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

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.

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

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: 258-264

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

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

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

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 = 0.001 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 171-295s = 1320 296-349 s = 1290 Greater than 350s = 1281 Chew D, et al., Circulation. 103(7):961-6, 2001.

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.

Efficacy and Bleeding by Tertiles of Maximum ACT 39% 37% ACT 244 - 292 n=678 ACT>292 n=676 32% ACT<244 n=661 Primary Endpoint Major TIMI Bleeding Tolleson T et al., J Am Coll Cardiol 41:386-393, 2003

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

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 1.9-12.

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=0.98+0.03 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

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.

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

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

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 70-100 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

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

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

Fondaparinux Factor Xa inhibitor Synthetic pentasaccharide t1/2 = 17-21 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

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):1464-76.

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):1464-76.

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 = 0.5 - 1.7 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

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)

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: 853-863

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 (0.80-1.06) 0.75 (0.61-0.93) 0.23 0.01 0.35 ST Deviation Yes (n=3197) No (n=6008) 13.0% 8.6% 13.7% 10.6% 0.96 (0.80-1.14) 0.81 (0.69-0.95) 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 (0.43-0.91) 0.01 9.4% 0.92 (0.77-1.10) 0.34 13.9% 15.2% 0.92 (0.76-1.11) 0.36 0.18 Pre Thienopyridine Yes (n=5192) No (n=4023) 9.2% 11.3% 12.2% 11.1% 0.76 (0.65-0.89) 1.02 (0.86-1.21) <0.001 0.83 0.02 Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et. al. NEJM 2007.

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 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Stone GW et al. NEJM 2008.

1-Year All-Cause Mortality 5 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

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

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

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

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 M118 75 anti-Xa IU/kg M118 100 anti-Xa IU/kg 7-day telephone interview 14-day f-u 30-day f-u

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)

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

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