Il punto sulla terapia antitrombotica nelle sindromi coronariche acute

Transcription

1 Santa Margherita Ligure TIGULLIO CARDIOLOGIA Febbrajo 2012 Il trattamento dell infarto miocardico acuto ad ST spraslivellato: dal territorio al laboratorio di emodinamica Il punto sulla terapia antitrombotica nelle sindromi coronariche acute Diego Ardissino

2 Ischemic vs Bleeding Risk in ACS Ischemic Risk Antithrombotic therapy in ACS Optimal practice Today s practice Risk Bleeding Risk Aggressiveness of Antithrombotic therapy

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4 Aspirin in Acute Myocardial Infarction Cumulative vascular mortality in days 0-35 Cumulative number of vascular deaths The Lancet Placebo Aspirin Streptokinase Streptokinase + aspirin Days from randomisation

5 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization Options for anticoagulation include UFH 60 IU/Kg iv bolus with GPIIb/IIIa inhibitor or UFH 100 IU/Kg iv bolus without GPIIb/IIIa inhibitor, (I C) or bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/h (I B). Antithrombins can be stopped after PCI for STEMI.

6 EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION ANTITHROMBOTIC THERAPY IN PRIMARY PCI Unfractionated heparin is standard anticoagulant therapy during PCI. i.v. bolus: 100 U/Kg (60 U/Kg if GP IIb/IIIa antagonists are used) target ACT during procedure: seconds ( seconds if GP IIb/IIIa antagonists are used) CLASS I EVIDENCE C

7 EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINES MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION ANTITHROMBOTIC THERAPY IN PRIMARY PCI Abiciximab can be administered in primary PCI. i.v. bolus: 0.25 mg/kg Infusion: mcg/kg/min (maximum 10 mcg/min for 12 hours) CLASS IIa EVIDENCE A

8 Abciximab as Adjunctive Therapy to Reperfusion in STEMI 30-day mortality Odds Ratio (95% CI) P Value RAPPORT ISAR-2 ADMIRAL CADILLAC Petronio et al Zorman et al ACE Petronio et al ASSENT-3 ENTIRE-TIME 23 GUSTO V Primary PCI Fibrinolysis Overall > De Luca G. et al, JAMA 2005; 293: Abciximab better Control better

9 Abciximab as Adjunctive Therapy to Reperfusion in STEMI Long-term (6 and 12 month) mortality Odds Ratio (95% CI) P Value RAPPORT ISAR-2 ADMIRAL CADILLAC Petronio et al Zorman et al ACE ASSENT-3 GUSTO V Primary PCI Fibrinolysis Overall De Luca G. et al, Jama 2005; 293: Abciximab better Control better

10 Abciximab vs Placebo in Primary PCI Death or re-infarction over 3 years of follow-up 1 Trials: ACE, ADMIRAL and ISAR Survival distribution function Abciximab Placebo P = Time Montalescot G. et al, Eur Heart J 2007; 28:

11 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization UPSTREAM GP IIb/IIIa INHIBITORS.the controversial literature data, the negative outcome of the only prospecitve RCT and the beneficial effects of faster acting and more efficacious ADP receptor blockers in primary PCI do not support pre-hospital or pre-catheterization use of GPIIb/IIIa inhibitors. CLASS III EVIDENCE B

12 Facilitated PCI in Patients with STEMI The FINESSE trial 16 Patients with Primary Composite End Point percent Primary PCI Abciximab-facilitated PCI Combination-facilitated PCI P = NS Ellis SG. et al, N Engl J Med 2008; 358: Days

13 Facilitated PCI in Patients with STEMI The FINESSE trial 30 TIMI Bleeding through Discharge/Day 7 25 Primary PCI with in Lab Abciximab ( n = 795 ) Abciximab facilitated PCI ( n = 805 ) Abciximab/Reteplase facilitated ( n = 814 ) P < P < P = Percentage P = P = P = P = P = P = TIMI major TIMI minor TIMI major or minor Ellis SG. et al, N Engl J Med 2008; 358:

14 Enoxaparin vs UFH in primary PCI ATOLL Study Design STEMI planned for 1 PCI Randomization (N = 850) ENOXAPARIN IV 0.5 mg/kg (± GP IIb/IIIa inhibitor) UFH IV IU/kg if GP IIb/IIIa IU/kg if no GP IIb/IIIa Dose adjusted to ACT 1 PCI and stenting Montalescot, ESC EP: Death, complication of MI, procedure failure or non-cabg major bleeding at 30 days Main 2 EP: Death, MI, refractory ischemia, urgent revasc. 6-month follow-up Patients who have already received UFH or LMWH or any other anticoagulant are excluded. All concomitant drugs accepted, except lytics; cross-over to other anticoagulant NOT accepted.

15 Enoxaparin vs UFH in primary PCI ATOLL trial Primary endpoint Death, complication of MI, procedure failure or maior bleeding 40 RRR=17% P= ,7 Percent of patients Montalescot, ESC 2010

16 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization ANTICOAGULATION.a recent study suggested bivalirudin monotherapy as an alterantive to UFH plus a GPIIb/IIIa inhibitor. CLASS I EVIDENCE B

17 Bivalirudin During Primary PCI in STEMI The HORIZONS-AMI trial 15 Net adverse clinical events Net Adverse Clinical Events percent Heparin plus GP IIB/IIIa Bivalirudin alone P = Days Stone GW. et al, N Engl J Med 2008; 358:

18 Bivalirudin During Primary PCI in STEMI The HORIZONS-AMI trial 8 Major adverse cardiovascular events Major Adverse cardiovascular Events percent Heparin plus GP IIB/IIIa Bivalirudin alone P = Stone GW. et al, N Engl J Med 2008; 358: Days

19 Bivalirudin During Primary PCI in STEMI The HORIZONS-AMI trial Major Bleeding percent Heparin plus GP IIB/IIIa Bivalirudin alone Major bleeding P < Days Stone GW. et al, N Engl J Med 2008; 358:

20 Bivalirudin During Primary PCI in STEMI The HORIZONS-AMI trial 5 Death from cardiac and non cardiac causes 4 Heparin plus GP IIB/IIIa Bivalirudin alone Death percent 3 2 P = 0.03 Cardiac Noncardiac Stone GW. et al, N Engl J Med 2008; 358: Days 0.2

21 Bivalirudin During Primary PCI in STEMI The HORIZONS-AMI trial 3-years follow up Endpoint Bival HR (95% CI) p Hep+GP IIb/IIIa (%) (%) Major bleeding ( ) <0.001 All-cause mortality ( ) 0.03 Cardiac mortality ( ) Reinfarction ( ) Stone GW. et al, TCT 2010

22 ANTITHROMBOTIC THERAPY IN STEMI Abciximab vs bivalirudin High ischemic risk Bivalirudin High bleeding risk Heparin Abciximab + Heparin AGGRESSIVENESS OF ANTITHROMBOTIC THERAPY

23 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization STEMI ANTITHROMBOTIC THERAPY Dual antiplatelet therapy consists of aspirin mg per os or mg bolus iv followed by mg daily, and prasugrel 60 mg loading dose, followed by 10 mg daily, or ticagrelor 180 mg loading dose, followed by 90 mg twice daily, depending on drug availability. Clopidogrel 600 mg loading dose, followed by 75 mg daily should be used primarily if the more effective ADP receptor blockers are controindicated or unavailable.

24 COMMIT / CCS-2 In-hospital death Death percent Placebo + ASA: 1845 deaths (8.1%) Clopidogrel + ASA: 1726 deaths (7.5%) 7 % (SE) relative risk reduction (2P = 0.03) Time since randomization (up to 28 days) COMMIT Collaborative Group Lancet 2005; 366:

25 Prevention of Myocardial Infarction During PCI Effect of Clopidogrel 300 mg Loading Dose MACE Placebo Clopidogrel p = 0.02 for treatment/timing interaction Steirhubl SR et al Circulation 2003;108:374 Hours prior to PCI of study drug loading dose

26 Impact of pre-treatment with clopidogrel on outcome in STEMI Primary composite endpoint at 30 days ( death, recurrent ACS, stent thrombosis, CHF) p<0.01 Patients (%) Fefer P et al. Am J Cardiol 2009; 104: n=116 n=80 n=97 n=64 Clopidogrel 600 mg Clopidogrel 300 mg

27 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization Prasugrel is superior to clopidogrel in reducing combined ischaemic endpoints and stent thrombosis in STEMI patients without increasing the risk of severe bleeding. CLASS I EVIDENCE B

28 Prasugrel vs clopidogrel in primary PCI TRITON TIMI-38 Primary endpoint: Cardiovascular death, non-fatal MI, non-fatal stroke 15 Cumulative incidence (%) 10 5 Clopidogrel Prasugrel p= p= Montalescot G et al, Lancet 2009; 373: Days from randomization

29 Prasugrel vs clopidogrel in primary PCI TRITON TIMI TIMI major bleeding Cumulative incidence (%) 10 5 Clopidogrel Prasugrel p= p= Days from randomization Montalescot G et al, Lancet 2009; 373:

30 Net Clinical Benefit Bleeding Risk Subgroups Post-hoc Analysis Risk percent Prior Stroke / TIA Yes No P inter = Age 75 < 75 P inter = Wgt < 60 Kg 60 Kg P inter = Overall Prasugrel better HR Clopidogrel better

31 ESC/ EACTS Guidelines on myocardial revascularization 2010 Antithrombotic treatment options in myocardial revascularization A predefinite subgroup analysis has demonstrated that STEMI patients referred to PCI significantly benefit from ticagrelor vs clopidogrel, with similar bleeding rates. CLASS I EVIDENCE B

32 Greater and More Consistent IPA with AZD6140 than Clopidogrel Final Extent 100 AZD mg bd 100 Clopidogrel Mean percent inhibition Day 1 Day 14 Hours Day 1 Day 14 Hours

33 Cumulative incidence (%) Ticagrelor vs clopidogrel in STEMI treated with primary PCI Primary efficacy endpoint Months Clopidogrel Ticagrelor T C Steg PG et al, Circulation 2010, 122: HR %CI p=0.07

34 Cumulative incidence (%) Ticagrelor vs clopidogrel in STEMI treated with primary PCI Cardiovascular death Months Clopidogrel Ticagrelor T C Steg PG et al, Circulation 2010, 122: HR % CI p=0.07

35 Ticagrelor vs clopidogrel in STEMI treated with primary PCI Major bleeding according to PLATO definition Cumulative incidence (%) HR %CI p=0.76 Clopidogrel Ticagrelor 0 Steg PG et al, Circulation 2010, 122: Months T C

36 Pre-hospital vs. In-hospital initiation of ticagrelor therapy in STEMI ATLANTIC study design STEMI patients planned for primary PCI (symptom onset < 6 hours) (n = 1.770) R Randomized, Parallel-group, Double blind, Placebo controlled phase IV trial Pre-hospital Ticagrelor loading dose (180 mg) followed by in-hospital matching placebo Pre-hospital placebo followed by in-hospital Ticagrelor loading dose (180mg) Primary endpoint: TIMI flow grade 3 of MI culprit vessel at initial angiography; ST-segment resolution up to pre PCI >70% Secondary endpoint: 30-days death, MI, urgent revascularization, stent thrombosis, life threatening bleeding, major and minor bleeding

37 PEGASUS TIMI 54 Study design Standard background care (ASA mg recommended) History of MI 1-3 years prior + > 1 additional atherothrombosis risk factor (n = 21,000) * Age 65yrs, diabetes, 2nd prior MI, multivessel CAD, PAD or chronic non-end stage renal dysfunction Randomize double blind Ticagrelor 90 mg BID Ticagrelor 60 mg BID Placebo Follow up Visits Q4 mos for 1 st ys, then Q6 mos Min 12 mos and average 24 mos follow-up Event driven trial Primary Efficacy Endpoint: CV death, MI or stroke Primary Safety Endpoint: TIMI major Bleeding

38 The cycle of continuous quality improvement Concept Outcomes Clinical Trials Performance Guidelines Califf RM et al. JACC 2002;40: Performance Indicators