FONDAMENTALE NELLA SINDROME CORONARICA ACUTA, DATA LA CENTRALITA DELLA CASCTA DELLA COAGULAZIONE NELLA SUA FISIOPATOLOGIA

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Mauro Paoli
4 anni fa
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1 Sulle sponde del Ticino. Novara 9 Maggio 2013

2 L INIBIZIONE DELLA TROMBINA RAPPRESENTA UN TARGET TERAPEUTICO LINIBIZIONE DELLA TROMBINA RAPPRESENTA UN TARGET TERAPEUTICO FONDAMENTALE NELLA SINDROME CORONARICA ACUTA, DATA LA CENTRALITA DELLA CASCTA DELLA COAGULAZIONE NELLA SUA FISIOPATOLOGIA

3 Advantages Multiple sites of action in coagulation cascade (IIa,Xa) Long history of successful clinical use Readily monitored by aptt and ACT Very inexpensive Disadvantages Indirect thrombin inhibitor (does not inhibit clotbound thrombin) Nonspecific binding to: Plasma proteins Endothelial cells Variable anticoagulation level Inhibited by platelet factor 4 reduced effect in ACS Causes platelet aggregation Risk of HIT

Il problema principale dell eparina è L IMPREVEDIBILITÀ dei livelli di Il problema principale dell eparina è L IMPREVEDIBILITÀ dei livelli di anticoagulazione

4 Il problema principale dell eparina è L IMPREVEDIBILITÀ dei livelli di Il problema principale dell eparina è L IMPREVEDIBILITÀ dei livelli di anticoagulazione che comporta vistose oscillazioni tra l inefficacia terapeutica (AUMENTO DEL RISCHIO TROMBOTICO) ed eccessivo effetto anticoagulante (AUMENTO DEL RISCHIO EMORRAGICO)

5 Emorragia mortale Emorragia grave: Instabilità emodinamica Scompenso cardiaco Attivazione infiammatoria Emotrasfusioni Sospensione terapia Ndrepepa G, et al. JACC 2008

6 Meheran R, et al. JACC Intv 2011 Phuong-Anh P et al. Vasc health Risk Manag 2011

7 BIVALIRUDINA: 1. INIBIZIONE COMPETITIVA 2. FARMACOCINETICA LINEARE 3. EMIVITA 25MIN, DOPO 2H COMPLETO RECUPERO 4. PECULIARITA RISPETTO A UFH

8 Bivalirudin inhibit both fibrin-bound i and soluble thrombin Bivalirudin does not require cofactors and is not neutralized by platelet products These differences with UFH make bivalirudin an attractive ti alternative ti in various clinical settings Lupi A et al. Cardiovasc Hematol Agents Med Chem. 2012

9 Studio REPLACE 2

10 6012 PCI Patients Urgent or elective Aspirin Plavix PCI 1 : 1 randomization PCI Bivalirudin 0.75 mg/kg g bolus Endpoints 1.75 mg/kg/h procedure 30-day Provisional abciximab or Death eptifibatide MI Revasc Hemorrhage Heparin Abciximab U/kg or Economics Eptifibatide 1-year mortality Linckoff et al. JAMA 2003

11 p=0.324 p=0.43 p=0.255 p=0.435 p<0.001 Linckoff et al. JAMA 2003

12 p<0.001 p=ns p=ns p=ns p=ns Linckoff et al. JAMA 2003

13 Studio ACUITY

14 13819 pts Moderatehigh risk ACS Aspirininall in Clopidogrel dosing and timing per local practice R* UFH or Enoxaparin + GP IIb/IIIa hy within 72h Medical management Bivalirudin + GP IIb/IIIa PCI Bivalirudin Alone Ang giograp CABG *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004

15 UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIaIIIa Bivalirudin alone Endpoint Rate Rate RR (95% CI) P Value Rate RR (95% CI) P Value Net clinical outcome 11.7% 11.8% 1.01 ( ) <0.001, % 0.86 ( ) <0.001, Composite Ischemia 7.3% 7.7% 1.07 ( ) 0.007, % 1.08 ( ) 0.01, 0.32 Non-CABG Major Bleeding 5.7% 5.3% 0.93 ( ) <0.001, % 0.53 ( ) <0.001, non-inferiority; superiority Stone GW et al. NEJM 2006

16 UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Ischem mic Com mposite (%) UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone day Estimate 7.4% 7.8% 7.9% P (log rank) 1 year Estimate 16.3% % % P (log rank) Bivalirudin+GPI vs. Hep+GPI HR[95%CI]=105( ( ) 16) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 ( ) Days from Randomization p=0.55 Stone GW et al. JAMA 2007

17 Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year HR ± 95% CI HR (95% CI) P-value 30 Day Major Bleed 3.77 ( ) < Day Myocardial Infarction 3.39 ( ) , Cox model adjusted for baseline predictors, with non-cabg major bleeding and MI as time-updated covariates

18 Studio HORIZONS-AMI

3,602 pts with STEMI with symptom onset 12 hours Aspirin, thienopyridine UFH

monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by

randomization R 1:3 Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent

19 3,602 pts with STEMI with symptom onset 12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) R 1:1 Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to primary PCI, CABG or medical therapy 3006 pts eligible for stent randomization R 1:3 Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years Stone GW. NEJM 2008

20 Unfractionated t heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Abciximab i b or double bolus eptifibatide tid as per investigator t discretion dosing per FDA label, renal adjusted; continued for 12 (abcx) or (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30 after last bolus Stone GW. NEJM 2008

21 Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800) 30 day event rates (% %) Diff = -2.9% [-4.9, -0.8] RR = 076[ [0.63, 092] 0.92] P NI P sup = Diff = -3.3% [-5.0, -1.6] RR = 060[ [0.46, 077] 0.77] P NI P sup Diff = 0.0% [-1.6, 1.5] RR = 099[ [0.76, 1.30] P sup = Net adverse clinical events Major bleeding (non CABG) MACE 1 endpoint 1 endpoint Major 2 endpoint

22 ding (%) jor Bleed Maj Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Time in Months Diff [95%CI] = -3.4% [-5.2, -1.7] 1.7]2 HR [95%CI] = 0.61 [0.48, 0.78] P< % 5.8% Mehran R, Lancet 2009

23 (%) MACE Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Time in Months Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P= % 11.9% Mehran R, Lancet 2009

24 NACE (% %) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Time in Months Diff [95%CI] = -2.6% [-5.1, -0.1] HR [95%CI] = 084[ [0.71, 098] 0.98] P= % 15.7% Mehran R, Lancet 2009

25 5 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% (%) Mortality Δ = 1.4% 3.4% 31% 3.1% Diff [95%CI] = 2.1% -1.5% [-2.8,-0.1] Δ = 1.0% HR [95%CI] = P= [0.50, 0.97] P= Time in Months Mehran R, Lancet 2009

26 eath or MI (%) D Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 45% 4.5% 3.8% Δ = 0.7% P=0.30 Time in Months HR [95%CI] = 0.77 [0.61, 0.98] P= % Δ = 1.9% 6.6% Mehran R, Lancet 2009

27 Stone GW, Lancet 2011

28 Overall death 30 days Overall death 1 year In hospital severe bleeding Lupi A et al. Cardiovasc Hematol Agents Med Chem. 2012

31 Lupi et al. Blood Coagulation & Fibrinolysis 2013

32 175 consecutive all comers patients with STEMI <12h treated with primary PCI received IC bivalirudin bolus + intravenous bivalirudin infusion 315 consecutive controls treated WITH ufh/2b3a before bivalirudin large scale employ Well balaced groups with similar baseline clinical and angiographic findings Intracoronary superselective injection of bivalirudin via export catheter or OTW

33 No reflow Reperfusion (ST segment)

34 In-hospital outcomes Bleed dings

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