1 Incidence, impact and preventative strategies for non- access site bleeding in the PCI patient Martial Hamon. MD. FESC University Hospital. Caen. France

Vascular Complications (%) P<0.001 For trend Doyle BJ et al. JACC Intervention 2008;1: Changing Incidence from the earliest (8.4%) to the contemporary time period (3.5%)

Doyle BJ et al. JACC Intervention 2008;1: Major Femoral Bleeding Complications After PCI Impact on Survival

Jolly S et al. Am Heart J 2009 Meta-analysis of 18 Randomized Trials Radial vs Femoral Access Impact on Major Bleeding RADIAL VS FEMORAL Favours RADIAL Favours FEMORAL Major Bleeding: 0.54% vs 2.32% (5 had no bleeding events) patients

Death,MI or Stroke Meta-analysis of Randomized Trials Radial vs Femoral Access Impact on Ischemic Outcomes Jolly S et al. Am Heart J 2009 RADIAL VS FEMORAL Favours RADIAL Favours FEMORAL Trend for reduction in composite of death.MI. stroke (2.5% vs 3.8%. P =.06)

Endpoint Measures at Day 30 Radial vs. Femoral 11.1%10.5%0.95 ( )0.62 Risk ratio ±95% CI Risk ratio ±95% CI Endpoint Net clinical outcome Ischemic composite Major bleeding Radial better Femoral better Radial (n=798) Femoral (n=11.988) OR (95% CI) adjusted p-value 7.4%8.1%1.10 ( ) %3.0%0.63 ( )0.02 ACUITY

7 ACUITY: Femoral vs. Radial Access Major or Minor Organ Bleeding Hamon M. Rasmussen LH. Manoukian SV. et al. EuroIntervention FemoralRadial Heparin+GPI Bivalirudin Major or minor organ bleeding were reduced to a similar extent in patients treated with bivalirudin alone compared to heparin plus a GPI and were present with both femoral access (4.1% vs 7.4% respectively. p<0.0001) and radial access (4.9% vs 7.2% respectively. p=0.26). 7.4% 4.1% 7.2%4.9%

ACUITY 30Days TRITON 3Days EARLY ACS 120hours SYNERGY 30Days OASIS 5 9days ABOARD 30Days Early Non-CABG Major Bleeding in ACS Trials in PCI-Treated Patients 88% Femoral Access 84% Radial Access Percent Protocol Major Bleed

9 Bleeding definitions Variation in definitions Intracranial hemorrhage Retroperitoneal hemorrhage Bleeding with 5g/dL fall in hemoglobin Bleeding with 3g/dL fall in hemoglobin 4g/dL fall in hemoglobin without site Blood transfusion  3 units TIMI Major TIMI Minor Gross hematuria or hematemesis Lincoff et al. JAMA 2003

Beyond Access Site Bleeding: Incidence, Sources, and Impact of Antithrombotic Therapy in the PCI Patient A Combined Analysis of 17,393 Patients REPLACE-2, ACUITY and HORIZONS-AMI Beyond Access Site Bleeding: Incidence, Sources, and Impact of Antithrombotic Therapy in the PCI Patient A Combined Analysis of 17,393 Patients REPLACE-2, ACUITY and HORIZONS-AMI Freek W.A. Verheugt, Steven R. Steinhubl, Martial Hamon, Harald Darius, Ph. Gabriel Steg, Marco Valgimigli, Steven P. Marso, Sunil V. Rao, Anthony H. Gershlick. Onze Lieve Vrouwe Gasthuis, Amsterdam

Bleeding Definitions - 30-day Endpoint 1.Protocol Major (different between REPLACE-2 and ACUITY, HORIZONS) 2.TIMI Major 3.TIMI Minor 4.TIMI Major + Minor 1.Protocol Major (different between REPLACE-2 and ACUITY, HORIZONS) 2.TIMI Major 3.TIMI Minor 4.TIMI Major + Minor

Purpose 1.To identify the incidence and source of bleeding events unrelated to access site among over 17,300 patients undergoing a PCI for a wide variety of clinical diagnoses. 2.Evaluate the impact of antithrombotic therapy (bivalirudin versus heparin + GPIIb/IIIa antagonist) on the occurrence of bleeding unrelated to the access site. 1.To identify the incidence and source of bleeding events unrelated to access site among over 17,300 patients undergoing a PCI for a wide variety of clinical diagnoses. 2.Evaluate the impact of antithrombotic therapy (bivalirudin versus heparin + GPIIb/IIIa antagonist) on the occurrence of bleeding unrelated to the access site.

Analysis Population: All PCI patients (ITT) from: REPLACE-2N = 6,002 ACUITYN = 7,789 HORIZONSN = 3,602 TotalN = 17,393* * For primary antithrombotic comparisons the GPIIb/IIIa antagonist + bivalirudin arm (n=2609) of ACUITY was excluded, leaving a total of 14,784 patients.

Patient Demographics – N=17,393 Age (years) Age ≥ 75 years (%) Weight (kg) Female (%) Diabetes (%) Current Smoker (%) CrCl < 60 Baseline Diagnosis STEMI NSTEMI Unstable Angina Stable Angina Other 62.3 ± % 85.6 ± % 25.1% 32.3% 17.0% 20.7% 30.0% 29.5% 8.6% 11.2%

Sources of Bleeding 1.Access Site Only 2.Both Access and Non-Access 3.Non-Access Site Only 4.No Identified Location 1.Access Site Only 2.Both Access and Non-Access 3.Non-Access Site Only 4.No Identified Location Location of bleeds were determined post hoc using investigator-identified location and without knowledge of randomized therapy. Intracranial Intraocular Gastrointestinal Genitourinary Pleural Pulmonary Head and Neck Epistaxis Hemoptysis Hematemasis Gingival Other

Sources and Incidence of TIMI Bleeding Among 17,393 PCI Patients 5.3% (n=925) of the study population experienced a TIMI (Major + Minor) bleeding event. Access-site only bleeds occurred in 357 (39.6%) of patients. Bleeding events not limited to the access site occurred in 568 (60.4%) of patients.

Figure 2 Incidence and Location of Bleeding Events Excluding Access Site

Adjusted Relative Risk of 1-Year Mortality Based on TIMI Bleeding Source Compared to No Bleeding P< for all bleeding versus none

Impact of Randomized Antithrombotic Therapy: All Bleeding Sources RR=0.52 P< RR=0.55 P< RR=0.55 P<0.0001

Relative RiskP-Value Access0.45< All Non-Access0.62< Both0.31< Non-Access Only No Location Bivalirudin betterHep + GPI better Figure 3 Impact of Randomized Antithrombotic Therapy on TIMI Major + Minor Bleeding by Source

Hep + GPI (%) Bivalirudin (%) Relative Risk Intracranial GI GU HEENT Pulmonary Other No Location All Non-Access Hep + GPI betterBivalirudin better Impact of Randomized Therapy on TIMI Bleeding by Location Exclusive of Access Site

Conclusions 1.Two-thirds of PCI patients with a TIMI bleed unrelated to the access site. 2.Bleeding, irrespective of the source, significantly associated with increased mortality at 1 year. 3.Non-access-related bleeding associated with double the risk of mortality compared to access bleeding. 4.The use of bivalirudin during a PCI associated with ~40% reduction in non-access site bleeding compared with heparin + a GPIIb/IIIa antagonist. 1.Two-thirds of PCI patients with a TIMI bleed unrelated to the access site. 2.Bleeding, irrespective of the source, significantly associated with increased mortality at 1 year. 3.Non-access-related bleeding associated with double the risk of mortality compared to access bleeding. 4.The use of bivalirudin during a PCI associated with ~40% reduction in non-access site bleeding compared with heparin + a GPIIb/IIIa antagonist.

23 Risk Factors For Bleeding in ACS Patients Patient relatedProcedural relatedTreatment related  Female gender  Older  Hypertension  Obesity  Low weight  Renal failure  Low platelet count. pre-existing aneamia  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  Alternative: 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 Antithrombotic Agents (Bivalirudin. Fondaparinux) Identification of Risk Factors For Bleeding in ACS Patients and Preventive actions Hamon M. et al. EuroIntervention 2007 Identification Prevention

24 PCI in ACS: Choice of Access Site 1. Radial Access Feasible? 2. Consider Bleeding risk? Radial Access Consider bleeding risk Femoral Access Adjunctive therapy needed? YESNO 3. Consider Ischemic Risk? LOW HIGHLOW HIGH Default radial operators Am J Cardiol 2009 Hamon et al. BivalirudinBivalirudin or GPI