THE MICHELANGELO OASIS 5 PROGRAM. MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) ( )

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1 THE MICHELANGELO OASIS 5 PROGRAM MichelAngelo : The Creation of Man (Fragment of the Sistine Chapel ceiling- Detail) ( )

2 Key Steps in Coagulation Pathway Intrinsic pathway Extrinsic pathway 1 Xa IXa VIIIa Ca 2+ PL X Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin 2 Xa II Va Ca 2+ PL IIa 50 Fibrinogen Fibrin Clot 1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20): Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71 8.

3 Fondaparinux: A Synthetic Factor Xa Inhibitor Intrinsic pathway Extrinsic pathway Antithrombin AT AT AT Xa Xa Fondaparinux II IIa THROMBIN Fibrinogen Fibrin clot Adapted with permission from Turpie AGG et al. N Engl J Med. 2001;344:619.

4 Overall Efficacy of Fondaparinux vs Enoxaparin in VTE Prevention: Meta- analysis Fondaparinux better Enoxaparin better Ephesus N = % Pentathlon 2000 N = % Penthifra N = 1250 Pentamaks N = % 63.1% Overall Odds Reduction % odds reduction % P = Overall odds reduction for proximal DVT = 57.4% [CI: ]; p = 10-6 Turpie et. al. Arch Intern Med 2002: 162:

5 Exclude Age < 21 Any contra-ind to Enox Hem stroke< 12 mo. Creat> 3 mg/dl/265 umol/l Patients with NSTE ACS, Chest discomfort < 24 hours 2 of 3: Age>60, ST Segment, cardiac markers Fondaparinux 2.5 mg sc once daily PCI <6 h: h IV Fonda 2.5 mg without IIb/IIIa,, 0 with IIb/IIIa PCI> 6 h: h IV Fonda 2.5 mg with and 5.0 mg without IIb/IIIa Study Design: Randomized, Double Blind Randomize N=20,000 ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice Enoxaparin 1 mg/kg sc twice daily PCI< 6 h, h No additional UFH PCI >6 h, h IV UFH With IIb/IIIa 65 U/kg Without IIb/IIIa 100 U/kg Outcomes Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk benefit: Death, MI, refractory ischemia, major bleeds 9 days Secondary: Above & each component separately at day 30 & 6 months Hypothesis: First test non-inferiority, then test superiority

6 Completeness of Follow-up (20,078 patients) Hospital Discharge 30 day Lost to follow-up 99.96% 99.94% 20 patients (< 0.1%) Coordinating Center: Population Health Research Institute, McMaster University Hamilton, Canada

7 Baseline Characteristics Outcome No. Rand. Troponin or CKMB > ULN ECG with ischemia ST depression 1mm T wave inversion (>3 mm) Female Suspected MI w/o ST elevation Prior Heart Failure Prior MI Hypertension Diabetic Current Smoker Enox (%) Fonda (%)

8 Therapies During Initial Hospitalization No. Rand. ASA GPIIb/IIIa Inhib During PCI Clopididogrel/Ticlopidine Beta-blockers Calcium Channel Blockers ACE Inhibitors/ARB Statins Enox (%) Fonda (%) % of patients recruited from centers with cath labs

9 Days of Study Treatment Compliance and Duration % who received 1 dose of drug 99.2% No. of days of therapy Mean (SD) Enox 5.2 (2.3) Fonda 5.4 (2.4)

10 Procedures by 9 Days in Centers With or Without Cath Labs in OASIS-5 No. Centers No. Patients Angiography PCI CABG Revasc. Cath Lab+ 420 (73%) 14,028 (70%) 73.2% 39.6% 6.8% 46.1% Cath Lab- 156 (27%) 6050 (30%) 27.7% 12.5% 1.8% 14.1%

11 RESULTS

12 Primary Efficacy Outcome Death/MI/RI at Day 9 Non-inferiority Margin= P-Value for Non-Inferiority= P-Value for Superiority= Fonda Better Enox Better Hazard Ratio

13 Efficacy Outcomes at Day 9 Death/MI/RI Enox 5.8% Fonda 5.9% Non-inferiority Margin=1.185 Death/MI 4.1% 4.1% Death 1.9% 1.8% MI 2.7% 2.7% Refract Isch 1.9% 2.05% Fonda Better Enox Better Hazard Ratio

14 Death/MI/RI: Day 9 HR % CI Enoxaparin Fondaparinux Days Cumulative Hazard

15 Major Bleeding: 9 Days Cumulative Hazard HR % CI P<< Enoxaparin Fondaparinux Days

16 Bleeding Rates: Day 9 Outcome Enox (%) Fonda (%) HR (95% CI) P value No. Randomized Total Bleed ( ) << Major Bleed ( ) << TIMI Major Bleed ( ) << Minor Bleed ( ) <<0.0001

17 Categories of Major Bleeds at 9 Days Enox (No. Pts) Fonda (No. Pts) P No. Rand Total Bleeding 404 (4.0%) 215 (2.1%) << Intracranial 5 6 Surgery req d to stop bleed Retroperitoneal Hb 3 g/dl Transfusion 2 units

18 No. of Patients Receiving Transfusions No. Randomized 1 Unit 2 Units 3 Units 4+ Units Any transfusion Enox No. (%) (0.5%) 183 (1.8%) 50 (0.5%) 164 (1.7%) 444 (4.4%) Fonda No. (%) (0.3%) 129 (1.3%) 56 (0.6%) 124 (1.3%) 340 (3.4%) P<<

19 Efficacy-Safety Balance Death/MI/RI/Maj Bleed: Day 9 Cumulative Hazard Enoxaparin Fondaparinux HR % CI P<< Days

20 Efficacy Outcomes at Day 30 Enox Fonda Death/MI/RI 8.8% 8.1% Death/MI 6.9% 6.2% P=0.077 Death 3.5% 2.9% P=0.022 MI 4.2% 3.9% RI 2.3% 2.2% Strokes Death/MI/Stroke P=

21 Mortality: Day 30 Enoxaparin Cumulative Hazard Fondaparinux HR % CI P= Days

22 Major Bleeding: Day 30 Cumulative Hazard Enoxaparin Fondaparinux HR % CI P<< Days

23 Death/MI/RI/Major Bleeds: Day 30 Cumulative Hazard Enoxaparin Fondaparinux HR % CI P<< Days

24 Efficacy at 6 Months Enox Fonda P value Death/MI/RI 13.1% 12.1% Death/MI 11.2% 10.3% Death 6.3% 5.6% MI 6.3% 6.0% 0.33 Strokes 1.6% 1.3% Death/MI/Stroke 12.3% 11.1%

25 Death or MI: 6 Months Cumulative Hazard Enoxaparin Fondaparinux HR % CI P= Days

26 Mortality at 6 Months Cumulative Hazard Enoxaparin Fondaparinux HR % CI P= Days

27 Major Bleeding: 6 Months Cumulative Hazard Enoxaparin HR % CI P<< Fondaparinux Days

28 Death, MI, RI, Major Bleeding Enoxaparin at 6 Months Cumulative Hazard Fondaparinux HR % CI P<< Days

29 Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality Nonfatal MI Refractory Ischemia Major Bleeds 30 Days 9.6 ( ) 4.0 ( ) 6.5 ( ) Crude Odds Ratio for Death (95% CI) 30 to 180 Days 2.2 ( ) 1.4 ( ) 2.1 ( ) 180 Days 5.6 ( ) 2.6 ( ) 4.1 ( ) Minor Bleeds 3.0 ( ) 1.5 ( ) 2.2 ( )

30 Does the Lower Bleeding Rate at 9 Days Translate into Lower Long Term Mortality? Patients with No Bleeds Minor Bleeds Major bleeds Total: No. Bleeds Minor Bleeds Major Bleeds Total: No. Deaths at 30 Days Enox Fonda No. Deaths at 180 Days Difference (68.4%) (85.5%)

31 Efficacy & Bleeding by Cath Lab vs No Cath Lab: Day 30 Efficacy With Cath Lab No Cath Lab Bleeding With Cath Lab No Cath Lab Efficacy+Bleeding With Cath Lab No Cath Lab Interaction P Fonda better Enox better

32 Efficacy & Bleeding by Prior Heparin: Day 30 Efficacy Prior Hep No Prior Hep Bleeding Prior Hep No Prior Hep Efficacy+Bleeding Prior Hep No Prior Hep Interaction P Fonda better Enox better

33 No Heparin With Heparin Bleeds at 9 Days Based on Open Label Heparin Use in Hospital Bleeding Enox Fonda HR (95% CI) P-value Total 5.8% 2.2% 0.37 ( ) << Major 3.1% 1.3% 0.41 ( ) << Minor 2.8% 0.9% 0.33 ( ) << TIMI Major 0.9% 0.4% 0.44 ( ) < Total 10.4% 5.7% 0.54 ( ) << Major 6.5% 4.3% 0.66 ( ) Minor 4.0% 1.5% 0.37 ( ) << TIMI Major 2.4% 1.5% 0.63 ( ) 0.021

34 Early Intervention: PCI Performed < 24 hours Post PCI Events at Day 30 Enox (%) Fonda (%) HR (95% CI) P value No. Rand Death ( ) 0.88 Death/MI/RI ( ) 0.43 Major Bleeds ( ) Death/MI/Maj Bleed ( ) 0.14

35 Conclusions 1. Fondaparinux is non-inferior compared with enoxaparin at 9 days, with substantially lower rates of important bleeds. The net benefit-risk balance clearly favors fondaparinux. 2. Bleeding increases the risk of death significantly. 3. At one month and at 6 months there is a significant reduction in mortality with fondaparinux. 4. Strokes are also significantly reduced, so that there is a clear reduction in death, MI, and strokes with fondaparinux 5. Consistent results are observed in those undergoing PCI (including early PCI) and in every other subgroup examined.

36 Clinical Implications Treating 1000 NSTE ACS patients with fondaparinux instead of enoxaparin prevents: - 10 deaths or MI - 4 strokes - 25 major bleeds THE OASIS 5 TRIAL CLEARLY DEMONSTRATES THAT FONDAPARINUX IS THE PREFERRED ANTICOAGULANT FOR TREATMENT OF ACS