Διαχείριση του θρομβωτικού κινδύνου με Rivaroxaban,σε ασθενείς με Αρτηριακή Υπέρταση και Κολπική Μαρμαρυγή

Διαχείριση του θρομβωτικού κινδύνου με Rivaroxaban,σε ασθενείς με Αρτηριακή Υπέρταση και Κολπική Μαρμαρυγή Θωμάς Κ. Μακρής, MD FACC, FESC Συντονιστής Διευθυντής Καρδιολογικού Τμήματος ΓΝΜ ΕΛΕΝΑ ΒΕΝΙΖΕΛΟΥ

Δήλωση σύγκρουσης συμφερόντων Τιμητική αμοιβή από τις των εταιρείες Novartis και Bayer

AF is the Most Common Cardiac Arrhythmia Ø AF affects 1 in 25 adults >60 years 1 1 in 10 adults >80 years 1 Ø 6.8 million patients with AF in EU and US* 1,2 EU 4.5 million US 2.3 million 0 1 2 3 4 5 * EU 2001, US 2006, both cited in 2006 guidelines 1. Go AS et al. JAMA 2001;285:2370-2375 2. Fuster V et al. J Am Coll Cardiol 2006;38:1231-1265

Conditions predisposing to, or encouraging progression of AF ESC Guidelines 2010 on the management of Atrial Fibrillation

Patients with hypertension, % Επίπτωση αρτηριακής υπέρτασης σε μελέτες ασθενών με κολπική μαρμαρυγή 90 AF populations 86.6 86.3 90 86 80 62.6 64.4 71 68 63 80 60 49 55 51 51 51.8 40 20 0

Hypertension and atrial fibrillation Hypertension is the most prevalent concomitant condition in patients with atrial fibrillation, in both Europe and the USA. Even high normal BP is associated with the development of atrial fibrillation, and hypertension is likely to be a reversible causative factor

Atrial fibrillation consequences Loss of atrial systolic function (atrial contribution to ventricular filling is lost) Irregular rapid ventricular contractions Right atrium Left atrium Cardiac output reduced Abnormal blood flow and stasis in the atria Formation of intra-atrial thrombus

AF is an Independent Risk Factor for Stroke AF patients have a near 5-fold increased risk of stroke 1 1 in every 6 strokes occurs in a patient with AF 2 Ischemic stroke associated with AF is typically more severe than stroke due to other etiologies 3 Stroke risk persists even in asymptomatic AF 4 1. Wolf et al. Stroke 1991;22:983-988 2. Fuster V et al. Circulation 2006;114:e257-e354 3. Dulli DA et al. Neuroepidemiology 2003;22:118-123 4. Page RL et al. Circulation 2003;107:1141-1145

The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* Congestive Heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke or TIA 2 10 Moderate- High risk >2 50-60 Low risk 0-1 40-50 VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

CHA 2 DS 2 -VASc Assessment of Thromboembolic Risk Congestive HF/ left ventricular dysfunction 1 Hypertension 1 Age 75 years 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1 (CAD, AoD, PAD) Age 65 74 years 1 Sex category (female) 1 OR for stroke if: Female: 2.53 (1.08 5.92), p=0.029; Vascular disease: 2.27 (0.94 5.46), p=0.063 Score 0 9 Score Annual stroke rate, % n 1,084 1 73,538 2 0 0 0.78 1 1.3 2.01 2 2.2 3.71 3 3.2 5.92 4 4.0 9.27 5 6.7 15.26 6 9.8 19.74 7 9.6 21.50 8 6.7 22.38 9 15.2 23.64 Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey AoD, arterial occlusive disease; CAD, coronary artery disease; OAC, oral anticoagulant; OR, odds ratio; PAD, peripheral artery disease; TE, thromboembolic event 1. Lip GY, et al. Chest 2010;137(2):263 272; 2. Olesen JB, et al. BMJ 2011;342:d124.

Current Treatment Strategies for AF Prevention of thrombo-embolism Rate control Rhythm control ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

Anticoagulation General Recommendations for prevention of thromboembolism in NVAF general Recommendations Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications. The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. I I A A The CHA 2 DS 2 -VASc score is recommended as a means of assessing stroke risk in NVAF. I A NVAF, non-valvular atrial fibrillation Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

Antithrombotic Drug Choices for Stroke Prevention Oral antithrombotic agents Antiplatelets Anticoagulants Aspirin Clopidogrel Vitamin K antagonists New oral anticoagulants Direct Thrombin Inhibitors Factor Xa Inhibitors

Warfarin compared with Aspirin for stroke prevention in AF Warfarin better Aspirin better AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II Age 75 yrs Age >75 yrs All trials RRR 38% (95% CI: 18 52%) 100 50 0 50 RRR (%)* 100 Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857 67

Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions Warfarin Better Antiplatelet Rx Better ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel n = 6,706 Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4,232 100% 50% 0-50% Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

AF-related stroke is preventable Effect of VKA compared to placebo Anticoagulation with a vitamin-k-antagonist (VKA) is recommended for patients with more than 1 moderate risk factor (age,hbp, CHF or LVD, Diabetes) 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-k-antagonist (INR 2-3) 1 A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in allcause mortality 1 Stroke 67% Death 26% 1. Hart RG et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-906

Odds Ratio Therapeutic Range for Warfarin INR Values at Stroke or ICH 15.0 Stroke 10.0 Intracranial Hemorrhage 5.0 1.0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR Fuster et al. J Am Coll Cardiol. 2001;38:1231-1266.

The HAS-BLED Score Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) H ypertension (>160 mmhg systolic) 1 A bnormal renal or hepatic function 1-2 S troke 1 B leeding history or anemia 1 L abile INR (TTR <60%) 1 E lderly (age >75 years) 1 D rugs (antiplatelet, NSAID) or alcohol 1-2 High risk (>4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (<2%.year) 0-1 Pisters R, et al Chest 2010 (online) http://chestjournal.chestpubs.org/content/early/2010/03/18/chest.10-0134

Underuse of oral anticoagulants in AF: A Systematic Review Underuse of oral anticoagulants for high-risk atrial fibrillation patients was found in most of the 54 studies (1998-2008) reporting both patient stroke risk and patients treated. Over two thirds of studies of atrial fibrillation patients with prior stroke or transient ischemic attack reported treatment levels of under 60% of eligible patients. Most studies based on CHADS2 score reported oral anticoagulant treatment levels of high-risk subjects below 70%. Ogilvie I et al Am J Med 2010;123:638

Advantages and Diasadvantages of Current Antithrombotics Advantages Used for many years Disadvantages Erratic INR control / frequent monitoring Well studied/experience Effective if INR kept in therapeutic range Well known drug and food interactions Low cost Antidote/easy to recover Narrow therapeutic index Medications adjustments often required Drug and food interactions Risk of bleeding Patients reluctance Underuse in high risk patients

New Oral Anticoagulants for Stroke Prevention in AF Direct inhibitors of factor Xa or thrombin

Novel Anticoagulants Warfarin Sites of Action II VII IX X X Fibrinogen TF/VIIa VIIIa Xa II IIa (Thrombin) IXa IX Fibrin Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban Idraparinux (SQ) LY517717 YM150 TAK-442 Direct Thrombin Inhibitors Ximelagatran Dabigatran AZD-0837 Circulation 2010; 121: 1523-1532

Comparison of Features of New Anticoagulants With Those of Warfarin Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few Monitoring Yes No Half-life Long Short Antidote Yes No

Atrial Fibrillation Phase 3 Study Timelines Dabigatran Rivaroxaban RE-LY RELYABLE ROCKET AHA 11/10 2009 2010 2011 ARISTOTLE Estimated completion November 2010 60. 000 patients!!! Apixaban

RE-LY: Stroke or Systemic Embolism Dabigatran 110 (twice daily) vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 (twice daily) vs. Warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Dabigatran better Warfarin better Connolly et al., NEJM, 2009

RE-LY: Results Dabigatran 110 mg (%/yr) Dabigatran 150 mg (%/yr) Warfarin (%/yr) Primary outcome 1.53 1.11 1.69 Major bleeding 2.71 3.11 3.36 Hemorrhagic stroke 0.12* 0.10* 0.38 Mortality 3.75 3.64 4.13 Dabigatran 110 mg twice daily Similar rate of ischemic stroke and systemic embolism Lower rate of major hemorrhage * P <.001 vs warfarin Dabigatran 150 mg twice daily Lower rate of ischemic stroke and systemic embolism Similar rate of major hemorrhage Conolly SJ et al. N Engl J Med 2009;361:1139-1151

ARISTOTLE Main Trial Results Stroke or systemic embolism ISTH major bleeding (twice daily) 21% RRR 31% RRR (twice daily) Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66 0.95); P=0.011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60 0.80); P<0.001 Median TTR 66% Granger CB et al. N Eng J Med 2011

ROCKET AF Trial Rivaroxaban Atrial Fibrillation Randomize Double blind / Double Dummy (n ~ 14,000) Risk Factors CHF Hypertension At least 2 Age 75 required Diabetes OR Stroke, TIA, or Systemic embolus Warfarin 20 mg (once daily) 15 mg for Cr Cl 30-49 INR target - 2.5 (2.0-3.0 inclusive) Monthly monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns systemic embolism Statistics: non-inferiority, >95% power, 2.3% warfarin event rate 45 countries, 1178 sites, 14,264 patients

ROCKET AF Rivaroxaban vs warfarin Patient characteristics Characteristic Rivaroxaban (N=7,131) Warfarin (N=7,133) Age, median (25th, 75th), years 73 (65, 78) 73 (65, 78) Female, % 39.7 39.7 Body mass index, median, kg/m 2 28.3 28.1 Blood pressure, median, mm Hg Systolic 130 130 Diastolic 80 80 Clinical presentation, n (%) Type of AF Persistent 5,786 (81.1) 5,762 (80.8) Paroxysmal 1,245 (17.5) 1,269 (17.8) Newly diagnosed/new onset 100 (1.4) 102 (1.4) Previous ASA use 2,586 (36.3) 2,619 (36.7) Previous VKA use 4,443 (62.3) 4,461 (62.5) ITT population Patel MR et al. N Engl J Med 2011;365:883 891

ROCKET-AF Baseline Demographics Demographic CHADS 2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) Rivaroxaban (N=7081) 3.48 13 43 29 87% 13 2 Warfarin (N=7090) 3.46 13 44 28 87% 12 2 Prior VKA Use (%) 62 63 Congestive Heart Failure (%) 63 62 Hypertension (%) 90 91 Diabetes Mellitus (%) 40 39 Prior Stroke/TIA/Embolism (%) 55 55 Prior Myocardial Infarction (%) 17 18

Baseline Patient Demographics: The Novel AC Trials CHADS 2 score (%) 0 1 2 3 ROCKET AF RE-LY ARISTOTLE <1 32 34 13 36 36 87 32 30 Median CHADS 2 score% 3.47% 2% 2% Risk factors (%) CHF or LVEF 35% 62 32 35 Hypertension 91 79 87 Age 75 years 44 31 Diabetes mellitus 40 23 25 Prior stroke, TIA, or non-cns SE 55 20 19 Rivaroxaban Dabigatran Apixaban

Cumulative event rate (%) Primary Efficacy Outcome Stroke and non-cns Embolism 6 5 4 Event Rate Rivaroxaban Warfarin 1.71 2.16 Warfarin 3 Rivaroxaban 2 HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 1 0 0 120 240 360 480 600 720 840 960 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

ROCKET-AF: Primary Safety Outcomes Outcome Major >2 g/dl Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death Rivaroxaban Event Rate or N (Rate) 3.60 2.77 1.65 0.82 0.24 Warfarin Event Rate or N (Rate) 3.45 2.26 1.32 1.18 0.48 HR (95% CI) 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) P-value 0.576 0.019 0.044 0.007 0.003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019 Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 4 (0.04) 1 (0.01) Mahaffey KW and Fox KAA. AHA 2010 Event Rates are per 100 patient-years Based on Safety on Treatment Population

Adverse Events and Liver Enzyme Data Adverse Events Any Adverse Event Any Serious Adverse Event AE leading to study drug discontinuation Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea Rivaroxaban (N=7111) 82.4 37.3 15.7 10.1 6.1 6.1 5.9 5.6 5.6 5.3 5.3 Warfarin (N=7125) 82.2 38.2 15.2 8.6 6.2 6.3 6.4 5.9 5.9 5.5 5.6 ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN 2.9 1.0 0.4 2.9 1.0 0.5 Values are N (%) Based on Safety Population

Possible drug-drug interactions Effect on NOAC plasma levels Dabigatran Apixaban Rivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect Digoxin P-gp no effect no data yet no effect Verapamil P-gp/ wk CYP3A4 +12 180% no data yet minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% minor effect Quinidine P-gp +50% no data yet +50% Amiodarone P-gp +12 60% no data yet minor effect Dronedarone P-gp/CYP3A4 +70 100% no data yet no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 +140 150% +100% up to +160%

Rivaroxaban Dosage and Administration Nonvalvular Atrial Fibrillation Dosing Normal Renal Function (CrCl > 50 ml/min) 20 mg once daily* Moderate Renal Impairment (CrCl 15 50 ml/min) 15 mg once daily* Severe Renal Impairment (CrCl < 15 ml/min) Avoid use

New oral anticoagulants Rivaroxaban Dabigatran Apixaban Dose once daily twice daily Median CHADS2 3.47% 2 % score

Recommendations Relating to Stroke Risk Recommendations Class Level In patients with a CHA 2 DS 2 -VASc score of 0 (i.e., aged <65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended. Ιn patients with a CHA 2 DS 2 -VASc score 2, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (ei.g., rivaroxaban, apixaban). is recommended, unless contraindicated. In patients with a CHA 2 DS 2 -VASc score of 1, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban). should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. I I IIa B A A Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

Switching between anticoagulant regimens VKA to NOAC INR <2.0: immediate INR 2.0 2.5: 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) NOAC to VKA NOAC to parenteral anticoagulant NOAC to NOAC Aspirin or clodiprogel to NOAC Start once UFH discontinued ( t½=2h ). May be longer in patients with renal impairment Start when next dose would have been given 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 ( 2.0 3.0 ) achieved Initiate when next dose of NOAC is due Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Switch immediately, unless combination therapy needed

Η καρδιοανάταξη σε ασθενείς με ΚΜ Η καρδιοανάταξη είναι μια θεραπευτική στρατηγική, η οποία έχει σαν στόχο, να επαναφέρει τον φυσιολογικό φλεβοκομβικό ρυθμό. Υπάρχουν δύο τύποι καρδιοανάταξης: - Φαρμακολογική (στρατηγική που προτιμάται σε ασθενείς που έχουν εκδηλώσει πρόσφατα ΚΜ, εντός 48 ωρών) - Ηλεκτρική (στρατηγική που προτιμάται όταν η ΚΜ είναι παρατεταμένη) Η καρδιοανάταξη σχετίζεται με αυξημένο κίνδυνο θρομβοεμβολικών επιπλοκών - Ο κίνδυνος μπορεί να περιοριστεί με χορήγηση επαρκούς αντιπηκτικής αγωγής στις εβδομάδες που προηγούνται της καρδιοανάταξης ή με αποκλεισμό της παρουσίας θρόμβων στον αριστερό κόλπο πριν από τη διαδικασία. 1. Trappe HJ et al. Dtsch Arztebl Int 2012;109:1 7; 2. Sulke N et al. Heart 2007;93:29 34; 3. Camm AJ et al. Eur Heart J 2010;31:2369 2429

Η καρδιοανάταξη σε ασθενείς με ΚΜ Οι κατευθυντήριες οδηγίες συνιστούν επαρκή αντιπηκτική αγωγή πριν και μετά την καρδιοανάταξη για ασθενείς με ΚΜ. Ο περιεπεμβατικός κίνδυνος θρομβοεμβολικών επεισοδίων υπό επαρκή αγωγή με VKA είναι 1%. Χωρίς επαρκή αντιπηκτική αγωγή, ο περιεπεμβατικός κίνδυνος θρομβοεμβολής είναι 5 7% Οι VKA είναι η συνιστώμενη αγωγή,η χρήση των νεότερων OAC σε αυτό το επίπεδο στηρίζεται σε περιορισμένα στοιχεία Ένας μικρός αριθμός ασθενών (n=285) υποβλήθηκε σε καρδιοανάταξη στη μελέτη ROCKET AF 1. Camm AJ et al. Eur Heart J 2010;31:2369 2429; 2. January CT et al. J Am Coll Cardiol 2014;14:1740-1749; 3. Gallagher M et al. J Am Coll Cardiol 2002;4:926 9333; 4. Stellbrink C et al. Circulation 2004;109:997 1003; 5. Piccini JP et al. J Am Coll Cardiol 2013;61:1998 2006

X-VeRT: study objectives Προοπτική, Τυχαιοποιημένη Μελέτη Να διερευνηθεί η αποτελεσματικότητα και η ασφάλεια της rivaroxaban μια φορά την ημέρα για την πρόληψη των καρδιαγγειακών επεισοδίων* σε ασθενείς με μη βαλβιδική ΚΜ που έχουν προγραμματιστεί για ηλεκτρική καρδιοανάταξη σε σύγκριση με VKA ρυθμιζόμενης δόσης Ezekowitz MD et al. Am Heart J 2014;167:646 652;

Cardioversion Cardioversion End of study treatment Design: randomized, open-label, parallel-group, active-controlled multicentre study Inclusion criteria: Age 18 years, non-valvular AF lasting >48 h or unknown duration, scheduled for cardioversion Rivaroxaban 20 mg od* Rivaroxaban 20 mg od* Early # R 1 5 days 42 days Cardioversion strategy 2:1 VKA Rivaroxaban 20 mg od* VKA Rivaroxaban 20 mg od* OAC 30-day follow-up Delayed R 2:1 21 days (max. 56 days) VKA 42 days VKA *15 mg if CrCl 30 49 ml/min; VKA with INR 2.0 3.0; # protocol recommended only if adequate anticoagulation or immediate TEE Ezekowitz MD et al. Am Heart J 2014;167:646 652;

X-VeRT: θεραπεία μελέτης Ριβαροξαβάνη 20 mg μία φορά ημερησίως - Η πρώτη δόση πρέπει να ξεκινήσει 4 ώρες τουλάχιστον πριν από την καρδιοανάταξη (ασθενείς που δεν έχουν λάβει OAC/θεραπεία) - Μείωση της δόσης έως 15 mg άπαξ ημερησίως για ασθενείς με μέτρια νεφρική ανεπάρκεια [CrCl 30 49 ml/min] - Συμμόρφωση κατά 80% τουλάχιστον πριν από την καρδιοανάταξη στην ομάδα καθυστερημένης καρδιοανάταξης VKA με στοχευόμενο INR 2,5 (εύρος τιμών 2,0 3,0) - Τύπος VKA σύμφωνα με τα τοπικά πρότυπα θεραπείας - Απαιτείται εβδομαδιαία μέτρηση του λόγου INR στη διάρκεια της μελέτης για να διασφαλιστεί ότι η τιμή του INR εμπίπτει στο στοχευόμενο εύρος - Τρεις διαδοχικές εβδομαδιαίες μετρήσεις του INR με τιμή πάνω από 2,0 πριν από την καρδιοανάταξη 1. Ezekowitz MD et al. Am Heart J 2014;167:646 652; 2. www.clinicaltrials.gov. NCT01674647

X-VeRT: main exclusion criteria (1) Severe, disabling stroke within 3 months or any stroke within 14 days before the randomization visit TIA within 3 days prior to randomization Acute thromboembolic events or thrombosis within the last 14 days prior to randomization Acute MI within the last 14 days prior to randomization Cardiac-related criteria: - Known presence of LA/LAA thrombus before study inclusion - Known presence of atrial myxoma - Known left ventricular or aortic thrombus - Valvular heart disease (either hemodynamically significant mitral valve stenosis or prosthetic heart valve) Ezekowitz MD et al. Am Heart J 2014;167:646 652;

X-VeRT: main exclusion criteria Active bleeding or high risk of bleeding contraindicating anticoagulant therapy Concomitant drugs/therapies: - Indication for anticoagulant therapy for a condition other than AF - Chronic ASA therapy >100 mg daily or dual antiplatelet therapy - Concomitant use of strong inhibitors of both CYP3A4 and P-gp and the following azole antimycotic agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically 1. Ezekowitz MD et al. Am Heart J 2014;167:646 652;

X-VeRT: δημογραφικά στοιχεία Ριβαροξαβάνη (n=1,002) VKA (n=502) Σύνολο (N=1,504) Ηλικία, μέση τιμή (SD), έτη 64,9 (10,6) 64,7 (10,5) 64,9 (10,5) Γυναίκες, % 27,4 26,9 27,3 CHADS2 score, μέση τιμή (SD) 1,3 (1,0) 1,4 (1,0) 1,4 (1,1) CHA2DS2VASc score μέση τιμή (SD) 2.3 (1.6) 2,3 (1,6) 2,3 (1,6) Υπέρταση, % 65,0 68,7 66,2 Συμφορητική καρδιακή ανεπάρκεια, % 19,7 14,9 18,1 Προηγούμενο εγκεφαλικό/πιε ή ΣΕ, % 6,7 9,8 7,7 Σακχαρώδης διαβήτης, % 20,3 20,5 20,3 Τύπος ΚΜ, %* Πρώτη διάγνωση 23,8 21,1 22,9 Παροξυσμική 17,2 22,7 19,0 Εμμένουσα 55,9 50,0 53,9 Μακροχρόνια εμμένουσα 3,0 5,2 3,7 *Απώλεια δεδομένων σε 7 ασθενείς. Νεφρική λειτουργία: 92,5% των ασθενών είχαν CrCl 50 ml/min πληθυσμός ITT Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: primary endpoints Primary efficacy endpoints A composite of: Stroke and TIA Primary safety endpoint Major bleeding (ISTH definition) Non-CNS systemic embolism Myocardial infarction Cardiovascular death All endpoints adjudicated by treatment assignment-blinded Clinical Endpoint Committee 1. Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; 2. Schulman S et al. J Thromb Haemost 2005;3:692 694

X-VeRT: study population Screening (N=1584) Randomized (N=1504) Excluded (n=80) Screening failure (n=71) Withdrawal by patient (n=7) Adverse event (n=2) Rivaroxaban (n=1002) Rivaroxaban (n=978) Rivaroxaban (n=988) 2:1 ITT population All patients randomized Safety population Patients receiving 1 dose of study drug mitt population (primary analysis set) All ITT patients without LA/LAA thrombi VKA (n=499) VKA (n=502) VKA (n=492) 34 patients (24 rivaroxaban, 10 VKA) were not included in the mitt population (n=1470; 978 rivaroxaban, 492 VKA) due to the identification of an LA thrombus Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; Cappato R. ESC Congress 2014. Oral presentation 4945

X-VeRT: primary efficacy endpoints Rivaroxaban (N=978) VKA (N=492) % n* % n* Risk ratio (95% CI) Primary efficacy endpoint 0.51 5 1.02 5 0.50 (0.15 1.73) Stroke 0.20 2 0.41 2 Haemorrhagic stroke 0.20 2 0 Ischaemic stroke 0 0.41 2 TIA 0 0 Non-CNS SE 0 0.20 1 MI 0.10 1 0.20 1 Cardiovascular death 0.41 4 0.41 2 *Number of patients with events; patients may have experienced more than one primary efficacy event mitt population Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: primary efficacy endpoint by population Rivaroxaban % n*/n VKA % n*/n Risk ratio (95% CI) Favours rivaroxaban Favours VKA mitt population 0.51 5/978 1.02 5/492 0.50 (0.15 1.73) ITT population 0.50 5/1002 1.00 5/502 0.50 (0.15 1.72) Safety population (on-treatment) 0.51 5/988 0.80 4/499 0.63 (0.17 2.34) 0,1 1 10 The trend in risk ratio in favour of rivaroxaban was consistent for all populations analysed *Number of patients with events Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: primary safety endpoints Rivaroxaban (N=988) VKA (N=499) % n* % n* Risk ratio (95% CI) Major bleeding 0.61 6 0.80 4 0.76 (0.21 2.67) Fatal 0.1 1 0.4 2 Critical-site bleeding 0.2 2 0.6 3 Intracranial haemorrhage 0.2 2 0.2 1 Hb decrease 2 g/dl 0.4 4 0.2 1 Transfusion of 2 units of packed RBCs or whole blood 0.3 3 0.2 1 *Number of patients with events; patients may have experienced more than one primary safety event Safety population Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

Days Patients (%) X-VeRT: time to cardioversion by cardioversion strategy Median time to cardioversion Patients cardioverted as scheduled* 100 80 60 Rivaroxaban VKA p=0.628 p<0.001 p<0.001 1 patient with inadequate anticoagulation 40 20 22 days 30 days 95 patients with inadequate anticoagulation 0 Early Delayed Delayed cardioversion *Reason for not performing cardioversion as first scheduled from 21 25 days primarily due to inadequate anticoagulation (indicated by drug compliance <80% for rivaroxaban or weekly INRs outside the range of 2.0 3.0 for 3 consecutive weeks before cardioversion for VKA) Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

Αποτελέσματα της X-VeRT: περίληψη Η πρώτη ολοκληρωμένη προοπτική, τυχαιοποιημένη μελέτη ενός καινοτόμου OAC σε ασθενείς με ΚΜ που υποβάλλονται σε ηλεκτρική καρδιοανάταξη. Χαμηλή και όμοια επίπτωση των επιπλοκών ως το κύριο τελικό σημείο αποτελεσματικότητας μεταξύ των ομάδων θεραπείας. Ανάλογη επίπτωση της σοβαρής αιμορραγίας. Το χρονικό διάστημα έως την καρδιοανάταξη ήταν το ίδιο (άμεση στρατηγική) ή εξαιρετικά μικρότερο (καθυστερημένη στρατηγική) κατά τη χρήση της Rivaroxaban έναντι του VKA. Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; Cappato R. ESC Congress 2014. Προφορική παρουσίαση 4945

Συμπεράσματα Η κολπική μαρμαρυγή είναι μια από τις συχνότερες επιπλοκές της ΑΥ. Η παρουσία της συνδέεται με κκ κίνδυνο και ιδιαίτερα με αυξημένη επίπτωση ΑΕΕ. Τα νέα αντιθρομβωτικά φάρμακα υπό προϋποθέσεις είναι ένα σύγχρονο όπλο στην πρόληψη των θρόμβο εμβολικών επεισοδίων. Πλεονεκτήματα Ανάλογο και πιθανώς επιπρόσθετο όφελος ως προς την μείωση των ΑΕΕ και μικρότερη πιθανότητα εμφάνισης σοβαρών και κυρίως ενδοκρανιακών αιμορραγιών Δεν απαιτείται παρακολούθηση INR Δεν επηρεάζεται η δράση τους από τροφές η φάρμακα Μειονεκτήματα Πως θα εκτιμήσουμε την συμμόρφωση Δεν υπάρχει προς το παρόν αντίδοτο ( αναμένεται σύντομα ) Συμπτωματική αντιμετώπιση των αιμορραγιών

Συμπεράσματα Η rivaroxaban έχει το πλεονέκτημα της μιας δόσης /24ωρο γεγονός το οποίο συμβάλει στη συμμόρφωση και παραμονή των ασθενών στη θεραπεία. Δεν έχει αλληλεπιδράσεις με τροφές και βασικά καρδιολογικά φάρμακα Έχει δώσει ευεργετικά αποτελέσματα σε ασθενείς πολύ υψηλότερου κκ κινδύνου συγκριτικά με τους άλλους εκπροσώπους της κατηγορίας, ενώ φαίνεται να είναι αποτελεσματική και ασφαλής στην ηλεκτρική ανάταξη της κολπικής μαρμαρυγής.

Properties of an Ideal Anticoagulant Properties Oral, once-daily dosing Rapid onset of action Benefit Ease of administration No need for overlapping parenteral anticoagulant Minimal food or drug interactions Simplified dosing Predictable anticoagulant effect No coagulation monitoring Extra renal clearance Safe in patients with renal disease Rapid offset in action Antidote Simplifies management in case of bleeding or intervention For emergencies

Cardioversion in patients with AF Cardioversion is a rhythm-control treatment strategy that, if successful, restores normal sinus rhythm Two types of cardioversion: - Pharmacological (preferred strategy in patients presenting with recent-onset AF; within 48 hours) 2 - Electrical (preferred strategy when AF is prolonged) 2 Cardioversion is associated with an increased risk of thromboembolic complications - Risk can be reduced by adequate anticoagulation in the weeks prior to cardioversion or by exclusion of LA thrombi before the procedure 3 1. Trappe HJ et al. Dtsch Arztebl Int 2012;109:1 7; 2. Sulke N et al. Heart 2007;93:29 34; 3. Camm AJ et al. Eur Heart J 2010;31:2369 2429

Cardioversion in patients with AF Current guidelines recommend sufficient anticoagulation before and after cardioversion for patients with AF - 1% perioperative risk of thromboembolic events with VKA Without adequate anticoagulation, the periprocedural risk of thromboembolism with cardioversion is 5 7% VKAs are the current standard of care, with limited evidence supporting the use of novel OACs in this setting - A small number of patients (n=285) underwent cardioversion in ROCKET AF 1. Camm AJ et al. Eur Heart J 2010;31:2369 2429; 2. January CT et al. J Am Coll Cardiol 2014;14:1740 1749; 3. Gallagher M et al. J Am Coll Cardiol 2002;4:926 9333; 4. Stellbrink C et al. Circulation 2004;109:997 1003; 5. Piccini JP et al. J Am Coll Cardiol 2013;61:1998 2006 X-VeRT: study objectives To explore efficacy and safety of once-daily rivaroxaban for the prevention of cardiovascular events* in patients with non-valvular AF scheduled for elective cardioversion compared with dose-adjusted VKAs

X-VeRT: study treatment Rivaroxaban 20 mg once daily - First dose should be started at least 4 hours before cardioversion (OAC-naïve/untreated patients) - Dose reduction to 15 mg once daily for patients with moderate renal impairment (CrCl 30 49 ml/min) - Compliance of at least 80% before cardioversion in the delayed cardioversion group VKA with target INR 2.5 (range 2.0 3.0) - VKA type according to local treatment standards - Weekly INR monitoring required throughout the study to ensure INR within the target range - Three consecutive weekly INR measurements >2.0 before cardioversion 1. Ezekowitz MD et al. Am Heart J 2014;167:646 652; 2. www.clinicaltrials.gov. NCT01674647

X-VeRT: baseline demographics Rivaroxaban (n=1,002) VKA (n=502) Total (N=1,504) Age, mean (SD), years 64.9 (10.6) 64.7 (10.5) 64.9 (10.5) Female, % 27.4 26.9 27.3 CHADS 2 score, mean (SD) 1.3 (1.0) 1.4 (1.0) 1.4 (1.1) CHA 2 DS 2 VASc score, mean (SD) 2.3 (1.6) 2.3 (1.6) 2.3 (1.6) Hypertension, % 65.0 68.7 66.2 Congestive heart failure, % 19.7 14.9 18.1 Previous stroke/tia or SE, % 6.7 9.8 7.7 Diabetes mellitus, % 20.3 20.5 20.3 Type of AF, %* First-diagnosed 23.8 21.1 22.9 Paroxysmal 17.2 22.7 19.0 Persistent 55.9 50.0 53.9 Long-standing persistent 3.0 5.2 3.7 *Data missing in 7 patients. Renal function: 92.5% of patients had CrCl 50 ml/min ITT population Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT results: summary First completed prospective, randomized trial of a novel OAC in patients with AF undergoing elective cardioversion Low and similar incidence of primary efficacy endpoint events between the treatment arms Similar incidence of major bleeding Time to cardioversion was similar (early strategy) or significantly shorter (delayed strategy) using rivaroxaban compared with VKA Oral rivaroxaban 20 mg once daily appears to be an effective and safe alternative to VKA, and allows prompt elective cardioversion in patients with AF Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; Cappato R. ESC Congress 2014. Oral presentation 4945

ARISTOTLE: Apixaban versus Warfarin in patients with AF End point Apixaban Warfarin HR(95% CI) p (%/year) (%/year) Stroke or systemic embolism* 1.27 1.60 0.79 <0.01 Major bleeding 2.13 3.09 0.69 <0.001 All-cause mortality 3.52 3.94 0.89 <0.047 Hemorrhagic stroke 0.24 0.47 0.51 <0.001 Ischemic/uncertai n stroke 0.97 1.05 0.92 <0.42 *Primary end point Granger CB et al. N Eng J Med 2011, on line

If anticoagulation must be discontinued to reduce the risk of bleeding with surgery, then Rivaroxaban should be stopped at least 24 hours before the procedure In deciding whether a procedure should be delayed until 24 hours after the last dose of Rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established -If oral medication cannot be taken after surgical intervention, consider a parenteral anticoagulant -Wait at least 18 hours after last dose before removal of epidural catheter, and do not restart until at least 6 hours after removal.

CrCl (ml/min) Recommended Once-daily Dose of XARELTO >50 20 mg 15 to 50 15 mg* <15 Avoid use

ESC 2012 Atrial Fibrillation Guidelines Update: Risk Assessment Risk Profile Class / Level CHA 2 DS 2 -VASc = 0 No antithrombotic therapy I B CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A (Favored) VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban I A (Favored)

Rivaroxaban Dosage and Administration Rivaroxaban Dosage and Administration Approved Dosage Forms 10, 15, & 20 mg tablets Nonvalvular Atrial Fibrillation Dosing Normal Renal Function (CrCl > 50 ml/min) Moderate Renal Impairment (CrCl 15 50 ml/min) Severe Renal Impairment (CrCl < 15 ml/min) 20 mg once daily* 15 mg once daily* Avoid use Prophylaxis of DVT 10 mg once daily with or without food

NOACS vs. Warfarin: Cochrane Database Efficacy and Safety Meta-Analysis Factor Xa Inhibitors Compared with Vitamin K Antagonists for the Prevention of Stroke and other Systemic Embolic Events in Patients with Atrial Fibrillation Illustrative Comparative Risks* (95% CI) Clinical Outcomes Stroke and other systemic embolic events (Follow-up: 12 weeks to 1.9 years) All strokes (Follow-up: 12 weeks to 1.9 years) Major bleedings (Follow-up: 12 weeks to 1.9 years) Intracranial hemorrhages (Follow-up: 12 weeks to 1.9 years) All-cause deaths (Follow-up: 12 weeks to 1.9 years) Assumed Risk Warfarin 32 per 1000 27 per 1000 46 per 1000 11 per 1000 51 per 1000 Corresponding Risk Factor Xa Inhibitors 25 per 1000 (0 to 38) 20 per 1000 (0 to 26) 39 per 1000 (0 to 55) 6 per 1000 (0 to 8) 45 per 1000 (0 to 66) Bruins Slot KM, Berge E. Cochrane Database Syst Rev. 2013 Aug 8;8:CD008980.

Rivaroxaban TF/VIIa Direct, specific, competitive factor Xa inhibitor X IX Half-life 5-13 hours VIIIa Va IXa Rivaroxaban Clearance : - 1/3 direct renal excretion - 2/3 metabolism via CYP 450 enzymes Xa Oral, once daily dosing with largest meal without need for coagulation monitoring II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

Switching between anticoagulant regimens VKA to NOAC INR <2.0: immediate INR 2.0 2.5: 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) NOAC to VKA NOAC to parenteral anticoagulant NOAC to NOAC Aspirin or clodiprogel to NOAC Start once UFH discontinued ( t½=2h ). May be longer in patients with renal impairment Start when next dose would have been given 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 ( 2.0 3.0 ) achieved Initiate when next dose of NOAC is due Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Switch immediately, unless combination therapy needed

X-VeRT: κύρια τελικά σημεία Κύρια τελικά σημεία αποτελεσματικότητας Ένα σύνθετο σημείο που αποτελείται από: Εγκεφαλικό επεισόδιο και ΠΙΕ Κύριο τελικό σημείο ασφάλειας Σοβαρή αιμορραγία (ορισμός ISTH) Συστηματική εμβολή εκτός ΚΝΣ Έμφραγμα μυοκαρδίου Θάνατος από καρδιαγγειακά αίτια 1. Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; 2. Schulman S et al. J Thromb Haemost 2005;3:692 694

Current Treatment Strategies for AF ACE inhibitors and angiotensin receptor blockers (and beta-blockers and mineralocorticoid receptor antagonists if heart failure coexists) should be considered as antihypertensive agents in patients at risk of new or recurrent atrial fibrillation. C IIa -- L C

Recommendations for cardioversion in patients with AF ESC 2012 recommendations: 1 Class Level Pericardioversion: For patients with AF of 48 h/unknown duration, OAC for 3 weeks before and for 4 weeks after, regardless of the method After cardioversion: Lifelong oral anticoagulation (VKA or novel OAC) irrespective of maintenance of sinus rhythm after cardioversion in patients with risk factors for stroke or AF recurrence I I B B 2014 AHA/ACC/HRS recommendations: 2 Class Level Cardioversion is recommended for AF or atrial flutter to restore sinus rhythm. If unsuccessful, repeat cardioversion attempts may be made Cardioversion is recommended for AF or atrial flutter with rapid ventricular response, that does not respond to pharmacological therapies Cardioversion is recommended for AF or atrial flutter and pre-excitation with haemodynamic instability It is reasonable to repeat cardioversions in persistent AF when sinus rhythm is maintained for a clinically meaningful time period between procedures I I I IIa B C C C 1. Camm AJ et al. Eur Heart J 2012;33:2719 2747; 2. January CT et al. J Am Coll Cardiol 2014 ;14:1740 1749

X-VeRT rationale and design X-VeRT - International, multicentre, randomized controlled trial - Rivaroxaban versus VKA in patients undergoing cardioversion for AF - First prospective study of a novel OAC in this setting Treatment arms - Rivaroxaban 20 mg once daily (15 mg once daily if CrCl 30 49 ml/min) - VKA with target INR 2.5 (range 2.0 3.0) Cardioversion strategies - Early cardioversion (TEE-guided strategy) - Early cardioversion (non-tee-guided but continued OAC strategy) - Delayed cardioversion (conventional OAC strategy) Ezekowitz MD et al. Am Heart J 2014;167:646 652

X-VeRT: κύρια τελικά σημεία Αποτελεσματικότητα Ένα σύνθετο σημείο που αποτελείται από: Εγκεφαλικό επεισόδιο και ΠΙΕ Συστηματική εμβολή εκτός ΚΝΣ Έμφραγμα μυοκαρδίου Θάνατος από καρδιαγγειακά αίτια Ασφάλεια Σοβαρή αιμορραγία (κυρίως ISTH ). Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367; Schulman S et al. J Thromb Haemost 2005;3:692 694

X-VeRT: κύρια τελικά σημεία αποτελεσματικότητας Ριβαροξαβάνη (N=978) VKA (N=492) % n* % n* Λόγος κινδύνου (95% CI) Κύριο τελικό σημείο 0,51 5 1,02 5 0,50 (0,15-1,73) Εγκεφαλικό 0,20 2 0,41 2 Αιμορραγικό ΑΕΕ 0,20 2 0 Ισχαιμικό ΑΕΕ 0 0,41 2 ΠΙΕ 0 0 ΣΕ εκτός ΚΝΣ 0 0,20 1 MI 0,10 1 0,20 1 Θάνατος από καρδιαγγειακά αίτια 0,41 4 0,41 2 *Αριθμός ασθενών που εμφανίζουν επεισόδια. Οι ασθενείς μπορεί να έχουν εκδηλώσει περισσότερα από ένα κύρια περιστατικά αποτελεσματικότητας. πληθυσμός Cappato R mitt et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: κύρια τελικά σημεία ασφάλειας Ριβαροξαβάνη (N=988) VKA (N=499) % n* % n* Λόγος κινδύνου (95% CI) Σοβαρή αιμορραγία 0,61 6 0,80 4 0,76 (0,21-2,67) Θανατηφόρος 0,1 1 0,4 2 Αιμορραγία κρίσιμου σημείου 0,2 2 0,6 3 Ενδοκρανιακή αιμορραγία 0,2 2 0,2 1 Μείωση Hb 2 g/dl 0,4 4 0,2 1 Μετάγγιση 2 μονάδων συσκευασμένων ερυθρών αιμοσφαιρίων ή ολικού αίματος 0,3 3 0,2 1 *Αριθμός ασθενών που εμφανίζουν επεισόδια. Οι ασθενείς μπορεί να έχουν εκδηλώσει περισσότερα από ένα κύρια περιστατικά ασφάλειας Πληθυσμός ασφάλειας Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367