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Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004.

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Presentation on theme: "Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004."— Presentation transcript:

1 Nuovi farmaci antitrombotici: che cosa cambierà in clinica nei prossimi anni? GF Gensini Livorno 27 marzo 2004

2 Currently available anticoagulants: largely unmet medical need LMWH/heparin No oral administration – less suited for outpatient use Risk of heparin-induced thrombocytopenia Vitamin K antagonists Narrow therapeutic interval, thus frequent monitoring required Significant food and drug interactions Slow on- and offset Increased incidence of severe bleeding complications Limited efficacy as thromboprophylaxis in high-risk patients

3 New anticoagulants Unmet clinical needs More effective and safer agents for VTE prophylaxis in high risk surgery (major orthopedic and cancer) More practical agents for post-discharge prophylaxis of VTE More practical agents for long-term treatment (no monitoring) of VTE More practical agents for long-term treatment (no monitoring) of atrial fibrillation Safer adjunctive treatment for STEMI and ACS More effective agents for secondary prophylaxis of MI

4 New antithrombotic agents Factor X Factor Xa Prothrombinase complex Fibrinogen Thrombin Prothrombin Selective anti-IIa inhibitors FIXa-FVIIIa, Phospholipids, Ca++ Tissue factor - FVIIa rNAPc2 Pentasaccharide Direct anti-Xa inhibitors

5 New anticoagulants Unmet clinical needs More effective and safer agents for VTE prophylaxis in high risk surgery (major orthopedic and cancer) More practical agents for post-discharge prophylaxis of VTE More practical agents for long-term treatment (no monitoring) of VTE More practical agents for long-term treatment (no monitoring) of atrial fibrillation Safer adjunctive treatment for STEMI and ACS More effective agents for secondary prophylaxis of MI

6 Adjusted-Dose Warfarin Compared with Placebo AFASAK I SPAF BAATAF CAFA SPINAF EAFT All trials (n=6) RRR 62% (95% CI 48-72%) 100%50%0- 50%- 100% Relative Risk Reduction of Stroke (95% CI) Warfarin BetterWarfarin Worse Hart et al Ann Intern Med 1999; 131: All cause mortality decreased [RRR 26% (4-43)]

7 Optimal Intensity for Warfarin Therapy INROdds Ratio INR 2.0 Odds Ratio for Stroke N Engl J Med 1996;335:

8 AFASAK I SPAF I EAFT ESPS II LASAF UK-TIA All trials (n=6) RRR 22% (95% CI 2-38%) Relative Risk Reduction of Stroke (95% CI) Aspirin BetterAspirin Worse Aspirin Compared with Placebo 100%50%- 50%- 100% 0 Hart et al Ann Intern Med 1999; 131: All cause mortality not significantly decreased

9 ATRIAL FIBRILLATION INVESTIGATORS Arch Intern Med 1994

10 Studio ISCOAT: età come fattore di rischio per emorragia Età% anni/paz. < 50 y y y 10.5 Analisi univariate : 70 y vs < 70 y RR = 1.75 (p<0.001) (da Palareti et al. Lancet 1996)

11

12 Complications During Long-Term OAC in 360 Patients With AF ComplicationAll Patients (n=360) Taking 3 Drugs (n=175) Taking >3 Drugs (n=185) Thromboembolic and bleeding events * Bleeding Total Minor Serious Life-threatening Fatal Thromboembolism Total Minor Serious Life-threatening Fatal Values are percentage per 100 patient-years. *P=0.0041; P =0.0073; P = Wehinger C, et al. Stroke : 2246

13 Br J Haematol 1998; 101:374 Blood 1999; 94: 3007 Negli anziani In pazienti con scompenso cardiaco In pazienti con epatopatia Bambini 0.2 mg/kg (W) dose

14 Vitamina K >40 μg/100 g INR Thromb Haemost 1997; 77: 504 Haemostasis 1993; riduzione

15 Vitamina K >40 μg/100 g INR Thromb Haemost 1997; 77: 504 Haemostasis 1993; riduzione

16 Vitamina K >40 μg/100 g INR Thromb Haemost 1997; 77: 504 Haemostasis 1993; riduzione

17 Vitamina K 5-40 μg/100 g

18 NECESSITA DI UNA VALUTAZIONE INDIVIDUALE DEL RAPPORTO RISCHIO BENEFICIO DELLA SCELTA PROFILATTICA Il cardiologo dovrebbe appoggiare il paziente ad un Centro di monitoraggio della TAO ?

19 ** ** Landefeld et al., 1993 Un buon monitoraggio della TAO consente di avere una efficacia ed una sicurezza paragonabili o migliori di quelle dei trial clinici

20 ** ** Landefeld et al., 1993 Un buon monitoraggio della TAO consente di avere una efficacia ed una sicurezza paragonabili o migliori di quelle dei trial clinici

21 Eventi clinici prima e dopo arruolamento in Centro Anticoagulati (paz con PVM) Cortelazzo et al. 1993

22 Pazienti in trattamento con anticoagulanti orali in Italia* Stima, Clin Cardiol PD 2002

23 Centri FCSA 2003 N=306

24 Considerazioni al momento di decidere il trattamento con AO (in particolare in un soggetto di età>75 anni) Fattori di rischio tromboembolico Storia di sanguinamento Patologie associate (ad es. ipertensione) Grado di attenzione (abbreviated mental test) Storia di cadute Possibilità di adeguato monitoraggio (più accurato e più frequente) Supporto familiare e/o sociosanitario

25 New anticoagulants Unmet clinical needs More effective and safer agents for VTE prophylaxis in high risk surgery (major orthopedic and cancer) More practical agents for post-discharge prophylaxis of VTE More practical agents for long-term treatment (no monitoring) of VTE More practical agents for long-term treatment (no monitoring) of atrial fibrillation Safer adjunctive treatment for STEMI and ACS More effective agents for secondary prophylaxis of MI

26 Fibrillazione atriale – Fase III ® Ximelagatran36 mg bid Warfarin Fino a 27 mesi 3000 paz. resto del mondo open label, : SPORTIF III 3000 paz. USA & Canada double-blind, double-dummy, sham INR : SPORTIF V

27 Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF III) Lancet 2003;362:

28 The SPORTIF III Study Randomised, parallel group, open-label treatment allocation, blinded event assessmentRandomised, parallel group, open-label treatment allocation, blinded event assessment 23 countries, 259 centers23 countries, 259 centers Exposure: mean 17 months, 4941 patient-years and 96 primary endpoints. Adjusted-doseWarfarin (INR 2-3) Fixed-doseximelagatran (36 mg b.i.d.) Nonvalvular atrial fibrillation patients with at least one aditional risk factor for stroke n=3 407 Primary objective: To establish the non-inferiority of ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

29 Non-Inferiority Testing Ximelagatran Superior Warfarin Superior -2%-2% Superiority Absolute Difference in Event Rates Equivalence 0%+2%+2% Non-inferiority Circulation 2003;108:2723

30 Paragone di vari eventi compositi SPORTIF III, Lancet 2003;362:

31 SPORTIF III Stroke e/o embolia sistemica (intention to treat) p= Durata (mesi) Warfarin Ximelagatran Eventi cumulativi (%) 56 eventi (2.3%/anno) 40 eventi (1.6%/anno) Presented at ACC 2003

32 4.6% Eventi (% per anno) Eventi primari + emorragie maggiori + morte 6.1% RRR=25% p = Eventi avversi maggiori (on treatment analysis) Ximelagatran Warfarin Presented at ACC 2003

33 Eventi (%) ALT >3x limite sup. norma p < % 0.7% Altri eventi avversi Aumento enzimi epatici Ximelagatran Warfarin Presented at ACC 2003

34 The SPORTIF V Study Randomised, double-blind, double-dummy, sham INR, blinded endpoint assessment USA and Canada, 409 centers Exposure: mean 20 months, 6405 patient-years and 88 primary endpoints. Adjusted-doseWarfarin (INR 2-3) Fixed-doseXimelagatran (36 mg bid) Nonvalvular atrial fibrillation patients with at least one aditional risk factor for stroke n=3 922 Primary objective: To establish the non-inferiority of fixed-dose ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

35 SPORTIF V - Stroke ed embolismo sistemico (Intention to treat) Ximelagatran Warfarin Ximelagatran Warfarin Mesi 51 events (1.6%/anno) 37 eventis (1.2%/anno) Eventi cumulativi (%/anno) p=0.13

36 SPORTIF V - Emorragie (Analisi on treatment) 3.1% 47% 0.1% 2.4% 37% Cerebrali Maggiori Maggiori + minori Warfarin Ximelagatran Eventi (% /anno) p< p=0.16 NS

37 SPORTIF Program Stroke and Systemic Embolism Intention-to-treat Analysis Months V SPORTIF III 1.2%/year1.2%/year Warfarin 2.3%/year2.3%/year 1.6%/year1.6%/year Ximelagatran 1.6%/year1.6%/year Halperin JL, Presented at AHA 2003 Cumulative Event Rate (%year)

38 SPORTIF (Analisi intention to treat) SPORTIF III SPORTIF V Differenza assoluta nella frequenza di eventi (Ximelagatran – Warfarin) Ximelagatran meglioWarfarin meglio Pooled -0.03

39 0% 20% 40% 60% 80% 100% <1.8 > Treatment duration (months) Time in range (%) 66% 81% Lancet 2003 SPORTIF III INR Values – Warfarin Group

40 Time in Range (%) 83% Treatment Duration (months) SPORTIF V INR Values – Warfarin Group >3.2 <1.8 Halperin JL, Presented at AHA %

41 SPORTIF Program Major Bleeding On-treatment Analysis SPORTIF V Pooled SPORTIF III p=0.054 Event Rate (% /year) 3.1% 2.5% 1.8% 1.3% 2.4% 1.9% Ximelagatran Warfarin Halperin JL, Presented at AHA 2003

42 0 10 SPORTIF Program ALAT >3X ULN 0.8% 6.0% 6.1% 6.3% Ximelagatran Warfarin Elevated bilirubin >2 x ULN Incidence (%) Halperin JL, Presented at AHA 2003 SPORTIF V Pooled SPORTIF III 0.8%

43 SPORTIF V - aumento transaminasi ALT >3 x val. normale WarfarinXimelagatran Mesi Numero di pazienti

44 Net Clinical Benefit Primary Events + Major Bleeding + Death On-treatment Analysis SPORTIF V Pooled SPORTIF III Event Rate (% /year) 6.2% 6.3% 5.8% 5.2% 4.6% RRR = 26% p=0.019 RRR = 7% p=0.527 RRR = 16 % p=0.038 Ximelagatran Warfarin Halperin JL, Presented at AHA 2003

45 Patients with AF, eligible for VKA treatment Randomization 2.5 mg idraparinux o.w. INR-adjusted VKA Idraparinux sodium (SanOrg34006) Phase III Amadeus AF Treatment 6-24 months open-label EFFICACY:All strokes and non-CNS embolism SAFETY:All bleeding

46 New anticoagulants Unmet clinical needs More effective and safer agents for VTE prophylaxis in high risk surgery (major orthopedic and cancer) More practical agents for post-discharge prophylaxis of VTE More practical agents for long-term treatment (no monitoring) of VTE More practical agents for long-term treatment (no monitoring) of atrial fibrillation Safer adjunctive treatment for STEMI and ACS More effective agents for secondary prophylaxis of MI

47 Randomized, double-blinded, dose-escalation, multicenter trial 154 pts with stable angina scheduled for elective PCI All pts treated with ASA, UH, clopidogrel (if stent) rNAPc2 3.5, 5.0, 7.5 and 10.0 microg/kg or placebo as a single sc administration 2-6 h after angioplasty Registration of minor and major bleeding and F1+2 levels as index of thrombin generation

48 § § all 3 pts treated also with GP IIb-IIIa inhibitor

49 Femoral compression time after sheath removal

50 Plasma levels of r-NAPc2 in relation to plasma levels of F1+2 at 36 hr Thrombin generation suppressed in all rNAPc2 groups for at least 36 hrs

51 New anticoagulants Unmet clinical needs More effective and safer agents for VTE prophylaxis in high risk surgery (major orthopedic and cancer) More practical agents for post-discharge prophylaxis of VTE More practical agents for long-term treatment (no monitoring) of VTE More practical agents for long-term treatment (no monitoring) of atrial fibrillation Safer adjunctive treatment for STEMI and ACS More effective agents for secondary prophylaxis of MI

52 Oral ximelagatran for secondary prophylaxis after myocardial infarction. The ESTEEM randomised controlled trial Wallentin L et al, Lancet 2003; 362:789-97

53 Dose-finding, doppio cieco, controllato con placebo in 1883 pazienti con recente infarto del miocardio Ximelagatran 24 mg, 36 mg, 48 mg, or 60 mg 2 volte/die, per 6 mesi Tutti i pazienti ricevevano anche ASA 160 mg Obiettivi primari: mortalità generale, infarto non fatale, recidiva ischemica grave ESTEEM Study Wallentin L et al. Lancet 2003; 362: 789–97

54 Cumulative risk of death, myocardial infarction, and stroke. Data are for all ximelagatran doses pooled. Analysis by intention-to-treat

55 ESTEEM- Emorragie Wallentin L et al. Lancet 2003; 362: 789–97

56 ESTEEM - Conclusioni Wallentin L et al, Lancet 2003; 362: Lassociazione ximelagatran-ASA è più efficace del solo ASA nella prevenzione di eventi cardiovascolari maggiori nei 6 mesi successivi ad infarto del miocardio

57 Thrombin Inhibitors: DS, Hirudin, Bivalirudin, Argatroban, Melagatran, Ximelagatran IXa inhibitors Xa inhibitors: Pentasaccharide TAP, Antistasin, DX 9065a, DPC 906 Protein C Activators aPC, Thrombomodulin Coagulation PathwayAntithrombotics in development Tissue Factor Pathway Inhibitors TFPI, rNAPc2, VIIa inhibitors Initiation Thrombin generation Thrombin activity TF/VIIa IIa II Xa IXa IXX VIIIa Va i New agents in clinical development: The search for selectivity

58 New anticoagulants Unmet clinical needs VENOUS THROMBOEMBOLISM More effective and safer agents for prophylaxis More practical agents for post-discharge prophylaxis More practical agents for long-term treatment (no monitoring) ATRIAL FIBRILLATION More practical agents for long-term treatment (no monitoring) STEMI and ACS Safer adjunctive treatment MYOCARDIAL INFARCTION More effective agents for secondary prevention

59 New anticoagulants Unmet (?) clinical needs VENOUS THROMBOEMBOLISM More effective and safer agents for prophylaxis More practical agents for post-discharge prophylaxis More practical agents for long-term treatment (no monitoring) ATRIAL FIBRILLATION More practical agents for long-term treatment (no monitoring) STEMI and ACS Safer adjunctive treatment MYOCARDIAL INFARCTION More effective agents for secondary prevention


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