A Future for the IABP in Cardiogenic Shock? Holger Thiele Medical Clinic II (Cardiology/Angiology/Intensive Care) University of Lübeck, Germany

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1 A Future for the in Cardiogenic Shock? Holger Thiele Medical Clinic II (Cardiology/Angiology/Intensive Care) University of Lübeck, Germany

2 Disclosures Funding: German Research Foundation German Heart Research Foundation German Cardiac Society EU Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte Terumo Lilly Maquet Cardiovascular Teleflex Medical Consulting: Maquet Cardiovascular, Lilly Speaker Honoraria: Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, Maquet Cardiovascular, Medicines Company

3 Death after 30 days (%) In-hospital Mortality USIK 1995, USIC 2000, FAST-MI France National Registry Shock (62-77) No Shock (56-70) (44-59) ( ) ( ) ( ) Aissaoui et al. Eur Heart J 2012; 33:

4 Randomized Trials in Cardiogenic Shock Trial Follow-up n/n n/n Revascularization (PCI/CABG) SHOCK SMASH Total 1-year 30 days 76/152 22/32 103/184 83/149 18/23 117/172 Relative Risk 95% CI Relative Risk 95% CI 0.80 (0.66;0.98) 0.87 (0.66;1.29) 0.82 (0.70;0.98) Early revascularization Medical therapy Thiele et al. Eur Heart J 2010; 31,

5 % of control Stunned Myocardium 100 ** N=5 ** 70 ** ** ** Control Hours Hours 7 Days Partial stenosis Reperfusion **P<0,05 vs. control Matsuzaki et al. Circulation 1983;68:

6 History History: 1962 Animal trials Moulopoulos et al, Am Heart J 1962;63: clinical description in shock Kantrowitz et al, JAMA 1968;203: Hemodynamic effects, mortality unchanged Scheidt et al, NEJM 1973;288: > 40 years > 1 Million patients treated, low complication rate, Benchmark registry Ferguson et al, JACC 2001;38:

7 Overview Hemodynamic effects in cardiogenic shock

8 mm Hg Arterial Pressure Curves 140 Diastolic Augmentation Improvement of coronary perfusion Reduction afterload Myocardial O 2 -consumption 120 Non-assisted Systole Assisted Systole Ballooninflation Non-assisted Aortic Pressure Assisted ed Aortic Pressure

9 Scheidt et al. NEJM 1973;288: Hemodynamics Cardiogenic Shock (n=78) Pre Post P-Value Heart rate (1/min) 110 ± ± 21 n.s. BP syst. (mmhg) 76 ± ± 17 < BP diast (mmhg) 53 ± ± 19 < BP mean (mmhg) 62 ± ± 21 n.s. CO (l/min) < 0.01

10 Cardiac output (l/min) Prondzinsky et al. Shock 2012:37: SHOCK I vs. Control Cardiogenic Shock (n=40) P=n.s No P<0.009 Prior 24 h 48 h 72 h 96 h Time

11 Thiele et al. NEJM 2012;367: Mean Blood Pressure pre + post PCI mmhg (59; 80) 68 (59; 80) P= (63; 87) 73 (63; 84) Control Pre PCI Post PCI

12 Overview Hemodynamic effects in cardiogenic shock

13 Guidelines in STEMI complicated by cardiogenic shock ACC/AHA Class 1B IIa B ESC Class IC IIb B Antman et al. Circulation 2004;110: O Gara et al. Circulation. 2013;127:e362-e425 Van de Werf et al. Eur Heart J 2008;29: Steg et al. Eur Heart J.2012;33:

14 Mortality vs - Metaanalysis Trial n/n No n/n 30-Day Mortality Risk Difference No reperfusion Moloupoulos 24/34 15/15 Total 24/34 15/ (-0,47 to -0.12) Thrombolysis Stomel 28/51 10/13 Kovack 10/27 13/19 Bengtson Waksman 48/99 11/20 58/101 17/21 GUSTO-1 SHOCK registry 30/62 220/ / /417 NRMI-2 TT 1068/ /3501 Total 1415/ / (-0.20 to -0.16) Primary PCI NRMI-2 PCI AMC CS 956/ / /955 26/93 Total 1049/ / (0.03 to 0.10) Total 2488/ / (-0.13 to -0.09) No Sjauw et al. Eur Heart J 2009;30:

15 Trial Flow and Treatment 790 patients with AMI and cardiogenic shock screened 600 randomized 190 excluded because of exclusion criteria - 60 no informed consent - 47 resuscitation >30 minutes - 19 shock duration >12 hours - 18 severe peripheral artery disease - 14 participation in another trial - 13 no intrinsic heart activity - 9 mechanical complication - 3 shock of other cause - 3 comorbidity with life expectancy <6 months - 2 severe cerebral deficit - 2 age >90 years 301 randomized to 288 received 13 did not receive - 10 died before insertion - 3 protocol violation (2 not suitable for revascularization, 1 serious kinking) 301 intended early revascularization 287 primary PCI 3 primary CABG 11 no revascularization - 3 not suitable for revascularization - 4 coronary artery disease with no identifiable culprit lesion - 4 no coronary artery disease Allocation Revascularization 299 randomized to control 269 received control therapy 30 cross-over to (22 first day, 8 day 1-8) - 4 mechanical complications - 25 protocol violation - 1 unknown reason 299 intended early revascularization 288 primary PCI 3 primary CABG 8 no revascularization - 1 not suitable for revascularization - 2 coronary artery disease with no identifiable culprit lesion - 5 no coronary artery disease 300 with 30-day follow-up - 1 lost to follow-up 300 primary endpoint analysis Follow-up Primary endpoint analysis 298 with 30-day follow-up - 1 withdrew informed consent 298 primary endpoint analysis Thiele et et al. al. NEJM 2012;367:

16 Serum lactate (mmol/l) Serum Lactate Thiele et al. NEJM 2012;367: P=0.09 P=0.43 Control P=0.12 P= P=0.32 P=0.32 P= Baseline 8 h 16 h 24 h 32 h 40 h 48 h

17 Mortality (%) Primary Study Endpoint (30-Day Mortality) Control 41.3% 39.7% P=0.92; log-rank test Relative risk 0.96; 95% CI ; P=0.69; Chi 2 -Test Time after randomization (days) Thiele et al. NEJM 2012;367:

18 Baseline Variable Subgroups (30-Day Mortality) N 30-Day Mortality (%) Control Relative Risk (95% CI) P-Value for Interaction Female Male ( ) 0.92 ( ) 0.61 Age <50 years Age years Age >75 years ( ) 0.95 ( ) 1.07 ( ) 0.09 Diabetes No diabetes ( ) 0.96 ( ) 0.82 Hypertension No hypertension ( ) 0.67 ( ) 0.05 STEMI/LBBB NSTEMI ( ) 0.98 ( ) 0.76 Anterior STEMI Non-anterior STEMI ( ) 1.16 ( ) 0.14 Previous infarction No previous infarction ( ) 0.86 ( ) 0.04 Hypothermia No hypothermia ( ) 0.89 ( ) 0.31 Blood pressure <80 mmhg Blood pressure 80 mmhg ( ) 0.92 ( ) Control Thiele et al. NEJM 2012;367:

19 Mortality 60% 50% 40% 30% Mortality 12-Month Follow-up 30-day Mortality 41.3% 39.7% 6-Month Mortality 48.7% 49.2% P=0.94; log-rank test Relative risk 1.02; 95% CI Month Mortality 51.8% 51.4% Control 20% 10% No. at risk Control 0% Days after randomization Thiele et al. Lancet 2013;382:

20 Mortality Mortality 12-Month Follow-up As Treated P=0.94; log-rank test Relative risk 1.02; 95% CI % 50% Control 40% 30% 20% P=0.41; log-rank Test Relative Risk 0.97; 95% CI ; P=0.68; Chi 2 -Test 10% 0% Days after randomization Thiele et al. Lancet 2013;382:

21 Subgroups (12-Month Mortality) Baseline Variable N 12-Month Mortality n (%) Control Relative Risk (95% CI) P-Value for Interaction Female Male (57.6) 98 (49.0) 48 (55.2) 104 (49.8) 1.06 ( ) 1.00 ( ) 0.72 Age <50 years Age years Age >75 years (25.0) 75 (48.4) 71 (65.7) 16 (47.1) 79 (44.6) 57 (67.1) 0.71 ( ) 1.07 ( ) 0.96 ( ) 0.13 Diabetes No diabetes (54.3) 95 (50.0) 53 (59.0) 99 (48.1) 0.90 ( ) 1.04 ( ) 0.45 History of hypertension No history of hypertension (57.6) 29 (35.4) 102 (51.5) 50 (51.0) 1.14 ( ) 0.76 ( ) 0.02 STEMI/LBBB NSTEMI (50.5) 53 (54.6) 106 (50.0) 46 (54.8) 1.01 ( ) 1.00 ( ) 0.94 Anterior STEMI Non-anterior STEMI (47.0) 49 (55.1) 52 (50.5) 54 (49.5) 0.93 ( ) 1.12 ( ) 0.36 Previous infarction No previous infarction (62.0) 111 (49.0) 31 (51.7) 121 (51.3) 1.27 ( ) 0.95 ( ) 0.20 Hypothermia No hypothermia (53.0) 100 (51.3) 67 (56.3) 85 (48.0) 0.93 ( ) 1.10 ( ) 0.43 Blood pressure <80 mmhg Blood pressure 80 mmhg (58.0) 108 (49.5) 48 (55.2) 104 (49.8) 1.07 ( ) 1.00 ( ) Control Thiele et al. Lancet 2013;382:

22 Randomized Trials in Cardiogenic Shock Trial Follow-up n/n n/n Revascularization (PCI/CABG) SHOCK SMASH Total 1-year 30 days 76/152 22/32 103/184 83/149 18/23 117/172 Relative Risk 95% CI Relative Risk 95% CI 0.80 (0.66;0.98) 0.87 (0.66;1.29) 0.82 (0.70;0.98) Catecholamines SOAP II (CS Subgroup) Glycoprotein IIb/IIIa-Inhibitors PRAGUE-7 NO Synthase Inhibitors TRIUMPH SHOCK-2 Cotter et al Total -SHOCK I -SHOCK II Total 28 days 64/145 50/135 Early revascularization Norepinephrine Medical treatment Dopamine 0.75 (0.55;0.93) In-hospital 15/40 13/ (0.59;2.27) 30 days 30 days 30 days 30 Tage 30 Tage 97/201 24/59 4/15 125/275 7/19 119/ /319 76/180 7/20 10/15 93/215 6/21 123/ /319 Up-stream Abciximab NO Synthase Inhibition Standard treatment Placebo Standard treatment 1.14 (0.91;1.45) 1.16 (0.59;2.69) 0.40 (0.13;1.05) 1.05 (0.85;1.29) 1.28 (0.45;3.72) 0.96 (0.79;1.17) 0.98 (0.81;1.18) Updated Thiele et al. Eur Heart J 2010; 31:

23 Overview Mechanical Placebo Hemodynamic effects in cardiogenic shock

24 ESC Revascularization Guidelines 2014 in cardiogenic shock ESC Class IC IIb B III?

25 Treatment Algorithm Medical therapy Inotropic support Vasopressor support Fluids Ventilatory support Revascularization Patient unstable LVAD support* Patient stable Weaning Cardiac function recovers No cardiac function recovery Cardiac function recovers Weaning Assess neurology / end organ function Impaired neurological function Normal neurological function Standard therapy Weaning Age, comorbidities? Destination therapy Consider surgical LVAD / BiVAD Age, comorbidities? Heart transplantation Thiele et al, EAPCI Textbook 2012; Kapitel 23

26 Cardiogenic Shock - Guidelines Steg et al. Eur Heart J.2012;33:

27 N Patients Stop no effect Stop slow recruitment Underpowered Stop slow recruitment Surrogate endpoint Patient Inclusion in Cardiogenic Shock Trials

28 Thank you for your attention

29 Randomized Trials in Cardiogenic Shock Trial Follow-up n/n n/n Revascularization (PCI/CABG) SHOCK SMASH Total 1-year 30 days 76/152 22/32 103/184 83/149 18/23 117/172 Relative Risk 95% CI Relative Risk 95% CI 0.80 (0.66;0.98) 0.87 (0.66;1.29) 0.82 (0.70;0.98) Catecholamines SOAP II (CS subgroup) Glycoprotein IIb/IIIa-Inhibitors PRAGUE-7 NO Synthase Inhibitors TRIUMPH SHOCK-2 Cotter et al Total -SHOCK I 28 days 64/145 50/135 Early revascularization Norepinephrine Medical treatment Dopamine 0.75 (0.55;0.93) In-hospital 15/40 13/ (0.59;2.27) 30 days 30 days 30 days 97/201 24/59 4/15 125/275 76/180 7/20 10/15 93/ days 7/19 6/21 Up-stream Abciximab NO Synthase Inhibition Standard treatment Placebo 1.14 (0.91;1.45) 1.16 (0.59;2.69) 0.40 (0.13;1.05) 1.05 (0.85;1.29) 1.28 (0.45;3.72) LVAD Thiele et al Burkhoff et al Seyfarth et al Total 30 days 30 days 30 days 9/21 9/19 6/13 24/53 9/20 5/14 6/13 20/47 LVAD Standard treatment 0.95 (0.48;1.90) 1.33 ( ) 1.00 ( ) 1.06 ( ) Thiele et al. Eur Heart J 2010; 31:

30 Thiele et al. NEJM 2012;367: Catecholamines Control P- Value Catecholamine; n/total (%) Dopamine Norepinephrine Epinephrine Dobutamine 15/298 (5.0) 220/298 (73.8) 76/298 (25.5) 160/298 (53.7) 11/297 (3.7) 222/297 (74.8) 80/297 (26.9) 156/297 (52.5) Catecholamine dose (μg/kg/min); median (IQR) Dopamine Norepinephrine Epinephrine Dobutamine 4.1 ( ) 0.3 ( ) 0.3 ( ) 10.2 ( ) 4.2 ( ) 0.4 ( ) 0.3 ( ) 9.0 ( )

31 STEMI - versus no - Metaanalysis Sjauw et al. Eur Heart J 2009;30:

32 Study Design Patel et al. JAMA 2011;306: MRI Core Lab University of Leipzig Heart Center USA Ireland U.K. Netherlands Belgium Germany France Italy Anterior MI without Shock pre PCI Randomised Open Label (n ~ 300) Min. 12 h post PCI Standard-PCI Inclusion criteria Anterior STEMI 2 mm in 2 contiguous leads or > 4 mm in anterior leads Planned primary PCI < 6 h India Routine Post PCI Treatment Cardiac MRI Day 3-5 post PCI Primary Endpoint: Infarct size in MRI 1. All Patients with MRI data 2. Patients with prox. LAD-occlusion TIMI 0/1 flow Australia Clinical Events 6 Months

33 Primary Endpoint Infarct Size Patel et al. JAMA 2011;306: Primary endpoint All (N=337) (N=161) Standard PCI (N=176) Infarct size (% LV), modified ITT all patients with MRI data 0.06 N Mean Median P Infarct size (% LV), modified ITT patients prox. LAD + TIMI flow 0/ N Mean Median