Efficacy and Safety of Fondaparinux in Elderly Patients With ST-Segment Elevation Myocardial Infarction: Data From the OASIS 6 Trial Ron J.G. Peters, MD Cardiologist Department of Cardiology University of Amsterdam Amsterdam, Netherlands

Efficacy and safety of fondaparinux in elderly patients with STEMI results of the OASIS 6 trial RJ Peters, C Joyner, JP Bassand, R Afzal, S Chrolavicius, JW Eikelboom, SR Mehta, Fox KAA, S Yusuf, For the OASIS 6 investigators

Disclosure Funded by Organon, Sanofi-Aventis, GSK All authors have received grants and honoraria from these companies and from several others

Fondaparinux: Mechanism of Action Intrinsic pathway Extrinsic pathway Antithrombin AT AT AT Xa Xa Fondaparinux II IIa THROMBIN Recycled Fibrinogen Fibrin clot Turpie AGG et al. N Engl J Med. 2001;344:619.

OASIS 6: Randomized, Double Blind, Double Dummy 12,000 Patients with STEMI < 12 h of symptom onset Inclusion: ST   2 mm prec leads or  1 mm limb leads Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo. Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late) Stratification UFH not indicated UFH indicated In the ISAR-REACT study, patients (N=2,159, mean age 66 years) received 600 mg clopidogrel at least 2 hours before a PCI procedure with aspirin and a heparin bolus of 70 U/kg. They were then randomized to either abciximab (bolus 0.25 mg/kg, infusion 0.125 mg/kg/min for 12 hours) or a placebo infusion. Thereafter, all patients received clopidogrel 75 mg twice daily until discharge and then 75 mg clopidogrel daily for at least 4 weeks along with aspirin (100 mg/d). All patients had symptomatic coronary artery disease, but patients with acute coronary syndromes and other patients considered to be at high risk were excluded.* *High-risk exclusion criteria: acute coronary syndromes; acute myocardial infarction within 14 days, ST-segment depression, positive biomarkers, insulin-dependent diabetes, chronic total occlusions, ejection fraction  30%, thrombus and lesions in bypass grafts. Schömig A, Mehilli J, Dotzer F, et al. ISAR-REACT: glycoprotein IIb/IIIa inhibition with abciximab in patients undergoing coronary stenting after pretreatment with a high loading dose of clopidogrel: a multicenter, randomized, double blind, placebo-controlled trial. Presented at: 52nd Annual Scientific Session of the American College of Cardiology; March 30-April 2, 2003; Chicago, Ill. Randomization Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH

Primary Efficacy Outcome Death/MI at 30 Days 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.86 95% CI 0.77-0.96 P=0.008 0.04 0.02 0.0 3 6 9 12 15 18 21 24 27 30 Days

Primary Efficacy Outcome Death/MI at 30 Days No. of Events (%) Control Fonda HR 95% CI P No. of Patients 6056 6036 Death or Re-MI 11.2 9.7 0.86 0.77-0.96 0.008 Death 8.9 7.8 0.87 0.77-0.98 0.026 Reinfarction 3.0 2.5 0.81 0.65-1.01 0.057

Death at Study End (3 or 6 months) 0.12 UFH/Placebo 0.10 Fondaparinux 0.08 0.06 Cumulative Hazard HR 0.88 95% CI 0.79-0.99 P=0.029 0.04 0.02 0.0 18 36 54 72 90 108 126 144 162 180 Days

Efficacy of Fondaparinux by Strata on Death/MI at Study End No. of Events (%) Control Fonda HR 95% CI Stratum I (n = 5658) (Fonda vs. Placebo) 17.3 15.9 0.87 0.76-0.99 Stratum II (n = 6434) (Fonda vs. UFH) 12.7 11.2 0.88 0.76-1.02

Pre-Specified Subgroup Analyses Death or MI at 30 days Interaction P value N UFH/Placebo Fonda Overall 12092 11.2% 9.7% Initial Reperfusion Rx 0.04 None 2867 15.1 12.2 Thrombolytic 5436 13.6 10.9 Primary PCI 3789 4.9 6.0 GRACE Risk Score 0.03 < 112 5958 4.3 4.6 >=112 6134 18.0 14.5 0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0 Fonda better UFH/Plac better Hazard Ratio

Severe Hemorrhage definition Fatal Intracranial Cardiac tamponade Clinically significant hemorrhage with decrease Hb > 5 gm/dl with each unit of transfusion counting for 1 gm/dl Hb

Severe Hemorrhage at 9 Days No. of Events Control Fonda HR 95% CI P Severe Hemorrhage 79 (1.3%) 61 (1.0%) 0.77 0.55-1.08 0.13 Fatal 49 35 0.72 0.47-1.10 ICH 10 11 1.10 0.47-2.60 0.82 Retroperitoneal 2 - Cardiac Tamponade 48 28 0.59 0.37-0.93 0.02 Hg drop ≥ 5 g/dL 17 19 1.12 0.58-2.15 0.74

Severe Hemorrhage by type of reperfusion therapy at 180 Days No. of Events Control Fonda HR 95% CI P None 1.8% 1.6% 0.84 0.47-1.50 0.55 Thrombolytics 2.3% 0.66 0.44-0.98 0.04 Primary PCI 1.0% 1.2% 1.18 0.63-2.22 0.60

Death and Net Clinical Benefit at Study End Death/MI/Stroke/ Severe Hemorrhage HR (95% CI) P No Reperfusion 0.84 (0.69-1.01) 0.06 0.81 (0.69-0.96) 0.016 Thrombolytic 0.85 (0.73-0.99) 0.04 0.83 (0.73-0.95) 0.007 1o PCI 1.09 (0.83-1.44) 0.52 1.12 (0.90-1.39) 0.29 Overall 0.88 (0.79-0.99) 0.029 (0.80-0.97) 0.009

Elderly patients with STEMI Higher risk of adverse outcome Higher risk of bleeding with thrombolytics Higher risk of bleeding with anticoagulants Net clinical outcome not predictable

Elderly patients in OASIS 6 methods Post hoc analysis  ≥ 75 years versus < 75 years Primary endpoints as in main study Net clinical benefit: death, MI, severe hemorrhage at 30 days

Death and MI at 30 days ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr

Death and MI at 30 days ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr

Severe hemorrhage at 30 days

Death/MI/sev.hemorrhage Net clinical benefit Death/MI/sev.hemorrhage Control Fonda difference HR <75 10.0% 8.6% 1.4% 0.85 (0.74-0.97) >= 75 25.6% 22.5% 3.2% 0.87 (0.72-1.05)

conclusions In patients with STEMI who are not treated with PPCI: The efficacy and safety of fondaparinux as compared to control treatment are consistent across age groups Consequently, the net clinical benefit of fondaparinux is consistent across age groups

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