Update on Antithrombotic Therapy in Acute Coronary Syndrome

Transcription

1 Update on Antithrombotic Therapy in Acute Coronary Syndrome Laura Tsang November 13, 2006

2 Objectives: By the end of this session, you should understand: The role of antithrombotics in ACS Their mechanisms of action The evidence for the use of enoxaparin, fondaparinux and bivalirudin.

3 Acute Coronary Syndrome Management Non ST elevation ST elevation Medical Therapy PCI ± stent Fibrinolysis

4 Goals of antithrombotic therapy Prevent progression of intracoronary thrombus Promote stabilization of atherosclerotic plaque Reduce myocardial ischemia Prevent cardioembolic stroke, VTE and death. Eikelboom, JW. et al. UFH and LMWH in ACS without ST elevation: a meta-analysis. Lancet. 2000; 355:

5 Unfractionated Heparin Mixture of polysaccharide chains Mean molecular weight: Metabolism: hepatic Onset: immediate Half-life: 1.5hrs Administration: IV infusion

6 Mechanism of Action X AT VIIa Xa HEPARIN II Va Ca 2+ IIa Fibrinogen Fibrin

7 Mechanism of Action Indirect inhibition by heparin requires the presence of antithrombin,, the actual inhibitor. Heparin (long yellow strand) binds to AT, causing a shape change that increases the ability of AT to inhibit thrombin. Hirsh J et al. Chest ;119(1 suppl):64s-94s. Weitz JI et al. Thromb Res ;106:V275-V284. V284.

8 Place in Therapy UA/ NSTEMI Class I Recommendations: Anticoagulation with SC LMWH or IV UFH should be added to antiplatelet therapy ACC/AHA UA/NSTEMI Guidelines. J Am Coll Cardiol 2002; 40: STEMI Class I Recommendations: UFH- 60U/kg/bolus (max 4000U) followed by an infusion at 12U/kg/hr (max 1000U/hr) ACC/AHA STEMI Guidelines J Am Coll Cardiol 2004; 44:

9 Low Molecular Weight Heparin Consists of fragments of unfractionated heparin Mean molecular weight: 5000 Metabolism: Hepatic Onset: 3-5 hrs Duration: 12 hrs Half life: hrs Administration: SC injection

10 Mechanism of Action X AT VIIa Xa LMWH II Va Ca 2+ IIa Fibrinogen Fibrin

11 Why consider LMWH? More predictable anticoagulant response Lower incidence of HIT As chain length shortens, prolongation of aptt is lost but ATIII complex ability is retained No need to monitor aptt Self administration

12 Is it better than UFH? NEJM 2006;354:

13 ExTRACT-TIMI TIMI 25 ENOXAPARIN < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h 75 y: No bolus SC 0.75 mg / kg q 12 CrCl < 30: 1.0 mg / kg q 24 h STEMI < 6 h n = 20, 506 ASA Lytic choice by MD (TNK, tpa, rpa, SK) n = 10,256 n = 10,223 UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Primary Endpoint: Death or Nonfatal MI at 30 days

14 ExTRACT-TIMI TIMI 25 Primary endpoint: Death or nonfatal MI at 30 days 15 Primary End Point (%) UFH 12.0% 17% RRR ENOX Relative Risk 0.83 (0.77 to 0.90) P< % Lost to follow up = Days

15 ExTRACT-TIMI TIMI 25 % RRR= 8% p= RRR= 33% p< UFH ENOX RRR=26 P= Death Nonfatal MI Urg Revasc

16 ExTRACT-TIMI TIMI 25 % Events 10 UFH ENOX P< P = P = Major Bleed (fatal + nonfatal) Nonfatal Major Bleed ICH 0.8

17 American Heart Journal 2005;149:S81-90.

18 SYNERGY High-Risk ACS Patients At least 2 of 3 required: Age 60 ST (transient) or (+) CK-MB or Troponin 1 mg/kg SC Q12H Enoxaparin Randomize (n = 10,000) IV Heparin 60 U/kg 12 U/kg/hr (aptt sec) Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA, β-blocker, ACE, clopidogrel, GP IIb/IIIa) Primary endpoint: Death or MI at 30d

19 SYNERGY Admission Randomization Crossover at PCI No prior UFH Enox U E U E U E U E U E U E U E U E U E

20 Primary Endpoint: Death and MI at 30 days 1.0 Freedom from Death / MI Enoxaparin UFH Non-Significant Hazard Ratio (95% CI) 30-Day Death/MI HR 0.96 ( ) Enoxaparin Better 1.1 UFH Better Days from Randomization

21 Bleeding events at 30 days Enox (%) UFH (%) P value GUSTO severe TIMI major Non-CABGrelated ICH <0.1 <0.1 NS TIMI minor NS Any transfusion NS

22 SYNERGY Admission Randomization Crossover at PCI No prior UFH Enox U E U E U E U E U E U E U E U E U E

23 Crossovers: Relation to Bleeding Enoxaparin GUSTO Severe UFH TIMI Major Total No Crossover Crossover Total No Crossover Crossover (n = 9978) (n = 9180) (n =798) (n = 9978) (n = 9180) (n =798)

24 Place in Therapy UA/ NSTEMI Class IIa Recommendations: Enoxaparin is preferable to UFH as an anticoagulant in patients with UA/NSTEMI, unless CABG is planned within 24hrs ACC/AHA UA/NSTEMI Guidelines. J Am Coll Cardiol 2002; 40: STEMI Class IIb Recommendations: Enoxaparin 30mg IV bolus followed by 1mg/kg SC every 12hrs until hospital discharge Class III Recommendations: LMWH should not be used for patients > 75yrs and with SrCr>2.5mg/dL in men or >2.0,mg/dL in women ACC/AHA STEMI Guidelines J Am Coll Cardiol 2004; 44:

25 Fondaparinux Synthetic polysaccharide Metabolism: Renal- Eliminated unchanged Half life: 17-21hrs Time to peak: 2-3 hrs Administration: SC injection

26 Mechanism of Action X AT VIIa Xa Fondaparinux II Va Ca 2+ IIa Fibrinogen Fibrin

27 OASIS 5 Trial Investigators. NEJM 2006:354:

28 OASIS-5 Pts with suspected ACS (UA/ MI) (n= ) Prophylaxis up to 8 days or hospital discharge Prophylaxis for at least 2 days and up to 8 days or until clinical stabilization Fondaparinux 2.5mg SC OD (n = ) Enoxaparin 1mg/kg SC BID (n = ) Primary Endpoint: Noninferiority of fondaparinux with respect to death, MI or refractory ischemia

29 Primary Endpoint: death, MI, refrac. isch Cumulative Hazard % CI Enoxaparin Fondaparinux Days

30 Major Bleeding through day 9: Cumulative Hazard HR % CI P<< Enoxaparin Fondaparinux Days

31 Cumulative Hazard Enoxaparin Fondaparinux HR % CI P<< Major Bleeding: Day Days Cumulative Hazard Enoxaparin HR % CI P<< Fondaparinux Major Bleeding: 6 mos Days

32 PCI Complications Enox Fonda P value Any complication 268 (8.6) 299 (9.5) 0.21 Abrupt closure, new thrombus with reduced flow, dissection or no reflow 161 (5.2) 188 (6.0) Catheter-related thrombus not resulting in clinical complications 3 (0.1) 9 (0.3) 0.08 All catheter related thrombi 8 (0.4) 29 (0.9) 0.001

33 JAMA 2006;295:

34 12,000 Patients with STEMI < 12 h of symptom onset Inclusion: ST 2 mm prec leads or 1 mm limb leads Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo. Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg.. late) Stratification UFH not indicated Randomization UFH indicated Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH Primary Endpoint: Death / MI at 30 days

35 Primary Outcome: Death / MI at 30 days Cumulative Hazard UFH/Placebo Fondaparinux HR % CI P= Days

36 Death at end of study (3-6 mos) Cumulative Hazard UFH/Placebo HR % CI P=0.029 Fondaparinux Days

37 Efficacy on death or reinfarction by stratum Placebo/ UFH Fonda HR (95% CI) At 9 days: Stratum (11.1) 239 (8.5) 0.76 ( ) Stratum (6.9) 205 (6.4) 0.92 ( ) At 30 days: Stratum (14.0) 317 (11.2) 0.79 ( ) Stratum (8.7) 268 (8.3) 0.96 ( ) Study End Stratum (17.3) 413 (15.9) 0.87 ( ) Stratum (12.7) 343 (11.2) 0.88 ( )

38 Severe Bleeding at 9 days Fonda Control p All patients 1% 1.3% 0.13 Stratum 1 vs placebo 1% 1.6% 0.06 Stratum 2 vs UFH 1.1% 1.1% 0.82

39 Bivalirudin What: Synthetic 20 amino acid peptide analogue of hirudin Direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin Metabolism: Renally Half life: 25 minutes Time to peak: minutes Administration: IV

40 Mechanism of Action X AT VIIa Xa Bivalirudin II Va Ca 2+ IIa Fibrinogen Fibrin

41 Mechanism of action Bivalirudin s effectiveness is not affected by variability in the concentration of a co-factor like AT Gibson CM, 2006.

42 JAMA 2003;289:

43 Replace-2 2 Study Design 6002 PCI Patients Urgent or elective PCI Aspirin Plavix Stent Bivalirudin 0.75 mg/kg bolus 1.75 mg/kg/h procedure Provisional abciximab or eptifibatide Heparin 65 U/kg Abciximab or Eptifibatide Endpoints 30-day Death MI Revasc Hemorrhage

44 30-day Endpoints p=0.329 p=0.328 p=0.197 p<0.001 p=0.178 p= % 9.2% Heparin + GPIIb/IIIa (N=3008) Bivalirudin (N=2994) 7.1% 7.6% 5.8% 6.6% 4.1% 2.4% 2.0% 1.6% 5.2% 3.5% Death, any MI, revasc, bleed Death, any MI, revasc CKMB >3xULN Major bleed Death, QMI, revasc Death, QMI, revasc, bleed

45 6-month mortality Heparin + GPIIb/IIIa (n=3008) Bivalirudin (n=2994) p-value = % % Time from randomization in days

46 Hemorrhagic Endpoints UFH + Bivalirudin p value GP 2b/3a Major bleeding 123/3008 (4.1) 71/2993 (2.4) <0.001 ICH 2/3008 (0.1) 1/2993 (0) NS Vascular access puncture 74/3008 (2.5) 25/2993 (0.8) <0.001 Related to CV surgery 18/3008 (0.6) 17/2993 (0.6) NS TIMI major bleed 26/3008 (0.9) 19/2993 (0.6) NS TIMI minor bleed 91/3008 (3.0) 39/2993 (0.6) <0.001

47 American Heart Journal 2004;148:

48 Study Design First Randomization Moderate and high risk UA/ NSTEMI (n=13,819) Aspirin in all Clopidogrel dosing and timing per local practice R* UFH/Enox + GP IIb/IIIa (n=4,603) Bivalirudin + GP IIb/IIIa (n=4,604) Bivalirudin Alone (n=4,612) Angiography within 72h Medical management PCI CABG

49 Study Design Second Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy UFH/Enox + GP IIb/IIIa (N=4,603) GPI upstream (N=2294) GPI CCL for PCI (N=2309) Moderate and high risk ACS (n=13,819 R* Bivalirudin + GP IIb/IIIa (N=4,604) GPI upstream (N=2311) GPI CCL for PCI (N=2293) Aspirin in all Clopidogrel dosing and timing per local practice Bivalirudin Alone (N=4,612)

50 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding Death from any cause Myocardial infarction Unplanned revascularization for ischemia

51 ACUITY Primary Results 30 day events (%) Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612) Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = % 11.8% 10.1% P NI = P Sup = % 7.7% 7.8% P NI <0.001 P Sup < % 5.3% 3.0% Net clinical outcome Composite ischemia Major bleeding (non- CABG) *Heparin=unfractionated or enoxaparin

52 Major Bleeding Endpoints Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612) Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P Sup =0.31 P Sup P Sup =0.38 P Sup < day events (%) 11.8% 11.1% 9.1% 5.7% 5.3% 3.0% All Major Bleeding (All, including CABG) Major Bleeding (Non-CABG related)

53 Place in Therapy STEMI Class IIa Recommendations: In patients with known HIT, it is reasonable to consider bivalirudin as a useful alternative to heparin to be used in conjunction with streptokinase. ACC/AHA STEMI Guidelines J Am Coll Cardiol 2004; 44:

54 Advantages/ Disadvantages LMWH Fondaparinux Bivalirudin Administration SC SC IV Efficacy - Non-inferior to LMWH Non-inferior to LMWH May convey some benefit Bleeding - Significantly decreased Significantly decreased Cost per day $32 $14 >$500 Adverse Effects Stent Thrombosis Clots

55 Questions?