1. TOTAL Stroke in the TOTAL trial: Randomized trial of manual aspiration Thrombectomy in STEMI TOTAL Trial Investigators

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

3. TOTAL The TOTAL Trial Study Design PCI Alone (only bailout thrombectomy) Routine Upfront Manual Thrombectomy followed by PCI Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days Safety Outcome: Stroke ≤30 days 1:1 Randomization between strategies 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 STEMI with Primary PCI ≤12 hours of symptom onset Sample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction Jolly SS, et al. Am Heart J. 2014. 167 (3):315-21.

4. TOTAL Key Findings of TOTAL Jolly SS, et al. N Engl J Med. 2015. 372:1389-1398. No Difference in Primary Efficacy Outcome Increase in Stroke Hazard ratio 0.99 (95% CI 0.85-1.15), P=0.86 Hazard ratio 2.00 (95% CI 1.25-3.20), P=0.003

5. TOTAL Objectives of Detailed Stroke Analysis To better understand Stroke findings in TOTAL trial To explore: Timing of Stroke Stroke severity Subtypes of Stroke Independent Predictors of Stroke To incorporate findings into updated Meta-analysis

6. TOTAL Objectives of Detailed Stroke Analysis To understand stroke findings, specifically: Timing of Stroke Stroke severity Subtypes of Stroke Independent Predictors of Stroke To incorporate findings into updated Meta-analysis All strokes were adjudicated by Neurologists blinded to treatment

7. TOTAL PCI Procedure and Therapies over follow up Thrombectomy N=5033 PCI alone N=5030 P Upfront Glycoprotein IIb/IIIa22.7%25.4%P=0.002 PCI Procedure time (median) 39 min35 min<0.001 ≤ 5 French Catheters0.8%2.5%<0.001 6 French Catheters96.7%95.4%0.001 ≥ 2 guide catheters12.9%11.9%0.10 No differences in oral antiplatelet, anticoagulant or anti-hypertensive therapy over follow up

8. TOTAL Landmark Analysis for Stroke Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR95% CI 0 to 48 hours15 (0.30%)5 (0.10%)3.001.09-8.25 >48 hours to <7 days 5 (0.10%)4 (0.08%)1.250.34-4.66 7 to <30 days13 (0.26%)7 (0.14%)1.850.74−4.65 30 to <90 days11 (0.23%)8 (0.16%)1.370.55-3.41 90 to 180 days8 (0.17%)2 (0.04%)3.990.85-18.8

9. TOTAL Stroke Severity Rankin Score Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp Minor or no disability (0-2) 18 (0.4%)13 (0.3%)1.380.68-2.820.37 Major disability or fatal (3-6) 35 (0.7%)13 (0.3%)2.691.42-5.080.002 1Full recovery from all symptoms4Patient needs help from another person to perform everyday activities 2Persistent symptoms which do not limit patient’s functional status 5Patient incapacitated, unable to perform everyday activities even with help 3Some functional impairment but patient can manage all activities independently 6Death Rankin Score

10. TOTAL Stroke Subtype during 180 days Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp Ischemic37 (0.7%)21 (0.4%)1.711.03-3.000.036 Primary hemorrhagic10 (0.2%)2 (0.04%)4.981.09-22.70.021 Uncertain Etiology5 (0.1%)3 (0.1%)1.660.40-6.960.48

11. TOTAL Cumulative Ischemic Neurologic Events (includes TIA) over time Thrombectomy (N=5033) (%) PCI alone (N=5030) (%) HR95% CIp 12 hours6 (0.12%)4 (0.08%)1.500.42-5.310.53 24 hours11 (0.22%)5 (0.10%)2.200.76-6.330.13 48 hours15 (0.30%)6 (0.12%)2.500.97-6.440.050 96 hours19 (0.38%)11 (0.22%)1.730.82-3.630.14 7 days21 (0.42%)14 (0.28%)1.500.76-2.950.24 14 days28 (0.56%)16 (0.32%)1.750.95-3.230.07 30 days35 (0.70%)19 (0.38%)1.841.05-3.220.030 90 days46 (0.91%)28 (0.56%)1.641.03-2.630.037 180 days52 (1.03%)29 (0.58%)1.791.14-2.820.011

12. TOTAL Subgroup Analysis Stroke 0.52.08.0 OVERALL TIMI Thrombus Grade: ≥4≥4 <4 Initial TIMI Flow: 0-1 2-3 Site Primary PCI Volume: Tertile 1 Tertile 2 Tertile 3 History of Hypertension: No Yes Age: <=65 yrs >65 yrs Previous Stroke: No Yes Gender: Male Female Access site: Radial Femoral Operator thrombectomy Volume: Tertile 1 Tertile 2 Tertile 3 10063 7919 2134 7443 2519 2450 2139 5474 5010 5049 6662 3401 9750 309 7797 2266 6865 3191 3522 3271 3243 Thrombectomy (%) 1.00 1.14 0.65 1.14 0.78 1.22 0.65 1.10 0.72 1.34 0.60 1.91 0.92 4.43 0.80 1.80 0.93 1.25 1.19 1.15 0.75 PCI Alone (%) 0.50 0.60 0.19 0.56 0.32 0.33 0.75 0.51 0.36 0.68 0.45 0.64 0.47 1.99 0.36 1.09 0.61 0.31 0.57 0.50 0.49 P (INTERACTION) 0.484 0.783 0.143 0.983 0.095 0.893 0.504 0.090 0.796 Favours ThrombectomyFavours PCI Alone

13. TOTAL Independent Predictors of Stroke 0.51.02.04.08.0 Thrombectomy vs PCI Age per 10 years Female Peripheral Vascular Disease Previous stroke Prior diabetes Intra aortic balloon CABG TIMI thrombus grade HR (95%CI) 2.00 (1.24-3.24) 1.27 (1.04-1.55) 2.10 (1.31-3.36) 2.56 (1.09-6.03) 2.54 (1.23-5.24) 2.41 (1.51-3.85) 2.98 (1.15-7.73) 2.16 (0.90-5.17) 1.20 (0.97-1.47) Stepwise Cox Regression Model

14. TOTAL Meta-Analysis for Stroke 0.8% Thrombectomy vs. 0.5% PCI alone, OR 1.59; 95% CI 1.11-2.27, p=0.01

15. TOTAL Meta-Analysis for Mortality 3.8% Thrombectomy vs. 4.3% PCI alone, OR 0.87; 95% CI 0.76-1.00, p=0.05

16. TOTAL Mortality of Stroke within 180 days 30.8% 3.4% Months of Follow-up Cumulative % of Death 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0123456 With Stroke Without Stroke Hazard ratio, 10.17 (95%CI, 6.70-15.45); P<0.0001) No. at Risk With Stroke Without Stroke 7862585654 53 9985971396589630961495979570

17. TOTAL Conclusions Routine thrombectomy was associated with increased risk of stroke that was evident within 48 hours Increase in primarily ischemic strokes but also hemorrhagic strokes Future trials of thrombectomy devices need to carefully collect stroke outcomes (safety) to determine safety and in addition to efficacy