Advanced Circulatory Support Trials Clifford J Kavinsky, MD, PHD Professor of Medicine and pediatrics Associate Director, Center for Congenital and Structural Heart Disease Rush University Medical Center

Conclusions Mechanical circulatory support devices do not improve survival or reduce infarct size in high risk patients undergoing PCI or in AMI complicated by cardiogenic shock There is no convincing randomized trial data that suggests that newer pVADs are superior to traditional IABP in terms of mortality benefit pVADs provide superior hemodynamic support then IABP Newer pVADs require a greater learning curve and their own set of complications mechanical circulatory support devices may provide greater hemodynamic stability and safety in performing coronary revascularization procedures in high risk and unstable patient subsets

Adrian Kantrowitz (1918-2008) Performed first Heart transplant in US (1967) Designed and implanted first LVAD (1972) Designed and first used Intra-aortic Balloon Pump (IABP)

Introduction of the IABP Kantrowitz et al 1968 JAMA 203:135

BenchmarkSM Counterpulsation Outcomes Registry* JACC 2001

856 patients with acute myocardial Infarction complicated by cardiogenic shock Examined impact of Thrombolytic therapy and IABP on mortality Shock Trial registry (Should we emergently revascularize Occluded Coronaries for cardiogenic shocK)

Shock Trial Registry In-hospital Mortality rates Revascularization rates differed in the four groups and impacted survival significantly No TT, No IABP-18% IABP only-70% TT only-20% TT and IABP-68% Mortality- 39% with revascularization and 78% without revascularization Sanborn et al 2000 JACC 36, Supp A:1123

Antman et al 2004 Circ 110:588

ACC/AHA Guidelines for STEMI Class I Indications for IABP Intra-aortic balloon counterpulsation should be used in STEMI patients with hypotension who do not respond to other interventions, unless further support is futile because of the patient’s wishes or contraindications/unsuitability for further invasive care (level of evidence B) Intra-aortic balloon counterpulsation is recommended for STEMI patients with low-output state (level of evidence B). when cardiogenic shock is not quickly reversed with pharmacologic therapy (level of evidence B) Intra-aortic balloon counterpulsation should be used in addition to medical therapy for STEMI patients with recurrent ischemic-type chest pain, poor LV function, or a large area of myocardium at risk (level of evidence C) 1) Hypotension defined as SBP <90 or 30 mm below baseline

Prophylactic IABP for High Risk AMI PCI Ongoing CP up to 12 hours ECG evidence of STEMI Cardiogenic shock excluded All went to cath lab. PCI deferred if infarct related vessel patent with ,70% lesion, or small vessel After cath procedure patients stratified into high or low risk groups High risk defined as one or more of the following: >70 y/o, LVEF <45%, vein graft occlusion, persistent ventricular arryhthmias, or suboptimal PCI result Multicenter, randomized trial (34 institutions) Primary PCI for AMI High risk patients randomized to 36-48 h IABP or not Primary endpoint: in-hospital death, reinfarction, vessel reocclusion, stroke, sustained hypotension or CHF Stone et al 1997 JACC 29:1459

Prophylactic IABP in High Risk AMI PCI Stone et al 1997 JACC 29:1459

Seven randomized trials of IABP therapy in STEMI 1009 patients. High risk had varying inclusion criteria: STEMI with suboptimal PCI result, STEMI with poor ST segment resolution, failed thrombolysis, Killip class >1, large ischemic area at risk. STEMI patients with cardiogenic shock (10,529 patients Seven randomized trials of IABP therapy in STEMI Nine non-randomized cohort studies of IABP therapy in STEMI patients with cardiogenic shock No randomized trial of STEMI patients in cardiogenic shock

IABP In High Risk STEMI IABP support was not associated with change in 30 mortality or LVEF Sjauw et al 2009 Eur H J 30:459

IABP in Cardiogenic Shock 11% reduction in mortality with IABP Sjauw et al 2009 Eur H J 30:459

IABP-SHOCK II Trial First randomized trial of IABP in Cardiogenic shock University of Leipzig and others, all in Germany randomized, prospective, open-label, multicenter trial 600 patients with cardiogenic shock complicated AMI randomized to IABP (301 patients) or not (299 patients) all patients were expected to receive early revascularization and best medical therapy 30-day all-cause mortality

IABP-SHOCK II Trial Clinical Outcomes Thiele et al 2012 NEJM 367:1287

IABP-SHOCK II Trial Time-to-Event Curves for the Primary End Point Thiele et al 2012 NEJM 367:1287

Open, multicenter, randomized controlled trial 337 patients with acute anterior STEMI without cardiogenic shock 30 sites in 9 countries IABP before primary PCI and continued for at least 12 hours Primary endpoint was Infarct size as determined by MRI (3-5 days) CRISP AMI-Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction Trial Patel et al 2011 JAMA 306:1329

CRISP-AMI Trial Among patients with acute anterior STEMI without shock, IABP plus primary PCI compared with PCI alone did not reduce Infarct size

TandemHeart™pLVAD CardiacAssist, Pittsburgh, Pa Left atrial-to-femoral arterial LVAD Low speed centrifugal continuous flow pump 21F venous transseptal cannula 17F arterial cannula Maximum flow 4L/minute FDA approved for up to 6 hours Used in over 2000 patients

TandemHeart™pLVAD p=NS Thiele- randomized followup study to compare use of IABP to TandemHeart for patients with AMI complicated by CS. Twenty patients in each arm. No difference in Mortality. Improved hemodynamics. Burkoff-Randomized multicenter trial in the US comparing TandemHeart to IABP for patients presenting within 24 hours of developing CS. Primary endpoint was superior hemodynamics. Secondary endpoint was 30 day survival. 33 patients randomized. TandemHeart provided greater increases in CI and decreases in PCWP. Independent data safety monitoring board reviewed data and concluded that hemodynamic effects of TandemHeart were superior and that no conclusion could be made regarding survival and the study was halted. Improved haemodynamic parameters (Cardiac Index, MAP,PCWP) Increase in bleeding, limb ischemia, and sepsis Thiele EHJ 2005;26:1276. Burkhoff AHJ 2006;152:e1

IMPELLA® RECOVER®2.5 pVAD System Advances retrograde across AV Single arterial access Advances over .018” wire 2.5 L/Min flow FDA approved for up to 6 hours no need for inotropic support

IMPELLA® RECOVER®2.5 pVAD System Clinical Studies

Protect II Randomized Trial A prospective Randomized Trial of Hemodynamic Support With Impella 2.5™versus Intra-Aortic Balloon Pump In Patients undergoing High risk Percutaneous Coronary Intervention O’neill et al 2012 Circ

Protect II Randomized Trial Elective PCI Unprotected Left main or last remaining patent coronary vessel Three vessel CAD LVEF 30-35% 1:1 randomization of Impella 2.5™ vs IABP Composite endpoint Major Adverse Events at discharge or 30 day followup all-cause death Myocardial infarction TIA/stroke Repeat revascularization Need for cardiovascular surgery Acute Renal Failure Severe hypotension Cardiopulmonary Resuscitation Ventricular Tachycardia requiring cardiovresion Aortic insufficiency Failed PCI Data and satety monitoring Board terminated trial early based on futility

Assessed for Eligibility Protect II Randomized Trial Assessed for Eligibility N=1082 Randomized Intent-to-Treat N=447 Intent-To-Treat (ITT) population (N=447) IMPELLA N= 224 90day F/U, N=222 IABP N= 223 90day F/U, N=220 (N=12) (N=9) 1 withdrew consent post PCI (alive) 1 EF >=35% 1 Not 3VD or ULM 3 Active MI 1 Severe PVD 1 Platelets<70000 1 Creatinine>4 2 withdrew consent post PCI (alive) 3 EF >=35% 3 Not 3VD or ULM 1 Active MI 2 Severe PVD or AS IMPELLA 30day N= 215 90day F/U, N=213 IABP 30day N= 211 90day F/U, N=210 Per Protocol (PP) population (N=426)

Protect II Randomized Trial Procedural Characteristics IABP (N=223) Impella (N=224) p-value Use of Heparin 82.4% 93.5% <0.001 IIb/IIIa Inhibitors 26.1% 13.5% 0.001 Total Contrast Media (cc) 241±114 267±142 0.037 Rotational Atherectomy (RA) 9.5% 14.9% 0.088 Median # of RA Passes/lesion (IQ range) 1 (1-2) 3 (2-5) Median # of RA passes/pt (IQ range) 2.0 (2.0-4.0) 5.0 (3.5-8.5) 0.004 Median RA time/lesion (IQ range sec) 40 (20-47) 60 (40-97) 0.005 RA of Left Main Artery 3.1% 8.0% 0.024 % of SVG Treatment or RA use 17.5% 25.4% 0.041 Total Support Time (hour) 8.2±21.1 1.9±2.7 Discharge from CathLab on device 37.7% 5.7%

Per Protocol= Patients that met all incl./ excl. criteria. PROTECT II MAE Outcome IABP IMPELLA MAE= Major Adverse Event Rate Intent to Treat (N=447) p=0.312 N=224 N=223 p=0.087 N=222 N=220 p=0.100 N=215 N=211 ↓ 21% MAE p=0.029 N=213 N=210 Per Protocol (N=426) Per Protocol= Patients that met all incl./ excl. criteria.

PROTECT II 90-day Outcome (PP) HRPCI w/o Atherectomy (N=371, 88%) HRPCI with Atherectomy (N=52, 12%) IMPELLA IABP IMPELLA IABP Composite 35.9% 51.1% (p=0.003) 68.8% 55.0% (p=0.316) Death MI (>3x ULN) Stroke/TIA Repeat Revascularization Vascular Complication Acute Renal Dysfunction Severe Hypotension CPR / VT Aortic Insufficiency Angio Failure 11.6% 8.9% (p=0.399) 12.5% 10.0% (p=0.784) 14.9% 17.4% (p=0.522) (p=0.03) 37.5% 10.0% 1.1% 2.6% (p=0.280) 3.1% 0.0% (p=0.425) 6.6% 10.5% (p=0.181) 3.1% 30.0% (p=0.006) 2.8% 3.7% (p=0.616) 0.0% 5.0% (p=0.202) 7.7% 11.6% (p=0.211) 21.9% 10.0% (p=0.271) 9.4% 12.1% (p=0.400) 18.8% 20.0% (p=0.911) 12.7% 10.0% (p=0.411) 9.4% 15.0% (p=0.537) 0.0% 0.0% 0.0% 0.0% 4.4% 2.1% (p=0.208) 0.0% 0.0% Per Protocol (PP)= Patients that met all incl./ excl. criteria.

Conclusions Mechanical circulatory support devices do not improve survival or reduce infarct size in high risk patients undergoing PCI or in AMI complicated by cardiogenic shock There is no convincing randomized trial data that suggests that newer pVADs are superior to traditional IABP in terms of mortality benefit pVADs provide superior hemodynamic support then IABP Newer pVADs require a greater learning curve and their own set of complications mechanical circulatory support devices may provide greater hemodynamic stability and safety in performing coronary revascularization procedures in high risk and unstable patient subsets