Ο ΡΟΛΟΣ ΤΗΣ ΕΞΑΤΟΜΙΚΕΥΣΗΣ ΣΤΗΝ ΕΠΙΛΟΓΗ ΑΝΤΙΠΗΚΤΙΚΗΣ ΑΓΩΓΗΣ

«Η ΠΡΟΣΤΙΘΕΜΕΝΗ ΑΞΙΑ ΤΟΥ APIXABAN ΣΤΗΝ ΔΙΑΧΕΙΡΙΣΗ ΑΣΘΕΝΩΝ ΜΕ ΜΗ ΒΑΛΒΙΔΙΚΗ ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ» Ο ΡΟΛΟΣ ΤΗΣ ΕΞΑΤΟΜΙΚΕΥΣΗΣ ΣΤΗΝ ΕΠΙΛΟΓΗ ΑΝΤΙΠΗΚΤΙΚΗΣ ΑΓΩΓΗΣ Παναγιώτης Ιωαννίδης Διευθυντής Τμήματος Αρρυθμιών & Επεμβατικής Ηλεκτροφυσιολογίας Βιοκλινικής Αθηνών Δορυφορικό Συμπόσιο ΠΑΝΕΛΛΗΝΙΑ ΣΕΜΙΝΑΡΙΑ ΟΜΑΔΩΝ ΕΡΓΑΣΙΑΣ Ιωάννινα, 12-2-2016

New era in the treatment of atrial fibrillation

Summary of the clinical trials of the non-vkas compared with warfarin Ziff et al. Am Heart J 2016;173:143-158

How to define non-valvular atrial fibrillation?

Exclusion criteria related to valve disease in phase III trials with NOACs in AF Study drug How to define non-valvular atrial fibrillation? Study Year of publication Atrial fibrillation exclusion criteria related to valve disease Apixaban AVERROES 1,2 2011 Valvular disease requiring surgery, prosthetic mechanical heart valve Apixaban ARISTOTLE 3,4 2011 Clinically significant (moderate or severe) mitral stenosis, prosthetic mechanical heart valve Dabigatran RE-LY 5,6 2009 History of heart valve disorder (including haemodynamically relevant valve disease and prosthetic valve) Rivaroxaban ROCKET-AF 7 2011 Haemodynamically significant mitral valve stenosis, prosthetic heart valve Edoxaban ENGAGE-AF-TIMI 48 8,9 2013 Moderate or severe mitral stenosis, unresected atrial myxoma, mechanical heart valve Betrixaban EXPLORE-Xa 10 2013 Prosthetic mechanical heart valve 1 Connolly et al. NEJM 2011;364:806-817 2 Eikelboom et al. Am Heart J 2010;159:348e1-3530e 3 Granger et al. NEJM 2011;365:981-92 4 Lopes et al. Am Heart J, 2010;159:331-339 5 Connolly et al. NEJM 2009;361:1139-1151 6 Ezekowitz et al. Am Heart J 2009;157:805-810 [10e1-2] 7 Patel et al. NEJM 2011;365:883-891 8 Giugliano and Ruff et al. NEJM 2013;369:2093-2104 9 Ruff et al. Am Heart J 2010;160:635-641 10 Connolly et al. Eur Heart J 2013;34:1498-1505

Pivotal NVAF NOAC trials Patients with concomitant VHD ARISTOTLE 1,2 (N=18,201) ROCKET-AF 3,4 (N=14,171) RE-LY 5,6 (N=18,113) No. of enrolled NVAF patients with concomitant VHD, n (%) 4808 (26.4%) 2003 (14.1%) 3950 (21.8%) LESION TYPES IN PATIENTS WITH CONCOMITANT VHD, n (%) Mitral regurgitation 3526 (73.3%) 1756 (89.6%) 3101 (78.5%) Aortic regurgitation 887 (18.4%) 486 (24.8%) 817 (20.7%) Aortic stenosis 384 (8.0%) 215 (11.0%) 471 (11.9%) Mitral stenosis (mild) 131 (2.7%) 193 (4.9%) Tricuspid regurgitation 2124 (44.2%) 1179 (29.8%) Other lesions Prior valve surgery: 251 (5.2%) 106 (5.3%) had other valve procedures including valvuloplasty or valvotomy NOAC, non-vitamin K antagonist oral anticoagulant; NVAF, non-valvular atrial fibrillation; VHD, valvular heart disease 1. Granger C et al. N Engl J Med 2011;365:981 992; 2. Avezum A et al. Circulation 2015;132:624 632; 3. Patel MR et al. N Engl J Med 2011;365:883 891; 4. Breithardt G et al. Eur Heart J 2014;35:3377 3385; 5. Connolly S et al. N Engl J Med 2009;361:1139-1151; 6. Ezekowitz M et al. J Am Coll Cardiol 2014;63(12_S). doi:10.1016/s0735-1097(14)60325-9

26.4% of patients in ARISTOTLE trial had a history of moderate or severe valvular heart disease or previous valve surgery Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease Avezum et al. Circulation. 2015;132:624-632

Pivotal NVAF NOAC trials Efficacy in patients with concomitant VHD TRIAL STROKE / SYSTEMATIC EMBOLISM HR (95% CI) INTERACTION P-VALUE APIXABAN 1 0.38 ARISTOTLE No VHD VHD RIVAROXABAN 2 0.76 ROCKET-AF No VHD VHD DABIGATRAN 150 mg 3 NS No VHD RE-LY VHD DABIGATRAN 110 mg 3 NS No VHD VHD 0.5 1 < NOAC better Warfarin better > 2 Adapted from Avezum A et al. Circulation 2015; Breithardt G et al. Eur Heart J 2014; Ezekowitz M et al. J Am Coll Cardiol 2014 HEAD-TO-HEAD STUDIES DO NOT EXIST, AND DIRECT COMPARISONS BETWEEN AGENTS MAY NOT BE MADE CI, confidence interval; HR, hazard ratio; NOAC, non-vitamin K antagonist oral anticoagulant; NS, not significant; NVAF, non-valvular atrial fibrillation; VHD, valvular heart disease 1. Avezum A et al. Circulation 2015;132:624 632; 2. Breithardt G et al. Eur Heart J 2014;35:3377 3385; 3. Ezekowitz M et al. J Am Coll Cardiol 2014;63(12_S). doi:10.1016/s0735-1097(14)60325-9

Pivotal NVAF NOAC trials Safety in patients with concomitant VHD TRIAL MAJOR BLEEDING HR (95% CI) INTERACTION P-VALUE APIXABAN 1 0.3 ARISTOTLE No VHD VHD RIVAROXABAN 2 0.01 ROCKET-AF No VHD VHD DABIGATRAN 150 mg 3 NS No VHD RE-LY VHD DABIGATRAN 110 mg 3 NS No VHD VHD 0.5 1 < NOAC better Warfarin better > 2 Adapted from Avezum A et al. Circulation 2015; Breithardt G et al. Eur Heart J 2014; Ezekowitz M et al. J Am Coll Cardiol 2014 HEAD-TO-HEAD STUDIES DO NOT EXIST, AND DIRECT COMPARISONS BETWEEN AGENTS MAY NOT BE MADE CI, confidence interval; HR, hazard ratio; NOAC, non-vitamin K antagonist oral anticoagulant; NS, not significant; NVAF, non-valvular atrial fibrillation; VHD, valvular heart disease 1. Avezum A et al. Circulation 2015;132:624 632; 2. Breithardt G et al. Eur Heart J 2014;35:3377 3385; 3. Ezekowitz M et al. J Am Coll Cardiol 2014;63(12_S). doi:10.1016/s0735-1097(14)60325-9

NOACs: Why not in mechanical valves?

Phase II dose-validation study Patients with aortic- or mitralvalve replacement within the past 7 days (Population A) and Pts with replacement 3 months (Population B) 2:1 randomization to dabigatran or warfarin Eikelboom et al. N Engl J Med 2013;369:1206-14

NOACs: Why not in mechanical valves? Anticoagulant Mechanisms of Action

NOACs in VHD: EHRA Recommendations 2015 Updated EHRA Practical Guide on the use of non-vka anticoagulants in patients with NVAF. Europace 2015;17:1467 1507

CHA 2 DS 2 VASc score and stroke rate 2010 ESC Guidelines for the management of AF. EHJ 2010;31:2369-2429

Risk of bleeding 2010 ESC Guidelines for the management of AF. EHJ 2010;31:2369-2429

2012 focused update of the ESC Guidelines for the management of AF Camm et al. EHJ 2012;33:2719-2747

PREVENTION OF THROMBOEMBOLISM Prevention of thromboembolism in patients with CHA2DS2-VASc Score 1 January et al. JACC 2014;64(21):e1-76

Defining The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation Net Clinical Benefit = ( TE rate 1.5 off warfarin TE rate 0.5 on warfarin ) Weight 1.5 X ( ICH rate 0.65 on warfarin ICH rate 0.05 off warfarin ) TE: Thromboembolic Events ICH: Intracranial Hemorrhages Rate: annual event rate % = Warfarin effective if annual TE rate 1.5 0.1 = Singer et al Ann Intern Med. 2009;151:297-305

New agent safe if Annual Stroke rate 0.9% Warfarine safe if Annual Stroke rate 1.7% Warfarin is preferred above a stroke rate of 1.7% per year Anticoagulation with a new, safer agent, leads to a lowering of the threshold for anticoagulation to a stroke rate of 0.9% per year Eckman et al. Circ Cardiovasc Qual Outcomes 2011;4:14-21.

Λόγος Πιθανοτήτων Οι περιορισμοί στη θεραπεία με ανταγωνιστές βιταμίνης Κ 20 15 Κίνδυνος ΑΕΕ Κίνδυνος ενδοκράνιας αιμορραγίας ΑΕΕ Ενδοκράνια Αιμορραγία 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR 1. Fuster V et al. J Am Coll Cardiol 2001;38:1231 1265 2. Hylek E and Singer D Ann Intern Med 1994;120:897 902 3. Hylek E et al. N Eng J Med 1996;335:540 546

Azoulay et al. European Heart Journal 2014;35:1881-87

Procoagulant Effect of Early Doses of Warfarin?

Stroke & Mortality outcomes with varying levels of INR control Comparison with non treated patients Stroke Warfarin control CHADS 2 score 2 CHADS 2 score = 1 All cases (CHADS 2 score 0-6) Stroke Exp(B) 95% CI p Exp(B) 95% CI p Exp(B) 95% CI p 0 30% 1.468 (0.844-0.174 1.770 (1.088-0.022 1.780 (1.293-0.000 2.551) 2.879) 2.452) 31 40% 1.215 (0.767-0.407 1.826 (1.160-0.009 1.584 (1.186-0.002 1.926) 2.873) 2.114) 41 50% 0.933 (0.628-0.729 1.718 (1.202-0.003 1.273 (.998-0.052 1.385) 2.455) 1.625) 51 60% 0.837 (0.554-0.399 0.834 (0.511-0.467 0.942 (.719-0.667 1.265) 1.361) 1.235) 61 70% 0.608 (0.335-0.103 0.466 (0.237-0.027 0.781 (.560-0.146 1.105) 0.915) 1.089) 71 100% 0.203 (0.050-0.820) 0.025 0.295 (0.073-1.193) 0.087 0.585 (.343-1.000) 0.050 Mortality CHADS2 score 2 CHADS2 score = 1 All cases (CHADS2score 0-6) 0 30% 1.259 (0.895-1.769) 31 40% 0.764 (0.543-1.076) 41 50% 0.653 (0.495-0.863) 51 60% 0.542 (0.405-0.725) 61 70% 0.231 (0.133-0.403) 71 0.201 (0.090-100% 0.451) 0.185 1.101 (0.828-1.463) 0.123 0.893 (0.670-1.189) 0.003 0.580 (0.451-0.747) 0.000 0.425 (0.318-0.569) 0.000 0.304 (0.211-0.440) 0.000 0.272 (0.146-0.509) 0.508 1.218 (1.006-1.474) 0.438 0.810 (0.666-0.985) 0.000 0.635 (0.539-0.747) 0.000 0.470 (0.393-0.562) 0.000 0.294 (0.229-0.377) 0.000 0.266 (0.184-0.385) Predicted hazard for stroke and mortality by % time in target INR range compared to patients treated without warfarin stratified by baseline stroke risk (CHADS 2 score). Morgan et al. Thromb Res. 2009;124:37-41 0.043 0.035 0.000 0.000 0.000 0.000 Mortality

Apostolakis et al. Chest 2013; 144:1555-1563

After a follow-up of 6 months, patients with a SAMe-TT 2 R 2 score <2 had a mean time in therapeutic range value of 67%±18% compared with a mean time in therapeutic range of 61%±16% among patients with a SAMe-TT 2 R 2 score 2 (P<.001). The odds ratio for having a low time in therapeutic range for patients with a SAMe-TT 2 R 2 score 2 was 2.10 (95% confidence interval, 1.44-3.06, P <.001). Roldan et al. Am J Med 2015;128:1237-43

Dabigatran and Warfarin in Vitamin K Antagonist Naive and Experienced Cohorts With Atrial Fibrillation Efficacy Safety Major Bleeding Intracranial Bleeding Ezekowitz et al. Circulation 2010;122:2246-2253

Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: A subgroup analysis of ROCKET AF trial 44.6% VKA-naïve patients in ROCKET AF Annual Event Rate (Stroke/SE) Warfarin Rivaroxaban Hazard Ratio [HR] (95% CI) VKA-naive patients 2.87 2.32 0.81 (0.64 to 1.03) VKA-experienced patients 2.09 1.98 0.94 (0.75 to 1.18) During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKAexperienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKAexperienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003). Mahaffey et al. Ann Intern Med 2013;158:861-8

Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with AF Insights from ENGAGE-AF/TIMI 48 Trial 41% naïve to Warfarin pts 60mg Edoxaban 30mg Edoxaban O Donoghue et al. European Heart Journal 2015;36:1470-1477

Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: Results from the ARISTOTLE Trial 43% naïve to Warfarin pts Garcia et al. Am Heart J 2013;166:549-58

NOACs outcomes in phase III trials

NOACs and Gastrointestinal Bleeding Achilles' heel of NOACs?

Pathophysiology of Gastrointestinal Bleeding Bioavailability Systemic anticoagulant effect Topical anticoagulant effect Warfarin ~100% Dabigatran 6-7% Systemic Circulation Rivaroxaban 66-100% Apixaban 50% Edoxaban 62% Warfarin is essentially completely absorbed after oral administration Incomplete absorption of the NOACs across the GI mucosa possibility for topical drug hyper-activity Upper / lower gastrointestinal tract bleeding: 53/47% for Dabigatran and 75/25% for Warfarin

Gastrointestinal Bleeding in RE-LY trial (Dabigatran) Warfarin (n=6022) Dabigatran 110 mg BID (n=6015) Dabigatran 150 mg BID (n=6076) Dabigatran 110 mg BID vs Warfarin (n=12 037) Dabigatran 150 mg BID vs Warfarin (n=12 098) Dabigatran 150 mg BID vs Dabigatran 110 mg BID (n=12 091) n %/y n %/y n %/y RR (95% CI) P RR (95% CI) P RR (95% CI) P Major bleeding 421 3.57 342 2.87 399 3.31 0.80 (0.70 0.93) 0.002 0.93 (0.81 1.07) 0.32 1.16 (1.00 1.34) 0.04 Gastrointestinal bleeding 148 1.25 162 1.36 223 1.85 1.09 (0.87 1.36) 0.44 1.49 (1.21 1.84) <0.001 1.37 (1.12 1.67) 0.002 Eikelboom et al. Circulation 2011;123:2363-2372

Gastrointestinal Bleeding in ROCKET AF (Rivaroxaban) Outcomes Rivaroxaban (n = 7,111) Events/100 Patient-Years (Total Events) Warfarin (n = 7,125) Events 100/Patient-Years (Total Events) Rivaroxaban vs. Warfarin Adjusted HR (95% CI) p Value Warfarin Rivaroxaban Major or NMCR bleeding 3.61 (394) 2.60 (290) 1.42 (1.22 1.66) <0.0001 Major bleeding 2.00 (221) 1.24 (140) 1.66 (1.34 2.05) <0.0001 Hemoglobin drop 2 g/dl 1.84 (204) 1.11 (125) 1.69 (1.35 2.12) <0.0001 Transfusion 1.27 (141) 0.85 (96) 1.56 (1.20 2.02) 0.0010 Transfusion 4U 0.47 (52) 0.41 (47) 1.19 (0.80 1.77) 0.39 Fatal 0.01 (1) 0.04 (5) 0.21 (0.02 1.76) 0.15 NMCR 1.75 (193) 1.39 (156) 1.28 (1.43 1.59) 0.023 Sherwood et al. JACC 2015;66:2271-2281

Gastrointestinal Bleeding in ENGAGE AF TIMI 48 trial (Edoxaban) Giugliano and Ruff et al. N Engl J Med 2013;369:2093-104

Κίνδυνος αιμορραγίας με NOACs έναντι της βαρφαρίνης Εκβάσεις αιμορραγίας Αpixaban ΑΚ (95% ΔΕ) Dabigatran 110 mg ΑΚ (95% ΔΕ) Dabigatran 150 mg ΑΚ (95% ΔΕ) Rivaroxaban ΑΚ (95% ΔΕ) Ενδοκρανιακή αιμορραγία (ICH) Μείζων αιμορραγία Μείζων Αιμορραγίες Γαστρεντερικό 0,89(0,68-1,16) 1,08(0,85-1,30) 1,46(1,17-1,85)* 1,45(1,19-1,79)* Κλινικά Σημαντική Μη Μείζων Αιμορραγία Δεν έχει αναφερθεί Δεν έχει αναφερθεί Οποιαδήποτε Άλλο Υπερτερεί το apixaban Υπερτερεί η βαρφαρίνη Υπερτερεί το Dabi 110 mg Υπερτερεί η βαρφαρίνη Υπερτερεί το Dabi 150 mg Υπερτερεί η βαρφαρίνη Υπερτερεί το Rivaroxaban Υπερτερεί η βαρφαρίνη ΠΡΟΣΟΧΗ: Δεν υπάρχουν μελέτες άμεσης σύγκρισης NOACs μεταξύ τους * p<0,05 Mitchell και Συν. Clin Appl Thromb Haemost 2013;19:619-31

Patients with chronic kidney disease and AF Chronic kidney disease constitutes a risk factor for both thromboembolic events and bleeding in AF patients Olesen et al NEJM 2012;367:625-35 Recent findings suggest that a creatinine clearance of <60 ml/min may even be an independent predictor of stroke and systemic embolism Piccini et al. Circulation 2013;127:224-232 R2CHADS2 Score CHA 2 DS 2 -VAScategory reatinine

Stroke Systemic Embolism All-cause Mortality Major Bleeding In patients with AF, renal impairment was associated with increased risk of cardiovascular events and bleeding. When compared with warfarin, apixaban treatment reduced the rate of stroke, death, and major bleeding, regardless of renal function. Patients with impaired renal function seemed to have the greatest reduction in major bleeding with apixaban Hohnloser et al. European Heart Journal 2012;33:2821-2830

12.4 11.5 12.9 12.4 30.2 26.1 20.1 16.6 53.2 48.5 40.8 34.0 Kakkar A. ESC Congress 2015 London, UK

GARFIELD AF Registry Kakkar at al. PLoS One 2013;8(5):e63479

Randomization AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes): Study Design Aged 50 years Atrial fibrillation 1 additional risk factor for stroke Not suitable for vitamin K antagonist N= 5,600 ~1,6 years Apixaban 2.5 mg bid or 5 mg bid Aspirin 81-324 mg qd Primary outcome measures: Time to composite outcome of stroke or systemic embolism Time to major bleeding Stuart et al. NEJM 2011;364:806-17

AVERROES: Results (efficacy) Apixaban significantly reduced risk of stroke or systemic embolic events by 54% The trial was stopped early as interim analysis showed significant benefit with apixaban Primary and secondary end points Stuart et al. NEJM 2011;364:806-17

AVERROES: Results (safety) The risk of major bleeding increased by a statistically nonsignificant 14% There was no increased risk of fatal or intracranial hemorrhage, two particular concerns with AF patients who receive anticoagulation therapy Bleeding events Stuart et al. NEJM 2011;364:806-17

Discontinuation Rates In USA NVAF Patients New To Anticoagulation (Jan 2013 Dec 2013) (Marketscan Commercial and Medicare) AF PATIENTS WERE INCLUDED IF THEY WERE NEWLY INITIATED ON ANTICOAGULANT TREATMENT THE STUDY PERIOD Retrospective analysis of Truven Marketscan Commercial and Medicare database Discontinuation rates (medication gap of 30 days) and time to discontinuation were measured during followup (max follow up: 12 months) Study period: Jan 2013 Dec 2013 (baseline assessment: Jan 2012 Dec 2012) Warfarin N=14,339 Rivaroxaban N=12,080 Dabigatran N=4,495 Apixaban N=2,956 Study Population Inclusion criteria Age 18 years old At least one year of baseline prior to the initiation of anticoagulation therapy Had at least 1 claim with diagnosis of AF (primary or secondary diagnosis using ICD- 9-CM code 427.31 (atrial fibrillation) or 427.32 (atrial flutter) during the one year baseline period prior to the index prescription. Exclusion criteria No use of warfarin and NOAC within the baseline period AF, atrial fibrillation Pan X et al. ESC 2014, Barcelona, Spain. Oral poster presentation, ESC 2014.

Discontinuation Rates In USA NVAF Patients New To Anticoagulation (Jan 2013 Dec 2013) (Marketscan Commercial and Medicare) BASELINE CHARACTERISTICS, N (%) Age, years 18 64 65 74 75 APIXABAN (N=2,956) 1075 (36.37) 687 (23.24) 1194 (40.39) DABIGATRAN (N=4,495) 2000 (44.49) 1078 (23.98) 1417 (31.52) RIVAROXABAN (N=12,080) 5261 (43.55) 2759 (22.84) 4060 (33.61) WARFARIN (N=14,339) 3881 (27.07) 3341 (23.30) 7117 (49.63) Female 1148 (38.84) 1589 (35.35) 4596 (38.05) 5983 (41.73) Valvular heart disease 835 (28.25) 1093 (24.32) 3163 (26.18) 3904 (27.23) Embolic or primary ischaemic stroke 216 (7.31) 303 (6.74) 830 (6.87) 1536 (10.71) Dyspepsia or stomach discomfort 448 (15.16) 594 (13.21) 1849 (15.31) 2517 (17.55) Congestive heart failure 689 (23.31) 1091 (24.27) 2857 (23.65) 4709 (32.84) Coronary artery disease 1108 (37.48) 1435 (31.92) 3947 (32.67) 5501 (38.36) Diabetes 812 (27.47) 1244 (27.68) 3237 (26.80) 4525 (31.56) Hypertension 2167 (73.31) 3235 (71.97) 8644 (71.56) 10693 (74.57) Renal disease 271 (9.17) 396 (8.81) 1088 (9.01) 2456 (17.13) Myocardial infarction 192 (6.50) 282 (6.27) 793 (6.56) 1211 (8.45) History of stroke or transient ischaemic attack 337 (11.40) 475 (10.57) 1260 (10.43) 2102 (14.66) History of bleeding 365 (12.35) 527 (11.72) 1558 (12.90) 2517 (17.55) Pan X et al. ESC 2014, Barcelona, Spain. Oral poster presentation, ESC 2014.

% OF PATIENTS WITH DISCONTINUATION Discontinuation Rates In USA NVAF Patients New To Anticoagulation (Jan 2013 Dec 2013) (Marketscan Commercial and Medicare) 70 60 50 40 30 20 10 0 Warfarin vs. Apixaban: Adjusted HR: 1.638 (95% Cl: 1.514 1.772) P<0.001 Rivaroxaban vs. Apixaban: Adjusted HR: 1.215 (95% Cl: 1.121 1.317) P<0.001 Dabigatran vs. Apixaban: Adjusted HR: 1.581 (95% Cl: 1.451 1.721) P<0.001 WARFARIN (n=14,339) DABIGATRAN (n=4,495) RIVAROXABAN (n=12,080) APIXABAN (n=2,956) The proportion of patients who discontinued during the follow-up period was: 23.32% for apixaban 46.96% for dabigatran 35.15% for rivaroxaban 46.28% for warfarin 0 30 60 90 120 150 180 210 240 270 300 330 360 390 TIME FROM ANTICOAGULATION INITIATION (DAYS) Analysis controlled for other variables including age, gender, onset of embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of TIA or stroke and history of bleeding Pan X et al. ESC 2014, Barcelona, Spain. Oral poster presentation, ESC 2014.

Ποσοστά διακοπής λήψης του φαρμάκου στις μελέτες των NOACs για την ΜΒ-ΜΚ Συνολικά Ποσοστά Διακοπής NOAC vs. βαρφαρίνη Apixaban ARISTOTLE Dabigatran 110 mg RE-LY Dabigatran 150 mg RE-LY Rivaroxaban ROCKET-AF HR (95% CI) 0,90 (0,84 0,96) 1,36 (1,23 1,49) 1,41 (1,29 1,55) 1,09 (1,01 1,18) Υπεροχή NOACs Υπεροχή βαρφαρίνης Προσαρμογή από Mitchell et al. Clin Appl Thromb Hemost 2013;19:619-31

Real World Comparison Of Major Bleeding Risk Among Non-valvular AF Patients Newly Initiated On Apixaban, Dabigatran, Rivaroxaban Or Warfarin (Retrospective cohort study using Truven MarketScan Commercial and Medicare supplemental data) 29,338 pts with newly prescribed oral anticoagulants from January 1, 2013 to December 31, 2013 Apixaban: n=2,402 Dabigatran: n=4,173 Rivaroxaban: n=10,050 Warfarin: n=12,713 Lip et al. Presentation code P6217 (Sept 01, 2015) ESC Congress 2015 London, UK

Selecting oral anticoagulation for stroke prevention in AF Patient less likely to do well on VKA (SAMeTT 2 R 2 score 2 Renal Impairment Previous GI bleeding High ischemic risk Low hemorrhagic risk Recurrent stroke despite well managed VKA or other NOAC Preferene of low pill burden High bleeding risk (HAS-BLED score 3) Elderly Any NOAC consider patient characteristics Apixaban Apixaban, Dabigatran 110mg Dabigatran 150mg Dabigatran 150mg Rivaroxaban, Edoxaban Apixaban, Dabigatran 110mg, Edoxaban Apixaban, Edoxaban

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Επιλογή στο δοσολογικό σχήμα Συμμόρφωση Αντιπηκτική κάλυψη

PDC: Proportion of Days Covered b.i.d. more adherent q.d. more adherent Laliberte et al. Adv Ther 2012;29:675 90

How frequently do patients miss consecutive doses? 1 ONCE-DAILY REGIMEN TWICE-DAILY REGIMEN 30 HOURS 56 HOURS 78 HOURS 18 HOURS 30 HOURS 42 HOURS 54 HOURS 66 HOURS 78 HOURS N=677 N=677 75.2% OF PATIENTS MISSED ONE DOSE AT LEAST ONCE OVER 30 DAYS H G K H G K 46.8% OF PATIENTS MISSED ONE DOSE AT LEAST ONCE OVER 30 DAYS 11% OF PATIENTS MISSED THREE CONSECUTIVE DOSES AT LEAST ONCE OVER 30 DAYS Adapted from Vrijens et al. 2014 1 1. Vrijens et al. Br J Clin Pharmacol 2014;77:746 755. Cardiovascular medications

CONCENTRATION Lower peak-to-trough ratio at steady state for twice-daily vs once-daily 1 REPEATED DOSING ASSUMING PERFECT ADHERENCE Theoretical PK profile, assuming T 1/2 ~12h; T max =3h DOSE X ONCE-DAILY DOSE X/2 TWICE-DAILY H G K 5 6 7 8 9 10 DAY Adapted from Vrijens & Heidbüchel. 2015 1 1. Vrijens & Heidbüchel. EP Europace. 2015; doi:10.1093/europace/euu311. PK: pharmacokinetic

CONCENTRATION One missed once-daily dose is about equivalent to missing three consecutive twice-daily doses 1 Theoretical PK profile, assuming T 1/2 ~12h; T max =3h DOSE X ONCE-DAILY DOSE X/2 TWICE-DAILY H G K 5 6 7 8 9 10 DAY Adapted from Vrijens & Heidbüchel. 2015 1 1. Vrijens & Heidbüchel. EP Europace. 2015; doi:10.1093/europace/euu311.

CONCENTRATION Simulating one single missed dose for twice-daily 1 Theoretical PK profile, assuming T 1/2 ~12h; T max =3h DOSE X ONCE-DAILY DOSE X/2 TWICE-DAILY H G K 5 6 7 8 9 10 DAY Adapted from Vrijens & Heidbüchel. 2015 1 1. Vrijens & Heidbüchel. EP Europace. 2015; doi:10.1093/europace/euu311.

CONCENTRATION Simulating one extra dose for twice-daily vs once-daily 1 Theoretical PK profile, assuming T 1/2 ~12h; T max =3h DOSE X ONCE-DAILY DOSE X/2 TWICE-DAILY H G K 5 6 7 8 9 10 DAY Adapted from Vrijens & Heidbüchel. 2015 1 1. Vrijens & Heidbüchel. EP Europace. 2015; doi:10.1093/europace/euu311.

DOSING TIME DOSING TIME CONCENTRATION CONCENTRATION Twice-daily regimen increases forgiveness for similar deviations in adherence 1 ONCE-DAILY* TWICE-DAILY* BLEEDING RISK BLEEDING RISK H G K H G K 03:00 24:00 21:00 18:00 15:00 15:00 12:00 09:00 06:00 03:00 THROMBOSIS RISK 03:00 24:00 21:00 18:00 15:00 15:00 12:00 09:00 06:00 03:00 THROMBOSIS RISK 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 DOSING TIMES (DAY) DOSING TIMES (DAY) 15% M I S S E D D O S E S 15 O N C E - DA I LY M I S S E D D O S E S V S 30 T W I C E - DA I LY M I S S E D D O S E S OV E R 1 0 0 DAY S Theoretical PK profile, assuming T 1/2 ~12h; T max =3h * Once-daily and twice-daily dosing for same agent and the same total daily dose Adapted from Vrijens & Heidbüchel. 2015 1 1. Vrijens & Heidbüchel. EP Europace. 2015; doi:10.1093/europace/euu311.

Choosing the right drug to fit the patient when selecting oral anticoagulation for stroke prevention in atrial fibrillation. Shields AM, Lip GY. J Intern Med. 2015;278(1):1-18

Indirect Network meta-analysis comparison of apixaban, dabigatran, rivaroxaban and edoxaban Outcome, HR (95% CrI) a Treatment comparison CHADS 2 score 2 Pts with previous stroke or TIA Stroke + SE Major bleeding Stroke + SE Major bleeding Apixaban vs. warfarin 0.78 (0.64,0.95) 0.73 (0.62,0.86) 0.76 (0.56, 1.02) 0.73 (0.55,0.98) Rivaroxaban vs. warfarin 0.88 (0.74, 1.03) 1.06 (0.92, 1.22) 0.94 (0.77, 1.16) 1.00 (0.82, 1.24) Dabigatran 110 mg BD vs. warfarin 0.89 (0.71, 1.12) 0.86 (0.73, 1.02) 0.87 (0.51, 1.46) 0.65 (0.41, 1.003) Dabigatran 150 mg BD vs. warfarin 0.67 (0.52,0.85) 1.01 (0.86, 1.18) 0.75 (0.43, 1.27) 0.99 (0.67, 1.46) Edoxaban 30 mg vs. warfarin 1.13 (0.98, 1.31) 0.47 (0.40,0.54) 1.11 (0.80, 1.54) 0.48 (0.33,0.73) Edoxaban 60 mg vs. warfarin 0.87 (0.75, 1.02) 0.80 (0.70,0.91) 0.85 (0.57, 1.22) 0.85 (0.60, 1.21) Apixaban vs. rivaroxaban 0.89 (0.69, 1.15) 0.69 (0.55,0.85) 0.81 (0.56, 1.16) 0.73 (0.51, 1.04) Apixaban vs. dabigatran 110 mg BD 0.87 (0.65, 1.18) 0.84 (0.67, 1.06) 0.88 (0.48, 1.60) 1.12 (0.67, 1.92) Apixaban vs. dabigatran 150 mg BD 1.16 (0.85, 1.59) 0.72 (0.57,0.91) 1.02 (0.55, 1.88) 0.74 (0.46, 1.20) Apixaban vs. edoxaban 30 mg 0.69 (0.54,0.88) 1.55 (1.24,1.94) 0.69 (0.44, 1.07) 1.50 (0.91, 2.48) Apixaban vs. edoxaban 60 mg 0.89 (0.69, 1.15) 0.91 (0.74, 1.12) 0.90 (0.56, 1.46) 0.86 (0.55, 1.35) Dabigatran 110 mg BD vs. rivaroxaban 1.02 (0.77, 1.35) 0.82 (0.66, 1.01) 0.92 (0.52, 1.61) 0.65 (0.40, 1.05) Dabigatran 150 mg BD vs. rivaroxaban 0.77 (0.57, 1.03) 0.95 (0.77, 1.17) 0.79 (0.44, 1.40) 0.98 (0.63, 1.53) Edoxaban 30 mg vs. rivaroxaban 1.30 (1.04,1.61) 0.44 (0.36,0.54) 1.18 (0.79, 1.75) 0.48 (0.31,0.77) Edoxaban 60 mg vs. rivaroxaban 1.00 (0.80, 1.25) 0.76 (0.63,0.91) 0.90 (0.58, 1.36) 0.84 (0.56, 1.26) Dabigatran 150 mg BD vs. dabigatran 110 mg BD 0.75 (0.58,0.96) 1.17 (0.99, 1.37) 0.86 (0.49, 1.50) 1.52 (0.99, 2.37) Edoxaban 30 mg vs. dabigatran 110 mg BD 1.27 (0.97, 1.66) 0.54 (0.44,0.68) 1.28 (0.70, 2.36) 0.75 (0.41, 1.38) Edoxaban 60 mg vs. dabigatran 110 mg BD 0.98 (0.74, 1.28) 0.93 (0.76, 1.14) 0.98 (0.51, 1.85) 1.31 (0.74, 2.31) Edoxaban 30 mg vs. dabigatran 150 mg BD 1.69 (1.27,2.25) 0.47 (0.38,0.58) 1.48 (0.79, 2.82) 0.49 (0.28,0.87) Edoxaban 60 mg vs. dabigatran 150 mg BD 1.30 (0.97, 1.74) 0.80 (0.65,0.97) 1.14 (0.59, 2.18) 0.86 (0.51, 1.44) Edoxaban 60 mg vs. edoxaban 30 mg 0.77 (0.66,0.90) 1.71 (1.46,2.00) 0.77 (0.51, 1.10) 1.74 (1.17,2.63) Abbreviations: BD, twice daily; CrI, credible interval; HR, hazard ratio; NMA, network meta-analysis; SE, systemic embolism; TIA, transient ischaemic attack. a Statistically significant results are shown in bold and italicised font. Lip et al. Int J Cardiol. 2016;204:88-94

Pattern of events at the beginning of the trial (first 30 days) according to prior warfarin use Insights from ARISTOTLE trial Warfarin-naıve to warfarin Warfarin-naïve to apixaban Patients Sroke/SE Stroke/SE % annual rate 3888 17 5,41% 3912 3 1,5% Granger et al. Am Heart J 2015;169:25-30

NOACs in AF and Coronary Artery Disease

AF in stable CAD OAC as monotherapy OAC + anti-platelet therapy (APT) Alternatively ASA or other APT as monotherapy?

Platelet-rich thrombus white clot associated with vascular disease Fibrin-rich thrombus red clot associated with AF

Adding aspirin to warfarin does not seem to prevent stroke and vascular events in patients with atrial fibrillation and stable vascular disease Bleeding risks are much higher in patients prescribed bothwarfarin and aspirin We should stop prescribing aspirin plus warfarin to prevent stroke and vascular events in stable patients with atrial fibrillation who are receiving anticoagulation treatment Lip GY. BMJ 2008;336:614 5

AF in stable CAD VKA NOAC OAC as monotherapy OAC + anti-platelet therapy (APT) Alternatively ASA or other APT as monotherapy?

Effect of apixaban vs. warfarin for safety and efficacy outcomes according to CAD status Bahit et al. International Journal of Cardiology 2013;170:215-220

AF in the setting of Elective PCI or Acute Coronary Syndrome 2015 Updated EHRA Practical Guide on the use of non-vka anticoagulants in patients with NVAF. Europace 2015;17:1467 1507

NOACs Risk of coronary events: a meta-analysis of large randomised trials Mak K-H. BMJ Open 2012;2:e001592

Summary Data of the RE-LY Study Connolly et al. NEJM 2009;361:1139-1151 Douxfils et al. J Am Heart Assoc. 2014 Jun 6;3(3):e000515

Apixaban σε ΚΜ/ΟΣΣ AUGUSTUS ΚΡΙΤΗΡΙΑ ΕΙΣΑΓΩΓΗΣ Κολπική μαρμαρυγή Αντιπηκτική αγωγή ΟΣΣ ή Αγγειοπλαστική P2Y12 αναστολείς για 6μήνες εντός 2 εβδομάδων από το ΟΣΣ ή αγγειοπλαστική ΤΥΧΑΙΟΠΟΙΗΣΗ n=4,600 Ασθενείς ΚΡΙΤΗΡΙΑ ΑΠΟΚΛΕΙΣΜΟΥ Αντένδειξη για διπλή αντιαιμοπεταλιακή θεραπεία (DAPT) Άλλος λόγος για λήψη ΑΒΚ (π.χ. προσθετική βαλβίδα, μέτρια/σοβαρή στένωση μιτροειδούς) CABG APIXABAN ΑΒΚ P2Y12 αναστολέα σε όλους τους ασθενείς για 6 μήνες Aσπιρίνη σε όλους την ημέρα του ΟΣΣ ή αγγειοπλαστικής Ασπιρίνη έναντι placebo μετά τη τυχαιοποίηση ASA PLACEBO ASA PLACEBO ΑΒΚ Ανταγωνιστής βιταμίνης Κ Source: Clinicaltrials.gov identifier: NCT02415400; EUDRACT: 2014-002004-24

2012 ESC valvular heart disease guidelines Anticoagulation TYPE OF REPLACEMENT ANTICOAGULANT REGIMEN EVIDENCE CLASS, LEVEL MECHANICAL VALVES OAC indefinitely (target INR 2.5 4.0, depending on thrombogenicity and patient risk factors) Class I, B Low risk Low-dose ASA (up to 3 months duration) Class IIa, C BIOPROSTHETIC VALVES High risk VKA (up to 3 months duration) Class IIa, C With AF OAC (life long) Class I, C TAVI Despite lack of evidence, combination of low-dose ASA and a thienopyridine is used early after TAVI, followed by ASA or a thienopyridine alone With AF: combination of VKA and ASA or thienopyridine is generally used, but should be weighed against increased risk of bleeding AF, atrial fibrillation; ASA, acetylsalicylic acid; ESC, European Society of Cardiology; INR, international normalised ratio; OAC, oral anticoagulant; TAVI, transcatheter aortic valve implantation; VKA, vitamin K antagonist Vahanian A et al. Eur Heart J 2012;33:2451 2496

NOACs in VHD Mechanical valves with or without AF RE-ALIGN 1 Phase 2 dose-validation study in patients who had undergone aortic or mitral valve replacement within the past 7 days or at least 3 months earlier Randomisation (2:1) to either dabigatran (150, 220, or 300 mg twice daily, based on kidney function) or warfarin After enrolment of 252 patients, study terminated prematurely because of: Excess of thromboembolic and bleeding events among patients in the dabigatran group Dabigatran contraindicated in this patient population No current data for apixaban, rivaroxaban or edoxaban in this setting CATHAR 2 Phase 2 study of rivaroxaban after aortic valve replacement Currently recruiting (n=30); anticipated completion July 2016 APIXABAN IS NOT RECOMMENDED FOR USE IN PATIENTS WITH PROSTHETIC HEART VALVES (WITH OR WITHOUT AF) 3 AF, atrial fibrillation; NOAC, non-vitamin K antagonist oral anticoagulant; VHD, valvular heart disease 1. Eikelboom J et al. N Engl J Med 2013;369:1206 1214; 2. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/nct02128841. Accessed 22 October 2015; 3. Apixaban European Summary of Product Characteristics. Updated 25 August 2015. Available at www.ema.europa.eu. Last accessed 22 October 2015

Ziff et al. Am Heart J 2016;173:143-158 Summary of the clinical trials of the non-vkas compared with warfarin 1.61 (1.07, 0.87 1.31)

Guideline CHA 2 DS 2 -VASc = 0 CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 AHA/ACC/HRS 2014 17 ESC 2012 23 NICE 2014 9 CCS 2014 147 Reasonable to omit antithrombotic therapy Recommend no antithrombotic therapy Do not offer stroke prevention therapy No additional risk factors: no antithrombotic Consider aspirin or no antithrombotic therapy Best option: dabigatran, rivaroxaban, apixaban. Alternative option: adjusted dose VKA (INR 2-3) Female patients <65 y and lone AF: no antithrombotic therapy Men with CHA2DS2-VASc = 1: consider anticoagulation including rivaroxaban, dabigatran, apixaban, and VKA; take bleeding risk into account. Female CHA2DS2-VASc = 1: do not offer stroke prevention therapy 65 y: OAC Prior stroke or TIA; or hypertension; or HF; or diabetes: OAC CAD or vascular disease: ASA NOAC should be used in preference to warfarin in nonvalvular AF Recommend: dabigatran, rivaroxaban, apixaban, warfarin. In CKD moderatesevere, consider reduced dose or dabigatran, rivaroxaban, or apixaban. If CrCl <15 ml/min, prescribe warfarin Best option: dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban Alternative option: adjusted dose VKA (INR 2-3) If CrCl <30 ml/min, avoid NOACs Offer anticoagulation, including rivaroxaban, dabigatran, apixaban, and VKA. Take bleeding risk into account Offer OAC NOAC should be used in preference to warfarin in nonvalvular AF AHA, American Heart Association; ACC, American College of Cardiology; ASA, acetylsalicyclic acid; CCS, Canadian Cardiovascular Society; HRS, Heart Rhythm Society; OAC, oral anticoagulant.

Primary events after transitioning from randomized to open-label therapy in ROCKET-AF and ARISTOTLE trial Patel et al. NEJM 2011;365:883-91 Granger et al. Am Heart J 2015;169:25-30

Η χρήση των ΝΟΑCs στην θεραπευτική πρακτική Τυχαιοποιημένες μελέτες Post hoc αναλύσεις Μετα-αναλύσεις Δεδομένα πραγματικού κόσμου (real world data) Λογική

ARISTOTLE: Σχεδιασμός και αντικείμενο μελέτης 1 18.201 ασθενείς Πληθυσμός Ασθενών 2 Ηλικία 18 έτη Ασθενείς με ΜΒ-ΚΜ και 1 παράγοντα κινδύνου για ΑΕΕ Τυχαιοποιημένη, διπλά τυφλή, με διπλό εικονικό φάρμακο Καθοδηγούμενη από συμβάματα* Apixaban 5 mg από του στόματος ΒD (2.5 mg ΒD σε επιλεγμένους ασθενείς [4.7%]) Βαρφαρίνη (ρυθμιζόμενη δόση για INR 2 3) *448 πρωτεύοντα συμβάματα χρειάζονταν στη μελέτη 2 από τα ακόλουθα: ηλικία 80 έτη, σωματικό βάρος 60 κιλά ή κρεατινίνη ορού 1.5 mg/dl (133 μmol/l) Ο πρωταρχικός στόχος της μελέτης ήταν να καθορίσει εάν το apixaban ήταν μη κατώτερο από τη βαρφαρίνη για την πρόληψη ΑΕΕ και ΣΕ. Εάν τα κριτήρια μη κατωτερότητας διασφαλίζονταν, ελέγχονταν τα ακόλουθα τελικά σημεία για ανωτερότητα 1,3 ΑΕΕ ή συστηματική εμβολή (πρωτεύον τελικό σημείο αποτελεσματικότητας) Μείζων αιμορραγία κατά ISTH (πρωτεύον τελικό σημείο ασφάλειας) Θάνατος οποιασδήποτε αιτιολογίας (κύριο δευτερεύον τελικό σημείο) 1. Granger et al. N Engl J Med 2011;365:981-992. 2. Lopes et al. Am Heart J 2010;159:331-9. 3. Apixaban SmPC 2014.

Ασθενείς με συμβάματα (%) ARISTOTLE: To Apixaban ήταν ανώτερο της βαρφαρίνης στην πρόληψη ΑΕΕ ή ΣΕ 4 3 Βαρφαρίνη 21% RRR 2 Apixaban 1 0 0 6 12 18 24 30 Μήνες HR 0.79 (95% CI: 0.66-0.95) p<0.001 για μη κατωτερότητα p=0.01 για ανωτερότητα Ασθενείς σε κίνδυνο Apixaban 9,120 8,726 8,440 6,051 3,464 1,754 Βαρφαρίνη 9,081 8,620 8,301 5,972 3,405 1,768 Προσαρμογή από Granger et al. N Engl J Med 2011;365:981-92.

ARISTOTLE: Αποτελεσματικότητα σύμφωνα με τον τύπο του ΑΕΕ Apixaban Βαρφαρίνη Αριθμός Συμβαμάτων (%/έτος) HR 95% CI ΑΕΕ/ ΣΕ 212 (1.27) 265 (1.60) 0.79 0.66-0.95 ΑΕΕ 199 (1.19) 250 (1.51) 0.79 0.65-0.95 Ισχαιμικό ή μη προσδιορισμένο ΑΕΕ* 162 (0.97) 175 (1.05) 0.92 0.74-1.13 Αιμορραγικό ΑΕΕ 40 (0.24) 78 (0.47) 0.51 0.35-0.75 ΑΕΕ που προκαλεί αναπηρία ή θανατηφόρο ΑΕΕ 84 (0.50) 117 (0.71) 0.71 0.54-0.94 0.0 0.5 1.0 1.5 2.0 Υπεροχή apixaban Υπεροχή Βαρφαρίνης *Μη προσδιορισμένου τύπου ΑΕΕ συνέβη σε 14 ασθενείς στην ομάδα του apixaban και σε 21 ασθενείς στην ομάδα της βαρφαρίνης. Μεταξύ ασθενών με ισχαιμικό ΑΕΕ, αιμορραγική μετατροπή συνέβη σε 12 ασθενείς με apixaban και 20 με βαρφαρίνη. Προσαρμογή από Granger et al. N Engl J Med 2011;365:981-92.

Ασθενείς με συμβάματα (%) ARISTOTLE: Το Apixaban μείωσε σημαντικά τον κίνδυνο μείζονος αιμορραγίας* συγκριτικά με τη βαρφαρίνη 8 Βαρφαρίνη 6 31% RRR 4 Apixaban 2 0 HR 0.69 (95% CI: 0.60-0.80); p<0.001 0 6 12 18 24 30 Μήνες Ασθενείς σε κίνδυνο Apixaban 9088 8103 7564 5365 3048 1515 Βαρφαρίνη 9052 7910 7335 5196 2956 1491 Adapted from Granger et al. N Engl J Med 2011;365:981-92. * Η μείζων αιμορραγία καθορίστηκε σύμφωνα με τα κριτήρια ISTH

Ποσοστό Συμβαμάτων (% / έτος) ARISTOTLE: Το Apixaban υπερείχε της βαρφαρίνης στη μείωση της θνησιμότητας από κάθε αίτιο Θνησιμότητα από κάθε αίτιο* 11% RRR HR: 0.89 95% CI: 0.80-0.998; p=0.047 3.94% 669/9081 3.52% 603/9120 Βαρφαρίνη Apixaban Γράφημα από δεδομένα των Granger et al. N Engl J Med 2011;365:981-92. *Κύριο δευτερεύον τελικό σημείο αποτελεσματικότητας

NOACs and AF ablation periprocedural management The two fundamental interventions reduced periprocedural stroke/tia in AF Ablation Irrigated tip catheters Performing the procedure on uninterrupted VKA

AXAFA AFNET 5: Study design Anticoagulation using the direct factor Xa inhibitor apixaban during Atrial Fibrillation catheter Ablation: Comparison to vitamin K antagonist therapy 1 630 patients, 50 centers (Europe and US) PROBE design Primary outcome: net clinical benefit (composite of bleeding and ischaemic events) 1 ClinicalTrials.gov Identifier:NCT02227550 MRI substudy in interested centers BD, twice daily; MRI, magnetic resonance imaging; TEE, transesophageal echocardiogram

Our practice in the perioperative management of NOACs Once daily (rivaroxaban) CHA 2 DS 2 -VASc Score < 3 CHA 2 DS 2 -VASc Score 3 Twice daily (dabigatran, apixaban) End of the procedure before 14:00 Day before Ablation Day before Ablation No dose missed (uninterrupted OAC therapy) Day before Ablation Day after 1 dose missed Day after Day after Start of the procedure after 14:00 End of the procedure after 14:00 Day before Ablation Day before Ablation 1 dose missed Day after 1 dose missed Day after 2 doses missed

Apixaban: δοσολογικό σχήμα για μη βαλβιδική κολπική μαρμαρυγή 5 mg 1 X 2 ή 2,5 mg 1 X 2 2 από τα ακόλουθα Ηλικία 80 έτη Σωματικό βάρος 60 κιλά Κρεατινίνη ορού 1.5 mg/dl (133 μmol/l) * Only 4.6% of patients in ARISTOTLE

NOACs Prescription Data Apixaban Rivaroxaban Dabigatran Q4 2014 Q4 2014 Q4 2014 Country 2.5mg 5mg 10mg 15mg 20mg 75mg 110mg 150mg UNITED STATES 24% 76% 6% 21% 73% 16% 0% 84% JAPAN 58% 42% 55% 45% 0% 40% 60% 0% GERMANY 41% 59% 4% 34% 61% 2% 61% 37% CANADA 38% 62% 6% 26% 68% 1% 52% 47% AUSTRALIA 39% 61% 2% 30% 68% 0% 63% 37% UNITED KINGDOM 42% 58% 6% 22% 71% 3% 51% 46% SPAIN 37% 63% 5% 33% 63% 3% 60% 38% FRANCE 46% 54% 0% 0% 0% 0% 0% 0% BEGIUM 30% 70% 2% 42% 56% 0% 60% 40% ITALY 35% 65% 2% 37% 61% 0% 63% 36% * In ARISTOTLE, 831/18,201 (4.6%) patients met dose reduction criteria. In practice, an unexpectedly high proportion of prescriptions for apixaban are for a reduced dose of 2.5 mg. Similar patterns are seen with rivaroxaban and dabigatran. Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria 5mg BID vs Warfarine No dose-reduction criteria 13,356 (73.9%) One dose-reduction criterion 3,966 (21.9%) Creatinine, only 904 (5.0%) Weight, only 1,426 (7.9%) Age, only 1,636 (9.1%) 2.5mg BID vs Warfarine Two dose-reduction criteria 733 (4.1%) Weight, Creatinine 51 (0.3%) Age, Creatinine 225 (1.2%) Age, Weight 457 (2.5%) Three dose-reduction criteria 18 (0.1%) Age, Weight, Creatinine Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

Probability of Event / Year ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria Major Bleeding by Creatinine 5 mg Twice Daily Dose Only Creatinine (mg/dl) at randomization Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

Probability of Event / Year ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria Major Bleeding by Age 5 mg Twice Daily Dose Only Age (years) at randomization Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

Probability of Event / Year ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria Major Bleeding by Weight 5 mg Twice Daily Dose Only Weight (Kg) at randomization Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

Probability of Event / Year ARISTOTLE Post hoc analysis: The safety and efficacy of Apixaban 5 mg twice daily vs. warfarin in patients with no and with one dose-reduction criteria Major Bleeding by Creatinine Clearance 5 mg Twice Daily Dose Only CrCL (ml/min) at randomization Alexander et al. (Abstract 2032) ESC Congress 2015 London, UK

Approved European labels for NOACs and their dosing in Chronic Kidney Disease 2015 Updated EHRA Practical Guide on the use of non-vka anticoagulants in patients with NVAF. Europace 2015;17:1467 1507

Νεότερα αντιπηκτικά και ανάταξη ΚΜ

A post-hoc analysis of ARISTOTLE trial for pts undergone cardioversion Major cardiovascular events after cardioversion of atrial fibrillation are rare and comparable between warfarin and apixaban Flaker et al. JACC 2014;63:1082-7

Μελέτη EMANATE: Apixaban σε προσφάτως διαγνωσθέντες ασθενείς με ΜΒΚΜ που ενδείκνυνται για πρόωρη καρδιομετατροπή Φάση IV, τυχαιοποιημένη, παράλληλων ομάδων, μελέτη ανοικτής επισήμανσης Περίοδος θεραπείας 30 Ημέρες (± 7 ημέρες) 1500 ασθενείς Προσφάτως διαγνωσθέντες ασθενείς με ΜΒΚΜ Ενδείκνυνται για καρδομετατροπή Τ Καρδιομετατροπή Τυπική αγωγή (Παρεντερική ηπαρίνη/αβκ*) 5 mg Apixaban δύο φορές την ημέρα 2,5 mg δύο φορές την ημέρα σε επιλεγμένους ασθενείς** T: Τυχαιοποίηση σε αναλογία 1:1 * Εξαιρούνται άλλα νέα από του στόματος αντιπηκτικά φάρμακα ** 2,5 mg δύο φορές ημερησίως εάν η κάθαρση κρεατινίνης είναι 15-29 ml/min ή εφόσον πληρούνται τα δύο ακόλουθα κριτήρια: ηλικίας 80 ετών, σωματικό βάρος 60kg ή κρεατινίνη 1,5 mg/dl (133 μmol) ΑΒΚ: ανταγωνιστές βιταμίνης Κ Κλινικά καταληκτικά σημεία Αγγειακό εγκεφαλικό επεισόδιο Συστημική εμβολή Μείζων αιμορραγία Κλινικά σημαντική μη μείζων αιμορραγία Θάνατος οποιασδήποτε αιτιολογίας NCT02100228 www.clinicialtrials.gov

A phase II study of apixaban in pts following total knee replacement Incidence of VTE plus death from any cause Incidence of bleeding events 5mg 10mg 20mg 5mg 10mg 20mg Lassen et al. J Thromb Haemost 2007;5:2368-75

How to deal with dosing errors? Updated EHRA Practical Guide on the use of non-vka anticoagulants in patients with NVAF. Europace 2015 Aug 31

The WOEST study Οpen-label, multicentre, randomised, controlled trial 573 pts on VKA OAC (~70% for AF) undergoing PCI (~30% for ΑCS) Randomization: VKA + Clopidogrel vs VKA + Clopidogrel + Aspirin Bleeding events Mortality Triple therapy Double therapy Dewilde et al. Lancet 2013;381:1107-15

Αποτελεσματικότητα και προφίλ ασφαλείας των NOACs σε σύγκριση με τη βαρφαρίνη Αγγειακό εγκεφαλικό επεισόδιο/συστημική εμβολή ΣΚ (95% ΔΕ) Μείζων αιμορραγία ΣΚ (95% ΔΕ) Apixaban ARISTOTLE 0,80 (0,67 0,95) 0,71 (0,61 0,81) Dabigatran 150mg RE-LY 0,66 (0,53 0,82) 0,94 (0,82 1,07) Edoxaban 60mg ENGAGE AF-TIMI 48 0,88 (0,75 1,02) 0,80 (0,71 0,90) Rivaroxaban ROCKET AF 0,88 (0,75 1,03) 1,03 (0,90 1,18) Συνδυασμός (τυχαιοποίηση) 0,81 (0,73 0,91) 0,86 (0,73 1,00) 0,5 1,0 1,5 0,5 1,0 1,5 Ευνοεί τα νέα από του στόματος αντιπηκτικά φάρμακα Ευνοεί τη βαρφαρίνη Ευνοεί τα νέα από του στόματος αντιπηκτικά φάρμακα Ευνοεί τη βαρφαρίνη Δεν υπάρχουν μελέτες άμεσης σύγκρισης και κατά συνέπεια δεν μπορούν να πραγματοποιηθούν συγκρίσεις μεταξύ των παραγόντων ΣE: συστημική εμβολή, ΣΚ: σχετικός κίνδυνος Ruff και Συν. Lancet 2014, 383:955-62

Primary events after transitioning from randomized to open-label therapy in ROCKET-AF and ARISTOTLE trial Patel et al. NEJM 2011;365:883-91 Granger et al. Am Heart J 2015;169:25-30

NOACs in Elderly

Sardar et al. J Am Geriatr Soc 2014;62:857-864

Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use Alexander et al. European Heart Journal 2014;35:224-232

Πρόληψη ΑΕΕ και αιμορραγικός κίνδυνος των ΝOACs σε σύγκριση με γουαρφαρίνη Αποτελεσματικότητα (Μείωση ΑΕΕ / ΣΕ) Dabigatran 150 mg BID RR 0.66 (95% CI, 0.53-0.82) Apixaban 5 mg BID HR 0.79 (95% CI, 0.66-0.95) Edoxaban 60 mg daily HR 0.87 (97.5% CI, 0.73-1.04) Rivaroxaban 20 mg daily HR 0.88 (95% CI, 0.74-1.03) Dabigatran 110 mg BID RR 0.91 (95% CY, 0.74-1.11) Edoxaban 30 mg daily HR 1.13 (97.5% CI, 0.96-1.34) ΚΑΛΥΤΕΡΟ ΠΡΟΦΙΛ ΧΕΙΡΟΤΕΡΟ ΠΡΟΦΙΛ Προφίλ Ασφάλειας (Μείζονα Αιμορραγία) Edoxaban 30 mg daily HR 0.47 (97.5% CI, 0.41-0.55) Apixaban 5 mg BID HR 0.69 (95% CI, 0.60-0.80) Dabigatran 110 mg BID RR 0.80 (95% CI, 0.69-0.93) Edoxaban 60 mg daily HR 0.80 (97.5% CI, 0.71-0.91) Dabigatran 150 mg BID RR 0.93 (95% CI, 0.81-1.07) Rivaroxaban 20 g daily HR 1.04 (95% CI, 0.90-1.20) Δεν υπάρχουν μελέτες άμεσης σύγκρισης και κατά συνέπεια δεν μπορούν να πραγματοποιηθούν συγκρίσεις μεταξύ των παραγόντων 1 Προσαρμογή από Schulman S. Thromb Haemost 2014; 111 : doii:10.1160/th13-09-0803

Patients with AF on NOACs undergoing a planned surgical intervention Trials have shown that about 1/4 of patients that are in need for anticoagulant therapy require temporary cessation within 2 years Healey et al. Circulation 2012;126:343-8 Bridging with LMWH or heparin is not necessary in NOAC-treated patients Peri-interventional management of NOACs in daily care: Results from the prospective Dresden NOAC registry 30% of all procedures were performed with bridging Rates of major cardiovascular events were similar for patients without heparin bridging Major bleeding complications were significantly more frequent in patients receiving heparin bridging (2.7%; 95% CI 1.1 5.5%) Beyer-Westendorf et al. European Heart Journal 2014;35:1888-96

NOAC management before elective surgical intervention When the intervention carries no clinically important bleeding risk and/or when adequate local haemostasis is possible (dental procedures, cataract, glaucoma ets) the procedure can be performed at trough concentration of the NOAC 2015 Updated EHRA Practical Guide on the use of non-vka anticoagulants in patients with NVAF. Europace 2015;17:1467 1507