A prospective, randomized trial of TATORT-NSTEMI: A prospective, randomized trial of Thrombus Aspiration in ThrOmbus containing culPriT lesions in Non-ST-Segment Elevation Myocardial Infarction Holger Thiele, MD Ingo Eitel, MD; Suzanne de Waha, MD; Steffen Desch, MD; Bruno Scheller, MD; Bernward Lauer, MD; Meinrad Gawaz, MD; Tobias Geisler, MD; Oliver Gunkel, MD; Leonhard Bruch, MD; Norbert Klein, MD; Dietrich Pfeiffer, MD; Gerhard Schuler, MD; Uwe Zeymer, MD on behalf of the TATORT-NSTEMI Investigators

Disclosures Funding: Unrestricted grants by Terumo Europe, Leuven, Belgium Lilly Germany, Bad Homburg, Germany Potential Conflict of Interest: Research Funding: Terumo, Lilly, Medicines Company, Maquet Cardiovascular, Teleflex Medical Speaker Honoraria: Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, Maquet Cardiovascular, Medicines Company

Thrombectomy Guidelines Background Thrombectomy Guidelines STEMI 2008 2010 2012 I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III ESC B A B 2009 2013 I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III ACC/AHA B B NSTEMI Might be considered, no data! Hamm et al. Eur Heart J 2011; 32:2999-3054 O‘Gara et al. Circulation 2013;127:e362-e425 Kushner et al. JACC 2009;54;2205-2241 Steg et al. Eur Heart J 2012;33:2569–2619 Wijns et al Eur Heart J 2010;31:2501-2555 Van de Werf et al. Eur Heart J 2008; 29, 2909–2945

Inclusion Criteria Grade Thrombus Description Methods NSTEMI with Ischemic symptoms > 20 minutes Last symptoms within 72 h pre randomization Elevated cardiac troponin T or I above 99. percentile Identifiable culprit lesion with relevant thrombus (TIMI thrombus-grade 2-5 in lesion) with intended PCI Grade Thrombus Description No Thrombus No angiographic characteristics for thrombus 1 Possible thrombus Angiography demonstrates thrombus characteristics such as reduced contrast density, haziness, irregular lesion contour or a smooth convex (meniscus) at the site of total occlusion suggestive but not diagnostic of thrombus 2 Thrombus present (small size) Definitive thrombus with greatest dimension ≤ ½ vessel diameter 3 (medium size) Definitive thrombus with greatest dimensions > ½ vessel diameter but < 2 vessel diameter 4 (large size) Definitive thrombus with greatest dimension > 2 vessel diameter 5 Total occlusion

Study Endpoints Primary Study Endpoint: Methods Study Endpoints Primary Study Endpoint: Microvascular obstruction day 1-4 in CMR Secondary Study Endpoints: Infarct size measured by delayed enhancement CMR day 1-4 “Myocardial salvage” by CMR Combined clinical endpoint: Mortality, reinfarction, TVR, and congestive heart failure 6 months after randomization Individual clinical endpoints of combined endpoint TIMI-flow post PCI Myocardial blush grade post PCI Enzymatic infarct size measured by Troponin T at 24 and 48 h de Waha et al. Trials. 2013;14:110

Late Microvascular Obstruction + Mortality Background Presence late MO 100 Extent late MO 80 60 40 20 10 30 Time to event (months) Survival (%) p=0.001 Tertile 3 Tertile 1 Tertile 2 100 80 60 Survival (%) p=0.01 40 20 No MO MO 10 20 30 40 Time to event (months) de Waha et al. Eur Heart J 2010; 31:2660-2668

Contrast-Injection 1,5 mmol/kg/BW Bolus Gd i.v. CMR Protocol Methods Contrast-Injection 1,5 mmol/kg/BW Bolus Gd i.v. 5 10 15 20 25 30 35 40 Time (min) Delayed enhancement 4CH + 2CH + SA Function 4CH + 2CH T2 SA Function SA Survey Area at risk EF, EDV, ESV Late MO + infarct size de Waha et al. Trials. 2013;14:110

Study Design, Flow, and Compliance Methods 460 NSTEMI patients 20 not randomized 440 NSTEMI patients 221 assigned to thrombectomy 219 assigned to standard PCI No CMR (n=40) Claustrophobia (n=11) PM/ICD (n=2) Obesity (n=1) Death (n=3) Renal insuff. (n=0) Other (n=23) No CMR (n=27) Claustrophobia (n=5) PC/ICD (n=3) Obesity (n=1) Death (n=3) Renal insuff. (n=1) Others (n=14) Primary endpoint analysis MO (n=181) Secondary endpoint MBG (n=221) Secondary endpoint TIMI-flow (n=221) Clinical follow-up 6 months (n=218) Primary endpoint analysis MO (n=192) Secondary endpoint MBG (n=219) Secondary endpoint TIMI-flow (n=219) Clinical follow-up 6 months (n=216)

Primary Study Endpoint - MO Results Presence of MO Extent of MO Thrombectomy Standard PCI Median [IQR] 1.95% [0.80;4.10] 1.40% [0.70;2.60] Extent of MO, %LV p=0.17 2 4 6 8 10 p=0.74 Presence MO, % 30.8% 29.2% Thrombectomy Standard PCI Core lab assessed

MO – Predefined Subgroups Mean Difference in MO %LV Results MO – Predefined Subgroups Baseline variable P-value for interaction Mean Difference in MO %LV (95% CI) All Patients Male sex Female sex Diabetes No diabetes TIMI thrombus grade 2-4 TIMI thrombus grade 5 TIMI-flow pre PCI 0-1 TIMI-flow pre PCI 2-3 Glycoprotein IIb/IIIa-inhibitor No glycoprotein IIb/IIIa-inhibitor 0.78 0.83 0.76 0.92 0.70 0.97 0.64 0.73 0.91 0.20 0.46 3 2 1 0 -1 -2 -3 Thrombectomy better Standard PCI better

Myocardial Blush Grade Results p=0.63 62.6% % 0 1 2 3 0 1 2 3 Myocardial Blush Grade Core lab assessed

Clinical Outcome 6 Months Results Clinical Outcome 6 Months 100 Thrombectomy Cumulative incidence of death, reinfarction, TVR, and new congestive heart failure (%) 90 Standard PCI p=0.20; log-rank test Evtl. weglassen und nur die Kaplan Meier Kurven zeigen 80 0 50 100 150 Time after randomization (days)

Summary + Conclusions In this first randomized, multicenter trial in patients with NSTEMI with thrombus containing lesions aspiration thrombectomy led to aspiration of thrombus material in 74%. This led to a higher rate of primary stent implantation in comparison to standard PCI. However, aspiration thrombectomy did not reduce the extent of microvascular obstruction in comparison to standard PCI without thrombectomy. The results are also supported by a lack of benefit in secondary endpoints.

Acknowledgement TATORT-NSTEMI Investigators from 7 sites in Germany Steering Committee Angio Core Lab Homburg H. Thiele (Chair) B. Scheller U. Zeymer B. Scheller (Chair) T. Dani CRO at Institut für Herzinfarktforschung S. Avsar (Chair) M. Horack M. Neumer CMR Core Lab Leipzig Sponsors I. Eitel (Coordinator) T. Arndt Lilly Germany Terumo Europe Study Sites Leipzig – Heart Center: H. Thiele Leipzig – University: N. Klein, D. Pfeiffer Berlin: L. Bruch Frankfurt (Oder): O. Gunkel Tübingen: T. Geisler, M. Gawaz Ludwigshafen: U. Zeymer Bad Berka: B. Lauer CEC S. Desch (Chair) H. Thiele