Come effettuare la terapia anticoagulante nello STEMI e nel NSTEMI

Transcription

1 Come effettuare la terapia anticoagulante nello STEMI e nel NSTEMI Dr.ssa Lidia Rossi Responsabile S.S.V.D. UTIC AOU Maggiore della Carità Novara

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3 ANNO 2007 ANNO 2013 Aspirina Clopidogrel Anti GPIIb IIIa UFH Enoxaparina Aspirina Clopidogrel Prasugrel Ticagrelor Anti GPIIb IIIa UFH Enoxaparina Fundaparinux Bivalirudina..NAO

4 In quale contesto clinico? In quale strategia?

5 ESC STEMI GUIDELINES 2012 TERAPIA ANTICOAGULANTE E FIBRINOLISI TERAPIA ANTICOAGULANTE E PPCI

6 STEMI Raccomandadazioni delle Linee Guida ESC 2012 per la scelta della terapia riperfusiva dell IMA Angioplastica Primaria E indicata in tutti i pazienti con dolore da meno di 12 ore e con una elevazione del tratto ST o di un (presunto) nuovo BBS, deve essere effettuata da un team esperto Livello di evidenza IA Trombolisi Va iniziata il più precomente possibile in assenza di controindicazioni e se una angioplastica primaria non può essere effettuata da un team esperto Livello di evidenza IA European Heart Journal 2012

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9 TERAPIA ANTICOAGULANTE E FIBRINOLISI 69 congresso SIEC roma 2008 EPARINA NON FRAZIONATA EFFICACIA ENF NEL RIDURRE LA MORTALITA DEI PAZ CON STEMI COLLINS BMJ 1996 RISULTATI DELLO STUDIO GUSTO I N ENG J MED 1993

10 TERAPIA ANTICOAGULANTE E FIBRINOLISI EPARINA NON FRAZIONATA RISULTATI DELLO STUDIO GUSTO I N ENG J MED congresso SIEC roma 2008

11 EPARINA NON FRAZIONATA 69 congresso SIEC roma 2008

12 TERAPIA ANTICOAGULANTE E FIBRINOLISI ENOXAPARINA ASSENT 3: Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding Probability (%) Unfractionated Heparin Abciximab Enoxaparin Log-rank test: P= Days to Death or Reinfarction or Refractory Ischemia or ICH or Major M Bleeding 17.0% 14.2% 13.8% In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase.

13 ExTRACT-TIMI 25: Background In STEMI patients, prolonged infusion of UFH has not been shown to prevent reocclusion following angiographically successful fibrinolytic therapy Therefore, current recommendations limit duration of infusion to 48 hours LMWH vs UFH provides a reliable level of anticoagulation without the need for therapeutic monitoring and with relatively greater proximal inhibition of the coagulation cascade ExTRACT-TIMI 25 compared LMWH (enoxaparin) and UFH as adjunctive therapy for fibrinolysis in STEMI Enoxaparin was administered for duration of hospitalization and dosed according to age and renal function Antman EM et al. N Engl J Med. 2006;354:

14 ExTRACT- TIMI 25

15 TIMI major bleeding at 30 days stratified by age cut-off of 75 years Enoxaparin 30 mg IV bolus, 1.0 mg/kg sc q12h* median 7 days Enoxaparin *Aged 75 yr: no IV bolus, 0.75 mg/kg sc q12h; CrCl <30 ml/min: ± IV bolus, 1.0 mg/kg sc q24h

16 Impact of enoxaparin on key outcomes In patients with STEMI treated with fibrinolytic therapy, the modified (reduced) dosing regimen of ENOX in patients > 75 years appears to have been helpful in reducing the magnitude of the relative increase in major bleeding,including the intracranial haemorrhage that has been observed in this age group in previous trials. The similar ARD and NNT in the elderly and young patients suggest that the reduced ENOX dose in the elderly did not compromise its efficacy in preventing death or MI. Thus, the ENOX strategy as implemented in ExTRACT-TIMI 25 is preferred to the standard UFH strategy in both younger and older STEMI patients treated with fibrinolysis.

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18 OASIS-6 Randomized Trial JAMA. 2006;295(13):

19 OASIS-6 Randomized Trial JAMA. 2006;295(13):

20 OASIS 6 Trial: Conclusions The benefit of Fondaparinux was confined to patients in Stratum 1 where placebo or no antithrombin was administered Fondaparinux was not superior to active control UFH Fondaparinux was associated with a hazard in those patients who underwent PCI including guiding catheter thrombosis Presented at ACC 2006

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23 Primary Endpoints at 30 Days Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800) 30 day event rates (%) Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] P NI sup = P sup Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] P NI sup P sup Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] sup = 0.95 P sup Net adverse clinical events Major bleeding (non CABG) MACE 1 endpoint 1 endpoint Major 2 endpoint Stone GW et al. NEJM 2008;358:

24 HORIZONS-AMI

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26 1-Year Net Adverse Clinical Events* Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) NACE (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa *MACE or major bleeding (non CABG) Time in Months 18.3% 15.7% Diff [95%CI] = -2.6% [-5.1, -0.1] HR [95%CI] = 0.84 [0.71, 0.98] P=0.03 Mehran R, TCT 2008

27 1-Year Net Adverse Clinical Events* Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) NACE (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa *MACE or major bleeding (non CABG) Time in Months 18.3% 15.7% 1-year analysis 12 of the HORIZONS-AMI trial shows that in patients with STEMI 10 undergoing PPCI, procedural anticoagulation with bivalirudin alone seemed to reduce haemorrhagic complications, late reinfarction 8 and early and late cardiac and all-cause mortality compared with UFH 6 plus the routine use of a GPI. Diff [95%CI] = -2.6% [-5.1, -0.1] HR [95%CI] = 0.84 [0.71, 0.98] P=0.03 Mehran R, TCT 2008

28 Conclusions In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: A significant 16% reduction in the 1-year rate of composite net adverse clinical events A significant 39% reduction in the 1-year rate of major bleeding Significant 31% and 43% reductions in the 1-year rates of allcause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year Mehran R, TCT 2008

29 Clinical Implications HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies Mehran R, TCT 2008

30 3-year MACE Components* UFH + GPI (N=1802) Bivalirudi n (N=1800) HR [95%CI] P Value Number needed to treat Death 7.7% 5.9% 0.75 (0.58,0.97) Cardiac 5.1% 2.9% 0.56 (0.40,0.80) Non cardiac 2.8% 3.1% 0.62 Reinfarction 8.2% 6.2% 0.76 (0.59,0.92) Q-wave 3.8% 3.4% Non Q-waveQ 4.9% 3.2% Death or reinfarction 14.5% 11.3% 0.72 (0.58,0.91) Ischemic TVR 12.1% 14.2% 0.06 Stroke 2.0% 1.7% 0.50 *Kaplan-Meier estimates, CEC adjudicated MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

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33 Conclusions: Pharmacology Randomization In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in: A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life) Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

34 3-year analysis of the HORIZONS-AMI trial shows that in patients with STEMI undergoing PPCI, procedural anticoagulation with bivalirudin alone seemed compared to heparin plus GPI resulted in: 36% reduction in major bleeding significant 24% reduction in reinfarction significant 44% reduction in cardiac mortality 25% reduction in all-cause mortality non significantly different rates of stent thrombosis, TVR and stroke

35 1-year analysis of the HORIZONS-AMI trial shows that in high-risk patients with STEMI undergoing primary PCI, procedural anticoagulation with bivalirudin alone seemed to reduce haemorrhagic complications,late reinfarction, and early and late cardiac and all-cause mortality compared with unfractionated heparin plus the routine use of a GPI.

36 ATOLL trial

37 ATOLL trial

38 - Intravenous enoxaparin compared with unfractionated heparin did not significantly reduce the ATOLL primary endpoint; however, significance was present in patients consistently treated with the study drug. - Intravenous enoxaparin did reduce secondary endpoints of adverse ischaemic events without a significant difference in bleeding endpoints compared with unfractionated heparin. > net clinical benefit was improved with enoxaparin in patients undergoing primary PCI.

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40 - Intravenous enoxaparin compared with unfractionated heparin did not significantly reduce the ATOLL primary endpoint; however, significance was present in patients consistently treated with the study drug. - Intravenous enoxaparin did reduce secondary endpoints of adverse ischaemic events without a significant difference in bleeding endpoints compared with unfractionated heparin. > net clinical benefit was improved with enoxaparin in patients undergoing primary PCI.

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43 Anticoagulants in NSTEMI-ACS Indirect inhibitors of coagulation Indirect thrombin inhibitors: Indirect factor Xa inhibitors: Direct inhibitors of coagulation Direct factor Xa inhibitors: UFH LMWHs LMWHs fondaparinux apixaban, rivaroxaban, otamixaban Direct thrombin inhibitors (DTIs): bivalirudin, dabigatran

44 OASIS 5 Fondaparinux is similar to enoxaparin in the short term in preventing ischemic events among patients with acute coronary syndromes without ST-segment elevation, but it is associated with substantially less bleeding, that translates into lower long-term mortality and morbidity. N Engl J Med 2006; 354,

45 Fondaparinux at a dose of 2.5 mg daily is similar to enoxaparin in the short term in preventing ischemic events among patients with acute coronary syndromes without STsegment elevation, but it is associated with substantially less bleeding an effect that translates into lower long-term mortality and morbidity. > fondaparinux is an attractive option as an anticoagulant in the short-term care of patients with acute coronary syndromes.

46 The FUTURA/OASIS-8 Randomized Trial

47 The FUTURA/OASIS-8 Randomized Trial

48 The FUTURA/OASIS-8 Randomized Trial

49 Low-dose compared with ACTguided standarddose heparin did not reduce peri-pci bleeding and vascular access site complications. Catheter thromboses are rare when using unfractionated heparin for PCI in patients with non ST-segment elevation acute coronary syndromes treated with fondaparinux. Therefore, patients with acute coronary syndromes treated with fondaparinux and undergoing PCI should receive the guidelinerecommended ACT-guided standard dose of unfractionated heparin.

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51 SYNERGY Randomized Trial

52 SYNERGY Randomized Trial

53 SYNERGY Randomized Trial

54 In high-risk patients with ACS treated with an early invasive strategy with frequent use of antithrombin therapy prior to enrollment and postrandomization crossovers, enoxaparin is not inferior to unfractionated heparin. Enoxaparin carries a modest increase in bleeding and is likely superior when started as initial first-line therapy without changing to alternative agents

55 ACUITY : PRIMARY EP Bivalirudin vs UFH + IIb/IIIa Primary endpoint Risk ratio ±95% CI Bivalirudin UFH + IIb/IIIa RR (95% CI) p value Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 10.1% 11.7% 0.86 ( ) % 7.3% 1.08 ( ) % 5.7% 0.53 ( ) <0.001 Bivalirudin better UFH +IIb/IIIa Stone G. et al New Engl J Med 2006; 355: 2203

56 JACC 2010; 55: 1416

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66 In quale contesto clinico? In quale strategia?

67 Take home messages In quale contesto clinico? In quale strategia? STEMI : FIBRINOLISI > ENOXAPARINA PPCI > BIVALIRUDINA NSTEMI: URGENT / EARLY INVASIVE > BIVALIRUDINA / UFH NON URGENT > FUNDAPARINUX TERAPIA CONSERVATIVA: ENOXAPARINA / FUNDAPARINUX

68 Take home messages 2 A quale paziente? Ndrepepa G, et al. JACC 2008

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