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

2. 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

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

4. 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

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

6. 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

7. 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)

8. ACS and Non-ACS PCI Pharmacology: NCDR 2005 to 2009
Variables
ACS
Non-ACS Q
(n = 92,534) Q
(n = 144,989)
p-value
(n = 50,532)
(n = 79,892)
Procedural Medications (%)
GP IIb-IIIa Inhibitors
57.3
44.5
<
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

9. -NEJM 355; 2006

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

13. 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)

14. 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: mg/kg bolus, mg/kg-min (max 10 mg/min) x 12 hrs
eptifibatide: 180 mg/kg double bolus, 2.0 mg/kg-min x hrs
· “Quadruple Endpoint” at 30 Days ·

15. 30 Day Primary Endpoint Components
Quadruple Endpoint
30 Day Primary Endpoint Components
p <0.001
-Lincoff AM et al. JAMA 2003

16. 1-Year Results Mortality -Lincoff AM et al. JAMA 2004 72 / 3008
HR = [ ]
p = 0.160
72 / 3008
= 2.46%
56 / 2994
= 1.89%
-Lincoff AM et al. JAMA 2004

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

18. -Smith SC et al. JACC 2006.

19. 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

20. 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
M anti-Xa IU/kg
M anti-Xa IU/kg
M 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

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

22. 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)
Time Post RB006 Administration (hrs) 22 22
Chan, M et al, JTH 2008 22

23. 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
RB % 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

24. 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