Seeking the Optimal Upstream Therapy for Patients with ACS: Fondaparinux- Low Bleeding Rate and Low Cost Sanjit S. Jolly MD, Interventional Cardiologist, Hamilton Health Sciences, McMaster University, Hamilton, Canada

Disclosures Received Grant Support from Medtronic Received Speakers honoria from GlaxoSmithKline, Sanofi-Aventis, Astra-Zeneca, Boehringer Ingelheim

Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS Patients GRACE Registry in 24,045 ACS patients *After adjustment for comorbidities, clinical presentation and hospital therapies **p<0.001 for differences in unadjusted death rates OR (95% CI) 1.64 (1.18 to 2.28*) Overall ACS UA NSTEMI STEMI 10 20 30 ** 5.1 18.6 3.0 16.1 5.3 15.3 7.0 22.8 In-hospital death (%) In hospital major bleeding Yes No 40 Moscucci et al. Eur Heart J 2003;24:1815-23 3

Strong, Independent Association Between Bleeding and Death, MI and Stroke OASIS Registry, OASIS-2, CURE N = 34,126 Outcome Major Bleed No Major Hazard (Adjusted) P- Value Death 60/470 (12.8%) 833/33676 (2.5%) 5.37 (3.97-7.26) <0.0001 MI 46/436 (10.6%) 1375/33710 (4.1%) 4.44 (3.16-6.24) Stroke 12/469 (2.6%) 187/33677 (0.6%) 6.46 (3.54-11.79) Eikelboom JW et al. Circulation 2006;114(8):774-82. 4

Fondaparinux has Highly Predictable Activity Fondaparinux concentration (µg/mL) Inhibition of thrombin generation (%) 10 20 30 40 50 60 70 1.5 3 4.5 6 7.5 Linear, dose-dependent inhibition of ex vivo thrombin generation in human platelet-depleted plasma Lormeau JC, Herault JP. Thromb Haemost 1995;74:1474–7

The OASIS 5 Study OASIS 5 N Engl J Med 2006;354:1464-76

OASIS 5: A Randomized, Double-Blind, Double-Dummy Trial 20,078 Patients with NSTE ACS, Chest discomfort < 24 hours 2 of 3: Age>60, ST Segment Δ,  cardiac markers Exclude Age < 21 Any contra-ind to Enox Hem stroke< 12 mo. Creat> 3 mg/dL/265 umol/L Aspirin, Clopidogrel, GPIIb/IIIa inhibitor, planned Cath/PCI as per local practice Randomization Fondaparinux 2.5 mg subcut daily up to 8 days or hospital discharge Enoxaparin 1 mg/kg subcut bid for 2-8 days 1 mg/kg subcut daily if ClCr<30mL/min Mean treatment : 5.4 days Mean time to PCI: 2.4 days Mean treatment : 5.2 days Mean time to PCI: 2.6 days Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 OASIS 5 Investigators. N Engl J Med2006;354: 1464-76

Majority of Patients Undergoing Catheterization Went Early OASIS 5 N = 14,206 50 44.2% 45 38.4% 40 35 30 25 Patients (%) 17.4% 20 15 10 5 <24 hrs 24-48 hrs >48 hrs Mehta SR. JACC. 2007;in press

Fondaparinux was Non-Inferior to Enoxaparin at Day 9 (Primary Efficacy) OASIS 5 Death/MI/RI Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06 1 2 3 4 5 6 7 8 9 Enoxaparin Fondaparinux HR: 1.01 95% CI: 0.90-1.13 P non-inferiority: 0.007 OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Fondaparinux Halved Major Bleeding versus Enoxaparin at Day 9 OASIS 5 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 1 2 3 4 5 6 7 8 9 HR: 0.52 95% CI: 0.44-0.61 p<0.0001 Enoxaparin Fondaparinux 4.1 % 2.2 % 48% relative risk reduction OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Fondaparinux Significantly Reduced Mortality vs. Enoxaparin at Day 30 OASIS 5 0.04 3.5 % 17 % RRR Enoxaparin 0.03 2.9 % Fondaparinux Cumulative Hazard 0.02 HR: 0.83 95% CI: 0.71-0.97 p=0.02 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Days Fondaparinux: 295 deaths Enoxaparin: 352 deaths OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Lower Rate of Ischemic Events at 6 Months with Fondaparinux OASIS 5 0.8 1 1.2 11.3% 12.5% Death/MI/Stroke 12.3% 13.2% Death/MI/RI 1.3% 1.7% Stroke 6.3% 6.6% MI 5.8% 6.5% Death 10.5% 11.4% Death/MI 0.06 0.05 NS 0.04 0.007 P value Fondaparinux better Enoxaparin better Enoxaparin Fondaparinux Hazard Ratio OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

OASIS 5 Investigators. N Engl J Med 2006;354:1464-76 The Reduction in Major Bleeding was Consistent in Almost All Categories OASIS 5 Major bleeding at day 9 Enoxaparin (No. patients) Fondaparinux (No. Patients) p value No. Randomized 10,021 10,057 Total Major Bleeds 412 (4.1%) 217 (2.2%) <0.001 Intracranial 7 NS Requiring surgery to stop bleeding 77 41 Retroperitoneal 37 9 Transfusion 287 164 Associated with death at study end 79 38 OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Days after Randomization Major Bleeding in PCI Patients According to the Day after Randomization. OASIS 5 Days after Randomization Fondaparinux N=3105 Enoxaparin N=3072 Relative Risk P value Same day 0.2 0.5 0.35 0.037 1 0.7 1.7 0.40 <0.001 2 1.1 2.8 3 1.4 3.6 4 4.0 0.42 5 1.8 4.3 6 2.0 4.7 7 2.2 5.0 0.43 8 2.4 0.45 Mehta SR., et al .JACC. 2007;50:1742-51.

Background: OASIS 5 Fondaparinux vs Background: OASIS 5 Fondaparinux vs. Enoxaparin in ACS patients undergoing PCI (n=6177) Outcome Day 9 Enox N = 3072 Fonda N = 3105 HR P value Death, MI or Stroke 6.2 6.3 1.03 0.79 Major Bleeding 5.1 2.4 0.46 <0.00001 Catheter Thrombosis 0.4 0.9 3.59 0.001 Data from OASIS 5, that unfractionated heparin may prevent catheter thrombosis but optimal dose uncertain FUTURA trial was designed to determine the optimal regimen of heparin to prevent catheter thrombus and ischemic events in fondaparinux treated patients,without increasing bleeding. Mehta SR., et al .JACC. 2007;50:1742-51 Mehta SR, et al. Circulation, 2008;118:2038-46

Does additional UFH eliminate catheter thrombus Schlitt A, et al. Coron Artery Dis 2008. 19:279-284.

UFH added to Fonda eliminate thrombus formation within catheter Schlitt A, et al. Coron Artery Dis 2008. 19:279-284.

How much heparin to use for PCI in patients treated with fondaparinux? Low vs. Standard Dose Unfractionated Heparin for PCI: the FUTURA/OASIS 8 How much heparin to use for PCI in patients treated with fondaparinux? First large scale RCT of heparin dose during PCI

Coronary Angiography/PCI to be performed within 72 hours Study Design Adjunctive therapy during PCI NSTEACS Fonda 2.5 mg sc Angio No PCI 30 Day Follow-Up Angio with PCI R Std Dose UFH (85 U/kg or 60 U/kg with GP IIb/IIIa) ACT guided* Low Dose UFH (50 U/kg irrespective of GP IIb/IIIa) – without ACT Coronary Angiography/PCI to be performed within 72 hours Double Blind With at least 2 of following: Age>60 elevated biomarkers ECG changes Patients were not eligible if required urgent coronary angiography (<120 min) due to clinical instability Registry *ACT Targets consistent with current guidelines

Standard dose UFH during PCI as per guidelines is recommended Standard Dose UFH (n=1002) Low Dose UFH (n=1024) OR 95% CI P Peri-PCI Major, Minor bleed and vascular complications 5.8% 4.7% 0.80 0.54-1.19 0.27 Peri-PCI major bleeding, death, MI, TVR 3.9% 1.51 1.00-2.28 0.05 Death, MI, TVR 2.9% 4.5% 1.58 0.98-2.53 0.06 Catheter thrombosis 0.1% 0.5%* 4.91 0.57-42.1 0.15 * One event occurred during coronary angiography after randomization

Comparison to OASIS 5 Major Bleeding (<48 h of PCI) Adjusted Major bleeding rate (95% CI) OASIS 5 PCI Fondaparinux Major bleeding OASIS 5 PCI Enoxaparin FUTURA standard dose UFH 1.1% (0.6-2.1) 1.5% 3.6% low dose UFH 1.2% (0.6-2.2) Unfractionated heparin + fondaparinux does not increase peri-PCI major bleeding with rates apparently lower than when enoxaparin is used.

Conclusions The benefits and safety of fondaparinux are preserved with adding UFH for PCI UFH as per guidelines eliminates catheter thrombus Fondaparinux can be used seamlessly in the cath lab now

Fondaparinux is simpler and cheaper Enoxaparin Fondaparinux Cost (red book) $35-40/day* $14/day Regimen Twice daily Once daily Formulation Animal Byproducts Synthetic Dose Adjustment needed in elderly and renal dysfunction Not necessary

Summary Fondaparinux is simple Fondaparinux is safer : Single dose 2.5 mg sc daily Fondaparinux is safer : lower mortality and lower bleeding compared to enoxaparin Fondaparinux is less expensive