Devices to Reduce Infarct Size in STEMI Gregg

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Devices to Reduce Infarct Size in STEMI Gregg W. Stone, MD The Zena and

Devices to Reduce Infarct Size in STEMI Gregg W. Stone, MD The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, NY and the Cardiovascular Research Foundation

Relevant Disclosures ¡ Consultant to Miracor, Ther. Ox, Abiomed ¡ Equity in QOOL Therapeutics

Relevant Disclosures ¡ Consultant to Miracor, Ther. Ox, Abiomed ¡ Equity in QOOL Therapeutics

Relationship Between Infarct Size and Adverse Events Following Primary PCI for STEMI A patient-level

Relationship Between Infarct Size and Adverse Events Following Primary PCI for STEMI A patient-level pooled analysis from 10 RCTs and 2, 632 pts All-cause mortality (%) 10 Q 1: 0% - ≤ 8% Q 2: >8% - ≤ 17. 9% Q 3: >17. 9% - ≤ 29. 8% Q 4: >29. 8% 8 P-value = 0. 0002 6 3. 8% 2. 8% 1. 4% 0. 9% 4 2 0 0 Number at risk: Q 1 Q 2 Q 3 Q 4 3 6 9 12 362 388 418 315 296 328 320 231 Time in months 677 636 653 656 655 611 622 620 542 556 561 512 Stone GW et al. JACC 2016; 67: 1674– 83

Relationship Between Infarct Size and Adverse Events Following Primary PCI for STEMI Heart failure

Relationship Between Infarct Size and Adverse Events Following Primary PCI for STEMI Heart failure hospitalization (%) A patient-level pooled analysis from 10 RCTs and 2, 632 pts 10 Q 1: 0% - ≤ 8% Q 2: >8% - ≤ 17. 9% Q 3: >17. 9% - ≤ 29. 8% Q 4: >29. 8% 8 P-value <0. 0001 6 5. 5% 4 3. 6% 2 1. 5% 0. 3% 0 0 Number at risk: Q 1 Q 2 Q 3 Q 4 3 6 9 12 265 324 342 180 229 290 283 143 Time in months 593 594 658 536 569 563 562 484 457 511 501 383 Stone GW et al. JACC 2016; 67: 1674– 83

Failed Device-based Cardioprotection Approaches in STEMI Aspiration Thrombectomy Distal protection Failed to reduce infarct

Failed Device-based Cardioprotection Approaches in STEMI Aspiration Thrombectomy Distal protection Failed to reduce infarct size or improve clinical outcomes in appropriately powered RCTs

Promising Device-based Cardioprotection Approaches in STEMI Intra-lesion GPIIb/IIIa Stent-based exclusion Some evidence for possible

Promising Device-based Cardioprotection Approaches in STEMI Intra-lesion GPIIb/IIIa Stent-based exclusion Some evidence for possible beneficial effects, but lack definitive randomized trial data

Proven Device-based Cardioprotection Approaches in STEMI Supersaturated Oxygen Delivery PO 2 760 -1000 mm.

Proven Device-based Cardioprotection Approaches in STEMI Supersaturated Oxygen Delivery PO 2 760 -1000 mm. Hg 90’ IC infusion Infusion catheters Tracker-38 - 7 F guide, 9 F sheath Inca-1 - 6 F guide, 8 F

SSO 2: Hyperoxemic Perfusion Porcine model 60’ balloon occlusion followed by 90’ IC infusion

SSO 2: Hyperoxemic Perfusion Porcine model 60’ balloon occlusion followed by 90’ IC infusion of hyperoxemic blood Control 4 -5 F infusion catheter SSO 2 Spears JR et al. ASAIO J 2003; 49: 716 -20; Spears JR et al. Int J Cardiol 2006; 113: 371– 5

AMIHOT II: Primary Efficacy Endpoint Infarct size by Tc-99 m-sestamibi SPECT (n=382) Pooled, adjusted

AMIHOT II: Primary Efficacy Endpoint Infarct size by Tc-99 m-sestamibi SPECT (n=382) Pooled, adjusted N=382 pts with anterior STEMI Difference of medians Infarct size, %LV -6. 5%* P Wilcoxon =0. 023 Bayesian Posterior Probability = 96. 9% Control N=124 Median [IQR] SSO 2 N=258 Median [IQR] *Consistent with a 22. 8% reduction in 6 -month mortality (Burns RJ et al. JACC 2002; 39: 30 -6) and a 25. 4% reduction in 1 -year mortality 25 [7, 42] 18. 5 [3. 5, 34. 5] Stone GW et al. Circ CV Int. 2009; 2: 366 -375 (Stone GW et al. JACC 2016; 67: 1674– 83

Optimized SSO 2 Therapy Procedure ARTERIAL PO 2 SHEATH DELIVERY CATHETER HYPEROXEMIC PO 2

Optimized SSO 2 Therapy Procedure ARTERIAL PO 2 SHEATH DELIVERY CATHETER HYPEROXEMIC PO 2 • Potentially safer: Point of infusion away from PCI injury zone; 5 F diagnostic inf catheter [BSC Impulse] • Shorter infusion: 100 ml/min x 60 min (AMIHOT: 75 ml/min x 90 min) • Potentially more effective: Infuse entire left coronary system Hanson ID et al. Cath CV Interv. 2015; 86 Suppl 1: S 51 -7

On April 2 nd, 2019 The FDA approved SSO 2 therapy for treatment of

On April 2 nd, 2019 The FDA approved SSO 2 therapy for treatment of pts with anterior MI undergoing primary PCI within 6 hours of symptom onset

Emerging Novel Device-based Cardioprotection Approaches in STEMI LV Unloading (Impella) Pressure-Controlled Intermittent Coronary Sinus

Emerging Novel Device-based Cardioprotection Approaches in STEMI LV Unloading (Impella) Pressure-Controlled Intermittent Coronary Sinus Occlusion (Pi. CSO) Mild Systemic Hypothermia

Cardioprotective Mechanisms of LV Unloading 1 Decreased myocardial O 2 demand 2 Increased myocardial

Cardioprotective Mechanisms of LV Unloading 1 Decreased myocardial O 2 demand 2 Increased myocardial perfusion (O 2 supply) 3 Activates a cardioprotective program Impella OFF Impella ON Meyns B et al. JACC 2003 Aqel RA et al. J Nucl Cardiol 2009 Esposito ML et al JACC 2018

Unloading Before not After Reperfusion is Required to Reduce infarct size LAD occlusion in

Unloading Before not After Reperfusion is Required to Reduce infarct size LAD occlusion in animal model Infarct Revascularization without unloading “door-to-balloon time” Infarct Unloading prior to revascularization “door-to-unload time” (DTU) Meyns et al. J Am Coll Cardiol 2003; 41: 1087 -95

The STEMI-DTU Pivotal Trial Acute anterior STEMI within 1 -5 hrs of symptom onset

The STEMI-DTU Pivotal Trial Acute anterior STEMI within 1 -5 hrs of symptom onset (n=688) Iliac and femoral Angiogram, LV-gram, LVEDP measurement Randomization 1: 1 Impella CP implanted, support initiated PCI ≥ 30 min after Impella CP initiation 4 -6 hrs Impella support PCI Follow-up at 30 days, 6 months, 12 months, 18 months and yearly through 5 years Primary endpoint: Infarct size on CMR at 3 -5 days PIs: Navin Kapur and William O’Neill Sponsor: Abiomed NCT 03947619

Pressure-Controlled Intermittent Coronary Sinus Occlusion (Pi. CSO) during PCI ¡ Intermittent occlusion of the

Pressure-Controlled Intermittent Coronary Sinus Occlusion (Pi. CSO) during PCI ¡ Intermittent occlusion of the coronary sinus increases coronary sinus pressure which translates into an increase in (arterial) wedge pressure over the ischemic area ¡ This results in: I. Redistribution of venous blood to the border zone of ischemic myocardium 1 II. Improved microcirculatory perfusion III. Enhanced washout of toxic metabolites from the microcirculation 2 ¡ Increases in coronary artery pressure and coronary sinus pressure amplitude 3 have also been associated with myocardial salvage, cardioprotection and angiogenesis 4 1. Ido A et al. Am J Physiol Heart Circ Physiol 2001; 280: 1361 -7; 2. Ikeoka et al. Jpn Circ J 1990; 54: 1258 -73; 3. Mohl W et al. Am J Cardiol 1984; 53: 923 -8; 4. Mohl, W et al. Cardiovasc Revasc Med 2015; 16: 36 -46.

Pi. CSO: Integration with Primary PCI Pi. CSO is placed and initiated after PTCA/aspiration

Pi. CSO: Integration with Primary PCI Pi. CSO is placed and initiated after PTCA/aspiration flow restoration, before stenting

Pi. CSO Pilot Studies (non-randomized) Pi. CSO in ACS 1 Ox. AMI-Pi. CSO 2

Pi. CSO Pilot Studies (non-randomized) Pi. CSO in ACS 1 Ox. AMI-Pi. CSO 2 22 Pi. CSO-treated anterior STEMI pts vs. 14 Pi. CSO-treated anterior STEMI pts with 56 propensity score matched control pts IMR >40 vs. 24 historical control pts with from (INFUSE-AMI ); c. MRI at 5 d) IMR >40; c. MRI at 6 mos P = 0. 006 P = 0. 02 median values 1 Egred M et al. Euro. PCR 2018 abstact; 2 De Maria G et al. Euro. Int 2018; 14: e 352 -9

Pi. CSO-AMI-I DESIGN: Prospective, randomized, controlled, parallel group, multi-center study OBJECTIVE: To evaluate the

Pi. CSO-AMI-I DESIGN: Prospective, randomized, controlled, parallel group, multi-center study OBJECTIVE: To evaluate the effect of Pi. CSO on infarct size when applied during p. PCI in STEMI patients PRIMARY ENDPOINT: Infarct size as % of LV at 5 days PRINCIPAL INVESTIGATOR: Adrian Banning PRIMARY RESULTS: Expected mid-late 2020 144 anterior STEMI pts, Sx ≤ 12 hrs, TIMI 0 -1 flow Patients randomized 1: 1 post flow restoration, prior to stenting Pi. CSO Group (n=72) Control Group (n=72) Pi. CSO start, stenting, Pi. CSO stop (45’) Stenting CMR 5± 2 days post PCI MACE 30± 7 days post PCI CMR 182± 30 days post PCI Yearly Clinical FU (1, 2 and 3 years) https: //clinicaltrials. gov/show/NCT 03625869; Sponsor: Miracor

Routes to Hypothermia Surface cooling (blankets/suits) Intravenous cooled saline infusion Endovascular IVC catheter (low/high

Routes to Hypothermia Surface cooling (blankets/suits) Intravenous cooled saline infusion Endovascular IVC catheter (low/high power) Intracoronary saline infusion Intraperitoneal lavage with lactated Ringer’s Transpulmonary delivery of frozen saline particles

Patient-level, Pooled Analysis of 6 Endovascular Hypothermia Trials n=629 pts, SPECT or MRI infarct

Patient-level, Pooled Analysis of 6 Endovascular Hypothermia Trials n=629 pts, SPECT or MRI infarct size within 1 month In hypothermia group, ~50% achieved core temp <35 °C before reperfusion Anterior MI (n=280) 60 60 P=0. 55 50 40 30 20 10 0 0 Mean ± SD 21. 0 ± 16. 9 Median [IQR] 19. 0 [5. 0 -35. 9] Hypothermia ≥ 35 C Hypothermia <35 C 19. 6 ± 16. 7 16. 8 [5. 0 -32. 4] 15. 3 ± 15. 2 10. 6 [1. 0 -24. 0] P=0. 34 40 10 Control P=0. 72 50 P=0. 02 Infarct Size (LV%) Non-anterior MI (n=349) Control Mean ± SD 8. 9 ± 10. 1 Median [IQR] 6. 5 [0 -15. 0] Dae M et al. J Interv Cardiol. 2018; 31: 269– 76 Hypothermia ≥ 35 C Hypothermia <35 C 9. 3 ± 9. 5 7. 0 [1. 0 -16. 0] 10. 1 ± 8. 8 8. 0 [2. 0 -15. 5]

Methods and Rate of Hypothermia Cooling method and study Cooling rate (various Time to

Methods and Rate of Hypothermia Cooling method and study Cooling rate (various Time to achieve % at ≤ 35°C at Mean temp at name (author, year) N locations) target temp reperfusion (measured in Surface cooling various locations) NICAMI (Ly, 2005) 9 0. 02 °C/min 235 min NA 34. 5°C Endovascular cooling catheter (+ cold saline) 235 min Dixon, 2002 42 0. 04 °C/min 95 min NA 34. 7°C 95 min NA COOL-MI (2003) 357 NA NA 35. 0°C LOWTEMP (2004) 18 0. 05 °C/min 80 min 0% 35. 4°C 80 min RAPID-MI-ICE (2010) 20 0. 14 °C/min 29 min 100% 34. 7°C 29 min Testori, 2013 19 0. 07 °C/min 78% 34. 4°C 57 min CHILL-MI (2014) 120 0. 1 °C/min 40 min 76% 34. 7°C COOL AMI EU Pilot (2017) 50 0. 16 °C/min 20 min 100% 33. 6°C Automated peritoneal lavage VELOCITY (Nichol, Stone 2015) 54 0. 13 °C/min 62 min 89% 34. 7°C Intracoronary infusion of saline SINTAMI (2017) 10 3 °C/min <2 min 100% 30. 7°C Transpulmonary delivery of frozen saline particles (investigational) QOOL Therapeutics pigs 0. 13 °C/min NA NA NA Mod from Otterspoor LC et al. Euro. Int 2017; 13: e 1475 -82 *Measured with a temperature sensor in the distal coronary artery

COOL-AMI EU Pivotal Trial d e l l o 468 pts with anterior STEMI

COOL-AMI EU Pivotal Trial d e l l o 468 pts with anterior STEMI <4. 5 hours duration r n e s No cardiogenic shock R 1: 1 Hypothermia + Primary PCI t p 5 Primary PCI t f a 7 ~ er 1 L forced 4°C saline + Proteus IVC catheter Target 32°C x 3 h then active rewarming to 36°C n i rm d e Primary endpoints: t a Effectiveness: Infarct size (c. MRI) at 4 -6 days (Sup) Safety: MACE (CD, MI, CI-TLR) at 30 days (NI) Te PI: Marko Noc Sponsor: Zoll Circulation Clinical. Trials. gov Identifier: NCT 03173313

EURO-ICE 200 pts with anterior STEMI <6 hours duration, LAD TIMI flow 0 or

EURO-ICE 200 pts with anterior STEMI <6 hours duration, LAD TIMI flow 0 or 1 No cardiogenic shock R 1: 1 IC Hypothermia + Primary PCI Balloon occlusion phase: NS infusion at room temp x 10’ through over-the-wire balloon Reperfusion phase: Balloon deflated, NS at 4°C infused x 10’ through balloon PPCI phase: Balloon withdrawn, PCI with stenting completed Primary endpoint: Infarct size (c. MRI) at 3 months (Superiority) PI: Nico Pijls Clinical. Trials. gov Identifier: NCT 03447834

Devices for Cardioprotection and Infarct Size Reduction in STEMI 1. Despite successful primary PCI,

Devices for Cardioprotection and Infarct Size Reduction in STEMI 1. Despite successful primary PCI, microvascular dysfunction and reperfusion injury often result in suboptimal myocardial salvage and large infact size with adverse LV remodeling, heart failure and death 2. SSO 2 is the first FDA-approved device-based therapy shown to safely reduce infarct size in a pivotal RCT 3. Other promising device-based approaches include intralesional abciximab infusion, mesh-covered stent-based thrombus exclusion, pre-PCI LV unloading (Impella), systemic hypothermia and Pi. CSO, of which the latter three are being tested in ongoing RCTs