU API315 High Bleeding Risk Patients

18 ISHT bleeding in ARISTOTLE EU API315 Lopes R, et al. Lancet 2012

19 Intracranial bleeding in ARISTOTLE EU API315 Lopes R, et al. Lancet 2012

20 Antithrombotic Therapy in AF: GI Bleeding EU API315 Clinical trial results demonstrate a lower risk for GI bleeding for Apixaban compared with warfarin Connolly et al, N Eng J Med 2009, Patel et al, N Eng J Med 2011, Granger et al, N Eng J Med 2011

21 EU API315 Elderly Patients

22 Stroke risk in AF is a dynamic process. EU API315

23 ARISTOTLE and elderly EU API315 Halvorsen S, et al. EHJ 2014

24 Apixaban in Elderly Adults-octogenarians EU API315 The benefits of apixaban are consistent in pts with AF regardless of age S. Halvorsen et al. European Heart Journal 2014

25 EU API315 Hypertensive pts

26 Patients with hypertension, % Prevalence of Hypertension in AF Trials 90 AF populations

27 Subclinical Atrial Fibrillation and Risk of Stroke Asymptomatic AF and stroke evaluation in pacemaker hypertensive patients in the ASSERT trial Outcome Hazard ratio 95% CI p Clinical AF <0.001 Ischemic stroke or systemic embolism Ischemic stroke or systemic embolism after adjustment for stroke predictors Healey JS et al. N Engl J Med 2012;366:178

28 The Unappreciated Role of HTN in AF Trials Manolis AJ et al. J Hypertens 2013;31:2109

29 The Unappreciated Role of HTN in AF Trials Manolis AJ et al. J Hypertens 2013;31:2109

30 ARISTOTLE: Poorly Controlled BP Greatly Increased Risk for Stroke in Patients with AF Of the pts enrolled in ARISTOTLE 87.5% had a history of HTN Poorly controlled HTN was independently associated with a 50% higher risk of stroke Patients with uncontrolled BP during the trial were at greater risk for major bleeding (HR=1.14%), and any bleeding (HR=1.11%) Meena Rao et al. ACC March 29,2014 Abs Dec 2012

31 Optimal Blood Pressure in Patients with AF: The AFFIRM Trial Badheka AO et al. Am J Cardiol 2014;114:727

32 In this analysis, the benefits of apixaban when compared with warfarin in reducing stroke or SE,mortality,and major bleending were consistent regardless of a history of hypertension.

33 Head to Head Trials..

34 EU API315 Real world Data???

35 Real world Data!!!! Data source Examples Patient selection Phase IV studies Societal registries Industry sponsored registries Nationwide cohorts Insurance claims datasets EU API315 XANTUS EORP-AF PINNACLE ORBIT-AF GARFIELD -AF GLORIA Danish Taiwan Medicare, US DoD, Truven MarketSca n, Optum Insight Informed consent Informed consent Informed consent All All Data quality Data amount Outcomes Other features ecrf Prespecified Adjudicated Prospective design ecrf Prespecified Investigator reported ecrf Diagnostic codes Disease codes Prespecified, extensive Investigator reported Independen t registries Detailed, extensive information Limited Data linking Rapid data collection, large N of pts Limited Data linking Rapid data collection, large N of pts

36 EU API315

37 EU API315

38 EU API315 Consistency of apixaban in all studies

39

40 FORTA CLASSIFICATION OF DOACs EU API315 40

41 FORTA CLASSIFICATION OF DOACS EU API315 41

42 EU API315 The ARISTOTLE example more than 40 published sub-analyses to day

43 Does our choices affect outcome???

44 Ευχαριστώ!!!!