an open, prospective, randomized, multicentre trial EARLY-MYO Trial EARLY routine catheterization after half-dose alteplase fibrinolysis vs. primary PCI in acute ST-segment–elevation MYOcardial infarction: an open, prospective, randomized, multicentre trial Ben He MD FACC FESC FSCAI for the EARLY-MYO Investigators Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, China

- Research contracts (Study grant from Boehringer Ingelheim to pe1form the EARLY-MYO trial, paid to the Shanghai Jiaotong niversity China)

Background Primary PCI (PPCI) within the guidelines recommended time window cannot be offered to all STEMI patients Pharmaco-invasive (PhI) strategy has been shown to be a valid alternative to PPCI for patients who cannot get PPCI within 1 hour after first medical contact (STREAM study and registries) We conducted the first randomized trial designed to evaluate the efficacy and safety of a PhI strategy with half-dose alteplase versus routine PPCI in STEMI patients

Study Aim To compare a pharmaco-invasive strategy of early fibrinolysis followed by coronary angiography within 3- 24 hours or rescue PCI (if needed) with routine PPCI in STEMI patients presenting within 6 h of symptom onset and with an expected “PCI-related delay time” ≥60 min (*Defined as estimated time of Door-To Device minus time of Door-to-Needle)

Primary Endpoint and Sample Size Primary endpoint：Complete epicardial and myocardial reperfusion after PCI defined as : TIMI flow grade 3 and TIMI myocardial perfusion grade 3 and ST-segment resolution => 70 % (core labs were blinded to allocated treatment) Sample size：with 175 patients per group (total 350 patients) the study has 80% power to show non-inferiority of the PhI strategy vs PPCI (to exclude a 30% worse relative outcome of the primary endpoint)

FLOW CHART

Treatment in both arms PhI group : Half-dose alteplase (8-mg bolus followed by 42 mg in 90 min) followed by coronary angiography within 3-24 h of randomization or rescue PCI PPCI group：Routine PPCI without fibrinolytic therapy

MEDIAN TIMES TO TREATMENT (min) Sx onset Randomize IWRS start rt-PA 190（136-251） 57（7-88） 210（166-270） 70 min difference Sx onset Randomize IWRS sheath insertion 185（137-242） 110（50-160） 280（214-340） n=344 2 Hours 3 Hours

MEDIAN TIMES TO TREATMENT (min) Sx onset Randomize IWRS start rt-PA 25.5% Rescue PCI at 2.1h 190（136-251） 57（7-88） 74.5% non-urgent cath at 10.2h Sx onset Randomize IWRS sheath insertion 185（137-242） 110（50-160） n=344 2 Hours 3 Hours

ST-Segment Resolution in PhI arm ± 60min after start rt-PA (judged by local Investigator) Pharmaco-invasive (N=161) ST segment resolution ≥ 50 % < 50 % 74.5% 25.5% Rescue PCI performed 25.5 % 25.5% 74.5% Successful fibrinolysis

Epicardial(A) and Myocardial(B) Perfusion Pre-PCI

Epicardial and Myocardial Perfusion Post PCI categorical measurements

Quantitative assessment of Epicardial and Myocardial Perfusion Post PCI Continuous measurements

PRIMARY ENDPOINT Post PCI Pharmaco-invasive (n=161) PPCI (n=167) P value ST=>70% 51.0%(n=82) 45.5%n=76) 0.377 TIMI Flow grade3 91.3%(n=147) 89.2%(n=149) 0.580 TIMI Perfusion grade3 65.8%(n=106) 62.9%(n=105) 0.730 Complete Reperfusion 34.2%(n=54) 22.8% (n= 39) P value for non-inferiority: <0.05 P value for superiority: 0.022

PRIMARY ENDPOINTS by Subgroups

Left Ventricular Function & Structure

Clinical Outcomes Clinical Outcome Total (n=344) PhI (n=171) PPCI (n=173) P value Death 3 (0.9) 1 (0.6) 2 (1.2) 1.000 Re-infarction 2 (0.6) Heart failure 51 (14.8) 23 (13.5) 28 (16.2) 0.545 Stroke - Combined clinical Endpoint 56 (16.3) 25 (14.6) 31 (17.9) 0.466

Kaplan–Meier survival curve

Safety Outcomes Outcome Total (n=344) PhI (n=171) PPCI (n=173) P value Minor non-ICH bleeding 65 (18.9) 47 (26.9) 18 (11.0) <0.001 Major non-ICH bleeding 1 (0.3) 1 (0.6) 0 (0) 0.497 ICH bleeding -

Conclusions In STEMI patients presenting within 6 hours of symptom onset for whom the expected PCI-related delay is > 60 min , a PhI strategy with half-dose alteplase and timely PCI is safe and shows significantly more complete epicardial and myocardial reperfusion than routine PPCI More clinical outcome data must be obtained to confirm the reperfusion benefit observed in this study If confirmed , a PhI treatment could be very beneficial for eligible STEMI patients, particularly in countries without well-organized STEMI networks or with significant system delays

Acknowledgments EARLY-MYO Investigators： Ben He, Jun Pu, Song Ding, Heng Ge Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Yaling Han General Hospital of Shenyang Military Region, Shenyang, China Jinchen Guo Beijing Luohe Hospital, Capital Medical University, Beijing, China Rong Lin Fujian Medical University Affiliated the First Quanzhou Hospital, Quanzhou, China Xi Su Wuhan Asia Heart Hospital, Wuhan, China Heng Zhang Bengbu Medical University Affiliated the First Hospital, Bengbu, China Lianglong Chen Union Hospital, Fujian Medical University, Fuzhou, China DSMB Members: Frans Van de Werf, MD, PhD, University of Leuven, Leuven, Belgium Junbo Ge, MD, PhD, Zhongshan Hospital, Fudan University , Shanghai, China Yingchun Zhou, PhD, School of Statistics, East China Normal University, Shanghai, China

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