on behalf of the TOTAL Investigators 1 year results of the TOTAL trial: Randomized trial of manual Thrombectomy in STEMI SS Jolly, JA Cairns, S Yusuf, MJ Rokoss, P Gao, B Meeks, S Kedev, G Stankovic, R Moreno, A Gershlick, S Chowdhary, S Lavi, K Niemelä, I Bernat, WJ Cantor, AN Cheema, PG Steg, RC Welsh, T Sheth, OF Bertrand, A Avezum, R Bhindi, MK Natarajan, D Horak, RCM Leung, S Kassam, SV Rao, M El-Omar, SR Mehta, JL Velianou, S Pancholy, V Džavík on behalf of the TOTAL Investigators

Disclosures TOTAL trial was funded by: Canadian Institutes of Health Research Canadian Network and Centre for Trials Internationally (CANNeCTIN) Medtronic Inc.

Background: Effect of Thrombectomy at 1 year Large effect size in TAPAS (2008) No difference in TASTE (2013) TAPAS trial (N=1071) showed a large benefit vs. TASTE (N=7244) showed no benefit of thrombus aspiration Vlaar PJ, et al. Lancet 2008;371:1915-20. Frobert O, et al. N Engl J Med 2013. Lagerqvist B, et al. N Engl J Med. 2014.

The TOTAL Trial Study Design STEMI* with Primary PCI ≤12 hours of symptom onset Sample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction 1:1 Randomization between strategies Routine Upfront Manual Thrombectomy followed by PCI PCI Alone (only bailout thrombectomy) Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days Safety Outcome: Stroke ≤30 days Bailout Thrombectomy allowed if PCI alone strategy fails: Persistent TIMI 0 or 1 flow with large thrombus after balloon pre-dilatation Persistent large thrombus after stent deployment at target lesion

Summary of Primary Results of TOTAL trial Improvement in Surrogate Outcomes (ST resolution, Distal embolization) Thrombectomy did not reduce primary outcome at 180 days Increase in stroke at 30 days Question: Would the benefit for surrogate outcomes translate into a long term benefit at 1 year? Jolly SS, et al. N Engl J Med. 2015;372:1389-1398.

TOTAL Recruitment from 87 sites in 20 countries Europe 5617 North America 3863 Asia Pacific 865 South America 387 10,732 patients randomized between August 2010 and July 2014

TOTAL Trial Flow and Adherence 10,732 enrolled and randomized Cross-over to Thrombectomy as initial strategy in 70 (1.4%) Bailout Thrombectomy in 354 (7%) Crossover to PCI alone in 231 (4.6%) TOTAL 5035 Manual Thrombectomy 5029 PCI Alone 5029 included in analysis 5035 included in analysis 10,064 underwent PCI for STEMI

Baseline and Procedural Characteristics Thrombectomy N=5035 PCI alone N=5029 Mean Age 61.1 years 60.9 years Killip Class ≥2 4.4% 4.2% Anterior MI 39.0% 40.9% Pre PCI TIMI 0-1 flow 3705 (73.6%) 3748 (74.5%) TIMI Thrombus Grade ≥3 4529 (90%) 4454 (88.6%) Upfront GP IIb IIIa inhbitor 1143 (22.7%) 1276 (25.4%) Drug eluting stent 2250 (44.7%) 2266 (45.1%)

Primary Outcome (CV death, MI, Shock or CHF) at 1 year

Primary Outcome at 1 year Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR 95% CI p CV death, MI, shock or class IV heart failure 395 (7.8) 394 (7.8) 1.00 (0.87 – 1.15) 0.99 CV death 179 (3.6) 192 (3.8) 0.93 (0.76 – 1.14) 0.48 Recurrent MI 125 (2.5) 118 (2.3) 1.05 (0.82 -1.36) 0.68 Cardiogenic Shock 95 (1.9) 105 (2.1) 0.90 (0.68 – 1.19) 0.47 Class IV heart failure 106 (2.1) 96 (1.9) 1.01 (0.83 – 1.45) 0.50

Safety Outcomes at 1 year   Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR 95% CI p Stroke at 1 year 60 (1.2) 36 (0.7) 1.66 (1.10 – 2.51) 0.015 Stroke or TIA at 1 year 73 (1.4) 44 (0.9) 1.65 (1.14 – 2.40) 0.008 Landmark Analyses Stroke 180 days to 1 year 7 (0.1) 10 (0.2) 0.70 (0.27 – 1.83) 0.46

Site Primary PCI Volume: Tertile 1 2450 8.1 8.4 Tertile 2 2139 8.4 7.8 Thrombectomy (%) PCI Alone (%) P (INTERACTION) OVERALL 10064 7.8 7.8 TIMI Thrombus Grade: ≥3 8983 8.0 8.2 <3 1073 6.0 4.9 0.407 TIMI Thrombus Grade: ≥4 7919 8.4 8.5 <4 2137 5.8 5.5 0.759 Symptom Onset: <6 hrs 8416 7.6 7.4 6-12 hrs 1645 9.3 10.2 0.480 Initial TIMI Flow: 0-1 7453 8.3 8.6 2-3 2517 6.8 5.7 0.195 Site Primary PCI Volume: Tertile 1 2450 8.1 8.4 Tertile 2 2139 8.4 7.8 Tertile 3 5475 7.5 7.6 0.823 MI Type: Anterior 4017 9.7 10.1 Non-Anterior 6039 6.7 6.3 0.509 Age: ≤65 yrs 6662 5.5 5.1 >65 yrs 3401 12.6 13.1 0.375 Favours Thrombectomy Favours PCI Alone 0.5 1.0 2.0

Updated Meta-analysis N=20,352 All-Cause Mortality OR 0.90 (95% CI 0.79-1.02) P=0.10

Stroke 0.9% thrombectomy vs. 0.6% PCI alone, OR 1.43 (95% CI 1.03-1.99) P=0.03

Conclusions Routine thrombectomy compared to PCI alone did not reduce CV death, MI, shock or heart failure at 1 year Routine thrombectomy was associated with increased rate of stroke Manual Thrombectomy can no longer be recommended as a routine strategy

Available Online at the Lancet

Acknowledgements Thank you for Grant Support from and Executive Committee S.S. Jolly (co-Principal Investigator) V. Džavík (co-Principal Investigator) J.A. Cairns L. Thabane S. Yusuf Data Monitoring Committee G. Wyse (Chair) J.P. Bassand D. Bhatt M. LeMay G. Wells J. Pogue (DMC statistician) Angiographic Core Lab C. Overgaard, V. Sharma, W. Chan, F. Fuchs, J. Chiha, T. Hamid, S. Bui, M. Sibbald, V. Džavík ECG Core Lab M. Eskola, K. Nikus, J. Koivumäki, K. Niemelä Adjudication Committee M. Rokoss (Chair), A. Avezum, K. Bainey, P. Domsik, G. Ducrocq, M. Eskola, G. Fodor, P. Hajek, B. Hart, P. Kanjana, J. Karasconyi, K. Kervinen, T. Lai, D. Mancevski, L. Morillo, A. Neskovic, K. Ng, K. Niemelä, W. Oczkowski, G. Oliveira, M. Pan, P. Paulu, D. Petrovska-Cvetskovska, I. Plaza, H. Romppanen, J.D. Schwalm, A. Shoamanesh, T. Sotirov, D. Topic, N. Valettas, K. Vondrak, P. Widimský, V. Zenios Quality Assurance Committee C. Ainsworth, D. Al Khdair, A. Alazzoni, N. Ali, A. Al-Saleh, A. Avezum, F. Botto, W. Chan, J. Cohen, M. Eskola, F. Fuchs, A. Gangasandra Basavaraj, P. Hajek, V. Hsieh, K. Jolly, K. Kervinen, J. Manolakos, M. Natarajan, G. Oliveira, J. Paikin, S. Pandie, P. Paulu, S. Pizzale, M. Rokoss, J.D. Schwalm, K. Shufelt, T. Sotirov, D. Topic, M. Tsang, N. Valettas, K. Vondrak, D. Wright PHRI Project Office Study Team B. Meeks (Program Manager) S. Ahmad (Research Coordinator) M. Lawrence L. Floyd M. McClelland M. Wild S. Batey A. Fatima Statisticians J. Pogue O. Shestakovska P. Gao Steering Committee A. Avezum M.K. Natarajan I. Bernat K. Niemelä O. Bertrand S. Pancholy R. Bhindi S.V. Rao W.J. Cantor M. Rokoss B. Meeks G. Stankovic A. Gershlick P.G. Steg S. Kedev J.M. ten Berg R. Moreno R.C. Welsh C.K. Naber P. Widimsky Y. Xu Thank you for Grant Support from and

TOTAL Investigators from 87 sites in 20 countries AUSTRALIA CANADA FINLAND NETHERLANDS UNITED KINGDOM A. Rahman S. Jolly K. Niemelä J.M. ten Berg A. Gershlick R. Bhindi A. Fung H. Romppanen NEW ZEALAND S. Chowdhary J. Weaver A. Cheema FRANCE G. Devlin A. Jain AUSTRIA O. Bertrand G. Sideris SERBIA N. Curzen I. Lang V. Džavík P.G. Steg G. Stankovic M. El-Omar BELGIUM S. Kassam N. Delarche SOUTH KOREA M. Seddon S. Pourbaix A. Della Siega F. Schiele W. Kim J. Shannon BRAZIL T. Cieza S. Marliere S. Jin Lee R. Oliver M. Andre Tebet S. Lavi GERMANY M-H. Jeong J. Gunn A. Kormann N. Nadeem N. Werner S-H. Kim S. Hetherington A. Zago R. Welsh C. Naber SPAIN K. Grosser P. Caramori W. Cantor M. Greif J. Mauri J. Glover V. Lima L. Bilodeau J. Torzewski N. Vazquez USA M.A. dos Santos R. Leung GREECE B. Garcia del Blanco N. Patel A. Abizaid J. Charania D. Alexopoulos A. Bethencourt I.J. Sarembock CHINA CZECH REPUBLIC Ziakas R. Moreno J. Blankenship Y. Xu P. Hajek HUNGARY A. Iniguez Romo D. Lasorda J. Qiu V. Kocka Ungi J. Escaned Barbos M. Sheldon S. Liu P. Cervinka B. Merkely H. Tizon-Marcos S. Pancholy H. Luo I. Bernat MACEDONIA C. Devireddy D. Horak S. Kedev S. Singh

Thrombectomy (%) PCI Alone (%) P (INTERACTION) OVERALL 10064 7.8 7.8 Diabetes: No diabetes 8206 6.8 7.1 Diabetes 1856 12.6 10.9 0.220 GP IIb/IIIa: No 6090 8.1 8.1 Yes 3973 7.4 7.5 0.853 Proximal lesions: No 5330 6.5 6.6 Yes 4734 9.3 9.3 0.902 3 criteria: No 7362 7.3 7.2 Yes* 2702 9.5 9.6 0.855 *proximal or mid LAD culprit lesion and TIMI 0-2 flow and symptom onset to device <=5 hours Favours Thrombectomy Favours PCI Alone 0.5 1.0 2.0