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FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011.

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Presentazione sul tema: "FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011."— Transcript della presentazione:

1 FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011 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

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

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

4 Limiti della terapia con antagonisti della Vitamina K Risposta non prevedibile Monitoraggio routinario dei fattori della coagulazione Lente insorgenza/termine dazione Resistenza al Warfarin La terapia con antagonisti della vitamina K presenta diversi limiti che ne rendono difficoltoso limpiego nella pratica clinica Numerose interazioni con altri farmaci Numerose interazioni alimentari Frequenti aggiustamenti della dose Finestra di trattamento stretta (INR range 2-3) 1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22: ; Nutescu EA, et al. Cardiol Clin 2008; 26:

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

6 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

7 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

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

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

10

11 Anticoagulation Control in Real Life in Italy % of INR Determinations by Range in VKA Treated Patients Range INR VKA Experienced meanmedian(p25 - p75) % INR < 2No33.4%28.8%(15.4% %) % INR < 2Yes25.3%20.0%(7.7% %) % INR No47.9%50.0%(33.3% %) % INR Yes56.3%58.3%(42.5% %) % INR > 3No16.9%13.3%(0.0% %) % INR > 3Yes17.9%14.3%(4.0% %)

12 The Promise of New Anticoagulants

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

14 N Engl J Med 2009;361(12):

15 N Engl J Med August 10, 2011

16 N Engl J Med August 28, 2011

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

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

19 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 DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

20 RE-LY ® – study design Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6000 Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 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: Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

21 21 v2 November 2010 TIME TO FIRST STROKE OR SSE Warfarin Years RRR 35% Cumulative hazard rates RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) P=0.30 (Sup) RR 0.65 (95% CI: 0.52–0.81) P<0.001 (NI) P<0.001 (Sup) 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: Dabigatran 150 mg BIDDabigatran 110 mg BID 3.0

22 22 v2 November 2010 MAJOR BLEEDING RATES 342 / 6, / 6, / 6,022 Rate per year (%) D110 mg BIDD150 mg BIDWarfarin RR 0.80 (95% CI: 0.70–0.93) P=0.003 (superiority) RR 0.93 (95% CI: 0.81–1.07) P=0.32 (superiority) 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: RRR 20% Events/n:

23 23 v2 November 2010 MAJOR BLEEDING AND COMPONENTS Characteristic Dabigatran 150 mg Dabigatran 110 mg Warfarin P value D150 vs. W P value D110 vs. W Number of patients6,0766,0156,022 Major bleeding rate (% per year) Life threatening Non-life threatening Gastro-intestinal < 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:

24 RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) Hemorrhagic stroke Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) Number of events 6,0156,0766, D110 mg BIDD150 mg BIDWarfarin 0.10% 0.38% RRR 69% RRR 74% 0.12%

25 Mortalità per qualsiasi causa

26 Mortalità vascolare

27 RE-LY Subgroup Analyses

28 RE-LY Subgroup Analysis: Prior TIA or Stroke

29 Lancet Neurology 2010; 9:

30 Prior stroke/TIA: time to primary outcome Years of follow-up Dabigatran 150 mg Dabigatran 110 mg Warfarin # at RiskYear D110 D150 W Cumulative Hazard Rates

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

32 RE-LY Subgroup Analysis: Age & Renal Function

33 Circulation 2011;123:

34 34 v2 November 2010 AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM 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 Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) < – Creatinine clearance (mL/min) 30– – > P=0.072 D 150 mg BID vs. warfarin P=0.76 D 110 mg BID vs. warfarin P=0.036P= Dabigatran better Warfarin better Dabigatran better Warfarin better 0 2.0

35 35 v2 November 2010 AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING 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 Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) < – Creatinine clearance (mL/min) 30– – > P= D 150 mg BID vs. warfarin P= D 110 mg BID vs. warfarin P=0.091P= Dabigatran better Warfarin better Dabigatran better Warfarin better 0 2.0

36 36 v2 November 2010 AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: HAEMORRHAGIC STROKE 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 Annual rate (%) D 110 mg BID D 150 mg BID Warfarin Age (yrs) < – Creatinine clearance (mL/min) 30– – > P=0.75 D 150 mg BID vs. warfarin P=0.51 D 110 mg BID vs. warfarin P=0.4P= Dabigatran better Warfarin better Dabigatran better Warfarin better 0 2.0

37 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

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

39 New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation RivaroxabanBayerPhase III ApixabanBMS / PfizerPhase III EdoxabanDaiichi SankyoPhase III BetrixabanPortola / MerckPhase II DarexabanAstellas PharmaPhase II LY LillyPlanned TAK – 442TakedaPlanned

40 New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation RivaroxabanBayerPhase III ApixabanBMS / PfizerPhase III EdoxabanDaiichi SankyoPhase III BetrixabanPortola / MerckPhase II DarexabanAstellas PharmaPhase II LY LillyPlanned TAK – 442TakedaPlanned

41 N Engl J Med August 10, 2011

42 42 Warfarin target INR 2–3 Rivaroxaban 20 mg once daily # Non-valvular AF History of stroke, TIA or non-CNS SE OR 2* of the following: CHF Hypertension Age 75 years Diabetes N=14,264 *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. ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven Patel MR et al, 2011 End of study 30-day follow-up R ~14 – 40 months

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

44 44 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 Favours rivaroxaban Primary efficacy endpoint: stroke or systemic embolism ITT on- and off-treatment: post hoc analyses Favours warfarin ITT269/7,081 (2.1) 306/7,090 (2.4) 0.88 (0.75,1.03)< 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 Hazard ratio and 95% CIs Patel MR et al, 2011.

45 45 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 bleeding395 (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)* Transfusion183 (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 bleeding27 (0.2)55 (0.5)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) Safety population – on-treatment analysis; *Statistically significant ROCKET AF – bleeding analysis Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* Hazard ratio and 95% CIs Favours rivaroxaban Favours warfarin Patel MR et al, 2011.

46 New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation RivaroxabanBayerPhase III ApixabanBMS / PfizerPhase III EdoxabanDaiichi SankyoPhase III BetrixabanPortola / MerckPhase II DarexabanAstellas PharmaPhase II LY LillyPlanned TAK – 442TakedaPlanned

47 N Engl J Med 2011;364(9):

48 AVERROES APIXABAN Phase 3 Clinical Trial vs Aspirin to Prevent Stroke or Embolism in AF Pts Apixaban 2.5 mg bid or 5 mg bid Aspirin mg qd Primary outcome measures: Time to composite outcome of stroke or systemic embolism Time to major bleeding Patient characteristics Aged 50 years Atrial fibrillation 1 additional risk factor for stroke Not suitable for vitamin K antagonist 1.6 years Randomization N=5600 N Engl J Med 2011;364(9):

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

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

51 N Engl J Med August 28, 2011

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

53 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 Warfarin P (non-inferiority)< % RRR Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism N Engl J Med 2011

54 Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI) P Value Event Rate (%/yr) Event Rate (%/yr) Stroke or systemic embolism* (0.66, 0.95)0.011 Stroke (0.65, 0.95)0.012 Ischemic or uncertain (0.74, 1.13)0.42 Hemorrhagic (0.35, 0.75)<0.001 Systemic embolism (SE) (0.44, 1.75)0.70 All-cause death* (0.80,0.998)0.047 Stroke, SE, or all-cause death (0.81, 0.98)0.019 Myocardial infarction (0.66, 1.17)0.37 N Engl J Med 2011 Efficacy Outcomes

55 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 Warfarin % RRR N Engl J Med 2011 Major Bleeding ISTH definition

56 Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI)P Value Event Rate (%/yr) Event Rate (%/yr) Primary safety outcome: ISTH major bleeding* (0.60, 0.80)<0.001 Intracranial (0.30, 0.58)<0.001 Gastrointestinal (0.70, 1.15)0.37 Major or clinically relevant non-major bleeding (0.61, 0.75)<0.001 GUSTO severe bleeding (0.35, 0.60)<0.001 TIMI major bleeding (0.46, 0.70)<0.001 Any bleeding (0.68, 0.75)<0.001 N Engl J Med 2011 Bleeding Outcomes

57 New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation RivaroxabanBayerPhase III ApixabanBMS / PfizerPhase III EdoxabanDaiichi SankyoPhase III BetrixabanPortola / MerckPhase II DarexabanAstellas PharmaPhase II LY LillyPlanned TAK – 442TakedaPlanned

58

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

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

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

62 Somiglianze e differenze tra gli studi

63 PK/PD of 5 Novel Oral Agents 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: DabigatranApixabanRivaroxabanEdoxaban (DU-176b) Betrixaban (PRT054021) Target IIa (thrombin) XaXaXaXa Hrs to Cmax NR CYP MetabolismNone15%32%NRNone Half-Life12-14h8-15h9-13h8-10h19-20h Renal Elimination80%40%33%35%<5% CYP = cytochrome P450; NR = not reported

64 Phase III AF Trials Re-LYROCKET- AF ARISTO TLE ENGAGE AF-TIMI 48 DrugDabigatranRivaroxabanApixabanEdoxaban Dose (mg) Freq 150, 110 BID 20 (15*) QD 5 (2.5*) BID 60*, 30* QD N18,11314,26618,206>21,000 DesignPROBE 2x blind AF criteria AF x 1 < 6 mths AF x 2 (>1 in 1 in <30d) AF or AFl x 2 <12 mths AF x 1 < 12 mths % VKA naive50%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

65 RELY Dabigatran 110 mg Dabigatran 150 mg Warfarin CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) C. Michael Gibson, M.S., M.D. ROCKET AF RivaroxabanWarfarin CHADS 2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) ARISTOTLE RivaroxabanWarfarin CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361: ; Granger C et al, N Eng J Med; %

66 Comparison of Trial Metrics RE-LYROCKET AFARISTOTLE 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: ; Granger C et al, N Eng J Med; 2011

67 Stroke 199 (1.19)250 (1.51) 184 (1.65)221 (1.96) NOAC Warfarin Favors NOAC Favors warfarin HR95% CI (1.44) 186 (1.58) Dabi 110 (ITT) Riva (safety AT) Apixaban (ITT) 122 (1.01)186 (1.58) Dabi 150 (ITT) No. of events (%/yr) 2.0 Not head to head comparison – For illustrative purposes only – adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: ITT: Intention to Treat – AT: as treated

68 Ischemic or Unspecified Stroke 162 (0.97)175 (1.05) 149 (1.34)161 (1.42) NOACWarfarin Favors NOAC Favors warfarin HR95% CI (1.34) 143 (1.21) Dabi 110 (ITT) Riva* ( safety AT) Apixaban* * (ITT) 111 (0.92)143 (1.21) Dabi 150 (ITT) 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. Not head to head comparison – For illustrative purpose only – adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: ITT: Intention to Treat – AT: as treated.

69 Hemorrhagic Stroke 40 (0.24)78 (0.47) 29 (0.26)50 (0.44) NOAC Warfarin Favors NOAC Favors warfarin HR95% CI (0.12) 45 (0.38) Dabi 110 (ITT) Riva (safety AT) Apixaban (ITT) 12 (0.10)45 (0.38) Dabi 150 (ITT) No. of events (%/yr) 2.0 Not head to head comparison – For illustrative purpose only – adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365: ITT: Intention to Treat – AT: as treated.

70 Major Bleeding 327 (2.13)462 (3.09) 395 (3.6)386 (3.4) NOACWarfarin Favors NOAC Favors warfarin HR95% CI (2.87) 421 (3.57) Dabi Riva Apixaban 399 (3.32)421 (3.57) Dabi No. of events (%/yr) 2.0 Not head to head comparison – For illustrative purpose only – adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365:

71 Death From Any Cause 603 (3.52)669 (3.94) 208 (1.87)250 (2.21) NOACWarfarin Favors NOAC Favors warfarin HR95% CI (3.75) 487 (4.13) Dabi 110 (ITT) Rivaroxab an (safety AT) Apixaban (ITT) 438 (3.64)487 (4.13) Dabi 150 (ITT) No. of events (%/yr) (4.5)632 (4.9) Rivaroxab an (ITT) Not head to head comparison – For illustrative purpose only – adapted from references Connolly et al. NEJM 2009; 361: Connolly et al. NEJM 2010; 363: Patel et al. NEJM 2011; 365: Granger et al. NEJM 2011; 365:

72 Treatment Discontinuation at the End of Follow-up 1. Connolly S et al. N Engl J Med ( /NEJMoa ) 30 Aug Patel M et al. N Engl J Med ( /NEJMoa ) 10 Aug Granger C et al. N Engl J Med ( /NEJMoa ) 28 Aug Connolly S et al. N Engl J Med ( /NEJMoa ) 10 Feb 2011

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

74 G Ital Cardiol 2011; 12(9):

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

76 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 laderenza del paziente alla terapia Mancanza di antidoto in caso di sovradosaggio o emorragie Inizio e termine dazione 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:

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

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

79 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 ?)

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

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

82 Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA di nuovo riscontro con indicazioni allanticoagulazione (naive) Pazienti con FA già in TAO in presenza di specifiche problematiche

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

84 Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale Futuri Scenari Clinici Pazienti con FA di nuovo riscontro con indicazioni allanticoagulazione (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

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

86 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

87 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

88 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

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

90 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 dallAmbulatorio TAO alla Sorveglianza clinica

91 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 ?)

92 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 (Servizio Ambulatoriale ± Ambulatorio TAO) Medico di Medicina Generale (NCP, MMG associati)

93 Attività essenziali per il trattamento con VKA o NAO AVKNAO Visita prescrizioneSI Giusta indicazione e doseSI Informazione /educazione pz.SI Controlli laboratorioSINO Aggiustamento doseSINO Controllo complianceNOSI Guida per condizioni rischioSI Controllo clinico periodicoNOSI

94

95 95 Rivaroxaban Selective, direct Factor Xa inhibitor 1 High oral bioavailability 2 Rapid onset of action 3 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 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, Rivaroxaban Xa IIa XIX IXa VIIIa Va II FibrinFibrinogen TF/VIIa Adapted from Weitz JI et al, 2005; 2008.

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

97 97 Warfarin target INR 2–3 Rivaroxaban 20 mg once daily # Non-valvular AF History of stroke, TIA or non-CNS SE OR 2* of the following: CHF Hypertension Age 75 years Diabetes N=14,264 *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. ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven Patel MR et al, 2011 End of study 30-day follow-up R ~14 – 40 months

98 98 Number of subjects at risk Rivaroxaban6,9586,2115,7865,4684,4063,4072,4721,496 Warfarin7,0046,3275,9115,5424,4613,4782,5391,538 ROCKET AF – primary efficacy endpoint Per-protocol population – as treated Warfarin Rivaroxaban Days since randomization HR=0.79 (0.66, 0.96) p<0.001 (non-inferiority) Cumulative event rate (%) Stroke or systemic embolism Patel MR et al, 2011.

99 99 ROCKET AF – major bleeding by site 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) Traumatic4 (0.1)2 (0.03) Intraventricular2 (0.03)4 (0.1) Subdural haematoma12 (0.2)22 (0.3) Subarachnoid4 (0.1)1 (0.01) Epidural haematoma01 (0.01) Macroscopic haematuria26 (0.4)21 (0.3) Bleeding associated with non-cardiac surgery19 (0.3)26 (0.4) Intraocular/retinal17 (0.2)24 (0.3) Intraarticular16 (0.2)21 (0.3) Epistaxis13 (0.2)14 (0.2) *Site based on blinded adjudication. # Combined gastrointestinal bleed rate p<0.001; p<0.05 Patel MR et al, 2011.

100 100 ROCKET AF – all-cause mortality Safety population – on-treatment analysis Hazard ratio and 95% CIs Favours rivaroxaban Favours warfarin Endpoints Rivaroxaban (N=7,061) Warfarin (N=7,082) Hazard ratio (95% CI) n (% per year) All-cause mortality208 (1.9)250 (2.2)0.85 (0.70,1.02) Vascular death170 (1.5)193 (1.7)0.89 (0.73, 1.10) Non-vascular death21 (0.2)34 (0.3)0.63 (0.36, 1.08) Unknown cause17 (0.2)23 (0.2)0.75 (0.40, 1.41) Patel MR et al, 2011.

101 101 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 oedema435 (6.1)444 (6.2) Dizziness433 (6.1)449 (6.3) Nasopharyngitis421 (5.9)455 (6.4) Cardiac failure397 (5.6)420 (5.9) Bronchitis396 (5.6)417 (5.9) Dyspnoea380 (5.3)394 (5.5) Diarrhoea379 (5.3)397 (5.6) Cough343 (4.8)353 (5.0) Back pain338 (4.8)347 (4.9) Upper respiratory tract infection336 (4.7)325 (4.6) Headache324 (4.6)363 (5.1) Arthralgia301 (4.2)331 (4.7) Haematuria*296 (4.2)242 (3.4) Urinary tract infection293 (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) Safety population; *p< 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, Slide notes contain data on file

102 102 ROCKET AF – secondary endpoints Safety population – on-treatment analysis. *Statistically significant 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 stroke184 (1.7)221 (2.0)0.85 (0.70, 1.03) Non-CNS SE5 (0.04)22 (0.2)0.23 (0.09, 0.61)* MI101 (0.9)126 (1.1)0.81 (0.63, 1.06) Vascular death170 (1.5)193 (1.7)0.89 (0.73, 1.10) All-cause mortality208 (1.9)250 (2.2)0.85 (0.70, 1.02) Patel MR et al, 2011.

103 103 *p-value for interaction Safety population – on-treatment analysis ROCKET AF – primary efficacy endpoint subgroup analysis RivaroxabanWarfarin p-value* n/N(%)n/N(%) Overall189/7, /7, Sex0.92 Male103/4, /4, Female86/2, /2, Age (years)0.11 <75107/3, /4, /3, /3, Weight (kg) /2, /2, –9092/3, /3, >9034/2, /1, CrCl (ml/min)0.72 <5050/1, /1, –8091/3, /3, >8047/2, /2, Hazard ratio and 95% CIs Favours rivaroxaban Favours warfarin Patel MR et al, 2011.

104 104 cTTR Rivaroxaban (% per year) Warfarin (% per year) Hazard ratio (95% CI) 0.0–50.6% (0.48, 1.03) 50.7–58.5% (0.62, 1.29) 58.6–65.7% (0.62, 1.28) 65.7–100.0% (0.49, 1.12) 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]) Hazard ratio and 95% CIs Favours warfarin Favours rivaroxaban Better INR control ROCKET AF – primary efficacy endpoint centre-based INR control* Patel MR et al, 2011.

105 105 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

106

107 Additional safety outcomes: Liver enzyme elevations D110D150Warfarin No. of patientsN=6,015N=6,076N=6,022 ALT or AST >3xULN % ALT or AST >3xULN and bilirubin >2xULN % Connolly SJ., et al. NEJM published online on Aug 30th DOI /NEJMoa Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

108 Dabigatran discontinuation rules before surgical procedures Renal function (CrCl ml/min) Estimated half-life (hours) Stop dabigatran before elective surgery Standard risk 80 ~ 1324 hours before 50 - <80 ~ days before 30 - <50 ~ days before ( > 48 hours)

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

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

111 Eerenberg ES et al. Circulation. 2011; 124:


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