Results From The Minimizing Adverse Haemorrhagic Events By Transradial Access Site And Systemic Implementation of Angiox-MATRIX Treatment Duration Program M. Valgimigli, MD, PhD Swiss Cardiovascular Center Bern, Inselspital, Bern, Switzerland on behalf of the MATRIX Group NCT

Declaration of Interest I, Marco Valgimigli, Served as a speaker, or advisor or consultant for: The Medicines Company and Terumo

Background The most effective anti-thrombotic regimen for preventing ischemic complications, while limiting bleeding risk, in patients with acute coronary syndromes undergoing invasive management remains unresolved Bivalirudin decreases bleeding events as compared to UFH±GPI but it also increases the hazard of stent thrombosis Whether prolonging bivalirudin after PCI mitigates ischemic without increasing bleeding risks is unknown

Objectives To determine whether the use of bivalirudin during intervention followed by a post-PCI infusion of ≥4 hours, as compared to no post-PCI infusion, reduces net adverse cardiovascular events (NACE), defined as the composite of death, MI, stroke, major bleeding, urgent TVR and ST To determine the impact of post-PCI bivalirudin on each component of the primary endpoint In a broadly inclusive ACS population undergoing invasive management via randomly assigned radial or femoral access

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≥ 4 hs infusion 1:1 Trans-Radial Access MATRIX Program NCT Lancet. 2015; 385(9986): ACC 2015, oral presentation ACCESS ANTITHROMBIN TYPE TREATMENT DURATION

Study Organization and Sites Sponsor Clinical Event Committee P. Vranckx, Chair S. Leonardi Co-Chair P. Tricoci Italian Society of Interventional Cardiology 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

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, Peter Jüni 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.

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

Do not randomise for anti- thrombin Primary Endpoints cohort for Acces Site Comparison Anti-Thrombin Type/Duration Randomization * PCINo PCI *: stratified by presenting syndrome and type of P2Y12i Primary endpoints Cohort for Anti-thrombin Comparison Access Site Randomization * PCI Planned Diagnostic Catheterisation STEMI Medical tx or CABG planned UA/NSTEMI

MATRIX Recruiting timelines: Anti-thrombin program 7,213 Cumulative enrollment by month First Recruited patient: 11 th Oct 2011 Last Recruited patient: 7 th Nov 2014 Complete follow-up information at 30 days available in all but 13 patients per group

3603 allocated to UFH MATRIX Patient Flow Chart: Treatment Duration program 7213 pts included in the Anti-thrombin program 3610 pts included in the Treatment Duration Study 1799 Post-PCI Bivalirudin 93.3% received allocated Intervention 1811 No post-PCI Bivalirudin 96.8% received allocated intervention 13 No post-discharge FUP 1790 (99.4%) Complete 30-day information 1807 (99.8%) Complete 30-day information

Endpoints The MATRIX Tx Duration Study had one pre-specified primary superiority endpoint at 30 days: NACE: Composite of death, MI or stroke, urgent TVR, stent thrombosis and major bleeding (BARC 3 or 5) The RR was assumed in the range of 0.70 with a background event rate of 7% and 10%, respectively. With an alpha error set at 5%, 1,700 patients per group would provide study power of 86% Major 2 EPs: Each component of the primary endpoint

Post-PCI Bivalirudin Rx Bivalirudin could be administered at*: the full PCI dose (1.75mg/kg/h) for up to 4 hours or the reduced dose of 0.25 mg/Kg/h for at least 6 hours Regimens and temporal distribution *: with the choice between those two regimens made at the discretion of the treating physicians Full PCI regimen Reduced regimen 34.4% Infusion duration: 264 ’ 59% Infusion duration: 433 ’ N=119 (6.6%) receiving no post-PCI bivalirudin in the post-PCI bivalirudin arm

Baseline Characteristics Post-PCI No post-PCI Bivalirudin (N=1,799) Bivalirudin (N=1,811) Age (years) 65.4± ±11.7 Age ≥ 75 ys (%) Male (%) Previous CVA (%) PAD (%) Cardiac Arrest (%) Killip > 1 (%) STEMI (%) NSTEMI (%) UA (%) 4.0% 5.1% Pre-LAB P2Y12i (%) Clopidogrel Ticagrelor/prasugrel Enoxaparin (%) Fondaparinux (%) UFH (%)

Procedural Characteristics Post-PCI No post-PCI Bivalirudin (N=1,799) Bivalirudin (N=1,811) PCI attempted (%) CABG (%) Medical Tx (%) Medications in the Lab (%) Clopidogrel Ticagrelor/prasugrel Gp IIb/IIIa inhibitors* § LMCA treated (%) Multi-vessel PCI (%) Total stent length (mm) 32±20 32±21 At least 1 implanted DES (%) At least 1 Complex lesion (%) Post dilatation (%) Success in all Tx lesion (%) index procedure §: p<0.05 *: restricted to bailout conditions

Primary EP: NACE 11.0% No post-PCI bivalirudin Post-PCI bivalirudin RR: 0.91; 95% CI: ; P= % Treatment Duration Study

1 EP Components Death, MI, Stroke, urg. TVR, ST and BARC 3 or 5 P=0.03 % –0.96 P= –3.53 P= –2.60 P= –2.56 P=0.99 P= –1.42

Stent Thrombosis Definite and Definite or Probable P=0.14 % –4.46 P= –2.33 P= –2.50 P= –15.35 P= –2.43

Bleeding BARC, TIMI and GUSTO definitions P=0.01 % –0.85 P= –1.31 P= –0.61 P= –3.45 P=0.99 P= –2.03

Bleeding Location BARC 3 or 5 in Patients on Bivalirudin According to Post-PCI Treatment Duration No. of Bleeding

Exploratory Analysis* Ischemic and Bleeding EPs according to bivalirudin regimen in the post-PCI bivalirudin arm % * The choice of post-PCI bivalirudin regimen was at discretion of the investigator 14.7

Exploratory Analysis* Stent thrombosis and BARC 3 or 5 bleeding according to bivalirudin regimen in the post-PCI bivalirudin arm % * The choice of post-PCI bivalirudin regimen was at discretion of the investigator Definite Stent ThrombosisBleeding

Favours Post-PCI Bivalirudin Favours NO Post-PCI Bivalirudin RATE RATIO (95% CI) P-VALUES Superiority Interaction 0.77 Intermediate ( ) 0.99 ( ) 0.75 ( ) Centre’s annual volume of PCI Low ( ) NSTE-ACS (tp–) ACS type STEMI <75 Age ≥ ( ) 0.86 ( ) Composite Outcome: Subgroup Analysis High ( ) 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 ( ) ( ) 2.10 ( ) ( ) ( ) 0.84 ( ) ( ) 0.87 ( ) ( ) 1.00 ( ) ( ) 0.87 ( ) ( ) 0.90 ( ) ( ) 0.86 ( ) Radial Access site Femoral ( ) 1.08 ( )

Summary The post-PCI infusion of bivalirudin for at least 4 hours after the intervention did not decrease the composite outcome of ischemic and bleeding events, including stent thrombosis. This finding was consistent across subgroups, including access site. Post-PCI bivalirudin infusion was safe and associated to lower risk of major bleeding according to BARC 3/5 or GUSTO scales.

Summary At exploratory analysis, the post-PCI 0.25 mg/kg/h bivalirudin regimen was associated to higher, whereas the 1.75 mg/kg/h full regimen to lower ischemic and bleeding risks compared to no post-PCI bivalirudin.