1. Anticoagulation in the Cath Lab
Sunil V. Rao MD
Assistant Professor of Medicine
Duke University Medical Center
Durham VA Medical Center
Duke Clinical Research Institute

2. Sunil V. Rao, MD DISCLOSURES Consulting Fees Honoraria
The Medicines Company, Bristol-Myers Squibb, Astra Zeneca
Honoraria
sanofi-aventis U.S. LLC
Grants/Contracted Research
Cordis, a Johnson & Johnson company, Momenta Pharmaceuticals, Inc., Portola Pharmaceuticals, Inc.
I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation.
I intend to reference Bivalirudin and Fondaparinux for ACS; Enoxaparin for PCI; Clopidogrel for stenting.

3. Disclosures Consultant, Speakers’ Bureau, Honoraria Sanofi-Aventis
The Medicines Company
Terumo Corporation
Astra Zeneca
Research funding
Cordis Corporation
Momenta Pharmaceuticals
Portola Pharmaceuticals
Off-label uses of drugs/devices will be discussed
Fondaparinux in NSTE ACS
Enoxaparin in PCI
Bivalirudin in NSTE ACS

4. Actions of Thrombin on Blood Cells and Blood Vessels
Lymphocyte
Endothelium
Monocyte
Thrombin
Cytokines
Growth factors
Autocoids
Proteases
Shape and
permeability
changes
Platelet
Key point: Thrombin’s effects go beyond coagulation. Thrombin is a key player in hemostasis, inflammation and restenosis.
This slide depicts the multiple actions of thrombin on blood cells and blood vessels
Thrombin is not only an important mediator in coagulation, it plays a significant role as a hormone-like effector. Thrombin provides signals to various cell types—such as platelets and endothelial cells— to effect responses in hemostasis, inflammation, and possibly other important physiological processes. It is the most effective agonist for platelet activation. Thrombin also elicits a host of responses in the vascular endothelium, including shape and permeability changes, mobilization of adhesive molecules to the endothelial surface and stimulation of autocoid (small molecule mediators such as prostaglandins and platelet-activating factor) and cytokine production. Thrombin is chemotactic for monocytes and mitogenic for lymphocytes and mesenchymal cells.
Serine protease generated at sites of vascular injury. Most effective platelet activator (PAR-protease activated receptor). Elicits host of responses in vascular endothelium: shape & permeability changes, mobilization of adhesive molecules to endothelial surface & stimulation of autocoid (small molecule mediators such as prostaglandins, PAF) & cytokine production. Chemotactic for monocytes. Mitogenic for lymphocytes & mesenchymal cells.
Neutrophil
Smooth
Muscle
cell
Coughlin SR, Nature 2000; 407:

5. Antithrombin Agents: Classification
Antithrombins
Heparins
Unfractionated Heparin
Low-molecular weight
Synthetic pentasaccharides (indirect anti-Xa)
Fondaparinux
Direct thrombin inhibitors
Bivalirudin, Lepirudin, Argatroban

6. Sites of action for anticoagulants
Factor Xa
Factor IIa (thrombin)
Unfractionated
Heparin
Fondaparinux
Otamixaban
Apixaban
Bivalirudin
Enoxaparin

7. Unfractionated Heparin (UFH)
5,000-30,000 Daltons
Heterogeneous mixture of polysaccharide chains with varying effects on anticoagulant activity
Accelerates the action of circulating antithrombin (AT), a proteolytic enzyme which inactivates factors IIa (thrombin), IXa, Xa
Prevents thrombus propagation, but does not lyse existing thrombi
UFH
bound to AT

8. Heparin in PCI Trials: Meta-Analysis
10.1%
11.1%
8.6%
8.9%
6.6%
7.5%
7.7%
9.8%
0.15
0.10
0.05
0.00
250
300
350
400
450
Minimum ACT at device activation
Probability of 7 Day Death, MI or Revasc
Probability of death, MI,
or revasc at 7-days
p = between 11.1% and 7.7%
This graph depicts the correlation between ACT and clinical outcomes. Based on this meta-analysis, an ACT of greater than 350 seconds provided the greatest degree of protection against ischemic complications.
ACT: N=5216
Less than 170s = 1325
s = 1320
s = 1290
Greater than 350s = 1281
Chew D, et al., Circulation. 103(7):961-6, 2001.

9. Heparin in PCI Trials: Meta-Analysis
16.9%
12.4%
8.6%
9.9%
13.7%
Maximum ACT during PCI
0.20
Probability of TIMI major + minor hemorrhage
0.15
0.10
0.05
0.00
250
300
350
400
450
Probability of major or
minor bleeding
In the same meta-analysis, fewer hemorrhagic complications were seen at ACT levels of 325 to 350 seconds.
N = 3485
Chew D, et al., Circulation. 103(7):961-6, 2001.

10. Efficacy and Bleeding by Tertiles of Maximum ACT
39%
37%
ACT
n=678
ACT>292
n=676
32%
ACT<244
n=661
Primary Endpoint
Major TIMI Bleeding
Tolleson T et al., J Am Coll Cardiol 41: , 2003

11. The Unfractionated Heparins - Limitations
variability of preparations
unpredictable neutralization by PF-4
binds to endothelial cells, plasma proteins, macrophages
poor clot penetration
indirect anticoagulant - relies on AT III levels, structure
stimulates platelet aggregation
HIT(TS)!!
made of beef and pork intestine (and sausage, manure)
Adapted from Hirsh and Fuster, Circulation 1994;89:1449

12. Low-Molecular-Weight Heparin (LMWH)
4,200-6,000 Daltons
Obtained through chemical or enzymatic depolymerization of polysaccharide chains of UFH
>18 saccharide units inactivate Xa and thrombin
<18 saccharide units inactivate Xa (25-50% of chains)
Relatively more inhibition of Xa than thrombin
Ratios of anti-factor Xa:IIa from

13. Enoxaparin in PCI in Patients with ACS
451 pts with UA/NQWMI rx’d with enoxaparin for 48 hrs.
293 underwent cath within 8 hrs of AM enox. dose
132 ad hoc PCI, no additional UFH/LMWH
30d: Death=1.5%, MI=3.0%, Maj. Bleeding = 0.8%
Mean anti-Xa at PCI= IU/ml, 25
N = 293 20 15
% of Patients 10 5
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Anti-Xa Activity (IU/mL)
Collet et al. Circulation 2001;103:658

14. Enoxaparin in PCI
0.3 mg/kg IV at 8 hours or more after last sc injection allows “optimal” therapeutic levels
Martin JL, et al. Presented at ESC 2001.

16. Category: PCI Research
Keywords: SYNERGY
Acute Coronary Syndromes
Cardiology
Catheterization
Mahaffey
Ferguson
The Journal of the American Medical Association

17. Anti-Xa Activity With LMWH Administration
Anti-Xa (IU/ml)
Time (hours) 5 10 15 20 25
Enoxaparin 1 mg/kg IV
Enoxaparin 0.75 mg/kg IV
Enoxaparin 1 mg/kg SQ
0.5
1.0
1.5

18. Elective PCI STEEPLE DRUG DOSE MONITORING IV UFH IV Enoxaparin
w/o GP IIb/IIIa
w GP IIb/IIIa
Elective PCI
IV UFH
IV Enoxaparin
0.75 mg/kg
0.50 mg/kg
Primary Safety EP: non-CABG bleedings at 30 days IU
50-70IU
ACT
Random. stratified with GP IIb/IIIa RA use
N > 3000
Main Efficacy EP: Success rate to reach ACT or anti-Xa target
Secondary Efficacy EP: Death / Re-MI / Urg revasc / Major Bleed
STEEPLE-defined major bleeding - bleeding resulting in death, retroperitoneal, intraocular, transfusion, hemodynamic compromise, requiring a procedure, clinically overt with hgb decrease 3 g/dl
Montalescot G. NEJM 2006

19. Incidence of Secondary End Points
STEEPLE
Incidence of Secondary End Points
*0.5 mg/kg arm stopped early due to increased mortality

20. STEEPLE Mortality: 1 month to 1 year
Enoxaparin 0.5
Enoxaparin 0.75
UFH
Days after 1 month 30 60 90
120
150
180
210
240
270
300
330
360
390
p = all NS
1.4%
2.0%
1.5%
Endpoint (%) 1 2 3 4 5
P=0.45
P=0.86 11 18 5 10 15 20 25 14
Patient Mortality (n)
Montalescot G. ESC 2007 presentation

21. Fondaparinux Factor Xa inhibitor Synthetic pentasaccharide
t1/2 = hrs
Inactive against thrombin already generated
Advantages over UFH
Decreased plasma protein, endothelial cell binding
More predictable, sustained anticoagulation
Once-daily dosing
No laboratory monitoring

22. OASIS-5: Study Design Patients w/ NSTE ACS Fondaparinux Enoxaparin
Exclude
Age < 21
Contraindication to enox
Hemorrhagic stroke < 12 mo
Creat > 3 mg/dL (265 umol/L)
Chest pain < 24 hours
2/3:
Age > 60
ST-segment ∆
↑ cardiac markers
Randomize
n = 20,000
Fondaparinux
2.5 mg sc qd
ASA, clopidogrel, IIb/IIIa, planned cath per local practice
Enoxaparin
1 mg/kg sc bid
PCI < 6 h: IV fondaparinux
2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa
PCI > 6h: IV fondaparinux
5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa
PCI < 6 h: no UFH
PCI > 6h: IV UFH
100 U/kg w/o IIb/IIIa
60 U/kg w/ IIb/IIIa
The study involved 20,000 patients with NSTE ACS. The trial was blinded, and patients were randomized to receive either fondaparinux, 2.5 mg sc once daily, or enoxaparin, 1 mg/kg sc q 12h. A transition strategy was defined for people coming forward to the catheterization laboratory, that involved supplemental iv UFH in relatively large doses in the enoxaparin-treated patients, and supplemental iv fondaparinux in fondaparinux-treated patients. The primary endpoint was the composite of death, MI and refractory ischemia at 9 days. Patients with serum creatinines > 3 were excluded from the trial, but no dose adjustments of enoxaparin were made for impaired renal function. The use of aspirin, clopidogrel, GP IIb/IIIa antagonists, and the timing of intervention, if done, was at the discretion of the investigators.
Outcomes
Primary Efficacy: Death, MI, refractory ischemia at 9 days
Safety: Major bleeding at 9 days
Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days
Secondary Above and each component separately at day 30 and 6 months
Yusuf S, et al. N Engl J Med. 2006;354(14):

24. OASIS 5: PCI Procedural Complications
<0.0001
1.6%
4.4%
Large hematoma
0.39
1.0%
Pseudo-aneurysm
3.3%
8.1%
Vascular access
0.001
1.3%
0.5%
Catheter thrombus
0.20
1.5%
1.1%
Abrupt closure
0.18
9.6%
8.6%
Any procedural complication
18.8%
53.8%
Any UFH during PCI
P value
Fondaparinux n=3118
Enoxaparin n=3089
Events (30 Days)
As one focuses on the subset of patients undergoing PCI in OASIS 5 (n=6,239), there are significant reductions in major bleeding at net clinical outcome with fondaparinux, but no difference in ischemic events (and trends that slightly favor enoxaparin). It is interesting to note that the close association between bleeding and mortality that was present in the overall patient cohort is NOT present in the PCI subset.
Yusuf S, et al. N Engl J Med. 2006;354(14):

25. Direct thrombin inhibitors
Hirudin
Argatroban
Modification of naturally occurring anticoagulant in saliva of Hirudo medicinalis: (Leu1, Thr2)-63-desulfato-hirudin
Inhibits all proteolytic activity of thrombin
t½b = hours, renal clearance
Approved for anticoagulation in pts with HIT (but not specifically for PCI)
Antigenic
Derivative of arginine amino acid
Univalent binding directly to catalytic site of thrombin
Dose-dependent prolongation of aPTT, ACT, PT
Short IV half-life (54 min)
Hepatic elimination
Approved for anticoagulation in pts with HIT

26. 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
t½ of 25 min
(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)

27. REPLACE-2 PCI Trial: Primary Endpoint-30d
% of patients
p = 0.324
p = 0.255
p = 0.430
p = 0.435
p < 0.001
Lincoff AM et al. JAMA 2003; 289:

28. Net Clinical Outcome Composite
UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Risk ratio
±95% CI
Bival
Alone
UFH/Enox
+ IIb/IIIa
RR (95% CI) P
Pint
Biomarkers (CK/Trop)
Elevated (n=5368)
Normal (n=3841)
12.2%
7.1%
13.3%
9.4%
0.92 ( )
0.75 ( )
0.23
0.01
0.35
ST Deviation
Yes (n=3197)
No (n=6008)
13.0%
8.6%
13.7%
10.6%
0.96 ( )
0.81 ( )
0.61
0.01
0.42
TIMI Risk Score
Low (0-2) (n=1291)
Intermed (3-4) (n=4407)
High (5-7) (n=2449)
6.4%
10.2%
0.63 ( )
0.01
9.4%
0.92 ( )
0.34
13.9%
15.2%
0.92 ( )
0.36
0.18
Pre Thienopyridine
Yes (n=5192)
No (n=4023)
9.2%
11.3%
12.2%
11.1%
0.76 ( )
1.02 ( )
<0.001
0.83
0.02
Bivalirudin alone better
UFH/Enox + IIb/IIIa better
Stone GW, et. al. NEJM 2007.

29. 30 Day Mortality 3.1% Death (%) 2.1% P=0.048 Time in Days
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
3.1%
Death (%)
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Stone GW et al. NEJM 2008.

30. 1-Year All-Cause Mortality5
Bivalirudin alone (n=1800)
4.8%
Heparin + GPIIb/IIIa (n=1802)
Δ = 1.4% 4
3.4%
3.1% 3
Mortality (%)
Diff [95%CI] =
-1.5% [-2.8,- 0.1]
HR [95%CI] =
0.69 [0.50, 0.97] P=0.029 2
2.1%
Δ = 1.0%
P=0.049 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
Bivalirudin alone
1800
1705
1684
1669
1520
Heparin+GPIIb/IIIa
1802
1678
1663
1646
1486

31. 30 Day Stent Thrombosis (N=3,124)
UFH + GP IIb/IIIa
(N=1553)
Bivalirudin
(N=1571) P
Value
ARC 30d definite or probable stent thrombosis*
1.9%
2.5%
0.30
- definite
1.4%
2.2%
0.09
- probable
0.5%
0.3%
0.24
- acute (≤24 hrs)
1.3%
0.0007
- subacute (>24 hrs – 30d)
1.7%
1.2%
0.28
*Protocol definition of stent thrombosis, CEC adjudicated

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

33. Sites of action for anticoagulants
Factor Xa
Factor IIa (thrombin)
Unfractionated
Heparin
Fondaparinux
Otamixaban
Apixaban
Bivalirudin
M118
Enoxaparin

34. Study Flow Chart Cardiac catheterization Randomization 1:1:1
Low-risk patients with stable CAD undergoing elective PCI
Pre-treat with aspirin (325 mg) and clopidogrel 300mg prior to PCI
Baseline ACT measurement
Cardiac catheterization
Randomization 1:1:1
UFH 70U/kg IV bolus
M anti-Xa IU/kg
M anti-Xa IU/kg
7-day telephone interview
14-day f-u
30-day f-u

35. Primary Endpoint
Composite of 30-day death, MI, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, or all bleeding (REPLACE-2 scale*).
* Transfusion of > 2 units whole blood or packed red blood cells
Intracranial hemorrhage
Retroperitioneal hemorrhage
Decreased in Hgb > 4 g/dl (12 % of hematocrit ) with no bleeding site
Spontaneous or non-spontaneous blood loss associated
with Hgb decrease > 3 g/dl (10% of hematocrit)

36. EMINENCE Results: Primary Endpoint, ITT*
Rao SV, et. al. Circulation (in press)

37. Summary Antithrombin therapy
Remember sites of action (direct vs. indirect)
Key points
Heparin dosing
Enoxaparin SQ vs. SQ + IV vs. IV
Fondaparinux – minimizes bleeding risk at expense of catheter thrombus
Bivalirudin – minimizes bleeding risk but need early aggressive thienopyridine (? Pre-Rx with UFH in STEMI)
New agents being studied