Antithrombin Controversies: Optimal Antithrombin Therapy in Elective PCI Robert A. Harrington, MD Professor of Medicine Director, Duke Clinical Research Institute Duke University Medical Center

Relationships Relevant to this Presentation Research grants/contracts to DCRI ACC, AHA, sanofi-aventis, TMC, Momenta, Regado Consulting Sanofi-aventis, Regado Full listing of all relationships with industry http://www.dcri.duke.edu/research/coi.jsp

Anticoagulant Therapy in Elective PCI Basic concepts of PCI antithrombotic therapy Elective PCI Available anticoagulants ACC/AHA/SCAI Guidelines New agents under investigation

Drug Treatment The patient is given aspirin (1.0 g per day) for three days, starting the day before the procedure. Heparin and low molecular-weight dextran are administered during dilatation; warfarin is Heparin Dose = 3000 U

Paradigm for Antithrombotic Drug Use in PCI Prevention of thrombosis Risk of bleeding

A Guidelines-Based Approach to Selecting Antithrombotic Therapies for Use During PCI Consider the clinical setting STE AMI, NSTE ACS, non-ACS Consider the anatomic complexities Diffuse CAD, MVD, small vessel, CTO, bifurcation disease, SVG disease Consider the technology complexities Ablation, thrombectomy, complex stenting Consider “other” patient features Advanced age, body size, gender, diabetes, CKD, recent bleeding, social support

Anticoagulants Available for Use or Under Active Investigation in PCI Unfractionated heparin (UFH) Low molecular weight heparins (LMWH) Direct thrombin inhibitors (DTIs) Bivalirudin, lepirudin, argatroban Factor Xa inhibitors (fondaparinux) “Engineered” heparins Factor IXa inhibitors (aptamer with antidote)

ACS and Non-ACS PCI Pharmacology: NCDR 2005 to 2009 Variables ACS Non-ACS Q1-2 2005 (n = 92,534) Q1-2 2009 (n = 144,989) p-value (n = 50,532) (n = 79,892) Procedural Medications (%) GP IIb-IIIa Inhibitors 57.3 44.5 < 0.0001 38.5 21.5 Unfractionated Heparin 63.9 58.7 49.9 38.2 LMW Heparin 23.1 19.1 7.5 7.1 0.01 Bivalirudin 27.1 43.4 37.8 -Roe MT, et al. JACC in press 2010

-NEJM 355; 2006

LMWH and Catheter Thrombosis 6 (5%) with catheter thrombus 122 pts. Within 8hrs of SQ enox 4504 pts. Undergoing PCI -CCI 70:847;2007

Bivalirudin Pharmacology Gly-Pro-Arg-Pro (active site binding region) Bivalent direct thrombin inhibitor High specificity and potency Lack of dependence on antithrombin-III Effect on clot-bound & free thrombin No platelet activation No inhibition by PF4 and others Reversible (Gly)4 Pharccology direct inhibitor of thrombin. nhibits clot bound thrombin, no activation of platelets. Reduction of thrombin induced platelet activaton Short acting. C-terminal dodecapeptide (exosite 1-binding region)

Trial Design Bivalirudin vs Heparin + GP IIb/IIIa During PCI N = 6010 Patients: Urgent or Elective PCI Randomization - double blind, triple dummy Heparin 65 U/kg initial bolus Planned GP IIb/IIIa (abciximab or eptifibatide) Bivalirudin 0.75 mg/kg initial bolus, 1.75 mg/kg-hr during PCI Provisional GP IIb/IIIa target ACT > 225 sec abciximab: 0.25 mg/kg bolus, 0.125 mg/kg-min (max 10 mg/min) x 12 hrs eptifibatide: 180 mg/kg double bolus, 2.0 mg/kg-min x 18-24 hrs · “Quadruple Endpoint” at 30 Days ·

30 Day Primary Endpoint Components Quadruple Endpoint 30 Day Primary Endpoint Components p <0.001 -Lincoff AM et al. JAMA 2003

1-Year Results Mortality -Lincoff AM et al. JAMA 2004 72 / 3008 HR = 0.779 [0.549 - 1.105] p = 0.160 72 / 3008 = 2.46% 56 / 2994 = 1.89% -Lincoff AM et al. JAMA 2004

Alternative Anticoagulants for Patients with HIT Shantsila, Lip, Chong. CHEST 2009; 135:1651–1664

-Smith SC et al. JACC 2006.

M118 Structure and Properties Low-molecular-weight heparin Increased anti-factor II activity compared with other LMWHs Constant Xa/IIa ratio over time Predictable PK/PD Effects are reversible or neutralized with protamine sulfate High bioavailability: IV and SC administration -Rao SV. TCT 2009

EMINENCE Study Design -Rao SV. TCT 2009 Low-risk patients with stable CAD undergoing elective PCI Pre-treat with ASA (325 mg) and clopidogrel 300 mg prior to PCI Baseline ACT measurement Cardiac catheterization Randomization; ASA + clopidogrel UFH 70 U/kg IV bolus M118 50 anti-Xa IU/kg M118 75 anti-Xa IU/kg M118 100 anti-Xa IU/kg 7-day telephone interview 14-day follow-up 30-day follow-up: Composite of death, MI, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, or all bleeding -Rao SV. TCT 2009

EMINENCE Results: Primary End Point -Rao SV. TCT 2009

Time Post RB006 Administration (hrs) RB007 Active Control Placebo 80 70 60 50 40 30 20 2:1 Inject RB007 1:1 0.5:1 0.2:1 0.125:1 Activated Partial Thromboplastin Time (seconds) 0 1 2 3 4 5 6 7 8 Time Post RB006 Administration (hrs) 22 22 Chan, M et al, JTH 2008 22

RADAR Trial Design NSTE-ACS, Planned Catheterization w/i 24 hrs n=800 UFH / LMWH + GP IIb/IIIa n=200 RB006 1mg /kg IV n=600 Randomize Femoral Cardiac Catheterization / Percutaneous Intervention Standard Care RB007 100% n=200 RB007 75% n=100 RB007 50% n=100 RB007 25% n=200 Primary Outcome: Acuity major bleeding Secondary Outcomes: Ischemic events / stent thrombosis Total bleeding, bailout RB007 dosing

Anticoagulants For Use During Elective PCI Anticoagulants are obligatory during PCI Multiple effective agents Use tailored approach based on patient and CAD characteristics; no single proven “optimal” agent Combination therapies (anticoagulants plus antiplatelets) appear most effective to date Active area of ongoing investigations