A randomized comparison of RadIal Vs. femorAL access for coronary intervention in ACS (RIVAL) SS Jolly, S Yusuf, J Cairns, K Niemela, D Xavier, P Widimsky, A Budaj, M Niemela, V Valentin, BS Lewis, A Avezum, PG Steg, SV Rao, P Gao, R Afzal, CD Joyner, S Chrolavicius, SR Mehta on behalf of the RIVAL Steering committee

R I V A LDisclosures Funded by: Sanofi-Aventis and Bristol-Myers Squibb (through CURRENT) Sanofi-Aventis and Bristol-Myers Squibb (through CURRENT) Population Health Research Institute Population Health Research Institute Canadian Network and Centre for Trials Internationally (CANNeCTIN, an initiative of Canadian Institutes of Health Research) Canadian Network and Centre for Trials Internationally (CANNeCTIN, an initiative of Canadian Institutes of Health Research)

R I V A L Bleeding is associated with Death and Ischemic Events Eikelboom JW et al. Circulation 2006;114(8): HR 5.37 ( ) HR 4.44 ( ) HR 6.46 ( )

R I V A L Prior Meta-analysis of 23 RCTs of Radial vs. Femoral (N=7030) Transradial betterTransfemoral better 1.0 PCI Procedure Failure Death Death, MI or stroke Major bleeding 1.31 ( ) 0.74 ( ) 0.71 ( ) 0.27 ( ) Jolly SS, et al. Am Heart J 2009;157:

R I V A L RIVAL Study Objective - To determine if Radial vs. Femoral access for coronary angiography/PCI can reduce the composite of death, MI, stroke or non-CABG major bleeding in ACS patients

R I V A L NSTE-ACS and STEMI (n=7021) Radial Access (n=3507) Femoral Access (n=3514) Primary Outcome: Death, MI, stroke or non-CABG-related Major Bleeding at 30 days Randomization RIVAL Study Design Key Inclusion: Intact dual circulation of hand required Interventionalist experienced with both (minimum 50 radial procedures in last year) Jolly SS et al. Am Heart J. 2011;161:

R I V A L Study Outcome Definitions Major Bleeding (CURRENT/ OASIS 7) Fatal > 2 units of Blood transfusion Hypotension requiring inotropes Requiring surgical intervention ICH or Intraocular bleeding leading to significant vision loss Major Vascular Access Site Complications Large hematoma Pseudoaneurysm requiring closure AV fistula Other vascular surgery related to the access site

R I V A L Final Recruitment RIVAL Stand-Alone After CURRENT N= 3190 RIVAL Total N=7,021 RIVAL sub-study during OASIS 7/CURRENT N= Follow-up complete in 99.9% CURRENT-OASIS 7. N Engl J Med. 2010;363: Mehta SR, et al. Lancet. 2010; 376:

R I V A L Participating Countries Middle East/Israel 239 Australia and New Zealand 64 North America 1614 South America 423 Asia 1117 Europe 3564

R I V A L Baseline Characteristics Radial (n =3507) Femoral (n =3514) Mean Age (years)62 Male (%) Diabetes (%) Diagnosis at presentation UA (%) NSTEMI (%) STEMI (%)

R I V A L Therapies - Initial Hospitalization Therapies - Initial Hospitalization Radial (n=3507) % Femoral (n=3514) % ASA Clopidogrel LMWH UFH Fondaparinux Bivalirudin GP IIb IIIa inhibitors PCI CABG8.88.3

R I V A L Operator Volume Procedure Characteristics Radial (n=3507) Femoral (n=3514) HR (95% CI) P value Operator Annual Volume PCI/year (median, IQR) 300 (190, 400) Percent Radial PCI ( median, IQR) 40 (25,70) PCI Success ( )0.83 Vascular closure devices used in 26% of Femoral group

R I V A L Primary and Secondary Outcomes Radial (n=3507) % Femoral (n=3514) % HR 95% CI P Primary Outcome Death, MI, Stroke, Non-CABG Major Bleed Secondary Outcomes Death, MI, Stroke Non-CABG Major Bleeding

R I V A L Other Outcomes Radial (n=3507) % Femoral (n=3514) % HR 95% CI P Death MI Stroke Stent Thrombosis * Post Hoc analysis

R I V A L Other Outcomes Radial (n=3507) % Femoral (n=3514) % HR 95% CI P Major Vascular Access Site Complications < TIMI Non-CABG Major Bleeding ACUITY Non-CABG Major Bleeding* < * Post Hoc analysis

R I V A L Other Outcomes Radial (n=3507) Femoral (n=3514) P Access site Cross-over (%) < PCI Procedure duration (min) Fluoroscopy time (min) < Persistent pain at access site >2 weeks (%) Patient prefers assigned access site for next procedure (%) 9049<0.0001

R I V A L Access Site Major Bleeds *All access site major bleeds actually occurred at femoral arterial site (in radial group due to cross-over or IABP) HR 0.50 (95% CI ) *

<75 ≥75 Female Male < >35 ≤ >142.5 Lowest Tertile Middle Tertile Highest Tertile NSTE-ACS STEMI Age Gender BMI Radial PCI Volume/year by Operator Radial PCI Volume by Centre Clinical Diagnosis Overall Radial better Femoral better Hazard Ratio(95% CI) Interaction p-value Death, MI, Stroke or non-CABG major Bleed Subgroups: Primary Outcome R I V A L

Radial better Femoral better Hazard Ratio(95% CI) High Medium Low High Medium Low High Medium Low High Medium Low High Medium Low Interaction p-value HR (95% CI) Primary Outcome Death, MI or stroke Non CABG Major Bleed Major Vascular Complications Access site Cross-over Results stratified by High*, Medium* and Low* Volume radial Centres R I V A L No significant interaction by Femoral PCI center volume Tertiles of Radial PCI Centre Volume/yr *High (>146 radial PCI/year/ median operator at centre), Medium (61-146), Low (≤60)

NSTE/ACS STEMI NSTE/ACS STEMI NSTE/ACS STEMI NSTE/ACS STEMI NSTE/ACS STEMI Radial better Femoral better Hazard Ratio(95% CI) Interaction p-value 2NRadial Femoral % Primary Outcome Death, MI or stroke Death Non CABG Major Bleed Major Vascular Complications Outcomes stratified by STEMI vs. NSTEACS R I V A L

Radial better Femoral better Hazard Ratio(95% CI) Pre-RIVAL RIVAL Combined Pre-RIVAL RIVAL Combined Pre-RIVAL RIVAL Combined Pre-RIVAL (Radial Expert Centre trials)* RIVAL (highest radial PCI centre tertile) Combined Heterogeneity p-value Radial(%) Femoral(%) Non-CABG Major Bleeds Major Vascular Access Complication Death,MI or Stroke Death, MI or Stroke (Radial Experts) Updated Meta-analysis of RCTs < P-value *Radial Expert Centres defined as centres default approach radial or known expert radial centre

R I V A LConclusion No significant difference in primary outcome of death, MI, stroke or non-CABG major bleeding No significant difference in primary outcome of death, MI, stroke or non-CABG major bleeding Rates of Primary outcome appeared to be lower in Radial group in high volume radial centres and STEMI Rates of Primary outcome appeared to be lower in Radial group in high volume radial centres and STEMI Radial had fewer major vascular complications but similar PCI success Radial had fewer major vascular complications but similar PCI success

R I V A LImplications Both radial and femoral approaches are safe and effective Both radial and femoral approaches are safe and effective The reduction in vascular complications may be a reason to use radial The reduction in vascular complications may be a reason to use radial With increasing experience the radial approach may be associated with better outcomes With increasing experience the radial approach may be associated with better outcomes

R I V A LAcknowledgements RIVAL Program Investigators from 158 sites in 32 countries Steering Committee S.S. Jolly (PI)S.R. Mehta (PI) S. Yusuf (Chair)C.D. Joyner (Adjudication Chair) S. ChrolaviciusM. Keltai A. AvezumF. Lanas A. BudajB. Lewis J. CairnsK. Niemela R. Diaz S.V. Rao V. DzavikP. G. Steg M.G. Franzosi V. Valentin C. B. Granger P. Widimsky D. Xavier DMC P. Sleight (Chair)) D. R. Holmes Jr. J.L. Anderson D.E. Johnstone D. DeMets J. Hirsh Project Office Study Team S. Chrolavicius (Project Manager) B. Jedrzejowski (Research Coordinator) M. Lawrence (Events Adjudication Coordinator) R. Manojlovic, L. Mastrangelo, E. Pasadyn, C. Agrippa, M. McClelland, (former ) C. Cramp, C. Horsman, A. Robinson, L. Blake, W. Chen, S. Diodato, A. Lehmann, T. Sovereign, L.Wasala Statisticians and Biometrics R. Afzal (IDMC-Associated) P. Gao L. Xu X. Yang E. Dai