The extracorporeal life support in patients with acute myocardial infarction complicated by cardiogenic shock (ECLS-shock) trial in perspective

Presenter: H. Tiele Cardiogenic shock (CS) is a life-threatening low cardiac output state resulting in end-organ hypoperfusion that complicates 6–10% of patients with an ST-segment elevation myocardial infarction (MI).1,2 In-hospital mortality rates despite revascularization are reported to be 40−50% and vary widely based on presenting CS Society for Cardiovascular Angiography and Interventions (SCAI) stage, underlying pathology, hemodynamics, and degree of end-organ hypoperfusion.1,3–5 Extracorporeal membrane oxygenation (ECMO) is a form of temporary mechanical circulatory support (tMCS) that provides robust bi-ventricular, oxygenation, and ventilatory support, and it has the potential to reverse and/or prevent vital end-organ hypoperfusion.6 Despite a paucity of high-quality evidence, there has been significant growth in its utilization in patients with CS.7,8 There have been two randomized controlled trials that have evaluated the efficacy and safety of ECMO in patients with CS published in the last year. The ECMO-CS trial enrolled 122 patients from four centres in the Czech Republic and reported no difference in the primary outcome of 30-day all-cause mortality, resuscitated cardiac arrest, or tMCS implantation.3 The study was not adequately powered for the endpoint of morality or cardiac arrest, and limitations included an unvalidated CS definition, and high protocolized cross-over to tMCS in the early conservative therapy arm which precluded a true comparison to medical therapy alone.9,10 EURO-Shock trial randomized 33 patients with persistent CS after primary percutaneous coronary intervention but was stopped before completion of recruitment.11 The authors reported no significant difference in morality, but vascular and bleeding complications were more frequent in the ECMO arm. Thus, no previous trials of patients with CS have been adequality powered to evaluate if timely ECMO support can reduce mortality. The ExtraCorporeal Life Support in patients with acute MI complicated by CS (ECLS [extra corporeal life support]-shock) trial is the largest randomized control trial of ECMO in patients with CS and the only study to date that is powered for a primary endpoint of all-cause mortality.12 ECLS-shock was designed to evaluate the efficacy and safety of ECMO in addition to early revascularization (with percutaneous coronary intervention or coronary artery bypass grafting) and optimal medical care in patients presenting with an acute MI complicated by CS.12 The primary outcome was 30-day all-cause mortality. Secondary clinical endpoints included length of mechanical ventilation and catecholamine support, intensive care and hospital lengths-of-stay, and acute renal failure. The safety endpoints included peripheral vascular complications requiring percutaneous or surgical intervention, Bleeding Academic Research Consortium (BARC) 3–5 bleeding, and stroke (ischaemic and haemorrhagic) or systemic embolism. ECLS-shock was an international, multi-center, open-label, and randomized controlled trial. Patients were randomized to ECMO plus medical therapy and revascularization or medical therapy and revascularization with escalation to another tMCS support device if necessary. Patients were allowed to cross-over to another tMCS device (IABP, Impella™ or Tandem Heart™) based on the following pre-specified criteria: (i) severe haemodynamic instability with impending haemodynamic collapse (resuscitation or excessive vasoactives); (ii) increase in lactate >3 mmol/L over 6 h h; or (iii) ≥ 50% increase in vasopressor dosing maintain mean arterial blood pressure >65 mmHg. Culprit-only percutaneous coronary intervention was preferred with future staging of the non-culprit lesion. Coronary artery bypass grafting could be considered with anatomy unsuitable for percutaneous revascularization. Notably, the study recommends treatment of left main stenoses or triple vessel disease should be revascularized by PCI whenever possible. The study’s planned sample size of 420 patients (including a 6% dropout rates) has an 80% power to detect a 14% absolute reduction in mortality in the ECLS arm. All endpoints were adjudicated by a Clinical Events Committee blinded to treatment assignment. A Data Safety Monitoring Board oversaw study safety. Patients 18–80 years of age were eligible for the study if they presented with either an ST- or non-ST segment elevation MI complicated by CS. The CS definition required an arterial lactate measurement > 3 mmol/L, in addition, a systolic blood pressure <90 mmHg >30 min or vasoactive agents to systolic pressure >90, and at least 1 organ hypoperfusion criteria (altered mental status, cold/clammy skin, or urine output <30 mL/h). Selected exclusion criteria included >45 min of resuscitation, MI mechanical complications, CS > 12 h, non-cardiac causes of shock, and life-expectancy <6 months. Patients not eligible for the study were enrolled in a prospective registry. The study enrolled 420 patients from 44 centres and the final study population was 417 patients.13 The median age of participants was 63 years, 81% were male, the median lactate was 6.8 mmol/L, and 52% of patients were categorized as SCAI CS stage C. A total of 78% of the study population experienced cardiopulmonary resuscitation (CPR) with a median of 20 min to return spontaneous circulation. Overall, 92% of patients that were assigned to ECMO were cannulated; among whom 52% were cannulated after revascularization and 5.8% received left ventricular unloading. In the control arm, 12.5% of patients crossed over to ECMO therapy and an additional 15.4% received other forms of tMCS. The primary outcome occurred in 47.8% of the ECLS arm and 49.0% of the control group [relative risk (RR), 0.98: 95% confidence interval (CI), 0.80–1.19; P = 0.81]. No significant interactions were observed in key subgroups when the mortality was stratified by age (≥ or <65), sex, Lactate levels (> or ≤ 6 mmol/L), or the provision of CPR. No differences were observed in the duration of catecholamine support, intensive care, and hospital lengths-of-stay, or incidence of renal failure. The median duration of mechanical ventilation was 1 (95% CI, 0–2) days longer in the ECLS arm. Both bleeding (23.4% vs. 9.6%; RR 2.44: 95% CI, 1.50–3.95) and peripheral vascular complications requiring intervention (11.0% vs. 3.8%; RR 2.86: 95% CI, 1.31–6.25) were significantly higher in the ECLS arm, respectively. No significant differences in the incidence of stroke of systemic embolism were observed (3.8% vs. 2.9%; RR 1.33: 0.47–3.76). ECMO cannulation was protocolized as femoral percutaneous access and did not allow for surgical side-grafts, subclavian, or central support. Left ventricular venting was protocolized if there was no arterial waveform pulsatility, no aortic valve opening assessed by echocardiogram, a left ventricular outflow tract time-velocity interval < 10 cm, or an increased left ventricular diameter. Pulmonary arterial catheterization monitoring was not protocolized and venting based on rising wedge pressures, pulmonary oedema, or north–south syndrome was not protocolized. All forms of left ventricular venting were accepted. Standardized ECMO weaning criteria were provided in the trial. The cause of death was determined to be refractory CS in approximately 53% and brain injury in 26% of the overall trial population with no differences between study arms. The ECLS-shock trial investigators should be congratulated for their remarkable effort in conducting a rigorous and robust randomized clinical trial powered for mortality in the setting of CS-complicating acute MI. Despite the disappointing results, the results of the ECLS trial provide high-quality evidence that should immediately influence current clinical practice. The routine utilization of ECMO in all patients with CS can no longer be supported given the lack of efficacy for meaningful clinical outcomes benefit, the increased cost and resource utilization together with the risk of bleeding and peripheral vascular complications. The benefits of an early revascularization strategy for CS-complicating MI were reported nearly 25 years ago and dramatically decreased mortality in this setting.14 The results of the ECLS-shock trial are a sober reminder that little further progress has been made in patients with a MI complicated by CS. Despite the development, maturation, and exponential increase in the utilization of reliable, tMCS devices, convincing evidence as to their clinical benefit remains lacking. The ECLS-shock investigators have shown us that well-done clinical trials in this challenging environment are feasible and can be accomplished. Their success in trial conduct will hopefully increase the design, conduct, and generation of high-level evidence in the CS setting. The rationale for the utilization of tMCS in CS complicating acute MI though simplistic, is sound. Preventing end-organ injury by supporting the circulation while facilitating revascularization and allowing recovery of salvaged jeopardized myocardium makes intuitive sense. The ECLS-shock trial however is not without limitations. If the benefits of revascularization in patients with late presentation and poor myocardial salvage or minimal residual contractile reserve are small to absent, the act of supporting the circulation only serves to delay the inevitable. While advanced heart failure options as an exit strategy may be considered, only two patients amongst the 417 enrolled in the trial went onto a durable left ventricular assist device or transplant highlighting the fact that these strategies remain rarely utilized/available in this setting. Secondly, the utilization of MCS will not improve mortality in patients with a cardiac arrest-associated hypoxic-ischaemic brain injury.15 While outcomes for patients experiencing cardiac arrest before randomization were similar to their nonarrest counterparts, our ability to identify irreversible neurological injury early remains elusive. In this current scenario, although a significant proportion of CS patients experience cardiac arrest, it may be reasonable to exclude these patients from future trials evaluating MCS so as not to miss a potential signal of benefit. The utilization of ECMO in the current trial was predominantly via the femoral-femoral approach and despite protocol guidance, venting strategies were minimally adopted. While alternate vascular approaches and more universal venting strategies may have modified outcome, it is unlikely to have altered the overall trial results. Overall, we believe the current studies signal that ECMO should not be used routinely for patients with CS. Three randomized controlled trials have shown a lack of efficacy and significant safety concerns with ECMO cannulation; thus, revascularization and medical therapies remain CS therapeutic cornerstones. The current trial however does not herald the end of the road for tMCS devices in this setting. Foremost, the ongoing ANCHOR trial may yield important additional insights into the efficacy and safety of ECMO with an intra-aortic balloon pump in a similar population. Future ECMO studies should also consider enhancing CS acuity by enrolling patients who are objectively unlikely to survive with medical therapy alone e.g. advanced SCAI D, early SCAI E, or CS associated with refractory hypoxia due to pulmonary oedema. The role for better tolerated, isolated LV support and unloading utilizing the Impella™ device is currently being tested in the DANGER shock trial and RECOVER-IV trials.16 Undoubtedly the ECLS-shock trial will also help inform patient selection and timing of support in future trials evaluating MCS utilization in CS complicating MI. Although elusive, the battle to reduce the unacceptably high mortality and morbidity with CS complicating acute MI continues. None declared. Data sharing not applicable; no new data generated.

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