Presentation is loading. Please wait.

Presentation is loading. Please wait.

Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali Giancarlo Casolo Genova, Hotel NH Marina 21/22 Ottobre 2011 HEARTLINE HSM.

Similar presentations


Presentation on theme: "Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali Giancarlo Casolo Genova, Hotel NH Marina 21/22 Ottobre 2011 HEARTLINE HSM."— Presentation transcript:

1 Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali Giancarlo Casolo Genova, Hotel NH Marina 21/22 Ottobre 2011 HEARTLINE HSM Genoa Cardiology Meeting NUOVI ORIZZONTI FARMACOLOGICI NELLA CARDIOPATIA ISCHEMICA

2

3 ESC Guideline 2010

4 Guidelines on myocardial revascularization

5 Prasugrel Ticagrelor

6 ESC Guideline 2011

7 STUDIO PLATO STUDIO TRITON TIMI 38 Current Oasis 7

8 STUDIO TRITON TIMI 38 STUDIO PLATO

9 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 9 TRITON-TIMI 38: Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies:Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 Wiviott SD et al AHJ 152: 627,2006 Adapted with permission from E.Antman

10 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 Adapted with permission from Wiviott SD et al NEJM 357:2007 TRITON: Results

11 HR 0.82 P=0.01 HR 0.80 P= Days Primary Endpoint (%) Prasugrel Clopidogrel Prasugrel Clopidogrel Loading DoseMaintenance Dose Timing of Benefit (Landmark Analysis)

12 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 12 B OVERALL No GPI GPI DES BMS DM No DM > <65 Female Male STEMI UA/NSTEMI Prasugrel Better Clopidogrel Better HR Age Reduction in risk (%) P inter = NS CV Death, MI, Stroke Major Subgroups CrCl > 60 CrCl < Wiviott SD et al NEJM 357: 2001, 2007 TRITON TIMI-38

13 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update Principali risultati nello studio TRITON TIMI 38

14 TRITON: Previous STOKE or TIA (3.8%) Wiviot SD et al. N Engl J Med 2007;357:

15 PLATO study design Primary endpoint: CV death + MI + Stroke Key secondary: CV death + MI + Stroke in patients intended for invasive management Total mortality + MI + Stroke CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events MI alone / CV death alone / Stroke alone / Total mortality Primary safety: Total major bleeding 6–12-month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) UA = unstable angina; PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack James S et al. Am Heart J 2009;157:

16 K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke) No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 5,096 5,161 4,047 4, Cumulative incidence (%) ,219 HR 0.84 (95% CI 0.77–0.92), p= Clopidogrel Ticagrelor Completeness of follow-up 99.97% = five patients lost to follow-up K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

17 Hierarchical testing of major efficacy endpoints All patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for ticagrelor (95% CI)P Value † Primary objective, n (%) CV death + MI + stroke864 (9.8)1,014 (11.7)0.84 (0.77–0.92) <0.001 Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke 901 (10.2) 1,290 (14.6) 504 (5.8) 353 (4.0) 125 (1.5) 1,065 (12.3) 1,456 (16.7) 593 (6.9) 442 (5.1) 106 (1.3) 0.84 (0.77–0.92) 0.88 (0.81–0.95) 0.84 (0.75–0.95) 0.79 (0.69–0.91) 1.17 (0.91–1.52) < Total death399 (4.5)506 (5.9)0.78 (0.69–0.89) <0.001 *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes included fatal bleeding and only traumatic fatal bleeds were excluded from the CV death category; † By Cox regression analysis Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

18 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,361 8,460 8,124 Days after randomisation 6,650 6,743 5,096 5,161 4,047 4, HR 0.84 (95% CI 0.77–0.92), p= Clopidogrel Ticagrelor , Time to death/myocardial infarction/stroke K-M estimated rate (% per year) Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

19 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177 Days after randomisation 6,703 6,796 5,136 5,210 4,109 4, Clopidogrel Ticagrelor ,279 HR 0.84 (95% CI 0.75–0.95), p=0.005 Time to myocardial infarction K-M estimated rate (% per year) Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

20 No. at risk Clopidogrel Ticagrelor 9,291 9, ,294 8,780 8,822 8,589 Days after randomisation 7,079 7,119 5,441 5,482 4,364 4, Clopidogrel Ticagrelor ,626 HR 0.79 (95% CI 0.69–0.91), p= Time to cardiovascular death K-M estimated rate (% per year) Wallentin L, Harrington R et al. New Engl J Med 2009;361 ( /NEJMoa ).

21 Steg G et al. Circulation. 2010;122: CV death, MI, stroke (%) End point primario nei pazienti dello studio PLATO avviati all’angioplastica primaria

22 PLATO Conservative Arm James et Al. BMJ 2011

23 Steg G et al. Circulation. 2010;122: PLATO Major Bleeding* (STEMI) * PLATO major bleeding was defined as significant disabling bleeding, a fall in hemoglobin of ≥3 g/dL or a need for transfusion of ≥2 U red cells.

24 Total major bleeding NS 0 K-M estimated rate (% per year) PLATO major bleeding TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding Ticagrelor Clopidogrel Major bleeding and major or minor bleeding according to TIMI criteria refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with definition described in (Wiviott SD et al. NEJM. 357: ); * Proportion of patients (%); NS = not significant Wallentin L et al. N Engl J Med Sep 10;361(11):

25 Non-CABG and CABG-related major bleeding p= p= NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Ticagrelor Clopidogrel Wallentin L et al. N Engl J Med Sep 10;361(11):

26 Dyspnoea All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) HR for ticagrelor (95% CI)P Value Dyspnoea *, % Any dyspnoea adverse event Discontinued due to dyspnoea (1.68–2.02) 6.12 (3.41–11.01) <0.001 * Combined incidence of dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea Wallentin L et al. N Engl J Med Sep 10;361(11):

27 Holter monitoring program Holter monitor first week Ticagrelor (n=1,451) Clopidogrel (n=1,415)P Value Ventricular pauses ≥3 seconds, n (%) Ventricular pauses ≥5 seconds, n (%) 84 (5.8) 29 (2.0) 51 (3.6) 17 (1.2) Holter monitor at 30 days Ticagrelor (n= 985) Clopidogrel (n=1,006) P Value Ventricular pauses ≥3 seconds, n (%) Ventricular pauses ≥5 seconds, n (%) 21 (2.1) 8 (0.8) 17 (1.7) 6 (0.6) Patients with Ventricular Pauses ≥3 seconds Ticagrelor (n=89) Clopidogrel (n=62) P Value Patients with symptomatic pauses, n (%)4 (4.5)8 (12.9)0.06 Wallentin L et al. N Engl J Med Sep 10;361(11):

28 Other findings All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186)P Value * Serum creatinine (% increase from baseline value), mean  SD During treatment Follow-up visit 10  22 8   22 < * P-values were calculated with the use of Fischer’s exact test Wallentin L et al. N Engl J Med Sep 10;361(11):

29 Conclusions Reversible, more intense P2Y 12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with STEMI and NSTEMI ACS provides – Reduction in MI and stent thrombosis – Reduction in CV and total mortality – No change in the overall risk of major bleeding – Raised risk for non-procedure-related bleeding Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS

30 Risultati principali TRITONmorte CV, IM, CVA 9.9 vs 12.1%, RRR -19% NNT 46 CABG related bleeding NNH 10 PLATO morte cause vascolari, IM,CVA 9.8 vs 11.7%, RRR -16% NNT 53

31 Platelets and Coronary Thrombosis Davies MJ. Am J Cardiol Aug 16;88(4A):2F-9F Coronary plaqueErosion/rupture Thrombotic occlusion

32 Adesione piastrinica Lisman et Al. Frontiers in Bioscience,2005

33 Meccanismi di attivazione piastrinica Wallentine L. Eur Heart J 2009

34

35 Slow onset of action (steady state platelet inhibition: hour after mg load) Modest inhibition of platelet aggregation (steady state mean platelet inhibition %) Slow offset of effect (at least 5 – 7 days) Large interindividual variability in inhibition of platelet aggregation (poor platelet inhibition response in % of pts) Limitations of clopidogrel

36 Clopidogrel Response Variability Baseline - 2hr (5  mol ADP) ∆ percent aggregation Gurbel PA et al. Circulation 2003; 107:2908 Number of patients ≤ , , , 0 0, 10 10, 20 20, 30 30, 40 40, 50 50, 60 60, 70 70, 80 > 80 Resistance = 63%

37 Major pathways leading to the formation of thienopyridine active metabolites Wallentine L. Eur Heart J 2009

38 Mega J L et al, N Engll J Med 2009; 360: < CYP2C19 CYP2C9 CYP2B6 CYP3A5 CYP1A Relative Percent Difference Percent difference in AUC o-t p value Genetic effects on pharmacokinetic responses to clopidogrel 162 healthy subjects

39 Cytochrome P450 2C 19 polymorphism Time course of ex-vivo platelet aggregation in response to 10 μM ADP Time (Days) Hulot et al. Blood 2006; 108: ADP 10 μmol/L-induced Platelet aggregation (%) CYP2C19 genotype *1/*1 CYP2C19 genotype *1/*2 Clopidogrel 75 mg/d P <0.003

40 Collet JP, et al, Lancet 2009; 373: CYP2C19*2 polymorphism Kaplan Maier estimates of the rates of first cardiovascular event at 5years of follow-up in young MI patients treated with clopidogrel The AFIJI Multicentre Registry (n= 259) Follow-up duration (years) Cumulative event- free survival (%) Non carriers Carriers HR 3.69 (95% CI ) p=0.0005

41 Cytochrome P450 2C19 polymorphism and stent thrombosis Sibbing et al, Eur Heart Journal 2009; 30: day incidence of stent thrombosis (%) CYP2C19 *1/*1 CYP2C19 *1/*2 CYP2C19 *2/*2 p= patients undergoing PCI and treated with clopidogrel

42 Attività piastrinica residua ed eventi cardiovascolari Price M et Al. Circulation 2011

43 Kaplan Meier Survival Curves Parodi G et Al. JAMA 2011 Cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow up 14.6% 8.7% 9.7% 4.3% 1789 Pazienti consecutivi 14% HRPP

44 Two-year clinical outcome Parodi G et Al. JAMA 2011

45 Analisi dei risultati Parodi G et Al. JAMA 2011

46 Verify-now LTA ADP WDA ADP PFA 100

47 ESC Guideline 2011

48 N S O O O F N F F S N O O N N N N O O N S O CI O Ticagrelor Prasugrel Clopidogrel Prasugrel Ticagrelor Hydrolysis by esterase CYP-dependent oxidation CYP1A2 CYP2B6 CYP2C19 CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6 Binding P2Y12 CYP-dependent oxidation CYP3A4/5 CYP2B6 CYP2C19 CYP2C9 CYP2D6 No in vivo biotransformation Active compoud Intermediate metabolite Prodrug Platelet Antiplatelets Drug metabolism

49 Diverso meccanismo d’azione degli inibitori del recettore P2Y12 Becker RC, Gurbel PA Thromb Haemost 2010

50 New Antiplatelet Agents

51 I nuovi antiaggreganti piastrinici Clopidogrel Prasugrel Ticagrelor Cangrelor Steady state Aggregazione 3-7 gg 3gg 2-3gg rapida Inizio anti- Aggreg. 2 h 30min 2 h rapida Legame reversibile NO SI Grado di inibizione 30-50% 70-80% SI Offset 5gg 4-5gg 36-48h --

52 Prasugrel farmacodinamica Jernberg et al, Eur Heart J 2006;27; clopidogrel prasugrel

53

54 Ticagrelor Pharmacodynamics % IPA Final Clopidogrel 75mg od AZD mg bd AZD mg bd AZD mg od AZD mg bd IPA: Inibition of Platelet Aggregation

55 Greater and More Consistent IPA with AZD6140 than Clopidogrel Final Extent Mean percent inhibition Hours AZD mg bd Day 1Day 14 Hours Clopidogrel Day 1Day 14

56 Circulation 2010

57 Onset Onset and Offset of the Antiplatelet Effects Ticagrelor vs Clopidogrel Time (hours) Inhibition of Platelet Aggregation (IPA) percent Gurbel PA et al, Circulation 2009; 120: Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) OffsetMaintenance Loading dose Last maintenance dose 6 weeks

58 Quale antiaggregante? Non esistono studi di confronto tra Prasugrel e Ticagrelor E’ possibile identificare una tipologia di paziente specifica per ciascun farmaco

59 Recent Meta-Analyses Montalescot G et al. J Am Coll Cardiol 2010

60 Recent Meta-Analyses Adjusted comparison of Prasugrel vs. Ticagrelor Biondi-Zoccai G et al. Int J Cardiol 2010

61 Prasugrel Azione rapida, legame irreversibile. soggetto “giovane”, nessuna storia di accidenti CV, peso > 60Kg,*. paziente con STEMI avviato alla PCI. ACS con anatomia coronarica nota e avviato alla PCI *Non indizi di malattia che meriti BPAC

62 Ticagrelor Azione rapida, legame reversibile. Paziente con ACS. Quadro angiografico ignoto. Clearance Creat >30 ml/min/1.73m2

63

64 P2Y12 reaction units (PRU) as assessed by the VerifyNow P2Y12 assay by protocol time and treatment Gurbel PA et al, Circulation 2009; 120:

65 Effetto dello switching tra farmaci Gurbel et Al. Circulation,2010

66 Conclusioni Una moderna terapia antiaggregante dei pazienti con malattia coronarica consente di ridurre gli eventi ischemici e la mortalità nei pazienti con SCA I nuovi antiaggreganti sono più potenti, risentono poco o nulla delle differenze individuali, e sono più efficaci rispetto al clopidogrel Poiché si associano ad un rischio emorragico maggiore la selezione dei pazienti diventa molto importante nella scelta del farmaco da utilizzare e richiede un utilizzo giudizioso soppesando il rischio trombotico e quello emorragico

67

68 Eseguito con il WASP

69 Reversibilità della inibizione e vantaggi potenziali Becker RC, Gurbel PA Thromb Haemost 2010

70

71

72


Download ppt "Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali Giancarlo Casolo Genova, Hotel NH Marina 21/22 Ottobre 2011 HEARTLINE HSM."

Similar presentations


Ads by Google