Transradial Approach for the Female Sex Update on the Study of Access Site For Enhancement of PCI for Women Study (SAFE-PCI for Women) Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit

Mitchell W. Krucoff, MD Contracted Research / Grant Support: Medtronic, Inc. Eli Lilly and Company Terumo Cardiovascular Systems Group OrbusNeich Medical Cordis Corporation Abbott Vascular Consulting Fees:

SAFE-PCI FOR WOMEN Principal Investigator: Sunil V. Rao MD Study Chair: Mitchell W. Krucoff MD Project Lead: William Barham RN

Background

Access sites bleeding in “real-world” PCI patients ASA Thienopyridines IIbIIIa inhibitors Anti-thrombin agents Novel anti-thrombotic agents 5.4% 12.7% Kinnaird et al Am J Cardio 2003

Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity Bleeding & 30 Day Mortality N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol. 2005

Scores Predicting Bleeding risk in PCI Mehran R, et. al. JACC 2010

Predictors of Major Femoral Bleeding N=17,901 pts from Mayo Clinic 1994-2005 Major femoral bleeding defined as hematoma > 4 cm, external bleeding requiring surgery or blood transfusion, or retroperitoneal hematoma Doyle BJ, et. al. JACC:Interventions 2008

PCI-related outcomes in women N=22,725 PCI pts in the BMC2 Registry Risk of PCI outcomes Women vs. Men Duvernoy CS, et. al. AHJ 2010

ACC-NCDR CATH-PCI Registry: USA Use of radial PCI Radial access: 1.32% Rao, S. V. et al. J Am Coll Cardiol Intv 2008;1:379-386

Transradial access and outcomes N=21 studies, 5600 patients 1.0 Transfemoral better Transradial better PCI Failure Access site crossover Death Death, CVA, or MI Major bleeding 0.27 (0.16-0.45) 0.71 (0.49-1.01) 0.74 (0.42-1.30) 3.82 (2.83-5.15) 1.31 (0.87-1.96) Jolly SS, AHJ 2008

2006 FDA – Duke/DCRI Memorandum Of Understanding (MOU) Cardiac Safety Research Consortium (CSRC) A Transparent Public-Private Partnership of Stakeholders www.cardiac-safety.org

The TREAT Initiative www.cardiac-safety.org

TransRadial Education, Assessment & Therapy: June 2010 Regulatory FDA: CDER CDRH OC OWH Societies ACC SCAI ESC SOLACI Academia Duke Harvard Cleveland Clinic Columbia Emory Wash Hrt Ctr Mayo Clinic Johns Hopkins Industry Abbott Medtronic Terumo Cordis/J&J The MEDCO Eli Lilly (Daichi) Sanofi/BMS Federal NIH AHRQ www.cardiac-safety.org

ACC National Cardiovascular Data Registries National EDC infrastructure Fully operational quality metrics (clinical enterprise) Widely vetted data fields Quality controls in place Multiple procedural & therapeutic areas www.cardiac-safety.org

National Cardiovascular Research Infrastructure (NCRI) NIH/NHLBI grant (#: 1RC2HL101512-01) PI: Robert Harrington Duke Clinical Research Institute

65% workload reduction per patient for site coordinators EDC using NCRI* extraction from ACC-NCDR: Imbedding an RCT into Ongoing Registry NCRI Data Interface Strategy 65% workload reduction per patient for site coordinators Part 11 Compliant Inform Database * Trial specific data is data that is not included in NCDR data. *NIH/NHLBI grant (#: 1RC2HL101512-01) www.cardiac-safety.org

TREAT Discussion Emphases Prospective RCT design Patient selection bias Confounding adjuncts: Anti-thrombotic therapy Vascular closure strategies Equipoise for randomization: female sex higher risk for vascular and bleeding complications Smaller, more tortuous limb vessels higher risk for bleeding even with transradial PCI

SAFE-PCI for Women Trial Structure Clinical and Data Coordinating Center - DCRI Study chair - Mitchell W. Krucoff MD, Principal Investigator - Sunil V. Rao MD DCRI Project lead – Britt Barham Sponsors Terumo Medical, Abbott Vascular, The Medicines Company, Eli Lilly others pending approval of applications Partners NIH-NCRI (David Kong, Eric Peterson, Bob Harrington), ACC, FDA Office of Women’s Health, CSRC, SCAI DSMB Spencer King (chair), Olivier Bertrand, Alexandra Lansky, Statistician TBD

Objectives: TRI vs. TFA Safety of TRI PCI in women Secondary: Procedure time, radiation dose, and contrast volume Resource use, patient preferences, and QOL Associations with 30-day death, vascular complications and repeat revascularization *If funding can be obtained

Bleeding ARC (BARC) Mehran R et al, Circulation. 2011;123:2736-2747.)

BARC Bleeding Type 2: Overt actionable type of bleeding Type 3 Does not meet criteria for Types 3, 4, or 5 Does require evaluation by a medical professional, require non- surgical intervention by a medical professional, lead to hospitalization or increased level of care Type 3 3a – Overt bleeding with hgb drop 3 to < 5 g/dl, or any transfusion 3b – Overt bleeding with hgb drop ≥ 5 g/dl, tamponade, requiring surgical intervention, requiring pressors 3c – ICH or intra-ocular Type 5: Fatal bleeding 5a – Probable fatal bleeding 5b – Definite fatal bleeding Mehran R, et. al. Circulation in press.

Primary efficacy and feasibility endpoints Efficacy – BARC Types 2, 3, and 5 bleeding or major vascular complications occurring within 72 hrs of PCI or hospital discharge, whichever comes first Vascular complications defined as: AV fistula Arterial pseudoaneurysm Arterial occlusion Primary feasibility endpoint Procedural failure – inability to complete the procedure from the assigned access site. CEC adjudication of Bleeding and vascular complication endpoints Requiring surgical intervention

Sample size assumptions and calculations Rate of primary composite endpoint in femoral arm – 8.0% Assume 50% reduction with radial approach Sample size: 1800 patients provides >90% power at 2-sided alpha=0.05

Inclusion/exclusion criteria Age > 18 years Female patient undergoing elective or urgent PCI or Undergoing diagnostic angiography to evaluate ischemic symptoms with the possibility of PCI Have capacity to sign informed consent Non-palpable radial or femoral pulses Bilateral IMA grafts Bilateral abnormal Barbeau tests Hemodialysis AV fistula or graft in arm to be used for PCI INR ≥ 1.5 Planned staged PCI within 30d of index PCI Valvular heart disease requiring surgery Planned RHC Primary PCI for STEMI

Study of Access site For Enhancing PCI for Women (SAFE-PCI for Women)* Female patient undergoing urgent or elective PCI Best background medical therapy Bivalirudin, Clopidogrel, Prasugrel 2b3a at investigator’s discretion N=1800 pts, 30 sites Sites from NCRI Patent hemostasis required Vascular closure devices allowed Radial Femoral Primary Efficacy Endpoint: BARC Types 2, 3, or 5 bleeding or Vascular Complications requiring surgical intervention Primary Feasibility Endpoint: Procedural failure Secondary endpoints: Procedure duration, total radiation dose, total contrast volume *Planned in collaboration with ACC, CSRC, FDA Office of Women’s Health

Site & Enrollment Update Active Sites: 22 Enrolling Sites: 17 Patients Randomized: 153 Patients Randomized with PCI: 49 (32%) Target Enrollment: 1800 women undergoing PCI

SAFE PCI for Women: Conclusions Female sex is associated with more bleeding and vascular complications with PCI Trans-radial PCI has potential but unproven benefits for women The SAFE-PCI for Women Study: Addresses an important public health issue with a prospective multicenter RCT Involves a unique collaboration across industry, federal agencies and professional societies Utilizes a uniquely efficient EDC strategy through combined NCDR-NCRI processes

Transradial Approach for the Female Sex Update on the Study of Access Site For Enhancement of PCI for Women Study (SAFE-PCI for Women) Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit