FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011 Giuseppe Di Pasquale Unità Operativa Cardiologia Ospedale Maggiore, Bologna

Disclosures Member of Advisory Board of Dabigatran, Rivaroxaban, Apixaban, Dronedarone Consulting fees / honoraria - Boehringer Ingelheim - Bayer AG - Sanofi Aventis - BMS

Antithrombotic Therapy for AFib Stroke Risk Reduction Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 -64% Antiplatelet drugs vs. Placebo 8 Trials n = 4,876 -19% 100% 50% - 50% Hart RG et al. Ann Intern Med 2007; 146: 857 3

Limiti della terapia con antagonisti della Vitamina K Risposta non prevedibile Frequenti aggiustamenti della dose La terapia con antagonisti della vitamina K presenta diversi limiti che ne rendono difficoltoso l’impiego nella pratica clinica Finestra di trattamento stretta (INR range 2-3) Numerose interazioni alimentari Monitoraggio routinario dei fattori della coagulazione Numerose interazioni con altri farmaci A causa dei limiti della terapia con antagonisti della vitamina K, è stato stimato che fino ad oltre il 50% dei pazienti elegibili per questo trattamento non ricevono terapia anticoagulante.(Rowan et al. JACC. 2007) Resistenza al Warfarin Lente insorgenza/termine d’azione 1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187. 4

Limiti della Terapia Anticoagulante Orale Conseguenze nella FA Un significativo numero di pazienti con FA a rischio di stroke non riceve la TAO

Steering Committee Giuseppe Di Pasquale (Chairman ANMCO), Giovanni Mathieu (Chairman FADOI), Francesco Chiarella, Fabrizio Colombo, Michele Gulizia, Gualberto Gussoni, Carlo Nozzoli, Domenico Panuccio, Salvatore Pirelli, Marino Scherillo, Giorgio Vescovo, Massimo Zoni Berisso 6 6

Setting of the Study 360 Participating Centers 7148 enrolled patients 164 Cardiology Departments Cardiology ward Cardiology ward and Cath Lab Cardiology ward with Cath Lab and CCH 196 Internal Medicine Dept. Hospital without cardiology Hospital with cardiology ward Hospital with cardiology ward and Cath Lab (with or without CCH) From each Center: Duration of the enrollment 4 weeks 7 7

Antithrombotic Treatments in F Antithrombotic Treatments in non valvular AF (4.845 pts) None Other ATT OAC

Limiti della Terapia Anticoagulante Orale Conseguenze nella FA Un significativo numero di pazienti con FA a rischio di stroke non riceve la TAO L’intensità della scoagulazione è spesso al di fuori del range terapeutico (INR 2.0 – 3.0)

Anticoagulation Control in Real Life in Italy % of INR Determinations by Range in VKA Treated Patients Range INR VKA Experienced mean median (p25 - p75) % INR < 2 No 33.4% 28.8% (15.4% - 47.9%) Yes 25.3% 20.0% (7.7% - 36.4%) % INR 2.0-3.0 47.9% 50.0% (33.3% - 66.7%) 56.3% 58.3% (42.5% - 73.1%) % INR > 3 16.9% 13.3% (0.0% - 25.0%) 17.9% 14.3% (4.0% - 26.7%)

The Promise of New Anticoagulants

New Anticoagulants Coagulation cascade Drug Tissue factor pathway inhibitors: NAPc2 Initiation TF/VIIa X IX IXa VIIa Indirect: fondaparinux, idraparinux Direct Oral: rivaroxaban, apixaban, edoxaban Propagation Xa Va II Thrombin activity Direct Parenteral: bivalirudin Direct Oral: ximelagatran, dabigatran, AZD0837 IIa Fibrinogen Fibrin

N Engl J Med 2009;361(12):1139-51

N Engl J Med August 10, 2011

N Engl J Med August 28, 2011

Atrial Fibrillation Phase 3 Study Timelines Rivaroxaban Edoxaban Dabigatran ROCKET AF Published August 2011 ENGAGE AF TIMI 48 Study ongoing Expected 2012 RE-LY Published 2009 2009 2010 2011 2012 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban 17 17

Atrial Fibrillation Phase 3 Study Timelines Rivaroxaban Edoxaban Dabigatran ROCKET AF Published August 2011 ENGAGE AF TIMI 48 Study ongoing Expected 2012 RE-LY Published 2009 2009 2010 2011 2012 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban 18 18

The RE-LY Study: Randomized Evaluation of Long-term anticoagulant therapY Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation 19

Atrial fibrillation with ≥ 1 risk factor Absence of contraindications RE-LY® – study design Atrial fibrillation with ≥ 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran etexilate 110 mg bid 150 mg bid Statistical testing in the RE-LY Study: Primary endpoint: Non-inferiority design allowing for statistical analysis of superiority once non-inferiority is achieved All other endpoints: Superiority testing. P < 0.05  superior (95% CI is below 1) P > 0.05  comparable (if 95% CI includes 1) Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Ezekowitz MD, et al. Am Heart J 2009;157:805-10. Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

TIME TO FIRST STROKE OR SSE Dabigatran 150 mg BID Dabigatran 110 mg BID Warfarin 0.05 0.04 RRR 35% 0.03 RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) P=0.30 (Sup) Cumulative hazard rates 0.02 RR 0.65 (95% CI: 0.52–0.81) P<0.001 (NI) P<0.001 (Sup) RE-LY® – Time to first stroke or systemic embolism (SSE) This figure shows the time to first stroke or SSE in the three treatment arms of the RE-LY® study.1 Dabigatran etexilate 150 mg bid was also non-inferior to warfarin (relative risk = 0.66 [95% CI: 0.53–0.82], P<0.001) but also met the criteria for superiority (P<0.001).1 Dabigatran etexilate 110 mg bid was non-inferior to warfarin (relative risk = 0.91 [95% CI: 0.74–1.11], P<0.001).1 Rates of stroke and SSE with warfarin and dabigatran etexilate 150 mg bid began to separate soon after starting treatment, with the separation then maintained over 2.5 years of treatment.1 Reference Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. 0.01 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years RR = relative risk; RRR = relative risk reduction; SSE = systemic embolism. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

MAJOR BLEEDING RATES 3.57 3.32 2.87 RR 0.93 (95% CI: 0.81–1.07) P=0.32 (superiority) RR 0.80 (95% CI: 0.70–0.93) P=0.003 (superiority) 1.0 2.0 3.0 4.0 5.0 RRR 20% 3.57 3.32 2.87 Rate per year (%) RE-LY® – Major bleeding rates Rates of major bleeding in the three treatment arms of RE-LY® were:1 dabigatran etexilate 150 mg BID = 3.32% per year dabigatran etexilate 110 mg BID = 2.87% per year warfarin = 3.57% per year. Rates of major bleeding with warfarin and dabigatran etexilate 150 mg BID were comparable (relative risk = 0.93 [95% CI: 0.81–1.07], P=0.32).1 Dabigatran etexilate 110 mg BID reduced the risk of major bleeding by 20% compared with warfarin (relative risk = 0.80 [95% CI: 0.70–0.93], P=0.003).1 Major bleeding was defined as any of the following:2 reduction in haemoglobin of 20 g/L transfusion of 2 units of blood symptomatic bleeding in a critical area or organ. References Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875–1876. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. D150 mg BID D110 mg BID Warfarin Events/n: 399 / 6,076 342 / 6,015 421 / 6,022 D = dabigatran; RR = relative risk; RRR = relative risk reduction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.

MAJOR BLEEDING AND COMPONENTS Characteristic Dabigatran 150 mg 110 mg Warfarin P value D150 vs. W D110 vs. W Number of patients 6,076 6,015 6,022 Major bleeding rate (% per year) 3.32 2.87 3.57 0.32 0.003 Life threatening Non-life threatening Gastro-intestinal 1.49 2.06 1.56 1.24 1.83 1.15 1.85 1.92 1.07 0.03 0.39 0.001 <0.001 0.65 0.52 RE-LY® – Major bleeding and components This slide shows the rate of major bleeding and its components (life-threatening bleeding, non-life-threatening bleeding and gastrointestinal bleeding) in the three treatment arms of the RE-LY® study.1 Dabigatran etexilate 110 mg BID reduced the rate of major bleeding compared with warfarin (P=0.003) while rates of major bleeding were comparable with warfarin and dabigatran etexilate 150 mg BID (P=0.32).1 Life-threatening bleeding was significantly reduced with both dabigatran etexilate 110 mg BID (P<0.001) and dabigatran etexilate 150 mg BID (P=0.03) compared with warfarin.1 Rates of non-life-threatening bleeding were comparable to warfarin with both dabigatran etexilate 110 mg BID (P=0.65) and dabigatran etexilate 150 mg BID (P=0.39). The rate of gastrointestinal bleeding was significantly higher with dabigatran 150 mg BID compared with warfarin (P=0.001), but did not differ significantly with dabigatran etexilate 110 mg bid.1 Major bleeding was defined as any of the following:2 reduction in haemoglobin of 20 g/L transfusion of 2 units of blood symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that comprised any of:2 fatal bleeding symptomatic intracranial bleeding bleeding with a 50 g/L decrease in haemoglobin level bleeding requiring transfusion of 4 units of blood or inotropic agents or necessitating surgery. References Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875–1876. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. D = dabigatran; W = warfarin. Data represent %/year. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

Hemorrhagic stroke 50 45 40 30 20 14 10 12 D110 mg BID D150 mg BID RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 0.38% RRR 69% RRR 74% 30 20 Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%. 14 10 12 0.12% 0.10% D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

Mortalità per qualsiasi causa

Mortalità vascolare Regarding vascular mortality, dabigatran etexilate 150mg BID was superior to warfarin with p=0.038. Dabigatran etexilate 110mg BID was statistically comparable to warfarin regarding vascular mortality. However, numerically there were fewer deaths with dabigatran etexilate 110mg BID compared to warfarin. Definition of vascular mortality: Vascular mortality includes both cardiovascular death and other types of vascular death: Cardiovascular death : - Sudden / arrhythmic death (e.g. documented asystole, documented ventricular flutter/fibrillation, recent myocardial infarction, other) - Pump failure death (e.g. cardiac heart failure/cardiac shock, cardiac tamponade, recent myocardial infarction, other) Other vascular death: resulting from stroke, pulmonary embolus, peripheral embolus, haemorrhage, unknown cause (but still classifiable as "vascular"), other

RE-LY Subgroup Analyses

RE-LY Subgroup Analysis: Prior TIA or Stroke

Lancet Neurology 2010; 9: 1157-63

Prior stroke/TIA: time to primary outcome 0.08 # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 D150 W 1195 1160 1132 908 573 289 1233 1201 1164 938 617 321 1126 895 565 262 Warfarin 0.06 Dabigatran 110 mg Cumulative Hazard Rates 0.04 Dabigatran 150 mg 0.02 0.0 0.5 1.0 1.5 2.0 2.5 Years of follow-up 30

Intra-cranial bleeding rates in patients with prior stroke or TIA RR 0.20 (95% CI: 0.08–0.47) p<0.001 RR 0.41 (95% CI: 0.21–0.79) P=0.007 Number of events RRR 80% RRR 59% 1195 1233 1195 31

RE-LY Subgroup Analysis: Age & Renal Function

Circulation 2011;123:2363-72

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) <65 1.48 0.69 1.35 65–74 1.26 0.98 1.43 ≥75 1.87 2.1 Creatinine clearance (mL/min) 30–50 2.26 1.33 2.65 51–80 1.65 1.24 1.76 >80 0.92 0.72 1 D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.76 P=0.072 P=0.58 P=0.036 RE-LY® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin.1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120. 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 Dabigatran better Warfarin better Dabigatran better Warfarin better BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) <65 0.76 0.79 2.32 65–74 2.12 2.45 3.08 ≥75 4.21 4.81 4.09 Creatinine clearance (mL/min) 30–50 5.07 4.85 5.17 51–80 2.62 3.04 3.44 >80 1.36 1.88 2.18 D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.0003 P=0.0001 P=0.1 P=0.091 RE-LY® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin.1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin.1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin.1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120. 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 Dabigatran better Warfarin better Dabigatran better Warfarin better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: HAEMORRHAGIC STROKE Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) <65 0.05 0.38 65–74 0.08 0.31 ≥75 0.2 0.15 0.47 Creatinine clearance (mL/min) 30–50 0.26 0.12 0.58 51–80 0.09 >80 0.03 0.13 D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.51 P=0.75 P=0.67 P=0.4 RE-LY® – Age and renal function subgroup analysis: Haemorrhagic stroke There was no significant interaction between either patient age or renal function and the rate of haemorrhagic stroke with either dose of dabigatran versus warfarin.1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120. 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 Dabigatran better Warfarin better Dabigatran better Warfarin better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

EMA approves PRADAXA with the flexibility of two dosing regimens Overall the 150 mg bid dose is recommended; the 110 mg bid dose is indicated for elderly patients aged 80 years at higher risk of bleeding and for those taking verapamil 4 August 2011 First, core epidemiology. Much of this information comes from the Framingham Study through the efforts of Dr. Philip Wolf and colleagues. Atrial fibrillation is the most common, significant cardiac rhythm disorder. Its prevalence is strongly age-dependent with 2% of those in their 60s having AF, rising to fully 10% of those 80 years or older. Most importantly for the current discussion, AF is a powerful risk factor for stroke, raising this risk 5-fold. Appreciate that the vast majority of AF is “non-rheumatic” or “non-valvular” AF, that is, patients without mitral stenosis or prosthetic heart valves. My comments will focus exclusively on non-valvular AF. 37

ANTITHROMBOTIC PROPHYLAXIS IN AF NEW PERSPECTIVES New oral direct thrombin inhibitors (other than ximelagatran) Oral Factor Xa inhibitors

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

N Engl J Med August 10, 2011

ROCKET AF – study design ROCKET AF enrolled 14,264 patients with non-valvular AF with a history of stroke or TIA or two or more risk factors for stroke including age ≥75 years, heart failure, diabetes, hypertension Median time on treatment was 590 days; median follow-up was 707 days; median follow-up off treatment was 117 days References Patel MR et al. Am Heart J 2010;159:340–347.e1. Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven Non-valvular AF History of stroke, TIA or non-CNS SE OR ≥2* of the following: CHF Hypertension Age ≥75 years Diabetes Rivaroxaban 20 mg once daily# N=14,264 R End of study 30-day follow-up References Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Warfarin target INR 2–3 ~14 – 40 months‡ *Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%. #Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven. Patel MR et al, 2011 42

Primary Efficacy Outcome Stroke and non-CNS Embolism   Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

ROCKET AF – primary efficacy endpoint on and off treatment Rivaroxaban n/N (% per year) Warfarin n/N (% per year) Hazard ratio (95% CI) p-value Non-inf. Sup. Per protocol, on treatment 188/6,958 (1.7) 241/7,004 (2.2) 0.79 (0.66,0.96) <0.001 Safety, on treatment 189/7,061 (1.7) 243 /7,082 (2.2) 0.79 (0.65,0.95) 0.02 Hazard ratio and 95% CIs ITT 269/7,081 (2.1) 306/7,090 (2.4) 0.88 (0.75,1.03) <0.001 0.12 ITT, on treatment 188 (1.7) 240 (2.2) 0.79 (0.66,0.96) 0.02 ITT, off treatment 81 (4.7) 66 (4.3) 1.10 (0.79,1.52) 0.58 Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Primary efficacy endpoint: stroke or systemic embolism ITT on- and off-treatment: post hoc analyses 0.5 1 2 Favours rivaroxaban Favours warfarin Patel MR et al, 2011. 44

ROCKET AF – bleeding analysis Parameter Rivaroxaban (N=7,111) Warfarin (N=7,125) Hazard ratio (95% CI) n (% per year) 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) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding 1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13) Hazard ratio and 95% CIs The principal safety outcome was defined as the composite of major and non-major clinically relevant bleeding P-values (2-sided for superiority of rivaroxaban versus warfarin in hazard ratio): Principal safety outcome: p=0.44 Major bleeding: p=0.58 Decrease in hemoglobin (≥2 g/dl): p=0.02 Transfusion: p=0.04 Critical bleeding: p=0.007 Fatal bleeding: p=0.003 Intracranial hemorrhage: p=0.02 Non-major clinically relevant bleeding: p=0.35 Major bleeding from a gastrointestinal site was more common with rivaroxaban (224 bleeds [3.2%] compared with warfarin (154 bleeds [2.2%]; p<0.001). Abbreviation ICH, intracranial haemorrhage Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* 0.2 0.5 1 2 5 Favours rivaroxaban Favours warfarin Safety population – on-treatment analysis; *Statistically significant Patel MR et al, 2011. 45

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

N Engl J Med 2011;364(9): 806-17

APIXABAN Phase 3 Clinical Trial vs Aspirin to Prevent Stroke or Embolism in AF Pts AVERROES ≈ 1.6 years Patient characteristics Randomization Apixaban 2.5 mg bid or 5 mg bid Aged 50 years Atrial fibrillation 1 additional risk factor for stroke Not suitable for vitamin K antagonist N=5600 Aspirin 81-324 mg qd Apixaban Phase 3 Clinical Trial vs Aspirin to Prevent Stroke or Embolism in AF Patients AVERROES is an ongoing phase 3 clinical trial for apixaban that randomized 5600 patients with atrial fibrillation to prophylactic treatment with apixaban 5 mg bid (or 2.5 mg bid in select patients) or aspirin 81 to 324 mg qd. Additional risk factors for stroke in the study inclusion criteria were symptomatic congestive heart failure or left ventricular ejection fraction ≤40%; hypertension requiring pharmacological treatment; age 75 years; diabetes; prior stroke, transient ischemic attack, or systemic embolism. The treatment period is expected to average 1.6 years. Follow-up will occur 30 days after discontinuation or completion of study. The primary efficacy outcome is prevention of the composite outcome of stroke or systemic embolism. The primary safety outcome is time to major bleeding. A secondary outcome measure is time to composite outcome of stroke, systemic embolism, myocardial infarction, or major vascular events. Reference National Institutes of Health. ClinicalTrials.gov. A phase 3 study of apixaban in patients with atrial fibrillation (AVERROES). www.clinicaltrials.gov/ct2/show/NCT00496769?term=apixaban&rank=1. Accessed January 16, 2008. Primary outcome measures: Time to composite outcome of stroke or systemic embolism Time to major bleeding N Engl J Med 2011;364(9): 806-17 48

AVERROES - Primary Efficacy Outcome N Engl J Med 2011;364(9): 806-17

AVERROES - Primary Safety Outcome N Engl J Med 2011;364(9): 806-17

N Engl J Med August 28, 2011

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Age ≥ 75 years Prior stroke, TIA, or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death N Engl J Med 2011 52

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.001 21% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011 No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 N Engl J Med 2011

Efficacy Outcomes Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI) P Value Event Rate (%/yr) Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80,0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 N Engl J Med 2011

Major Bleeding ISTH definition 31% RRR 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 No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491 N Engl J Med 2011

Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI) P Value Event Rate (%/yr) Primary safety outcome: ISTH major bleeding* 2.13 3.09 0.69 (0.60, 0.80) <0.001 Intracranial 0.33 0.80 0.42 (0.30, 0.58) Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding 4.07 6.01 0.68 (0.61, 0.75) GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) Any bleeding 18.1 25.8 0.71 (0.68, 0.75) N Engl J Med 2011

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

ENGAGE-AF-TIMI 48 (Study for Evaluation of DU-176b vs Warfarin in Subjects with AF) AF on ECG < 12 mos Intended oral A/C CHADS2 Score > 2 n~16,500 Randomization Strata: 1. CHADS2 2-3 vs 4-6 2. Drug clearance R Low Exposure Strategy DU-176b 30 mg QD (n=5500) High Exposure Strategy DU-176b 60 mg QD (n=5500) Active Control Warfarin (n=5500) Median Duration of Followup 24 months 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EP’s = Major Bleeding, Hepatic Function 59 59

Atrial Fibrillation Phase 3 Study Timelines Rivaroxaban Edoxaban Dabigatran ROCKET AF Published August 2011 ENGAGE AF TIMI 48 Study ongoing Expected 2012 RE-LY Published 2009 2009 2010 2011 2012 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban 60 60

E’ possibile un confronto tra dabigatran, rivaroxaban e apixaban ?

Somiglianze e differenze tra gli studi

PK/PD of 5 Novel Oral Agents Dabigatran Apixaban Rivaroxaban Edoxaban (DU-176b) Betrixaban (PRT054021) Target IIa (thrombin) Xa Hrs to Cmax 2 1-3 2-4 1-2 NR CYP Metabolism None 15% 32% Half-Life 12-14h 8-15h 9-13h 8-10h 19-20h Renal Elimination 80% 40% 33% 35% <5% CYP = cytochrome P450; NR = not reported Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160:635-41

Phase III AF Trials Re-LY ROCKET-AF ARISTO TLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose (mg) Freq 150, 110 BID 20 (15*) QD 5 (2.5*) 60*, 30* N 18,113 14,266 18,206 >21,000 Design PROBE 2x blind AF criteria AF x 1 < 6 mths AF x 2 (>1 in <30d) AF or AFl x 2 <12 mths < 12 mths % VKA naive 50% 38% 43% 40% goal *Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

RELY ROCKET AF ARISTOTLE Dabigatran 110 mg Dabigatran 150 mg Warfarin CHADS2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 30.9 37.0 32.1 ROCKET AF Rivaroxaban Warfarin CHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.5 13 43 29 2 44 28 12 3+ 87% ARISTOTLE Rivaroxaban Warfarin CHADS2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 34 35.8 30.2 C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

Comparison of Trial Metrics RE-LY ROCKET AF ARISTOTLE Time in Therapeutic Range (TTR) 64% 67% warfarin-experienced 61% warfarin-naïve Mean 55% Median 58% Mean 62% Median 66% C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

Stroke 199 (1.19) 250 (1.51) 184 (1.65) 221 (1.96) NOAC Warfarin 0.5 1.0 Favors NOAC Favors warfarin HR 95% CI 0.65-0.95 0.79 0.70-1.03 0.85 171 (1.44) 186 (1.58) Dabi 110 (ITT) 0.74-1.12 0.91 1.5 0.0 Riva (safety AT) Apixaban 122 (1.01) Dabi 150 0.51-0.81 0.64 No. of events (%/yr) 2.0 ITT: Intention to Treat – AT: as treated Not head to head comparison – For illustrative purposes only – adapted from references 1-4 1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. 67

Ischemic or Unspecified Stroke 162 (0.97) 175 (1.05) 149 (1.34) 161 (1.42) NOAC Warfarin 0.5 1.0 Favors NOAC Favors warfarin HR 95% CI 0.74-1.13 0.92 0.75-1.17 0.94 159 (1.34) 143 (1.21) Dabi 110 (ITT) 0.88-1.39 1.11 1.5 0.0 Riva* (safety AT) Apixaban** 111 (0.92) Dabi 150 0.59-0.97 0.76 No. of events (%/yr) 2.0 *Only ischemic strokes are counted here. The no. of strokes with unknown type were 7 and 11 in the rivaroxaban and warfarin groups, respectively. ** Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with ischemic strokes, hemorrhagic transformation occurred in 12 patients with apixaban and 20 patients with warfarin. ITT: Intention to Treat – AT: as treated. Not head to head comparison – For illustrative purpose only – adapted from references 1-4 1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. 68

Hemorrhagic Stroke NOAC Warfarin HR 95% CI 40 (0.24) 78 (0.47) 29 (0.26) 50 (0.44) NOAC Warfarin 0.5 1.0 Favors NOAC Favors warfarin HR 95% CI 0.35-0.75 0.51 0.37-0.93 0.59 14 (0.12) 45 (0.38) Dabi 110 (ITT) 0.17-0.56 0.31 1.5 0.0 Riva (safety AT) Apixaban 12 (0.10) Dabi 150 0.14-0.49 0.26 No. of events (%/yr) 2.0 ITT: Intention to Treat – AT: as treated. Not head to head comparison – For illustrative purpose only – adapted from references 1-4 1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. 69

Major Bleeding NOAC Warfarin HR 95% CI 327 (2.13) 462 (3.09) 395 (3.6) 386 (3.4) NOAC Warfarin 0.5 1.0 Favors NOAC Favors warfarin HR 95% CI 0.60-0.80 0.69 0.90-1.20 1.04 342 (2.87) 421 (3.57) Dabi 110 0.70-0.93 0.80 1.5 0.0 Riva Apixaban 399 (3.32) Dabi 150 0.81-1.07 0.93 No. of events (%/yr) 2.0 The rate of major bleeding with warfarin was higher in RELY than in some previous trials.1-3 This is partly explained by the more inclusive definition of major bleeding in the RELY study. 1. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. 2. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066-78. 3. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-12. The yearly incidence of major bleeding in the warfarin group was 3.36%. This rate is much higher than that previously reported by the same author (1.78 to 2.92%)1 and than that reported for warfarin groups in clinical trials of anticoagulants such as ximelagatran (1.8%)2 and idraparinux (1.4%)3 in the treatment of AF. This may be explained by the fact that the high percentage of patients concomitantly treated with aspirin in the recent report by Connolly et al. (about 20%) contributed substantially to the unusually high incidence of bleeding. In one study, patients with AF who received aspirin in combination with warfarin had almost double the rate of bleeding in patients who received warfarin alone (17.7% vs. 9.3%).3 Subgroup analysis by Connolly et al. should help to establish whether concomitant administration of aspirin with warfarin was responsible for the high rate of major bleeding. This difference results in part from the greater use of aspirin in RELY. It also results from the fact that in RELY a drop in hemoglobin levels of ≥20 g/L was considered a major bleeding episode, whereas in previous studies, such as the ACTIVE–W, this degree of decline in hemoglobin levels was not considered a major bleeding episode. 1. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029-37. 2. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-8. 3. Amadeus Investigators, Bousser MG, Bouthier J, et al. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008;371:315-21. The benefit of dabigatran may be explained in part by the twice-daily dosing regimen. Since dabigatran has an elimination half-life of 12 to 17 hours, twice-daily dosing reduces variability in the anticoagulation effect, especially as compared with the anticoagulation effect of warfarin, which is difficult to control. Warfarin broadly inhibits coagulation (inhibiting factors II, VII, IX, and X and proteins C and S). By selectively inhibiting only thrombin, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. In ARISTOTLE, with respect to the outcome of major bleeding, the only baseline characteristics for which the interaction was significant were diabetes status and renal function, with a greater reduction in bleeding among patients who did not have diabetes (P = 0.003 for interaction) and among patients with moderate or severe renal impairment (P = 0.03 for interaction). Not head to head comparison – For illustrative purpose only – adapted from references 1-4 1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. 70

Death From Any Cause NOAC Warfarin HR 95% CI 603 (3.52) 669 (3.94) 208 (1.87) 250 (2.21) NOAC Warfarin 0.5 1.0 Favors NOAC Favors warfarin HR 95% CI 0.80-0.99 0.89 0.70-1.02 0.85 446 (3.75) 487 (4.13) Dabi 110 (ITT) 0.80-1.03 0.91 1.5 0.0 Rivaroxaban (safety AT) Apixaban 438 (3.64) Dabi 150 0.77-1.00 0.88 No. of events (%/yr) 2.0 582 (4.5) 632 (4.9) 0.82-1.03 0.92 Rivaroxaban (ITT) Not head to head comparison – For illustrative purpose only – adapted from references 1-4 1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92. 71

Treatment Discontinuation at the End of Follow-up RELY1 Discontinuation rate (%) 20.7% 30 25 20 15 10 Dabi 110 Dabi 150 21.2% 16.6% ROCKET-AF2 ARISTOTLE3 5 Warfarin 23.7% Riva 22.2% 25.3% Apix 27.5% AVERROES4 17.9% ASA 20.5% P=0.03 P=0.001 Dabigatran vs. Warfarin P<0.001 P=? 1. Connolly S et al. N Engl J Med (10.1056/NEJMoa0905561) 30 Aug 2009 2. Patel M et al. N Engl J Med (10.1056/NEJMoa1009638) 10 Aug 2011 3. Granger C et al. N Engl J Med (10.1056/NEJMoa1107039) 28 Aug 2011 4. Connolly S et al. N Engl J Med (10.1056/NEJMoa1007432) 10 Feb 2011 72

Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici? G Ital Cardiol 2010; 11 (4): 263-268 William Turner, The Fighting Temeraire (National Gallery, Londra)

G Ital Cardiol 2011; 12(9): 556-65

Nuovi Anticoagulanti Orali non VKA Antagonisti Vantaggi Dose – risposta prevedibile : dose fissa giornaliera Non necessità di monitoraggio dell’anticoagulazione Elevata efficacia e sicurezza Significativa riduzione del rischio emorragico Inizio e termine d’azione rapidi: non necessità di bridge con eparina Minime interazioni farmacologiche Assenza di interazioni alimentari Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

Nuovi Anticoagulanti Oralianti non VKA Antagonisti Svantaggi Aggiustamento empirico del dosaggio Necessità di nuovi test laboratoristici da eseguire in caso di eventi emorragici o trombotici Difficoltà di valutare l’aderenza del paziente alla terapia Mancanza di antidoto in caso di sovradosaggio o emorragie Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti con bassa aderenza terapeutica Possibile ridotta consapevolezza della terapia da parte del paziente Costo elevato Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Problemi Aperti Per quali pazienti (A chi ?)

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Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Problemi Aperti Per quali pazienti (A chi ?) Con quale sorveglianza (Come ?) Con quale responsabilità di presa in carico (Da chi ?)

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Problemi Aperti Per quali pazienti (A chi ?)

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA di nuovo riscontro con indicazioni all’anticoagulazione (naive)

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Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA di nuovo riscontro con indicazioni all’anticoagulazione (naive) Pazienti con FA già in TAO in presenza di specifiche problematiche Pazienti con FA già in TAO in assenza di specifiche problematiche Pazienti con FA attualmente non in TAO

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA di nuovo riscontro con indicazioni all’anticoagulazione (naive) NAO come terapia di scelta, soprattutto nei pazienti con difficoltà logistiche per la gestione della TAO

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA già in TAO in presenza di specifiche problematiche ▪ qualità TAO non soddisfacente (TTR < 55-50%) ▪ dosi giornaliere molto basse di VKA ▪ difficoltà logistiche (assistenza domiciliare) ▪ pregressa emorragia cerebrale ▪ farmaci associati interferenti necessari ▪ non disponibilità ai controlli periodici proponibile lo switch dalla TAO ai NAO

Futuri Scenari Clinici Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA già in TAO in assenza di specifiche problematiche non ragionevole uno switch immediato ai NAO da non trascurare però le preferenze del paziente adeguatamente informato

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA non in TAO ▪ pazienti esclusi dalla TAO a causa di elevato rischio emorragico dubbi candidati per i NAO (dabigatran bassa dose in pazienti selezionati ?) ▪ pazienti esclusi dalla TAO per problemi logistici possibili candidati ai NAO, previo accertamento della compliance

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Problemi Aperti Per quali pazienti (A chi ?) Con quale sorveglianza (Come ?)

Dalla Sorveglianza Laboratoristica alla Sorveglianza Clinica Colloquio ad inizio terapia (medico, infermiere) Controlli clinici periodici (ogni 3-4 mesi ?) per verificare tolleranza, compliance, eventi emorragici (visite brevi) Controlli periodici funzionalità renale (cadenza individualizzata) Trasferimento di risorse infermieristiche e mediche dall’Ambulatorio TAO alla Sorveglianza clinica

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Presa in carico del paziente con FA anticoagulato con i nuovi anticoagulanti orali Possibili Attori Centri TAO FCSA (solo 20% dei pazienti anticoagulati) Cardiologie Ospedaliere (Servizio Ambulatoriale ± Ambulatorio TAO) Cardiologie Territoriali Medicine Interne / Geriatrie Medico di Medicina Generale (NCP, MMG associati)

Attività essenziali per il trattamento con VKA o NAO AVK NAO Visita prescrizione SI Giusta indicazione e dose Informazione /educazione pz. Controlli laboratorio NO Aggiustamento dose Controllo compliance Guida per condizioni rischio Controllo clinico periodico

Rivaroxaban Selective, direct Factor Xa inhibitor1 TF/VIIa Selective, direct Factor Xa inhibitor1 High oral bioavailability2 Rapid onset of action3 Half-life:2–4 5–9 hours in young healthy individuals 11–13 hours in the elderly Dual mode of elimination:5 1/3 of active drug excreted unchanged by the kidneys 2/3 of drug metabolized by the liver; half of which is excreted renally, half excreted via the hepatobiliary route X IX IXa VIIIa Rivaroxaban Va Xa Rivaroxaban Rivaroxaban is a direct Factor Xa inhibitor that has a once-daily dosing regimen for stroke prevention in patients with AF1 Rivaroxaban has no requirement for routine coagulation monitoring The clinical development programme for rivaroxaban is the largest among the newer OACs Dosing is optimized for each indication Extensive clinical experience exists for rivaroxaban across many different indications References Perzborn E et al. J Thromb Haemost 2005;3:514–521. Kubitza D et al. Clin Pharmacol Ther 2005;78:412–421. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–880. Kubitza D et al. Curr Med Res Opin 2008;24:2757–2765. Weinz C et al. Drug Metab Dispos 2009;37:1056–1064. Weitz JI, Bates SM. J Thromb Haemost 2005;3:1843–1853. Weitz JI et al. Chest 2008;133:234S–256S. II IIa Fibrinogen Fibrin 1. Perzborn E et al, 2005; 2. Kubitza D et al, 2005; 3. Kubitza D et al, 2005; 4. Kubitza D et al, 2008; 5. Weinz C et al, 2009. Adapted from Weitz JI et al, 2005; 2008. 95

Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation

ROCKET AF – study design ROCKET AF enrolled 14,264 patients with non-valvular AF with a history of stroke or TIA or two or more risk factors for stroke including age ≥75 years, heart failure, diabetes, hypertension Median time on treatment was 590 days; median follow-up was 707 days; median follow-up off treatment was 117 days References Patel MR et al. Am Heart J 2010;159:340–347.e1. Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven Non-valvular AF History of stroke, TIA or non-CNS SE OR ≥2* of the following: CHF Hypertension Age ≥75 years Diabetes Rivaroxaban 20 mg once daily# N=14,264 R End of study 30-day follow-up References Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Warfarin target INR 2–3 ~14 – 40 months‡ *Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%. #Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven. Patel MR et al, 2011 97

ROCKET AF – primary efficacy endpoint Stroke or systemic embolism 120 240 480 600 720 1 2 3 4 5 6 840 360 Cumulative event rate (%) HR=0.79 (0.66, 0.96) p<0.001 (non-inferiority) Warfarin Rivaroxaban Please note: as treated = on-treatment (used in previous communication) = during treatment = time patient was exposed to study drug = time from first to last study drug intake + 2 d Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Days since randomization Number of subjects at risk Rivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496 Warfarin 7,004 6,327 5,911 5,542 4,461 3,478 2,539 1,538 Per-protocol population – as treated Patel MR et al, 2011. 98

ROCKET AF – major bleeding by site Rivaroxaban (N=7,111) Warfarin (N=7,125) Major bleeding, n (%) 395 (5.6) 386 (5.4) Gastrointestinal (upper, lower, rectal)# 224 (3.2) 154 (2.2) Intracranial‡ 55 (0.8) 84 (1.2) Intraparenchymal‡ 37 (0.5) 56 (0.8) Non-traumatic‡ 33 (0.5) 54 (1.8) Traumatic 4 (0.1) 2 (0.03) Intraventricular Subdural haematoma 12 (0.2) 22 (0.3) Subarachnoid 1 (0.01) Epidural haematoma Macroscopic haematuria 26 (0.4) 21 (0.3) Bleeding associated with non-cardiac surgery 19 (0.3) Intraocular/retinal 17 (0.2) 24 (0.3) Intraarticular 16 (0.2) Epistaxis 13 (0.2) 14 (0.2) ROCKET AF – major bleeding by site The principal safety outcome – the composite of major and non-major clinically relevant bleeding events – was similar in both treatment arms (14.9% vs 14.5% per year [HR=1.03; 95% CI 0.96–1.11; p=0.442). Individually, major bleeding and non-major clinically relevant bleeding rates were each also similar to warfarin Significantly higher rates of ≥2 g/dl falls in haemoglobin concentration (HR=1.22; 95% CI 1.03–1.44; p=0.019) and transfusion of ≥2 units of whole blood or packed red blood cells (HR=1.25; 95% CI 1.01–1.55; p=0.044) were observed for rivaroxaban This included a significantly higher rate of gastrointestinal bleeding (upper, lower and rectal) for rivaroxaban compared with warfarin (3.2% vs 2.2%; p<0.001) Importantly, significantly lower rates of intracranial haemorrhage (HR=0.67; 95% CI 0.47–0.93; p=0.02), critical organ bleeding (HR=0.69; 95% CI 0.53–0.91; p=0.007) and fatal bleeding (HR=0.50; 95% CI 0.31–0.79; p=0.003) were reported for rivaroxaban Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). *Site based on blinded adjudication. #Combined gastrointestinal bleed rate p<0.001; ‡p<0.05 Patel MR et al, 2011. 99

ROCKET AF – all-cause mortality Endpoints Rivaroxaban (N=7,061) Warfarin (N=7,082) Hazard ratio (95% CI) n (% per year) All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70,1.02) Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) Non-vascular death 21 (0.2) 34 (0.3) 0.63 (0.36, 1.08) Unknown cause 17 (0.2) 23 (0.2) 0.75 (0.40, 1.41) Hazard ratio and 95% CIs All-cause mortality P-values: All-cause mortality: p=0.07 Vascular death: p=0.29 Non-vascular death: p=0.09 Unknown cause: p=0.37 Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). 0.2 0.5 1 2 5 Safety population – on-treatment analysis Favours rivaroxaban Favours warfarin Patel MR et al, 2011. 100

ROCKET AF – most frequent treatment-emergent adverse events Adverse event, no. (%) Rivaroxaban (N=7,111) Warfarin (N=7,125) Total patients with treatment-emergent AEs# 5,791 (81.4) 5,810 (81.5) Epistaxis* 721 (10.1) 609 (8.6) Peripheral oedema 435 (6.1) 444 (6.2) Dizziness 433 (6.1) 449 (6.3) Nasopharyngitis 421 (5.9) 455 (6.4) Cardiac failure 397 (5.6) 420 (5.9) Bronchitis 396 (5.6) 417 (5.9) Dyspnoea 380 (5.3) 394 (5.5) Diarrhoea 379 (5.3) Cough 343 (4.8) 353 (5.0) Back pain 338 (4.8) 347 (4.9) Upper respiratory tract infection 336 (4.7) 325 (4.6) Headache 324 (4.6) 363 (5.1) Arthralgia 301 (4.2) 331 (4.7) Haematuria* 296 (4.2) 242 (3.4) Urinary tract infection 293 (4.1) 321 (4.5) ALT >3× ULN and bilirubin >2× ULN either on same day or within following 30 days 33 (0.5) 35 (0.5) ROCKET AF – most frequent treatment-emergent adverse events The incidence of dyspepsia was similarly low in both treatment arms (1.56% for rivaroxaban and 1.28% for warfarin) – DATA ON FILE Abbreviations ALT, alanine aminotransferase; TBL, total bilirubin; ULN, upper limit of normal Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Data on file. Safety population; *p<0.05. 15 most frequent based on rivaroxaban treatment arm. #Events that started on or after the first dose and up to 2 days after the last dose of study medication. Patel MR et al, 2011. Slide notes contain data on file 101

ROCKET AF – secondary endpoints Rivaroxaban (N=7,061) Warfarin (N=7,082) Hazard ratio (95% CI) n (% per year) Composite of stroke, non­CNS SE, vascular death 346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)* Composite of stroke, non-CNS SE, vascular death and MI 433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)* Components of major secondary endpoints All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03) Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06) Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02) Secondary endpoints While on treatment, rivaroxaban demonstrated a favourable cardiovascular profile compared with warfarin: Rivaroxaban showed a significant 15% RRR of the composite of all-cause stroke, MI, non-CNS SE and vascular death In addition, when looking at secondary endpoints individually, rivaroxaban showed a trend for fewer MIs and less all-cause mortality compared with warfarin HR (95% CI) and p-value from Cox proportional hazard model with treatment group as a covariate P-values (2-sided for superiority of rivaroxaban versus warfarin): Composite of stroke, non­CNS SE, vascular death: p=0.03 Composite of stroke, non-CNS SE, MI, vascular death: p=0.01 All-cause stroke: p=0.09 Non-CNS SE: p=0.003 MI: p=0.12 Vascular death: p=0.29 All-cause mortality: p=0.07 Abbreviations RRR, relative risk reduction Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Safety population – on-treatment analysis. *Statistically significant Patel MR et al, 2011. 102

ROCKET AF – primary efficacy endpoint subgroup analysis Hazard ratio and 95% CIs Rivaroxaban Warfarin p-value* n/N (%) Overall 189/7,061 2.7 243/7,082 3.4 Sex 0.92 Male 103/4,270 2.4 136/4,283 3.2 Female 86/2,791 3.1 107/2,799 3.8 Age (years) 0.11 <75 107/3,988 119/4,005 3.0 ≥75 82/3,073 124/3,077 4.0 Weight (kg) 0.78 ≤70 63/2,004 78/2,008 3.9 70–≤90 92/3,022 129/3,133 4.1 >90 34/2,033 1.7 36/1,940 1.9 CrCl (ml/min) 0.72 <50 50/1,485 60/1,456 50–80 91/3,290 2.8 128/3,396 >80 47/2,278 2.1 54/2,221 Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). *p-value for interaction Safety population – on-treatment analysis 0.1 0.2 0.5 1 2 5 10 Favours rivaroxaban Favours warfarin Patel MR et al, 2011. 103

ROCKET AF – primary efficacy endpoint centre-based INR control* cTTR Rivaroxaban (% per year) Warfarin (% per year) Hazard ratio (95% CI) 0.0–50.6% 1.8 2.5 0.70 (0.48, 1.03) 50.7–58.5% 1.9 2.2 0.89 (0.62, 1.29) 58.6–65.7% 2.1 0.89 (0.62, 1.28) 65.7–100.0% 1.3 0.74 (0.49, 1.12) Hazard ratio and 95% CIs Better INR control Primary efficacy endpoint – INR control Patient TTR was calculated using the Rosendaal method2 The centre TTR (cTTR) was calculated using the total number of INR values in target range (2–3 inclusive) for all warfarin-treated patients within a centre, and dividing it by the total number of INR values from all warfarin-treated subjects within the centre. This was done as, unlike patient TTR, it accounted for covariation in other aspects of patient care between the centres The centres were then divided into quartiles based on the cTTR, as a measure of the degree of INR control achieved across the centres (quartile 4 = best INR control) This median TTR value was somewhat lower than in other trials with new OACs. However, no previous trials have enrolled patients with such a high degree of co-morbidity across such diverse geographic regions. The only previous blinded study was with ximelagatran in North America, a region characterized by higher quality INR control than many other parts of the world. Indeed, variation in the quality of INR control across different geographic regions is widely expected to have contributed to the lower overall TTR observed in the ROCKET AF trial A similar pattern of reduced rates in both study groups in centers with good INR control may reflect differences in the general management of cardiovascular medications across the various centres Hazard ratios indicate a consistent improvement in efficacy with rivaroxaban vs warfarin Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638). Rosendaal FR et al. Thromb Haemost 1993;69:236–239. cTTR, centre-based time in therapeutic range Based on Rosendaal method with all INR values included *p-value for interaction=0.74 Safety population (N=7,061 [rivaroxaban], N=7,082 [warfarin]) 0.5 1 2 Favours rivaroxaban Favours warfarin Patel MR et al, 2011. 104

ROCKET AF – conclusions Based on the prespecified primary efficacy outcome: A once-daily fixed dose regimen of rivaroxaban was non-inferior to warfarin for prevention of stroke or non-CNS systemic embolism Rivaroxaban was superior to warfarin while patients were taking study drug Less MIs and vascular death with rivaroxaban (not statistically significant) Safety: Similar overall incidence of bleeding and adverse events Increase in gastrointestinal bleeds with rivaroxaban fewer intracranial haemorrhages with rivaroxaban less fatal bleeding with rivaroxaban Less overall mortality (not statistically significant) Implication: Rivaroxaban, once approved in the indication, is a once-daily, proven alternative to warfarin with superior efficacy ‘on treatment’, similar overall bleeding and fewer intracranial haemorrhages 105

Additional safety outcomes: Liver enzyme elevations Warfarin No. of patients N=6,015 N=6,076 N=6,022 ALT or AST >3xULN 121 111 126 % 2.0 1.8 2.1 ALT or AST >3xULN and bilirubin >2xULN 11 14 22 0.2 0.4 The benefits of dabigatran etexilate regarding efficacy and safety occurred with no sign of hepatoxicity. In RE-LY®, a comprehensive liver monitoring plan was embedded in the protocol. The incidence rate of liver enzyme elevations (ALT or AST > 3x ULN, ALT or AST > 3 x ULN with concomitant bilirubin > 2 x ULN, hepatobiliary disorders) were low and comparable between dabigatran etexilate at either dose and warfarin. Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation 107

Dabigatran discontinuation rules before surgical procedures Renal function (CrCl ml/min) Estimated half-life (hours) Stop dabigatran before elective surgery Standard risk  80 ~ 13 24 hours before 50 - <80 ~ 15 1-2 days before 30 - <50 ~ 18 2-3 days before (> 48 hours)

Meta-analysis of ischaemic stroke or systemic embolism RE-LY in perspective Meta-analysis of ischaemic stroke or systemic embolism Category W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs ximelagatran W vs dabigatran 150 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Camm J.: Oral presentation at ESC on Aug 30th 2009.

Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici? G Ital Cardiol 2010; 11 (4): 263-268 William Turner, The Fighting Temeraire (National Gallery, Londra)

Eerenberg ES et al. Circulation. 2011; 124:1573-79