Direct Thrombin Inhibitors and Gp 2b/3a Receptor Blockers in the Cardiac Cath Lab. Eric J Dippel, MD FACC

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1 Midwest Cardiovascular Research Foundation Direct Thrombin Inhibitors and Gp 2b/3a Receptor Blockers in the Cardiac Cath Lab Eric J Dippel, MD FACC

2 Plaque Rupture Stable Angina Unstable Angina Non Q-wave MI Q-wave MI Adapted from Cannon CP. J Thrombolysis. 1995;2:

3 Thrombus Formation

4

5 Events Leading to Thrombus Formation Adhesion Activation Aggregation

6 Platelet Activation α - Granules (secreted proteins) Plasma proteins (fibrinogen, fibronectin, vwf, Factor V, plasminogen) Platelet-specific proteins (PF4, β -thromboglobulin proteins) Non platelet-specific proteins (thrombospondin, PDGF, amyloid protein precursor) ther (vascular permeability factor, IL-1, PADGEM) Amine Storage Granules (Serotonin, ADP, ATP, Ca ++ ) Thromboxane Lysosomes (enzymes) galactosidases Resting proteases Platelet Activated Platelet

7 Coagulation Cascade

8 Coagulation Cascade

9 Coagulation Cascade

10 Coagulation Cascade

11

12 Ruptured Plaque

13 Coagulation Cascade

14 Coagulation Cascade

15 Coagulation Cascade

16 Coagulation Cascade

17 Targets for Anti-Thrombotics Tissue Factor Inhibitors Direct Xa Inhibitors Pentasaccharides AT LMWH Heparin AT Bivalirudin Hirudin Argatroban Tissue factor Plasma clotting cascade Factor Xa Prothrombin Thrombin Fibrinogen Fibrinolytics Aspirin Conformational activation of GPIIb/IIIa Platelet aggregation Fibrin Collagen Thromboxane A 2 ADP Thrombus Ticlopidine Clopidogrel GPIIb/IIIa inhibitors

18 Treatment of cclusive Coronary Thrombus Platelets Fibrin Antiplatelet therapy Aspirin Thienopyridines GP IIb/IIIa inhibitors Thrombin Antithrombin therapy Heparin LMWH Direct thrombin Plasminogen activators tpa rpa SK TNK-tPA Cannon CP. J Am Coll Cardiol 1999;34:

19 Plasmin cleaves fibrin Lyses clot FDPs (antiplatelet and anticoagulant) Fibrinogen Reperfusion Platelets Fibrin Thrombin Thrombus occluding coronary artery Thrombolytic therapy Exposes clot-bound thrombin Activates platelets PAI-1, thromboxane A 2, New thrombin fibrinogen generation Platelet activation Platelet activation Cleaves fibrinogen Thrombin production to fibrin Vasoconstriction Inhibits plasminogen activators Thrombus formation Vessel reocclusion Cannon CP. J Am Coll Cardiol 1999;34:

20 Heparin Recipe Kleiman. J Inv Card, Dec 2000.

21 Major Saccharide Components in Pharmaceutical Heparin C 2 - H S CH 2 S 3 H NHS 3 - Trisulfated Disaccharide CH 2 H - C 2 H H - - S 3 NHS 3 C 2 - H H CH 2 S 3 - H NHS 3 - Disulfated Disaccharide - CH 2 S 3 H NHAc - C 2 - CH 2 S C 2 H S 3 H - H NHS 3 S CH 2 S 3 H - NHS C CH 2 2 S 3 CH 2 S C 2 H S H 3 H - - NHS 3 H NHS 3 S CH 2 S 3 H - NHS 3 Antithrombin III Pentasaccharide Binding Sites

22 Heparin Non-specific binding to circulating proteins, acute phase reactants, and cellular binding sites Directly activates platelets Potentiates the platelet response to low levels of agonists such as ADP Unpredictable dose response

23 Antithrombotic Therapies and Platelet Aggregation in Normals 14 Saline UFH LMWH ARG 12 * p < 0.05, ** p < 0.01 vs. control Percent Maximum ** * * 2 0 ADP ( μ M) TRAP (0.625 μ M) Xiao Z, Theroux P. Circ 1998;97:

24 Platelet Activation by Unfractionated Heparin Fibrinogen Binding Index Unstimulated ADP 1.0 ( μ mol.1-1 ) UFH LMWH Heparin / fragmin (units.ml -1 ) (Normal Subjects) Knight CJ et al. Eur Heart J. 1998;19:1239

25 Prothrombin F 1.2 Va Ca ++ Xa Platelet F1.2 Thrombin Platelet Activation Fibrinogen AT III FPA Fibrin 1 TAT III

26 Thrombin Rebound After Cessation of Intravenous Heparin FPA Time 0 3 Hr 6 Hr 10 Hr 24 Hr 1 Miller, Granger, Califf. Circ. 1993;88:I FPA F (*p<0.03; **p<0.001) F1.2

27 Thrombin Generation Follows Heparin Discontinuation in Patients with Acute Coronary Syndromes 5 4 Baseline D/C Heparin IV Heparin Wean SC Heparin Wean F1.2 (nm) Baseline 1 Hour 4 Hours 24 Hours 1 Becker RC. JACC 1999;34:1020

28 Disadvantages of UFH Bleeding Thrombocytopenia Unfractionated Heparin Poor Bioavailability Stronger Drug Interactions Anticoagulant Response Variations

29 Heparin/LMWH: mechanism of action Heparin/AT complex inhibits thrombin and Factor Xa Must have adequate AT present for anticoagulant effect Thrombin inhibition requires bridging by heparin chain (at least 18 units) Antithrombin LMWH has greater activity against Xa than thrombin 2 Thrombin 1 Heparin Antithrombin Pentasaccharide sequence Heparin chains with pentasaccharide sequence (~30%) bind to AT causing a conformational change LMWH Antithrombin Pentasaccharide sequence Factor Xa X/E//109.a.1

30 Hirudin: : mechanism of action Binds directly to two sites on thrombin Binding is highly specific and almost irreversible very very long half-life life may account for the high bleed rates seen with hirudins in clinical trials 2 Hirudin Thrombin 1 Inactivates both circulating and clot-bound thrombin hirudin displaces thrombin from fibrin Fibrin X/E//110.a.1

31 Structure of Thrombin: Gly-Pro-Arg-Pro (active-site-binding portion) 2 Thrombin (Gly) 4 1 C-terminal dodecapeptide (Exosite 1-binding portion) Fibrin Active Site: : cleaves fibrinogen and coagulation factors Exosite Site 1: activates platelets, activates protein C, anchors fibrinogen A/E//20.b.1

32 Bivalirudin: mechanism of action Gly-Pro-Arg-Pro (active-site-binding portion) (Gly) 4 2 Thrombin 1 Inactivates both circulating and clot-bound thrombin bivalirudin competitively displaces thrombin from fibrin Thrombin slowly cleaves Arg 3 -Pro 4 bond, resulting in recovery of thrombin active site function C-terminal dodecapeptide (Exosite 1-binding portion) Fibrin A/E//20.b.1

33 Direct Thrombin Inhibitors Thrombin Refludan (lepirudin) Refludan Irreversible Indication: : HIT T1/2 = 1.3 hr Angiomax (bivalirudin) Novastan (argatroban) Angiomax Reversible PTCA 25 min Novastan Reversible HIT 45 min

34 Argatroban: : mechanism of action Argatroban only binds near the active site on thrombin Argatroban has a short half-life life 2 54% of argatroban binds to human serum proteins Argatroban Thrombin 1 X/E//111.a.1

35 Pharmacokinetic Profile Bolus 0.75 mg/kg [Bivalirudin] Mean ng/ml Infusion 2.5 mg/kg/h t ½ = 25 min. Clearance = 3.4 ml/min/kg Time from start of bivalirudin bolus (hours)

36 Hemorrhagic outcomes 10% 8% 6% 4% p < p < p < p < p = Heparin (N=2151) Bivalirudin (N=2161) 2% 0% Any major bleed 3g/dL [Hgb] Transfuse 2U 5g/dL [Hgb] RP or IC bleed

37 Bleeding by renal function B A T Incidence of major bleeding 25% 20% 15% 10% 5% 0% 3.1% 1.2% n=256 None ( 90 ml/min) heparin bivalirudin 8.5% 1.9% Mild (60 89 ml/min) 12.7% 6.0% Moderate (30 59 ml/min) 20.0% 0.0% n=275 n=461 n=454 n=250 n=301 n=7 n=12 Severe (<30 ml/min) Robson, J Invas Cardiol. 2000, 12SupplF: 33F-36F

38 Plaque Rupture Thrombus Mechanical Vasoconstrictive Distal Embolization Mechanical Plugging Serotonin Release Vasoconstriction

39 Microvascular Injury Activated IIb/IIIa stained red Platelet aggregate plugging a small vessel

40 Comparing the Physical Differences of the Glycoprotein 2b/3a Inhibitors Fibrinogen abciximab Small Molecules 2b/3a MAC-1 Platelet Surface 2b/3a av/β3

41 Response to Platelet Activation GP IIb/IIIa receptor antagonist Agonist Inhibition of platelet aggregation GP IIb/IIIa receptors occupied by antagonists ADP, thrombin, collagen and others Resting platelet GP IIb/IIIa receptors in unreceptive state Fibrinogen Aggregating platelets GP IIb/IIIa receptors occupied by fibrinogen which forms bridges between adjacent platelets

42 Major Differences Among GPIIb/IIIa Inhibitors Abciximab Eptifibatide Tirofiban Platelet-bound half-life Long Short Short (hours) (seconds) (seconds) Plasma half-life Short Long Long (minutes) (2.5 hr) (1.8 hr) Drug-to-receptor ratio ,500 1 >250 2 % of dose in bolus ~75% 3 <2 5% <2 5% Dosage adjustment in renal insufficiency None Yes Yes 1 IMPACT-II and PURSUIT doses. 2 RESTRE and PRISM- PLUS doses. 3 For any individual receiving a weight-adjusted, 12-hour infusion.

43 Major Differences Among GPIIb/IIIa Inhibitors Anticoagulant Properties Abciximab Eptifibatide Tirofiban Thrombin generation Activated clotting time +35 sec +25 sec N/A Reversibility* 12 hrs 4 6 hrs >4 hrs Reversibility with platelets Yes No No *50% Return of platelet function without platelet transfusion

44 During Drug Infusion Abciximab Small Molecule 80% 80% 80% 80% 80% 80% 80% 80% 80% Total dose of abciximab is an ~twofold molar excess over GPIIb/IIIa Total dose of small molecule antagonist is a >100-fold molar excess over GPIIb/IIIa Numbers represent GPIIb/IIIa receptor occupancy and are an approximation

45 Platelet Transfusion Rapidly Normalizes Bleeding Time Abciximab -

46 Immediately After Platelet Transfusion Abciximab Small Molecule 80% 80% 0% 80% 0% 80% 80% 20% 80% 80% 80% 80% 79% 80% 80% Very little free drug to block transfused platelets Large pool of free drug to block transfused platelets Numbers represent GPIIb/IIIa receptor occupancy and are an approximation

47 Absolute Differences over Time Effects of Small Molecule Therapy on Mortality % change vs placebo IMPACT II (n = 4,010) PURSUIT (n = 9,461) ESPRIT (n = 2,007) RESTRE (n = 2,141) PRISM+ (n = 1,570) PARAGN A (n = 7,232) Months after randomization IMPACT II: Lancet 1997; 349: , ACC 1999 ral presentation, PURSUIT: NEJM 1998; 339:436-43, ESC 1998; ral Presentation,PRISM-PLUS: NEJM 1998; 338: , RESTRE: Circ. 1997; 96: , JACC 1998; 32:28-34, PARAGN A: Circ 1998; 97: ESPRIT: SCAI 2000, ral Presentation.

48 Absolute Differences over Time Effects of Abciximab Therapy on Mortality EPIC (B&I) (n = 1404) EPILG (n = 2792) 0 EPISTENT (n = 1603) % change vs placebo * Abciximab p = * p = p = ERASER (n = 225) RAPPRT (n = 483) CAPTURE (n = 1265) Neumann(n = 401) ADMIRAL (n = 300) Months since randomization EPIC: NEJM 1994; 330:956-61, Lancet 1994; 343:881-86, JAMA 1997; 278:479-84, CAPTURE: Lancet 1997; 349: , ACC 2000 oral., EPILG: Internal Data, Centocor, EPISTENT: Lancet 1998; 352:87-92, NEJM 1999; 341:319-27, Lancet 1999; 354: , RAPPRT:. 1998; 98:734-41, ERASER: Circ. 1999; 100; , ADMIRAL: ETC 2000, oral pres., Neumann : JACC 2000; 35: pres Circ

49 Mortality at Maximum Duration of Follow-Up: All Patients Intention to Treat HR 0.83 ( )

50 Platelet Thrombi Cause Vessel cclusion at Site of Injury and Downstream Platelet Aggregation Platelet Attachment at Site of Endothelial Injury Transient Platelet Aggregation Mechanical bstruction Vasoconstriction Mechanical bstruction Vasocconstriction

51 Stenting the Tip of the Iceberg

52 Coronary Tree --Stenting the Tip of the Iceberg

53 SIRIUS - Clinical Events All Events (to 270 days) P<0.001 % 16.7% 4.7% TLR 3.2% 3.8% 7.4% 0.5% 7.2% ut-of-hosp death MI 3.7% 2.4% In-hosp MACE 1.0% Sirolimus (n=190) TVR (Non-TL) Control (n=210) In-hospital MACE ut-of-hosp death MI TVR (Non-TL) TLR

54 Meta-analysis analysis of Balloon vs. Stent Trials Balloon Stent p=0.106 p= % Patients * 3314 pts ** 4345 pts (17 trials) p=0.970 p= Day* 6 Month** 30 Day 6 Month DEATH DEATH / MI 1 Kong, Hasselblad, Topol, Califf (submitted)

55 Mortality Follow-up - Abciximab Latest Follow-up in All Randomized Trials % of Patients EPIC (3 years) 6.8 EPILG (1 year) EPISTENT (1 year) p = CAPTURE (4 years) ERASER (6 months) 0.0 RAPPRT (6 months) ADMIRAL (6 months) Neumann (1 year) EPIC: JAMA 1997; 278:479-84, CAPTURE: Simoons, oral presentation, ACC 2000, EPILG: Internal Data, Centocor, EPISTENT: Lancet 1999; 354: , RAPPRT: Circ. 1999; 98:734-41, ERASER Circ. 1999;100: , Neumann: JACC 2000; 35(4): , personal comm, JF Neumann; ADMIRAL: Montelescot, oral presentation, ACC Placebo Abciximab

56 Clinical Results of CACHET BC Trial Hemorrhage Death, MI, revasc Bivalirudin + ReoPro (24%) n = % 2.8% 75% reduction p-value <0.013 Heparin + ReoPro (100%) n = % 7.8% % of patients with events at 7 days

57 REPLACE-2: Design Multicenter international trial United States 78% of patients Europe 15% Canada 7% Double-blind, double dummy design 6002 Urgent or elective PCI patients Aspirin Clopidogrel Stent Bivalirudin Provisional GPIIb/IIIa Heparin Abciximab or Eptifibatide Endpoints 30-day Death MI Revasc Hemorrhage Economics, ischemia 6, 12m follow up Lincoff M et al. JAMA 2003

58 30-day endpoints All pre-specified endpoints of the trial were met 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 Lincoff AM et al JAMA 2003; 289:

59 Mortality vs. heparin at 6 mo Karvourni et al 2003 J Am Coll Cardiol 2003; 41: trials 20,137 patients (Risk ratio) Kong et al 2003 Am J Cardiol 2003; 92: trials 20,186 patients (dds ratio) New Rx better Heparin better New Rx better Heparin better GPIIb/IIIa meta-analysis Bivalirudin REPLACE-2 N= Risk ratio ±95% CI for death at 6 months dds ratio ±95% CI for death at 6 months

60 Background: Current Management of ACS Early invasive strategy if moderate-high risk 1,2 Median time to cath 21 hours 3 Revascularization with PCI or CABG 1,2 55% PCI, 12% CABG, 33% medical mgt 3 Triple anti-platelet therapy 1,2 Aspirin Clopidogrel (initiated pre or post angiography) GP IIb/IIIa inhibitors - started upstream in all pts or in the CCL for PCI Unfractionated or LMW heparin 1,2,4 1 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; SYNERGY. JAMA 2004;292:45-54

61 Bivalirudin in ACS: Hypotheses In moderate-high risk patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors: Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

62 ACUITY Design. Stone GW et al. AHJ 2004;148: Study Design First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderatehigh risk ACS Aspirin in all Clopidogrel dosing and timing per local practice R* UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone Angiography within 72h Medical management PCI CABG *Stratified by pre-angiography thienopyridine use or administration

63 ACUITY Design. Stone GW et al. AHJ 2004;148: Study Design Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderatehigh risk ACS Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin Routine upstream GPI in all pts R GPI started in CCL for PCI only R Bivalirudin Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Alone Angiography within 72h Medical management PCI CABG

64 Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI Primary endpoint Risk ratio ±95% CI Bival UFH/Enox + IIb/IIIa + IIb/IIIa RR (95% CI) p value (non inferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.8% 11.7% 1.01 ( ) 7.7% 7.3% 1.07 ( ) 5.3% 5.7% 0.93 ( ) < < Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better

65 Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone Primary endpoint Risk ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa RR (95% CI) p value (non inferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 10.1% 11.7% 0.86 ( ) 7.8% 7.3% 1.08 ( ) 3.0% 5.7% 0.53 ( ) < <0.001 <0.001 Bivalirudin alone better UFH/Enox + IIb/IIIa better

66 Components of the Ischemic Composite UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612) 30 day events (%) P Sup = 0.32 P Sup = 0.34 P Sup = 0.35 P Sup = % 7.7% 7.8% 4.9% 5.0% 5.4% 2.3% 2.7% 2.4% 1.3% 1.5% 1.6% Ischemic composite Death Myocardial infarction Unplanned revasc for ischemia

67 Major Bleeding Endpoints UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612) P Sup =0.31 P Sup <.001 P Sup =0.38 P Sup < day events (%) 11.8% 11.1% 9.1% 5.7% 5.3% 3.0% All major bleeding Non CABG major bleeding (primary endpoint)

68 Net Clinical utcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa RR (95% CI) P P int Biomarkers (CK/Trop) Elevated (n=5368) Normal (n=3841) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) ST Deviation Yes (n=3197) No (n=6008) 13.0% 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) TIMI Risk Score Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) Pre Thienopyridine Yes (n=5192) No (n=4023) 6.4% 10.2% 0.63 ( ) % 10.2% 0.92 ( ) % 15.2% 0.92 ( ) % 11.3% 12.2% 11.1% 0.76 ( ) 1.02 ( ) < Bivalirudin alone better UFH/Enox + IIb/IIIa better

69 Conclusions Heparin has significant limitations Requires a cofactor (ATIII) Non-specific protein binding Variable dose response Activates platelets Thrombocytopenia Thrombin rebound Would not gain FDA approval in 2007

70 Conclusions Low risk elective PCI Bivalirudin alone provides superior clinical outcomes compared to UFH alone, and no difference compared to UFH / Gp 2b3a Provided they have been adequately pre- treated with ASA and Plavix Bivalirudin alone has less bleeding than UFH / Gp 2b3a

71 Conclusions Moderate to high risk PCI No difference in ischemic complications comparing bivalirudin alone vs UFH / Gp 2b3a vs bivalirudin / Gp 2b3a Provided patients are adequately pre-loaded with ASA and Plavix Less bleeding with bivalirudin alone vs UFH / Gp 2b3a vs bivalirudin / Gp 2b3a

72 Death is a very good way to cut down on expenses. Woody Allen Love and Death