Are Benefits of Fondaparinux Maintained According to Various Procedural Strategies? Insights from OASIS 5 Martial Hamon, MD, FESC University Hospital of Caen Normandy, France

Pooled Relative Risks of Mortality Increase* Random-effects Meta-analysis of 10 Studies Hamon M. et al. EuroIntervention 2007 Prognostic Impact of Major Bleeding in Patients With Acute Coronary Syndromes A Systematic Review and Meta-analysis (*in hospital or 30-Day) Total (95% CI) 450/ / [ ] Study Major Bleeding No Major Bleeding RR (95% CI) Ali et al /89 24/ [ ] Eikelboom et al / / [ ] Feit et al /194 9/ [ ] Kinnaird et al /588 54/ [ ] Lenderink et al /98 120/ [ ] Manoukian et al / / [ ] Moscucci et al / / [ ] Rao et al / / [ ] Segev et al /79 86/ [ ] Yusuf et al / / [ ] Test for overall effect: Z = (P < ) Lower Mortality Higher Mortality Deaths. No. / Patients. No. RR (95% CI) Random Effects Model N= patients Major Bleeding 2.7%

Entry site complications: Radial vs Femoral Meta-analysis of randomized studies Pooled Relative Risks of Access site complications Decrease* Random-effects Meta-analysis of 17 Studies Adapted and updated from Agostoni et al J Am Coll Cardiol 2004 Study Radial Femoral RR (random) n/N 95% CI ACCESS 0/300 6/ [ ] Achembach 0/152 4/ [ ] BRAFE Stent 1/56 3/ [ ] CARAFE 0/140 2/ [ ] FARMI 2/57 11/ [ ] Gorge 1/214 1/ [ ] Grinfeld 0/138 3/ [ ] Mann /76 4/ [ ] Mann /74 3/ [ ] Moriyama 0/108 3/ [ ] OCTOPLUS 3/192 12/ [ ] OUTCLAS 0/322 1/ [ ] RADIAL-AMI 1/25 1/ [ ] RADIAMI 0/50 3/ [ ] Reddy 0/25 1/ [ ] TEMPURA 0/77 2/ [ ] Tian 0/189 2/ [ ] Total (95% CI) 8/ / [ ] Test for overall effect: Z = 5.09 (P < ) Favours Radial Favours Femoral Incidence: 0.36% vs 2.9% RR 0.22 [ ]. 78% reduction NNT 39

PCI Population in Oasis 5 during treatment period (Access sub-study analysis) 5565 PCI patients* 4971 Femoral access594 Radial access 2519 Fondaparinux2452 Enoxaparin319 Fondaparinux275 Enoxaparin * Patients randomized and that got treatment up to discharge or up to 8 days * Patients with deferred PCI, brachial access or whose records lacked access-site information excluded Impact of TRI on efficacy and bleeding in ACS patients treated with a contemporary pharmacological regimen? Post hoc analysis to examine the impact of the TRA vs TFA on PCI- related: major bleeding and patients’outcomes

Baseline Clinical Characterstics 70% 75% 24% 20% 7% 7% 22% 17% % 15% 9% 4% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% Male*Diabetes*Heart FailurePrior MI*Prior PCIPrior CABG* Femoral = 4971 Radial = 594 *p<0.05 TFA 89% and TRA 11%

Similar High-risk Features in both Femoral and Radial access groups Troponin Positive ST Depression > 1mm 68.1% 43.8% 71.9% 41.6% 0% 10% 20% 30% 40% 50% 60% 70% 80% FemoralRadial

Treatment Recommendations 1 and Oasis 5 PCI Patients 1.ESC Guidelines for the management of NSTEACS Eur Heart J 2007;28: [P<0.05 for ACEI and GPI]

High revascularization success rate whatever the vascular access 7944 lesions 7095 with femoral access849 with radial access 3585 under Fondaparinux3510 under Enoxaparin460 under Fondaparinux389 under Enoxaparin 92.1%91.7%93.7%94.6%

91.6% 92.9% 70.7% 70.5% 25.4% 30.0% 8.4% 7.1% Any stentBare stentDrug Eluting Stent*No Femoral = 7095 Radial = 849 Procedural Details Stenting by Access site Percutaneous coronary interventions (analysis per lesion) *P<0.05

Most PCI’s performed within 72 hours At day 3: 75% in femoral group At day 3: 71% in radial group % PCI per day

Endpoint Measures at Day 9 Radial vs. Femoral 11.4%8.6%0.74 ( )0.043 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=594) Femoral(n=4971) HR (95% CI) p-value 8.5%7.9%0.93 ( ) %1.0%0.27 ( )

Endpoint Measures at Day 30 Radial vs. Femoral 12.8%9.1%0.70 ( )0.013 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=594) Femoral(n=4971) HR (95% CI) p-value 9.5%8.4%0.88 ( ) %1.2%0.28 ( )<

Endpoint Measures at 6 months Radial vs. Femoral 15.9%11.1%0.69 ( )0.003 Hazard ratio ±95% CI Hazard ratio ±95% CI Endpoint Net clinical outcome Death/MI/RI Major bleeding Radial better Femoral better Radial(n=594) Femoral(n=4971) HR (95% CI) p-value 12.3%10.1%0.82 ( ) %1.5%0.31 ( )<

Endpoint Measures: Radial vs Femoral Death, MI, RI* *Primary endpoint of the study 8.5% 9.5% 12.3% 7.9% 8.4% 10.1% 0% 2% 4% 6% 8% 10% 12% 14% day 9day 30day 180 FemoralRadial Death, MI, RI

Mortality at 6 Months Radial vs. Femoral HR % CI [ ] p=0.09 Days Cumulative Hazard Non-adjusted: HR 0.68 [ ] p= % 2.4% NNT~100 Femoral Radial

Primary endpoint: Death, MI, RI in PCI patients at Day 9 P = 0.77P = 0.47 (N=275)(N=319)(N=2452)(N=2519) HR % CI [ ] (during blind study drug administration) HR % CI [ ] 8.0%7.8% 8.2%8.8%

P = 0.85P <0.001 (N=275)(N=319)(N=2452)(N=2519) HR % CI [ ] (during blind study drug administration) HR % CI [ ] 1.1% 0.9% 5.1% 2.3% Protocol Major Bleeding in PCI patients at Day 9

5595 patients GPI (43%) GPI (57%) 1173 Enoxaparin 1224 Fondaparinux 1568 Enoxaparin 1630 Fonaparinux GPI’s use in PCI patients Endpoints Measures at day 9 during blind study drug administration Major Bleeding HR 0.51 (95% CI, ) P=0.002 GPI+GPI- p=<0.001 Major Bleeding HR 0.37 (95% CI, ) EnoxaparinFondaparinux

5565 patients GPI (43%) GPI (57%) 2057 femoral 332 Radial 2914 Femoral 262 Radial P=0.02 GPI+ GPI- P=0.08 P=0.03 P=0.08 GPI’s use in PCI patients Endpoints Measures at day 9 Comparing Radial vs Femoral FemoralRadial

Conclusions Insights from OASIS 5 I.Most PCI’s in NSTE-ACS patients are currently performed within 72 hours of admission by trans-femoral approach (TFA). is associated with similar rates of ischemia and significant reduction of major bleeding, leading to better net clinical outcome. I.Compared to TFA, TRA is associated with similar rates of ischemia and significant reduction of major bleeding, leading to better net clinical outcome. I.Wether TRA by reducing major bleeding can impact event-free survival warrants a randomized trial adequately powered. OASIS 5 access sub-study: post’hoc analysis (non randomised), hypothesis-generating analysis rather than hypothesis-testing. II.A fondaparinux strategy: - Provides similar rates of ischemia compared to Enoxaparin either by TRA or TFA - Reduces major bleeding and Improves net clinical outcome in TFA compared to an enoxaparin based regimen with or without GPI. Modifiable factors : Arterial access site & Antithrombotic regimen

Risk Factors For Bleeding in ACS Patients Patient relatedProcedural relatedTreatment related  Female gender  Older  Hypertension  Obesity  Low weight  Renal failure  Platelet low count  Medical history (GI disease)  Puncture site (femoral vs radial)  Level of puncture (femoral)  Larger arterial sheath  Prolonged sheath time  IABP placement  Concomitant venous sheath  Need for repeat intervention  Over anticoagulation  Type of anticoagulation (antiXa, direct thrombin inhibtor or LMWH and UFH)  GP IIb/IIIa inhibitors  Thrombolytic Reducing Bleeding Risk: Preventive Actions Patient levelProcedural levelTreatment level  Patient information (coughing, heavy lifting to be avoided after femoral puncture)  Nurse training for early recognition of retroperitoneal hemorrhage  Perfect puncture site  Angiographic control before closure device use  Radial Access  Different access sites for staged procedures  Decrease size of arterial sheath  ACT during procedures for anticoagulation monitorring  Discontinuation of antithrombin after uncomplicated PCI  New anticoagulant agents (Bivalirudin, Fondaparinux) Identification of Risk Factors For Bleeding in ACS Patients and Preventive actions Hamon M. et al. EuroIntervention 2007 Identification Prevention