1. Results From The Minimizing Adverse Haemorrhagic Events By Transradial Access Site And Systemic Implementation of Angiox-MATRIX Access Program M. Valgimigli, MD, PhD Erasmus MC Rotterdam, The Netherlands on behalf of the MATRIX Group NCT01433627

2. I, Marco Valgimigli, have received: Institutional research grant from Medtronic and The Medicines Company/Terumo (current study) honoraria for lectures/advisory board from Merck, Correvio, Astra Zeneca, The Medicines Company, St Jude, Abbott Vascular, Alvimedica and Terumo.

3. Background Compared with the femoral, the radial artery is more superficial and has a smaller calibre. This characteristic makes access site haemostasis more predictable, but the procedure itself technically demanding Previous studies have come to differing conclusions with regards to the role of radial access in reducing adverse outcomes in patients with ACS It remains unclear whether avoiding access site bleeding and vascular complications through routine transradial intervention improves outcomes in unselected patients with ACS undergoing invasive management

4. 1:1 1:1 NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker Trans-Femoral Access Heparin ±GPI Bivalirudin Mono-Tx Stop Infusion Prolong≥ 6 hs infusion 1:1 Trans-Radial Access MATRIX Access Q: Is TRI superior to TFI ? MATRIX Program registered at ClinicalTrials.gov, number NCT01433627 Am Heart J. 2014 Dec;168(6):838-45.e6.

5. Study Organization and Sites Sponsor Clinical Event Committee P. Vranckx, Chair S. Leonardi Co-Chair P. Tricoci Gruppo Italiano Studi Emodinamica Grant suppliers: The Medicines Company and Terumo Principal Investigator: Marco Valgimigli, MD, PhD Study Director: Maria Salomone. MD, PhD 78 Sites across 4 EU countries recruited patients Statistical Committee (CTU) P.Jüni, MD, Chair M. Rothenbühler Dik Heg National Coordinating Investigators and CROs Paolo Calabrò, MD, PhD, Italy; Trial Form Support Arnoud W J van‘t Hof, MD, The Netherlands; Trial Form Support Manel Sabate’, MD, PhD, Spain; FLS-Research Support Elmir Omerovic, MD, PhD, Sweden; Gothia Forum Data Mng E. Frigoli, Eustrategy Project Leader

6. Executive Committee Steering Committee Committee Members Marco Valgimigl, (PI and Chair), Andrea Gagnor; Paolo Calabrò, Paolo Rubartelli, Stefano Garducci, Giuseppe Andò, Andrea Santarelli, Mario Galli; Roberto Garbo; Ezio Bramucci; Salvatore Ierna, Carlo Briguori, Bernardo Cortese; Ugo Limbruno, Roberto Violini; Patrizia Presbitero; Nicoletta de Cesare; Paolo Sganzerla; Arturo Ausiello; Paolo Tosi; Gennaro Sardella; Manel Sabate’; Salvatore Brugaletta. Giovanni Saccone; Pietro Vandoni, Antonio Zingarelli; Armando Liso; Stefano Rigattieri, Emilio Di Lorenzo, Carlo Vigna; Cataldo Palmieri; Camillo Falcone, Raffaele De Caterina, Marcello Caputo; Giovanni Esposito; Alessandro Lupi; Pietro Mazzarotto, Fernando Varbella; Tiziana Zaro; Marco Nazzaro; Sunil V. Rao, Arnoud WJ van‘t Hof; Elmir Omerovic.

7. MATRIX Access Cumulative enrollment by month 8,404 8,404 patients with ACS undergoing coronary angiography ± PCI from 11 th Oct 2011 to 7 th Nov 2014 Operator Eligibility Criteria: Interventional cardiologist expertise in TRI and TFI including at least 75 transradial coronary interventions and at least 50% of interventions performed via radial route in the year preceding site initiation Complete follow-up to 30 days available in 4183 (99.7%) of radial and 4191 (99·6%) of femoral cohorts Am Heart J. 2014 Dec;168(6):838-45.e6.

8. Patient Eligibility UA/NSTEMI New or worsening ischaemia, occurring at rest or with minimal activity within 7 days AND At least 2 high-risk criteria: Age > 60 High Tp T I or CK-MB ECG changes suggesting ischemia STEMI Chest pain for >20 min with ST-segment elevation ≥1 mm in two or more contiguous leads, or with a new left LBBB or true posterior myocardial infarction AND Admission <12 hs OR Between 12 and 24 hs with evidence of continuing ischemia or lysis Of note: Cardiogenic shock, severe PVD and prior CABG were eligible

9. Key Exclusion Criteria LMWH in the previous 6 h Glycoprotein IIb/IIIa inhibitors in the previous 3 days Any PCI performed in the previous 30 days Of note: Cardiogenic shock, severe PVD and prior CABG were eligible

10. Endpoints The MATRIX Access program had two pre-specified primary superiority endpoints at 30 days: MACE: composite of death, MI and stroke NACE: composite of death, MI or stroke and major bleeding (BARC 3 or 5) For both the RR was assumed in the range of 0.70 with a background event rate of 6% and 9%, respectively. With an alpha error set at 2.5%, 3,400 patients per group would provide study power greater than 90% and 99% for MACE and NACE, respectively. Major 2 EPs: each component of the co-primary endpoints, any bleeding according to BARC, TIMI and GUSTO scales and stent thrombosis

11. Radial (N=4,197) Femoral (N=4,207) Age (years) 67±12 67±12 Age ≥ 75 ys (%) 28.3 29.3 Male (%) 74.5 72.4 BMI (kg/m 2 ) 27.1±4.1 27.1±4.1 Previous CVA (%) 4.6 5.5 PAD (%) 8.1 8.8 Renal failure (%) 1.1 1.4 Previous PCI (%) 13.9 14.7 Previous radial access (%) 2.8 2.0 Killip > 1 (%) 9.6 9.7 STEMI (%) 47.7 47.8 NSTEMI (%) 46.5 45.9 UA (%) 5.8 6.4 Enoxaparin (%) 16.3 17.5 Fondaparinux (%) 10.2 11.1 UFH (%) 29.5 29.4 Baseline Characteristics

12. Procedural Characteristics Radial (N=4,197) Femoral (N=4,207) PCI attempted (%) 80.3 79.8 CABG (%) 3.7 3.7 Medical Tx (%) 11.7 11.9 Medications in the Lab Clopidogrel (%) 6.4 6.0 Ticagrelor/prasugrel (%) 17.1 16.3 GP IIb/IIIa inhibitors (%) 13.7 12.4 UFH (%) 49.9 45.5 Bivalirudin (%) 40.1 40.7 IABP (%) 1.9 2.3 Treated vessel(%) LMCA 4.6 3.5 LAD 50.3 49.2 Multivessel PCI (%) 13.7 13.7 Stent lenght (mm) 31.8 31.4

13. Cross Over and Procedural Success Rates 94.1% of radial and 97.4% of femoral cohorts received respective treatment as allocated In 5.8% of radial and 2.3% of TF cohort the allocated access was attempted but failed. In 3 (0.1%) in the radial and 13 (0.3%) patients in the femoral groups the allocated access was not attempted P=0.77P<0.001 * *: TIMI 30% %

14. 8.8% 10.3% 15% significant reduction at nominal 5% alpha which is however NOT significant at the pre-specificed alpha of 2.5% Primary EP: MACE Femoral Radial

15. Rate Ratio 0.83; 95% CI, 0.73 to 0.96; p=0.0092 11.7% 9.8% NNTB: 53 Femoral Radial Primary EP: NACE

16. MI and CVA endpoints: Any MI, STEMI, NSTEMI, unclassified*, stroke, TIA P=1.00 P=0.059 P=0.20 *: LBBB, paced rhythm or unavailability of interpretable ECG % %

17. Fatal and ST EPs: All-Cause, Cardiac, non-CV mortality, type of stent thrombosis % RR:0.72 (0.53-0.99) P=0.045 RR: 0.75 (0.54-1.04) P=0.08 P=0.69 P=0.66 % MortalityStent Thrombosis NNTB: 167

18. Bleeding endpoints: BARC, TIMI, GUSTO, access vs non-access related 1.4% 2.5% % P=0.013 RR: 0.67 0.49-0.92 P=0.0004 RR: 0.37 0.21-0.66 BARC 3 or 5 P=0.0098 RR: 0.64 0.45-0.90 P=0.08 RR: 0.72 0.50-1.04 P=0.20 RR: 0.78 0.53-1.14 Major or minor moderate or severe P=0.82 P=0.68

19. Rardial Better Femoral Better 1 HAZARD RATIO (95% CI) P-VALUES Superiority Interaction 0.89 Intermediate (548-991) 0.75 (0.60-0.94) 1.04 (0.82-1.32) 0.76 0.011 Centre’s annual volume of PCI Low (247-544) Intermediate (65.4-79.0%) Centre’s Proportion of radial PCI Low (14.9-64.4%) NSTE-ACS (tp–) ACS type STEMI <75 Age ≥75 0.23 0.88 (0.70-1.09) 0.82 (0.68-0.97) 0.023 0.62 NACE: Subgroup Analysis High (1000-1950) High (80.0-98.0%) NSTE-ACS (tp+) Men Sex Women <25 BMI ≥25 No Ticagrelor or prasugrel Yes No Diabetes Yes <60 GFR ≥60 No History of PVD Yes 2 0.25 0.50 0.75 (0.58-0.97) 0.025 0.0048 1.01 (0.79-1.29) 0.95 (0.75 -1.22) 0.71 0.95 0.64 (0.51-0.80) <0.001 0.44 0.86 (0.68-1.08) 0.58 (0.33-1.03) 0.059 0.19 0.85 (0.71-1.02) 0.07 0.012 0.72 (0.56-0.93) 0.89 (0.76-1.05) 0.16 0.18 0.09 0.86 (0.73-1.02) 0.79 (0.63-0.99) 0.038 0.53 0.07 0.83 (0.68-1.02) 0.84 (0.70-1.01) 0.06 0.94 0.45 0.91 (0.71-1.17) 0.80 (0.68-0.94) 0.08 0.43 0.01 0.78 (0.65-0.94) 0.86 (0.70-1.07) 0.18 0.51 0.60 0.91 (0.64-1.30) 0.83 (0.71-0.96) 0.012 0.64 No interaction between access and anticoagulant use in a post- hoc analysis of the subgroup of 7,213 patients randomized to bivalirudin or unfractionated heparin for the two co-primary outcomes, all-cause mortality, or BARC 3 or 5 bleeding

20. Radial Better Femoral Better 1 HAZARD RATIO (95% CI) P-VALUES Superiority Interaction Intermediate (65.4-79.0%) Centre’s Proportion of radial PCI Low (14.9-64.4%) NSTE-ACS (tp–) ACS type STEMI Subgroup Analysis High (80.0-98.0%) NSTE-ACS (tp+) 2 0.0157 1.28 (0.71-2.32) 0.69 (0.40 -1.19) 0.18 0.41 0.48 (0.28-0.81)0.006 0.10 0.87 (0.59-1.29)0.49 0.49 (0.28-0.87)0.012 Intermediate (65.4-79.0%) Centre’s Proportion of radial PCI Low (14.9-64.4%) NSTE-ACS (tp–) ACS type STEMI High (80.0-98.0%) NSTE-ACS (tp+) 0.20 0.90 (0.54-1.50) 0.57 (0.31 -1.03) 0.06 0.68 0.56 (0.32-0.97) 0.035 0.54 0.62 (0.41-0.94) 1.66 (0.28-10.0) 0.58 0.022 0.70 (0.42-1.17) 0.17 Mortality Bleeding 4 0.500.25 1 2 0.50 0.25

21. Updated Meta-analysis 19,328 ACS patients being randomly allocated to radial or femoral access Rardial Better Femoral Better 1 4 0.25 0.50 2 Pre-Rival RIVAL Post-RIVAL MATRI X Combined Non-CABG major bleeds Death, myocardial infarction or stroke Death Myocardial Infarction Stroke Pre-Rival RIVAL Post-RIVAL MATRI X Combined Pre-Rival RIVAL Post-RIVAL MATRI X Combined Pre-Rival RIVAL Post-RIVAL MATRI X Combined Pre-Rival RIVAL Post-RIVAL MATRI X Combined SUBGROUPRisk Ratio (95%CI)P Value Heterogenity P Value I2I2 0.73 (0.43-1.23) 0.39 (0.23-0.67) 0.58 (0.46-0.72) 0.41 (0.22-0.76) <0.00010% 0.5 1 0.67 (0.48-0.93) 0.86 (0.76-0.98) 0.86 (0.77-0.95) 0.98 (0.76-1.27) 0.00510% 0.9 7 0.58 (0.39-0.87) 0.73 (0.53-0.99) 0.72 (0.60-0.88)0.0011 0% 1.0 0 0.85 (0.39-1.90) 0.91 (0.78-1.06) 0.91 (0.79-1.04) 0.92 (0.65-1.31) 0.1 6 0%0.8 8 0.68 (0.49-0.92) 0.82 (0.52-1.29) 0.77 (0.46-1.28) 0.86 (0.58-1.29) 0.73 (0.12-4.47) 1.40 (0.45-4.40) 1.00 (0.50-2.00) 1.05 (0.69-1.60) 1.43 (0.72-2.83) 0.8 0 0% 0.7 5 0.26 (0.06-1.23)

22. Summary Among patients with an ACS, with or without ST-segment elevation who underwent invasive management, the use of radial access for coronary angiography ± PCI reduced the rate of net adverse clinical events, with a number needed to treat for benefit of 53 –Differences between groups were driven by reductions in BARC major bleeding unrelated to CABG and all-cause mortality with radial access. Our results, in conjunction with the updated meta- analysis, suggest that radial approach should become the default access for patients with ACS undergoing invasive management

23. MATRIX Access Program http://dx.doi.org/10.1016/S0140-6736(15)60507-4