Optimal Upstream Therapy: Low Molecular Weight Heparin with GP IIb-IIIa Antagonists Neal Kleiman Director Cardiac Catheterization Laboratory Methodist DeBakey Heart Center Professor of Medicine Weill Medical College of Cornell University

Neal S. Kleiman, MD DISCLOSURES Grants/Contracted Research Bristol-Myers Squibb, Sanofi-Aventis U.S. LLC, Schering-Plough Corp./ Merck & Co., Inc.

A Two Part Question

Part I: What about GP IIb-IIIa Antagonists? Are they a relic of days gone by: have we gotten so good with modern PCI and front-loading of clopidogrel that we don’t need them anymore?

Myocardial (re)Infarction 30-Day Death or Myocardial (re)Infarction 1.00 Eptifibatide + Enoxaparin (n=380) Eptifibatide + Heparin (n=366) 0.98 0.96 0.954 Event-free Survival 0.94 Log Rank p=0.0282 0.92 0.909 0.90 5 10 15 20 25 30 -- Goodman Circulation 2003;107:238-44. Days from Randomization

Distribution of Clopidogrel Dosing in Wave 4 (2007) LD <599 mg LD >600 mg % LD <599 mg LD >600 mg Any clopid. pre-procedure Post Procedure only Chronic Clopid.

“Adequate” Clopidogrel Loading by Hospital WAVE 2 “Adequate” Clopidogrel Loading by Hospital IQR = 24% - 45% Median = 32% Participating Hospitals

96-hour Primary Efficacy Results Prespecified Subgroups 0.7 0.8 0.5 0.6 0.9 1 2 Odds Ratio for Upstream Eptifibatide (95% CI) Routine Early Eptifibatide, % Delayed Provisional 9.3 10.0 9.1 9.8 9.7 10.4 8.6 9.5 11.4 10.6 7.7 6.8 8.9 Early Eptifibatide Better Delayed Provisional Eptifibatide Better Baseline Characteristic Overall Men Women Age < 75 yr Age > 75 yr Troponin positive Troponin negative Diabetes No Diabetes Early clopidogrel intended No early clopidogrel intended 8.8 10.8 11.5

Early ACS: 30-day Death or MI Prespecified Subgroups 0.7 0.8 0.5 0.6 0.9 1 2 Overall 11.2 12.3 Men 11.4 12.0 Women 10.7 13.0 Age < 75 yr 10.2 11.6 14.0 14.6 Troponin positive Troponin negative 8.1 8.4 Diabetes 11.7 13.8 No Diabetes 10.9 Early clopidogrel intended 10.3 No early clopidogrel intended 13.7 13.4 Baseline Characteristic Early Eptifibatide Better Delayed Provisional Eptifibatide Better Age > 75 yr Odds Ratio for Upstream Eptifibatide (95% CI) Routine Early Eptifibatide, % Delayed Provisional 21 hours randomization to cath

Safety Results (through 120 hours) Routine Early Eptifibatide (n=4686) Delayed Provisional Eptifibatide (n=4643) OR (95% CI) P Bleeding (all patients, %) TIMI major 2.6 1.8 1.42 (1.07-1.89) 0.015 TIMI major or minor 5.8 3.4 1.75 (1.43-2.14) <0.001 GUSTO severe 0.8 0.9 0.99 (0.64-1.55) 0.97 GUSTO moderate or severe 7.6 5.1 1.52 (1.28-1.80) <0.001 PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001 Bleeding (CABG) Re-operation for bleeding (%) 6.0 8.4 0.70 (0.39-1.27) 0.24 Chest tube output (mL/24 H) 720 770 -- 0.41 Thrombocytopenia (<100K, %) 3.3 2.8 1.19 (0.93-1.51) 0.17 Stroke (total, %) 0.6 0.8 0.79 (0.48-1.30) 0.36

Small Molecule GP IIb/IIIa Inhibition in NSTE ACS PURSUIT PRISM PRISM PLUS PARAGON B PARAGON A Theroux COMBINED 1998 (n = 23,967) 0.88 (0.79-0.97) EARLY ACS ACUITY Timing EARLY ACS + ACUITY 0.92 (0.82-1.01) COMBINED 2009 (n = 42,666) 0.89 (0.84-0.95) 0.25 0.50 1.0 2.0 4.0 Odds Ratio for 30-day Death or MI Relative to Control

Part II: What About Upstream Use of Low Molecular Weight Heparins?

High-Risk ACS Patients At least 2 of 3 required: Age  60 ST  (transient) or  (+) CK-MB or Troponin Study Design Randomize (n = 10,000) Enoxaparin IV Heparin 60 U/kg  12 U/kg/hr (aPTT 50-70 sec) 1 mg/kg SC Q12H Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa) 56% GP IIb/IIIa 98% Angiography 48% PCI Primary endpoint: Death or MI at 30 days 24

Death or MI at 30 Days 5 10 15 20 25 30 0.8 0.85 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization UFH Enoxaparin 1.1 HR 0.96 (0.86-1.06) Caution: 75% of pts received at least one dose of heparin or LMWH prior to randomization

PCI Performed within SYNERGY logit Prob {hcdm30=1} -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -2.1 -2.0 -1.9 -1.8 -1.7 -1.6 -1.5 -1.4 -1.3 -1.2 Time to PCI (Hours) 5 10 15 20 25 30 35 40 45 50 UFH Enoxaparin PCI Performed within SYNERGY 9978 Randomized CABG 1864 (18.7%) PCI 4687 (47%) Cons Rx 3427 34.3%) Logit Prob. Death/MI Enoxaparin 2323 UFH 2364 Stent 86.5% 86.2% GP IIb/IIIa 70.4% 69.6% Abr V C 1.3% 1.7% White AHJ 2006;152:1042

Enoxaparin with Thrombolytic Drugs: ExTRACT TIMI 25 Protocol Design STEMI <6 h Lytic eligible N= 20,497 Lytic choice by physician (TNK, tPA, rPA, SK) ASA Double-blind Enoxaparin 30 mg IV bolus; SC 1.0 mg/kg q 12 h to hosp. discharge (No IV bolus, 0.75 mg/kg q 12 h if 75 y) UFH bolus 60 U/kg Infusion 12 U/kg/h for 48 h Day 30 Primary efficacy endpoint: Death/MI Primary safety endpoint: TIMI major haemorrhage N=20,479; 17% RRR in Death/MI Antman EM et al. N Engl J Med 2006;354:1477-1488.

EXTRACT: Primary End Point Death or Nonfatal MI (n=20,479) UFH 12.0% 17% RRR 9.9% Primary End Point (%) ENOX Relative Risk 0.83 (0.77 to 0.90) P<0.0001 The findings for the primary end point are shown here. Through 30 days Death or nonfatal MI was reduced from 12.0 % in the UFH group to 9.9% in the enoxaparin group. This 2.1% absolute risk difference corresponded to a 17% RRR with P <0.0001. Only 3 of the nearly 21,000 patients were lost to followup ! Lost to follow up = 3 Days Antman et al N Engl J Med 2006

EXTRACT-TIMI 25 PCI Cohort 3 6 9 12 15 5 10 20 25 30 Death/MI (%) Enox. 9.9% UFH 12.0% RRR = 17% p < 0.001 Days N = 20,479 patients ExTRACT-TIMI 25 n = 10,256 Enox. n = 10,223 UFH ~115 hours 3 6 9 12 15 5 10 20 25 30 Death/MI (%) RRR = 23% p = 0.001 Days Enox. 10.7% UFH 13.8% n = 2,272 PCI by 30 days The primary efficacy end point of this substudy was the composite of all cause mortality or nonfatal recurrent myocardial infarction (MI) through 30 days. The risk of death or nonfatal recurrent MI was significantly reduced among those patients who underwent PCI by 30 days receiving enoxaparin vs UFH (10.7% vs 13.8%; 0.77 relative risk [RR]; P<0.001). This difference emerged prior to PCI, and then persisted for up to 30 days. In addition: ENOX administration was associated with a significantly lower incidence of nonfatal recurrent MI among patients undergoing PCI (7.8% vs 10.9%, ORadj 0.69, 95% CI 0.56-0.85, p<0.001). ENOX vs UFH was associated with a 12 hour median delay in the timing of performance of PCI (122 vs 109 hours, p=0.006) and also a reduction in the incidence of PCI (22.8% vs 24.2%, p=0.027). n = 2,404 PCI by 30 days PCI on blinded study drug: N=2,178: Adjusted RRR =34% ~60 hours Gibson et al: JACC:2007;49:2238 AND Antman EM, et al. NEJM. 2006;354:1477-88.

Reviparin vs UFH in Acute MI: The CREATE Study HR= 2.49 (1.61-3.87) 20,201 Patients with STEMI Overall Population 15,570 Randomized 7780 Reviparin Weight-adjusted: <50 kg – 50% dose 51-70 kg – 75% dose 7790 Placebo t-PA or PCI (N=1,062) Death, MI, CVA, RI Implications: PCI-treated pts may benefit from LMWH With conservative rx, weight adjustment of LMWH may reduce bleeding Open label heparin for PCI 1 EP : Death/MI/Stroke @ 7 Days

Pentasaccharides Fondaparinux (Arixtra® ) Once-a-day Org31550 MOST LIKE NATURAL Once-a-day Org31550 MORE POTENT New binding site discovered Idraparinux (SanOrg34006) SIMPLIFIED Once-a-week Pentasaccharide have been built to mimic the sequence in heparins, responsible for AT binding. First step was to copy this sequence as closely as possible Second was to improve “nature” by adding a sulphoxy at H3. Third was to make simpler, safer and cheaper alternatives and to further titrate the elimination half-life to once-a-week use. OCH3 OCH3

OASIS-5; Outcomes with Fondaparinux in NSTE ACS The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, N Engl J Med 2006;354:1464-1476

PCI Related Complications: Fondaparinux vs Enoxaparin % The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, N Engl J Med 2006;354:1464-1476

Conclusions It depends how you define “upstream” and how you define “low molecular weight heparin”. If upstream refers to prolonged marination of the patient, the combination looks good, particularly in terms of ischemic events. The bleeding issue doesn’t look so good until you recognize that fondaparinux is the ultimate low molecular weight heparin.