Θωμάς Κ. Μακρής, MD FACC, FESC

Κλινικές Μελέτες και Καθημερινή Κλινική Πρακτική των Νεότερων από του Στόματος Αντιπηκτικών: Διαφέρουν ή ταυτίζονται; Θωμάς Κ. Μακρής, MD FACC, FESC Συντονιστής Διευθυντής Καρδιολογικού Τμήματος ΓΝΜ ΕΛΕΝΑ ΒΕΝΙΖΕΛΟΥ

Δήλωση σύγκρουσης συμφερόντων Τιμητική αμοιβή από τις των εταιρείες Novartis, Bayer, Menarini, Win Medica, BIANEX

Η κολπική μαρμαρυγή είναι η συχνότερη καρδιακή αρρυθμία Ø Η κολπική μαρμαρυγή είναι παρούσα 1 in 25 ενήλικες >60 ετών 1 1 in 10 ενήλικες >80 ετών 1 Ø 18 εκατομμύρια ασθενείς με κολπική μαρμαρυγή σε EU and US* 1,2 EU 10 εκατομμύρια US 8 εκατομμύρια 0 1 2 3 4 5 1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434; 2. 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

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

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

Η κολπική μαρμαρυγή είναι ανεξάρτητος παράγοντας κίνδυνου για ΑΕΕ Οι ασθενείς με κολπική μαρμαρυγή έχουν 5 πλάσιο κίνδυνο να εκδηλώσουν ΑΕΕ. 1 στα 6 ΑΕΕ αφορά ασθενείς με κολπική μαρμαρυγή. Τα ισχαιμικά ΑΕΕ που σχετίζονται με κολπική μαρμαρυγή είναι περισσότερο σοβαρά από ΑΕΕ άλλης αιτιολογίας. Ο κίνδυνος ΑΕΕ υπάρχει ακόμα και σε ασυμπτωματική κολπική μαρμαρυγή 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 2. Olesen JB, et al. BMJ 2011;342:d124.

Current Treatment Strategies for AF Prevention of thrombo-embolism Rate control Rhythm control Camm AJ, et al. Europace 2012;14(10):1385 1413; Camm AJ, et al. Eur Heart J 2012;33(21):2719 2747.

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.

AF-related stroke is preventable Anticoagulation with a vitamin-kantagonist (VKA) is recommended for patients with more than 1 moderate risk factor (age, HBP, CHF or LVD, Diabetes). Effect of VKA compared to placebo Stroke Death 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-k-antagonist (INR 2-3). 67% 26% A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality 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 INR 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 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

% INRs INR Control in Routine Practice Is Suboptimal Retrospective, multicentre cohort study (ISAM) Many patients on VKAs have INR outside of the therapeutic range 100 80 Time in therapeutic range INR <2 INR 2 3 INR >3 60 40 20 0 US Canada France Italy Spain Ansell J et al. J Thromb Thrombolysis 2007;23(2):83-91

Πλεονεκτήματα και Μειονεκτήματα των ανταγωνιστών της βιταμίνης Κ (VKA) Πλεονεκτήματα Είναι σε χρήση για πολλά χρόνια Καλές μελέτες/ μεγάλη εμπειρία Αποτελεσματικοί εάν επιτευχτεί το θεραπευτικό εύρος του INR Γνωστές αλληλεπιδράσεις με τροφές και φάρμακα Μειονεκτήματα Προβλήματα στη ρύθμιση του INR/ Συχνός έλεγχος Στενά περιθώρια του θεραπευτικού δείκτη Αλληλεπιδράσεις με φάρμακα και τροφές Κίνδυνος αιμορραγιών Χαμηλό κόστος Υπάρχει αντίδοτο Απροθυμία των ασθενών Δεν χορηγείται στο βαθμό που επιβάλλεται σε ασθενείς υψηλού κινδύνου. Ogilvie I et al Am J Med 2010;123:638

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 Yes Mueck W et al. Thromb Haemost. 2008;100(3):453-461; Raghavan N et al. Drug Metab Dispos. 2009;37(1):74-81; Shantsila E, Lip GY. Curr Opin Investig Drugs 2008;9(9):1020-1033; Ageno W et al. Chest 2012;141(2):e44S-e88S

Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2,900 Patients NOACs vs. Warfarin 71,683 Patients 6 Trial of Warfarin vs. Placebo 1989-1993 ROCKET AF (Rivaroxaban) 2010 ENGAGE AF-TIMI 48 (Edoxaban) 2013 RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

NOAC Τι έχουν δείξει οι κλινικές μελέτες;

Comparing Phase III Trials: Results are Consistent for Reduction in Stroke/SE Meta-analysis of four phase III trials: Stroke/SE Novel OAC (events)* Warfarin (events) RR (95% CI) p-value RE-LY (dabigatran) 134/6,076 199/6,022 0.66 (0.53 0.82) 0.0001 ROCKET AF (rivaroxaban) 269/7,081 306/7,090 0.88 (0.75 1.03) 0.12 ARISTOTLE (apixaban) 212/9,120 265/9,081 0.80 (0.67 0.95) 0.012 ENGAGE AF-TIMI 48 (edoxaban) 296/7,035 337/7,036 0.88 (0.75 1.02) 0.10 Combined (random) 911/29,312 1,107/29,229 0.5 Favours novel OAC 1 Favours 2 warfarin 0.81 (0.73 0.91) <0.0001 Heterogeneity: I²=47%; p=0.13 Different risk profiles *Novel OAC doses as follows: Dabigatran 150 mg BID, Rivaroxaban 20 mg OD, Apixaban 5 mg BID, Edoxaban 60 mg OD Ruff CT et al. Lancet. 2014;383(9921):955-962

Comparing Phase III Trials: Results are Consistent for Major Bleeding Meta-analysis of four phase III trials: Major bleeding Novel OAC (events)* Warfarin (events) RR (95% CI) p-value RE-LY (dabigatran) 375/6,076 397/6,022 0.94 (0.82 1.07) 0.34 ROCKET AF (rivaroxaban) 395/7,111 386/7,125 1.03 (0.90 1.18) 0.72 ARISTOTLE (apixaban) 327/9,088 462/9,052 0.71 (0.61 0.81) <0.0001 ENGAGE AF-TIMI 48 (edoxaban) 444/7,012 557/7,012 0.80 (0.71 0.90) 0.0002 Combined (random) 1,541/29,287 1,802/29,211 0.86 (0.73 1.00) 0.06 0.5 Favours novel OAC 1 Favours 2 warfarin Heterogeneity: I²=83%; p=0.001 Different risk profiles *Novel OAC doses as follows: Dabigatran 150 mg BID, Rivaroxaban 20 mg OD, Apixaban 5 mg BID, Edoxaban 60 mg OD Ruff CT et al. Lancet. 2014;383(9921):955-962

NOACs vs. Warfarin: Overall Outcomes Risk ratio (95% CI) Absolute risk reduction, % Risk ratio (95% CI) p-value Ischaemic stroke 0.21 Haemorrhagic stroke 0.46 Myocardial infarction 0.07 All-cause mortality 0.78 0.92 (0.83 1.02) p=0.10 0.49 (0.38 0.64) p<0.0001 0.97 (0.78 1.20) p=0.77 0.90 (0.85 0.95) p=0.0003 0.2 0.5 1 2 Favours Favours NOAC warfarin Ruff CT et al, Lancet 2014;383:955 962

NOAC Διαφορές ως προς τα χαρακτηριστικά των ασθενών και τη δοσολογία Τι έχουν δείξει οι κλινικές μελέτες;

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

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 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 Patel MR et al. N Engl J Med 2011;365:883 891

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 1 HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 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: Significant Reduction in Critical Bleedings vs. Warfarin Parameter Rivaroxaban (N=7,111) n (%/year) Warfarin (N=7,125) n (%/year) Hazard ratio (95% CI) Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.96 1.11) Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90 1.20) Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03 1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01 1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53 0.91)* Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 (0.47 0.93)* Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31 0.79)* Non-major clinically relevant bleeding Major bleeding and non-major clinically relevant bleeding; *Statistically significant, p<0.05 Safety on-treatment population 1,185 (11.8) 1,151 (11.4) 1.04 (0.96 1.13) 0.2 0.5 1 2 5 Favours rivaroxaban Favours warfarin Patel MR et al. N Engl J Med. 2011;365(10):883-891

ROCKET AF: Consistent Benefit Across Different Co-morbidities for the Challenging AF Patients Primary Efficacy Endpoint: Stroke/SE (n=14,171) Comorbidity / risk factor Patient (%) HR (95% CI) C CHF 62 0.91 (0.74 1.13) H Hypertension 91 0.87 (0.73 1.03) A Elderly 75 years 43 0.80 (0.63 1.02) D Diabetes 40 0.74 (0.54 1.01) S 2 Prior stroke or TIA Mean CHADS 2 Score 3.5 55 0.94 (0.77 1.16) 0.1 Favours rivaroxaban 1 1.5 Favours 2.0 warfarin Per-protocol population Patel MR et al. N Engl J Med. 2011;365(10):883-891

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 Patel MR et al. N Engl J Med 2011;365:883 891

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 Patel MR et al. N Engl J Med 2011;365:883 891

Comparing Phase III Trials: There are Differences in Patient Characteristics and Dosage Rivaroxaban Dabigatran Apixaban Dose once daily twice daily Median CHADS2 3.47% 2 score Patel MR et al. N Engl J Med 2011;365:883 891

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.

Χρειαζόμαστε μελέτες πραγματικού πληθυσμού Δηλαδή μελέτες σε μη επιλεγμένους πληθυσμούς Οι μελέτες φάσης ΙΙΙ μας παρέχουν το gold standard για την εκτίμηση της αποτελεσματικότητας και της ασφάλειας σε σχέση τις τρέχουσες φροντίδες υγείας. Όμως Λόγω των πολύ αυστηρών πρωτοκόλλων καθώς των κριτηρίων εισόδου και αποκλεισμού στη μελέτη, αποκλείουν ασθενείς και περιορίζουν την επέκταση των αποτελεσμάτων της φάσης ΙΙΙ σε πραγματικό πληθυσμό ασθενών(real word population). Επομένως χρειαζόμαστε μελέτες πραγματικού πληθυσμού, δηλαδή μελέτες σε μη επιλεγμένους πληθυσμούς, αλλά αυτούς που αντιμετωπίζουμε στη καθημερινή κλινική πράξη. Μελέτες, που προσφέρουν επιπρόσθετες πληροφορίες αναφορικά με σπάνια περιστατικά ασφαλείας η την καθημερινή κλινική πρακτική, όπως η αντιμετώπιση σοβαρών αιμορραγιών. Eur Heart J. 2015 Sep 1. pii: ehv466. [Epub ahead of print]

XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. XANTUS is the first international, prospective real-world non-vitamin K antagonist oral anticoagulant (NOAC) study in patients with AF. Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, van Eickels M, Turpie AG; XANTUS Investigators. Eur Heart J. 2015 Sep 1. pii: ehv466. [Epub ahead of print]

XANTUS: Prospective Design To collect real world data on adverse events in patients with NVAF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice Primary outcomes: major bleeding (ISTH definition), all-cause mortality, any other adverse events Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention N=6,784 Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature Final visit: 1 year # *Exact referral dates for follow-up visits not defined (every 3 months recommended); # for rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed 1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Participating Countries Patients were enrolled from June 2012 to December 2013 from 311 centres in Europe and Canada Participating countries included: Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Israel, Moldova, The Netherlands, Norway, Poland, Portugal, Russia, Slovakia, Slovenia, Sweden, Ukraine, UK 1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434; 2Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Patient Flow Primary analysis population: defined as all patients who had taken at least one dose of rivaroxaban Screened (N=10,934) Enrolled (N=6785) Safety population (N=6784) 4149 patients excluded* Patient decision (n=1222) Administrative reason (n=456) Availability of drug (n=18) Medical guidelines (n=399) Price of drug (n=473) Medical reasons (n=442) Internal hospital guidelines (n=30) Type of health insurance (n=183) Other (n=1454) 1 patient Did not take any rivaroxaban (n=1) Rivaroxaban 20 mg od (n=5336) Rivaroxaban 15 mg od (n=1410) Another dose (n=35) # * Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Baseline Demographics Clinical Characteristics Age (years) Rivaroxaban (N=6784) Mean ± SD 71.5±10.0 Age <65, n (%) 1478 (21.8) Age 65 75, n (%) 2782 (41.0) Age >75, n (%) 2524 (37.2) Gender (male): n (%) 4016 (59.2) Weight (kg): mean ± SD 83.0±17.3 BMI (kg/m 2 ): mean ± SD 28.3±5.0 BMI >30 kg/m 2, n (%) 1701 (25.1) AF, n (%) First diagnosed 1253 (18.5) Paroxysmal 2757 (40.6) Persistent 923 (13.6) Permanent 1835 (27.0) Missing 16 (0.2) Creatinine clearance, n (%) Rivaroxaban (N=6784) <15 ml/min 20 (0.3) 15 <30 ml/min 75 (1.1) 30 <50 ml/min 545 (8.0) 50 80 ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4) Existing co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-cns SE/TIA 1291 (19.0) Congestive HF 1265 (18.6) Prior MI 688 (10.1) Baseline hospitalization, n (%) 1226 (18.1) Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Baseline Demographics Distribution of Stroke Risk Factors Mean score±sd = 2.0±1.3 Mean score±sd = 3.4±1.7 CHADS 2 score CHA 2 DS 2 -VASc score* Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Treatment-Emergent Bleeding Events Incidence proportion, n (%) Rivaroxaban (N=6784) Incidence rate, %/year (95% CI)* Major bleeding 128 (1.9) 2.1 (1.8 2.5) Fatal 12 (0.2) 0.2 (0.1 0.3) Critical organ bleeding 43 (0.6) 0.7 (0.5 0.9) Intracranial haemorrhage 26 (0.4) 0.4 (0.3 0.6) Mucosal bleeding # 60 (0.9) 1.0 (0.7 1.3) Gastrointestinal 52 (0.8) 0.9 (0.6 1.1) Haemoglobin decrease 2 g/dl 52 (0.8) 0.9 (0.6 1.1) Transfusion of 2 units of packed RBCs or whole blood 53 (0.8) 0.9 (0.6 1.1) Non-major bleeding events 878 (12.9) 15.4 (14.4 16.5) Patients could experience multiple bleeding events in different categories. *Events per 100 patient-years; # numbers are for major mucosal and gastrointestinal bleeding events; representing major bleeding Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Treatment-Emergent Thromboembolic Events and All-Cause Death Rivaroxaban (N=6784) Incidence proportion, n (%) Incidence rate, %/year (95% CI)* All-cause death 118 (1.7) 1.9 (1.6 2.3) Thromboembolic events (stroke, SE, TIA, and MI) 108 (1.6) 1.8 (1.5 2.1) Stroke/SE 51 (0.8) 0.8 (0.6 1.1) Stroke 43 (0.6) 0.7 (0.5 0.9) Primary haemorrhagic 11 (0.2) Primary ischaemic 32 (0.5) SE 8 (0.1) 0.1 (0.1 0.3) TIA 32 (0.5) 0.5 (0.4 0.7) MI 27 (0.4) 0.4 (0.3 0.6) *Events per 100 patient-years 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Incident Rate for Treatment-Emergent Stroke/SE, Major Bleeding andall-cause Death by CHA 2 DS 2 -VASc Score Patients (n) 174 685 1313 1578 1405 837 789 6781 Events were centrically adjudicated *Events per 100 patient-years Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;

XANTUS: Outcomes According to Dosing (20/15 mg od) Major bleeding, all-cause death and thromboembolic events (stroke/se/tia/mi) occurred at higher incidence rates for the 15 mg od versus the 20 mg od dose *Events per 100 patient-years Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;

XANTUS: Management of Major Bleeding Major bleeding occurred in 1.9% of patients (n=128) 1 Major bleeding was mostly treated using conservative methods 1 0.8% of patients (n=53) received transfusions of 2 units of packed RBCs or whole blood Throughout the study use of non-specific reversal agents such as prothrombin complex concentrate (PCC) - was low 1 Use of PCC documented in two patients Use of tranexamic acid documented in three patients Use of etamsylate documented in one patient These findings are in line with outcomes from ROCKET AF 2 and the Dresden NOAC Registry 3 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Piccini JP et al, Eur Heart J 2014; 35(28):1873-80; 3. Beyer-Westendorf J et al, Blood 2014; 124(6):955-62

Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS 2 Prior stroke # ROCKET AF 1 3.5 55% XANTUS 2 2.0 19% # Includes prior 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

XANTUS: Conclusions XANTUS is the first large, international prospective study to describe rivaroxaban use in a broad patient population with NVAF. Patients were at lower overall risk than in the phase III ROCKET AF trial The results demonstrate low rates of both major bleeding (including intracranial and GI bleeding) and stroke/se in patients taking rivaroxaban in routine clinical practice. XANTUS showed that the majority of patients (80%) persisted on their treatment with rivaroxaban throughout the one year study period, whereas other recent data on VKAs has shown a persistence rate of 62% after one year. Treatment persistence is especially important as discontinuation of anticoagulation leaves patients with AF unprotected from the risk of stroke. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

Συμπεράσματα Η κολπική μαρμαρυγή είναι η συχνότερη αρρυθμία στη καθημερινή κλινική πράξη. Η παρουσία της συνδέεται με αυξημένο κκ κίνδυνο και ιδιαίτερα με αυξημένη επίπτωση ΑΕΕ. Τα νέα αντιθρομβωτικά φάρμακα υπό προϋποθέσεις είναι ένα σύγχρονο όπλο στην πρόληψη των θρομβοεμβολικών επεισοδίων. Πλεονεκτήματα Ανάλογο και πιθανώς επιπρόσθετο όφελος ως προς την μείωση των ΑΕΕ και σημαντικά μικρότερη πιθανότητα εμφάνισης σοβαρών και κυρίως ενδοκρανιακών αιμορραγιών. Δεν απαιτείται παρακολούθηση INR Δεν επηρεάζεται η δράση τους από τροφές η φάρμακα

Συμπεράσματα Η rivaroxaban μειώνει σημαντικά την επίπτωση των ΑΕΕ και συνοδεύεται από χαμηλή συχνότητα σοβαρών αιμορραγιών. 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 Η χορήγηση της σε ασθενείς υψηλού (μελέτη ROCKET) όσο και χαμηλού μέτριου κινδύνου (μελέτη XANTUS ) είναι ασφαλής και αποτελεσματική. Είναι μια δελεαστική θεραπευτική πρόταση για ασθενείς με κολπική μαρμαρυγή, που έχουν ένδειξη για λήψη αντιθρομβωτικής αγωγής στη καθημερινή κλινική πράξη

Rivaroxaban clinical trials program Stroke prevention Arterial thromboembolism Venous thromboembolism Registries N >100,000 Ongoing N >75,000 Completed N >100,000 Over 275,000 patients studied after finalization of study program

Possible drug-drug interactions Effect on NOAC plasma levels part 1 Dabigatran Apixaban Edoxaban Rivaroxaban Atorvastatin P-gp/ CYP3A4 +18% Digoxin P-gp no effect Verapamil P-gp/ wk CYP3A4 no data yet no data yet +12 180% no data yet no effect no effect + 53% (slow release) no effect no effect minor effect Diltiazem P-gp/ wk CYP3A4 Quinidine P-gp +50% Amiodarone P-gp +12 60% Dronedarone P-gp/CYP3A4 +70 100% Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 no effect +40% No data minor effect no data yet no data yet no data yet +80% +50% no effect minor effect +85% no data yet +140 150% +100% no data yet up to +160%

Switching between anticoagulant regimens VKA to NOAC Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) \ Low molecular weight heparin (LMWH) 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 Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment Start when next dose would have been given NOAC to VKA NOAC to parenteral anticoagulant NOAC to NOAC Aspirin or clodiprogel to NOAC 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

Important Benefits of direct OACs Over VKAs Fast onset Predictable anticoagulation Reduced potential for food and drug interactions Simplified, fixed dosing regimen No need for routine coagulation monitoring Less labour-intensive Less impact on patients daily life Improved compliance Reduced administrative costs Improved QoL Improved benefitrisk profile 1. Ansell J et al. Chest 2004;126(3):204S-233S; 2. Mueck W et al. Int J Clin Pharmacol Ther. 2007;45(6):335-344; 3. Mueck W et al. Clin Pharmacokinet. 2008;47(3):203-216; 4. Mueck W et al. Thromb Haemost. 2008;100(3):453-461; 5. Raghavan N et al. Drug Metab Dispos. 2009;37(1):74-81; 6. Shantsila E, Lip GY. Curr Opin Investig Drugs 2008;9(9):1020-1033; 7. Ageno W et al. Chest 2012;141(2):e44S-e88S

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