The extracorporeal membrane oxygenation in the therapy of cardiogenic shock (ECMO-CS) trial in perspective

Patients with cardiogenic shock suffer unacceptable morbidity and mortality with the rate of in-hospital death ranging from 30 to 50% depending on the subtype of cardiogenic shock and severity at presentation.1 Haemodynamic stabilization and restoration of end-organ perfusion with temporary mechanical circulatory support remains an attractive proposed intervention to reduce irreversible end-organ dysfunction and improve survival.2 However, the only adequately powered randomized trial to address this hypothesis demonstrated no benefit of intra-aortic balloon counter-pulsation in patients with cardiogenic shock due to acute myocardial infarction.3 Nevertheless, it is possible that advanced temporary mechanical circulatory devices that provide greater augmentation or replacement of cardiac output would improve outcomes. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) can provide >5 L/min of flow and observational studies have suggested the possibility of favourable outcomes using VA-ECMO in patients with refractory cardiogenic shock.4,5 However, to date, no adequately sized randomized outcome trials of VA-ECMO in this population have been completed. One trial was terminated prematurely due to inadequate recruitment.6 Three randomized trials of VA-ECMO have remained ongoing,7–9 of which the Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS) trial has now been reported and is discussed herein.10 The aim of the ECMO-CS trial was to assess the efficacy and safety of immediate VA-ECMO vs. early conservative therapy for rapidly deteriorating or severe cardiogenic shock. The primary efficacy endpoint, evaluated at 30 days, was a composite of death from any cause, resuscitated circulatory arrest, or implantation of another mechanical circulatory support device. Secondary endpoints included all-cause mortality and neurological outcomes (using cerebral performance score). Safety endpoints included bleeding, leg ischaemia, infections, and technical complications. ECMO-CS was a multicentre, randomized, parallel group, unblinded trial with blinded endpoint assessment. Patients with deteriorating or severe cardiogenic shock were randomized to either immediate VA-ECMO support or early conservative therapy. Except for immediate VA-ECMO implantation, all other diagnostic and therapeutic procedures were to be provided according to the standard of care at the participating centre. Implantation of other mechanical support devices, including VA-ECMO, was permitted in the control (‘conservative’) group if shock was progressing with a rise in serum lactate by ≥3 mmol/L during the prior 24 h. The study was designed with a planned sample size of 120 participants to provide 80% power to detect a 50% relative reduction in the primary endpoint, assuming 40% mortality and 20% incidence of an advanced temporary mechanical circulatory support device implantation in the early conservative arm. Eligible patients met the following inclusion criteria: Rapidly deteriorating cardiogenic shock, defined as progressive haemodynamic instability necessitating repeated bolus administration of vasopressors to maintain mean arterial pressure >50 mmHg + left ventricle ejection fraction (LVEF) < 35% or LVEF 35–55% in case of severe mitral regurgitation or aortic stenosis. or Severe cardiogenic shock defined by meeting both haemodynamic and metabolic criteria in the absence of hypovolaemia. Haemodynamic: Cardiac index < 2.2 L/min/m2 + norepinephrine dose >0.1 μg/kg/min + dobutamine dose >5 μg/kg/min or systolic blood pressure <100 mmHg + norepinephrine dose >0.2 μg/kg/min + dobutamine dose >5 μg/kg/min + (LVEF <35% or LVEF 35–55% + severe mitral regurgitation or aortic stenosis) Metabolic: Lactate—two consecutive values ≥3 mmol/L (with ≥30 min between samples), with a non-decreasing trend on steady doses of inotropes and/or vasopressors or SvO2—two consecutive values <50% (≥30 min apart), with a non-increasing trend on steady doses of inotropes and/or vasopressors Hypovolaemia excluded by central venous pressure >7 mmHg or pulmonary capillary wedge pressure >12 mmHg Selected exclusion criteria: Comatose state after cardiac arrest, known encephalopathy, life expectancy <1 year, high suspicion of pulmonary emboli or cardiac tamponade as a cause of shock, significant bradycardia or tachycardia as the cause of instability, hypertrophic obstructive cardiomyopathy, aortic dissection, moderate-to-severe aortic insufficiency, peripheral artery disease prohibiting femoral cannulation, or uncontrolled bleeding. Although not included explicitly as part of the inclusion criterion, the entry criteria were most consistent with Society for Cardiovascular Angiography and Interventions (SCAI) cardiogenic shock stages D and E. Left ventricular venting and leg ischaemia prophylaxis protocols were not defined in the protocol. Between September 2014 and August 2022, four centres in the Czech Republic enrolled 122 patients with shock and 117 patients (45 patients with rapidly deteriorating cardiogenic shock and 72 with severe cardiogenic shock) were included in the primary analysis. The median age was 66 years (range 25–86 years) and the most common underlying aetiology was ST-segment elevation myocardial infarction (50.4%). The median baseline lactate and vasoactive-inotropic scores were 5.3 mmol/L and 59.9 in the ECMO arm and 4.7 mmol/L and 61.0, respectively, in the conservative arm. There was not a significant difference in the primary composite endpoint between the early ECMO (63.8%) and conservative (71.2%) arms (hazard ratio, 0.72; 95% confidence interval, 0.46–1.12; P = 0.21). There was no difference in all-cause death at 30 days (50.0 vs. 47.5%), or resuscitated cardiac arrest (10.3 vs. 13.6%) between the ECMO and early conservative arms. Downstream mechanical circulatory support device use was higher in the early conservative arm (17.2 vs. 42.4%) with 23 of 25 new devices in the conservative group being VA-ECMO. There was not a difference in cerebral performance category scores between treatment arms. There was no heterogeneity in the primary result between the two groups of patients with qualifying cardiogenic shock. Total adverse events did not differ between the two randomized treatment groups (60.3 vs. 61.0%). However, trends towards higher rates of bleeding (31 vs. 20%) and limb ischaemia (14 vs. 5%) were present in the group allocated to immediate VA-ECMO. In this modestly sized, randomized, controlled trial of VA-ECMO vs. early conservative therapy in patients with cardiogenic shock, there was not a significant difference in the primary efficacy endpoint at 30 days. Although a favourable trend in the primary endpoint was apparent, this pattern was driven by a predictable excess of new implantation of advanced mechanical support in the conservative group with no apparent difference in 30-day mortality or resuscitated cardiac arrest. The overall mortality rate of ∼50% supports that the investigators enrolled a population relevant to clinical practice with SCAI stages D and E shock. Therefore, this trial provides no support for a strategy of immediate VA-ECMO vs. initial medical therapy with bail-out advanced mechanical support. The findings should be interpreted in the context of an insufficient sample size to detect a smaller sized, but clinically relevant, effect, if one exists. Additional limitations include the use of a unique trial-specific definition of severe cardiogenic shock that will make future cross-study comparisons difficult. Although the study population appears reasonably reflective of patients with refractory cardiogenic shock who are candidates for mechanical support in clinical practice, the lack of a more parsimonious age selection criterion may have reduced the possibility of clinical benefit and candidacy for destination therapies after early VA-ECMO implantation. As such, the result may be less relevant to contemporary clinical practice in many shock centres which limit use of VA-ECMO to a younger population of patients. Finally, the use of bail-out mechanical circulatory support in nearly half of the early conservative arm may have diminished any potential difference between the randomized treatment strategies. We also note the lack of independent clinical event adjudication. The ECMO-CS trial does not provide support for routine use of VA-ECMO in patients with severe cardiogenic shock. However, given its limitations, there remains equipoise between early VA-ECMO implantation vs. an initial conservative strategy in patients with medically refractory cardiogenic shock. Nevertheless, the ECMO-CS trial suggests that any potential survival advantage with VA-ECMO is not likely to be large. The larger ECLS-SHOCK and ANCHOR trials will provide additional important insights into the overall efficacy and safety of ECMO in patients with cardiogenic shock.

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