Testing the Value of Novel Strategy and Its Cost Efficacy in Order to Improve the Poor Outcomes in Cardiogenic Shock (EUROSHOCK)

Testing the Value of Novel Strategy and Its Cost Efficacy in Order to Improve the Poor Outcomes in Cardiogenic Shock

EURO SHOCK Testing the Value of Novel Strategy and Its Cost Efficacy in Order to Improve the Poor Outcomes in Cardiogenic Shock

European Commission, University of Glasgow, KU Leuven, University of East Anglia, Deutsches Herzzentrum Muenchen, A.O. Ospedale Papa Giovanni XXIII, Chalice Medical Ltd, Ludwig-Maximilians - University of Munich, University of Tromso, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Paula Stradina Liniska Universitates, Accelopment AG, Universiteit Antwerpen, Cardiovascular European Research Centre (CERC)

Cardiogenic shock (CGS) affects up to 10% of patients suffering acute coronary syndrome. It has a 30 day mortality of 45-50%. No pharmacological nor intervention/device trials have had any impact on this mortality in the last 20 years. The EURO SHOCK Trial (supported by the European Union Horizons 2020 programme) will randomise 428 patients with CGS following acute coronary syndrome from 44 EU centres to early intervention with Extra Corporeal Membrane Oxygenation (ECMO) therapy or to standard treatment (with no ECMO). This intervention is a high cost specialist centre procedure that warrants further investigation including economic appraisal. Multiple mechanistic and hypothesis generating sub-studies will be undertaken.

The EURO SHOCK trial tests the novel use of early deployment of mechanical support device in Cardiogenic Shock (CGS) in a randomised, strategy trial, with evidence of benefit or otherwise measured by recording hard clinical end-point outcomes. Extra Corporeal Membrane Oxygenation (ECMO) is already used in CGS. This is therefore not a novel therapy. It is the use of ECMO early in the development of CGS that is the novel aspect of this project. The Investigators will test whether a strategy of very early ECMO can ameliorate the rapid decline that many CGS patients suffer. The value of deploying a clinically used and approved device prospectively and early in the natural history of CGS compared to standard practice has not been tested before and will be the basis of the EURO SHOCK project. This trial itself will be a prospective randomized, open label, design study that will compare two groups of patients: Both will receive appropriate percutaneous coronary intervention (PCI) as is current practice as they arrive at the hospital. Group 1 will receive immediate PCI + standard care (pharmacological support). Group 2 will receive immediate PCI plus support with early peripheral veno-arterial ECMO + standard care (pharmacological support). The Investigators will also compare the cost-effectiveness of early VA-ECMO, as compared to current standard of care. EURO SHOCK will also evaluate novel CMR protocols in these unwell patients, and also whether systems of urgent flagged transfer of the unwell patient is practical and beneficial. The Investigators will determine whether there are biological and ECG markers that predict worse patient outcomes, which could thus help select most appropriate patients for expedited treatments (the patient is only transferred if needed). Although at the centre of the project there is a randomised trial, other important objectives will therefore be delivered. The research study will additionally focus, through a-priori, post-hoc analyses, on higher risk and vulnerable sub groups such as the elderly (>75 years) and females, the importance of site of infarct and on those with multi-morbidities such as diabetes. These post-hoc data will be published separately. The trial will include patients with out of hospital cardiac arrest (OHCA) who have documented return of spontaneous circulation (ROSC) but with certain caveats (see exclusion criteria). The primary outcome is the all-cause mortality at 30 days following admission with acute coronary syndrome with cardiogenic shock. Key secondary outcomes will include all- cause mortality or admission with heart failure at 12 months, all-cause mortality at 12 months and admission to hospital with heart failure at 12 months. A cornerstone of this research programme will be to determine the cost-efficacy of ECMO in this setting. Cost benefit will be measured both immediately and in the longer term testing for example any impact of need for heart failure therapies. This will be undertaken with evaluations of the cost-effectiveness of the device and evaluation of quality of life using the EuroQuol-5D-5L and the Minnesota Living with Heart Failure Questionnaire. The EUROSHOCK trial will also include the following sub-studies: Cardiovascular MRI: Cardio-Renal Imaging Sub-study using novel shortened, non-breath-holding protocols. Platelet Function Sub-study designed to access the impact of novel ECMO coatings on platelet activation. The programme will be developed and run through a carefully thought through management structure comprising 8 separate but interlinked work programmes (each targeted at one aspect of the project and headed by an experienced clinical trialist or trial manager) and involve the dissemination of results through a designated dissemination work package. Attention to translating the results to subsequent on-the-ground patient care will be an important aim for the management and dissemination team, and will involve patient support groups, professional societies and information delivered directly to the medical and non- medical staff caring for CGS patients.

Group 1 will receive immediate revascularisation with Percutaneous Coronary Intervention (PCI) to the culpirit lesion only) + standard care (pharmacological support titrated to attain SBP >90mmHg). No mechanical support device allowed.

Group 2 will receive immediate PCI plus standard pharmacological support with early peripheral veno-arterial ECMO.

Primary PCI or early/immediate PCI for NSTEMI will be undertaken according to recommended Guideline standards of care. This will include appropriate pre-loading with dual anti-platelet therapy, a preferred radial approach, intra-procedural anti-coagulation (with measure of ACT if considered appropriate every 30 minutes) and the use of drug eluting stents. Treatment will be delivered essentially to the culprit vessel only. A successful procedure will be one considered to have achieved TIMI 2-3 flow and residual stenosis < 50%. PCI failure will not be an exclusion itself from the trial.

Use of pharmacological agents (Norepinephrine, Dobutamine, Levosimendan) according to ESC Guidelines to maintain mean arterial pressure >75 mmHg in accordance with recognised standards of care. Changes in pharmacotherapy will NOT be regarded as escalation therapy. However the number of and dose of inotropes will be documented in the CRF.

Following PCI of the culprit lesion, patients will have ECMO initiated as soon as echocardiography (to exclude mechanical causes) has been completed, once they have been assessed as having failed to improve (with the aim to start ECMO as early as possible from 30 mins after completed P-PCI procedure ad fully established within 6 hours after randomisation). Peripheral Veno-arterial ECMO will be employed with a flow rate according to individual patient needs. Other methods of LV unloading, distal limb perfusion, maintenance of ejection/aortic valve opening and anti-coagulation will be instituted as per sites' usual care. A minimum 24 hours be allocated to the randomised therapy in order that strategy failure is demonstrated but this will be at the physicians' discretion.

Death from any cause, or admission to hospital for heart failure with typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.

Admission to hospital with clinical syndrome of heart failure, defined as per the ESC guidelines as typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.

Death due to cardiovascular causes, including myocardial infarction, heart failure, cardiac arrhythmias, stroke, and sudden death suspected from cardiac aetiology.

Acute neurological deficit lasting longer than 24 hours. The type of stroke will be categorised as: 1) Primary Haemorrhagic: either intracranial haemorrhage or subdural haematoma. 2)non-hemorrhagic cerebral infarction. 3)non-hemorrhagic cerebral infarction with haemorrhagic conversion. 4)Uncertain (any stroke without brain imaging [CT or MRI] or autopsy definition of type, or if tests are inconclusive).

Defined as the presence of ischaemic symptoms of angina-type pain lasting longer than 20mins, its evidence of either ST-segment elevation/new Left Bundle Branch Block on ECG, or evidence of new Troponin elevation by greater than 20% of the last non-normalised reading, or angiographic evidence of re-occlusion of a previously opened artery or graft.

Evidence of Bleeding as per the Bleeding Academic Research Consortium classification Type 3, Type 4 or Type 5.

The use of either Impella or Tandem-Heart or LVAD support devices in patients with persistent cardiogenic shock despite revascularisation and uptitation of pharmacological support. Use of ECMO or non ECMO MSD in standard care group or to non ECMO device in intervention (ECMO) group will be regarded as a protocol violation and managed statistically as such in the final analysis.

Complications affecting the peripheral vasculature, defined by the Valve Academic Research Consortium (VARC)-2 classifications.

Evidence of Acute Kidney Injury according to the RIFLE (Risk, Injury, Failure, Loss and End-stage kidney disease) classification stage 1 - 3.

combined endpoint of all-cause mortality, repeat MI, stroke and re-hospitalization for heart failure.

Death due to cardiovascular causes, including myocardial infarction, heart failure, cardiac arrhythmias, stroke, and sudden death from cardiac aetiology.

Defined as the presence of ischaemic symptoms of angina lasting longer than 20mins, its evidence of either ST-segment elevation/new Left Bundle Branch Block on ECG, or evidence of new Troponin elevation by greater than 20% of the last non-normalised reading, or angiographic evidence of re-occlusion of a previously opened artery or graft.

Acute neurological deficit lasting longer than 24 hours. The type of stroke will be categorised as: 1) Primary Haemorrhagic: either intracranial haemorrhage or subdural haematoma. 2)non-hemorrhagic cerebral infarction. 3)non-hemorrhagic cerebral infarction with haemorrhagic conversion. 4)Uncertain (any stroke without brain imaging [CT or MRI] or autopsy definition of type, or if tests are inconclusive).

Need for unplanned (Ischaemia-Driven) repeat revascularization (PCI and/or CABG) after index procedure [staged procedures excluded]

REvascularisation procedure (either PCI or CABG) undertaken after index procedure in the context of ischaemic symptoms and evidence of myocardial ischaemia (ECG, stress perfusion scan, acute myocardial infarction) either to the culprit or non-culprit lesion. Planned elective staged procedures to the non-culprit lesion will not be included.

Patient remains an in-patient in hospital for on-going medical care following the index admission with acute coronary syndrome complicated by cardiogenic shock.

Evidence of Bleeding as per the Bleeding Academic Research Consortium classification Type 3, Type 4 or Type 5.

The size of myocardial infarction, quantified as the percentage of myocaridum demonstrating late gadolinium enhancement consistent with acute myocardial injury.

The cost effectiveness of using early ECMO in patients with cardiogenic shock complicating acute myocardial infarction will be assessed using the Incremental Cost Effectiveness Ratio (ICER)

Assess the participants' general health status and self-reported quality of life using the EQ5D questionnaire. This is a 5 level EQ-5D standardised measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EuroQuol (EQ)-5D-5L questionnaire assesses quality of life in study participants according to 5 domains (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each scored according to a scale of 1 (no problems) to 5 (indicating extreme problems) and generating a 5-digit code corresponding to quality of life. This will be used at discharge, 6 months and 12 months, and the within-subject change in EQ-5D-5L scores will be measured for this secondary outcome.

Quality of Life assessed using the Minnesota Living with heart failure questionnaire (measured at discharge, 6 and12 months)

This is a standardised measure of quality of life for patients living with heart failure. The questionnaire includes 21 physical, emotional and socio-economic ways in which heart failure can adversely affect the patients life, each domain is scored from 0 to 5 indicating how much heart failure has prevented the patient from living how he or she wanted to live over the preceding 4 weeks. This will be assessed for each patient at time of discharge, at 6-months and again at 12 months. The within-subject change in the MLFHQ questionnaire will be measured for each group.

Inclusion Criteria: Willing to provide informed consent/assent. Presentation CGS within 24 hours of onset of Acute Coronary Syndrome (ACS) symptoms. CGS can only be secondary to ACS (Type 1 MI STEMI or N-STEMI) or secondary to ACS following previous recent PCI (acute/sub-acute stent thrombosis ARC) PCI has been attempted. Persistence of CGS 30 minutes after successful or unsuccessful revascularisation of culprit coronary artery to allow for echocardiography and clinical assessment. CGS will be defined by the following 2 criteria: • Systolic blood pressure <90 mmHg for at least 30 minutes, or a requirement for a continuous infusion of vasopressor or inotropic therapy to maintain systolic blood pressure > 90 mmHg. Clinical signs of pulmonary congestion, plus signs of impaired organ perfusion with at least one of the following manifestations: altered mental status. cold and clammy skin and limbs. oliguria with a urine output of less than 30 ml per hour. elevated arterial lactate level of >2.0 mmol per litre. Provision of informed assent followed by patient consent; [or relative or physician consent if the patient is unable to consent]. Exclusion Criteria: Unwilling to provide informed assent/consent. Echocardiographic evidence) of mechanical cause for CGS: eg ventricular septal defect, LV-free wall rupture, ischaemic mitral regurgitation (recorded within 30 mins of end of PCI procedure). Age <18 and>90 years. Deemed appropriately frail (≥ 5 Canadian frailty score) Shock from another cause (sepsis, haemorrhagic/hypovolaemic shock, anaphylaxis, myocarditis etc.). Significant systemic illness Known dementia of any severity. Comorbidity with life expectancy <12 months. Severe peripheral vascular disease (precluding access making ECMO contra- indicated). Severe allergy or intolerance to pharmacological or antithrombotic anti-platelet agents. Out-of-hospital cardiac arrest (OHCA) under any of the following circumstances:- without return of spontaneous circulation (ongoing resuscitation effort). without pH or >7 without bystander CPR within 10 minutes of collapse. Involved in another randomised research trial within the last 12 months. Arterial lactate level of <2.0 mmol per litre.