Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial

Ostadal et al | Circulation| November 2022

DOI: 10.1161/CIRCULATIONAHA.122.062949

Clinical Question

In patients with severe cardiogenic shock does immediate initiation of VA-ECMO, compared to a trial of conservative therapy and the possibility of rescue VA ECMO, reduce a composite outcome of death, resuscitated cardiac arrest or commencement of another mechanical circulatory support?

Background

• Cardiogenic shock (CS) remains a condition with a high morbidity and mortality
• VA ECMO can be used as a temporary cardiac and pulmonary support in patients with refractory cardiogenic shock
• A small prospective randomised study comparing ECMO with standard therapy showed no mortality benefit, however observational data and a systematic review have suggested that VA ECMO may reduce mortality in patient with the most severe cardiogenic shock

Design

•  Multicentre, randomised, unblinded, parallel-group, investigator-initiated clinical trial
• Randomly assigned 1:1 between intervention and control arm using an automated web-based system with permuted blocks
• Written, informed consent from patient where possible, otherwise obtained retrospectively or from next of kin
• Intention-to-treat analysis
• 120 patients provided between 80% power to detect a 50% reduction in the primary outcome This was based on a predicted mortality of 40%.

Setting

• Conducted in 4 tertiary Czech ICUs between September 2014 to January 2022

Population

Inclusion Criteria

• Rapidly deteriorating or severe cardiogenic shock (corresponding to SCAI stage D or E) defined as:
  • Progressive hemodynamic instability necessitating repeated bolus administration of vasopressors to maintain mean arterial pressure > 50 mmHg + impaired left ventricle systolic function (Left ventricle ejection fraction (LVEF) < 35% or LVEF 35-55% in case of severe mitral regurgitation or aortic stenosis)
  • OR all of the following:
    • Cardiac Index (CI) < 2.2 L/min/m2 OR + norepinephrine dose > 0.1μg/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)
    • Lactate > 3 or SvO₂ < 50 on two occasions
    • Hypovolaemia excluded (CVP > 7mmHg or PCWP >12mmHg)

Exclusion Criteria

• Age < 18 years
• Life expectancy lower than 1 year
• High suspicion of pulmonary emboli or cardiac tamponade as a cause of shock
• Significant bradycardia or tachycardia which might be responsible for hemodynamic instability and not treated by pacing or cardioversion
• Cardiac arrest survivors remaining comatose
• Hypertrophic obstructive cardiomyopathy
• Peripheral artery disease disabling insertion of outflow cannula to femoral artery
• Moderate to severe aortic regurgitation
• Aortic dissection
• Uncontrolled bleeding or TIMI major bleeding within last 6 months
• Known encephalopathy

 

• 122 randomised
  • 61 immediate ECMO, 3 no consent = ITT population of 58
  • 61 initial conservative strategy, 2 no consent = ITT population of 59

Baseline characteristics

Immediate ECMO vs Initial Conservative Therapy – well balanced apart from smoking status (all data below are means)

• Mean age: 67 vs 65
• Male: 74% vs 73%
• Cardiovascular history
  • Chronic coronary syndrome 38% vs 31%
  • Chronic heart failure 25% vs 22%
  • Dilated cardiomyopathy 11% vs 16%
  • Peripheral artery disease 6% vs 12%
  • Hypertension 63% vs 66%
  • Diabetes 29% vs 36%
  • Current smoker 26% vs 47%
• Physiology
  • Lactate 5.3 vs 4.7
  • MAP 63.3 vs 64.5
• Organ Supports at randomisation
  • IABP 11% vs 16%
  • Ventilation 75% vs 70%
  • Receiving noradrenaline 86.2% vs 84.7%
  • Noradrenaline dose (mcg/kg/min) 0.48 vs 0.5
  • Receiving Dobutamine 53.4% vs 55.9%
  • Dobutamine dose (mcg/kg/min) 6.1 vs 5.1
  • Similar proportions also receiving Milrinone, Vasopressin and Levosimendan

 

• Cause of cardiogenic shock were similar between groups, with roughly 50% in both groups being caused by STEMI

Intervention

• Immediate commencement of VA ECMO -according to local procedures

Control

• Initial conservative therapy as per local procedures
•  ECMO could be initiated if there was haemodynamic worsening (defined as lactate rise by > 3mmol from lowest level in preceding 24 hours)

Management Common to both groups

• Remainder of haemodynamic management at discretion of treating hospital(including other cardiovascular interventions like PCI, and other mechanical support)
• No pre-defined protocol for use of left ventricular venting

Outcomes

• Primary outcome: Composite of death from any cause, resuscitated circulatory arrest, and implementation of another mechanical circulatory support at 30 days
  • No significant difference (37 patients(63.8%) vs 42 patients (71.2%); risk difference -7.4 with a 95% CI of 024.3 to 9.5)
  • Looking at components of the primary outcome:
    • Death 50% vs 47%
    • Another mechanical support 17.2% vs 42.4%
    • Resuscitated cardiac arrest 10.3% vs 13.6%
• Prespecified secondary outcomes:
  • all-cause mortality at 30 days,
  • Neurological outcome at 30 days
  • Clinically significant bleeding
  • Leg ischaemia
  • Pneumonia
  • Sepsis
  • Technical complications
• No significant difference in any secondary outcomes
• Notably 23 patients (39%) of patients in the control arm required downstream VA-ECMO support
  • 12 (52.2%) died

Adverse Events

• No difference in total number of serious adverse events or any individual adverse event.
• Numerically higher number of combined ECMO specific complications (bleeding, leg, ischaemia, stroke) in early VA group. (37.9% vs 23.7% p=0.096)

Authors’ Conclusions

Immediate implementation of VA-ECMO in patients with rapidly deteriorating or severe cardiogenic shock (corresponding to SCAI stage D-E) was feasible but did not improve clinical outcomes compared with an early conservative approach permitting downstream use of VA-ECMO in cases of hemodynamic worsening

Strengths

• Rare to successfully complete a randomised trial of VA-ECMO
• Web-based randomisation
• Pragmatic design
• Multi-centre study performed in the emergency setting
• Minimal loss to follow up
• Similar baseline characteristics between groups

Weaknesses

• Patients on high levels of haemodynamic support at time of randomisation so arguably this would not consititute ‘early’ VA ECMO
• Composite outcome makes finding harder to interpret particularly as additional mechanical support included- especially relevant as use of further mechanical support was significantly reduced in the ECMO group without changing the overall composite outcome
• Goals of ECMO initiation not clearly defined- separating out who was being “bridged to recovery” vs “bridge to therapy” or “bridge to decision” would help separate out potential responses
• High levels of crossover (39% of patients in early conservative arm received VA ECMO); this would dilute any potential effect of the intervention
• No independent adjudication of primary end point
• Very large predicted effect size increases risk of type 2 error
• Relatively long recruitment periods inceases possibity of changes in treatment over time
• Venting strategy was not standardised; this could be important as a recent study demonstrated that the combination of IABP (a common venting device) and ECMO was associated with improved outcomes over ECMO alone

The Bottom Line

• Currently I would not routinely place patients on to VA ECMO early in the face of rapidly deteriorating cardiogenic shock without initially trying conservative measures
• I would however have a low threshold to transition to rescue ECMO if there was no improvement and with a defined treatment direction (bridge to recovery, decision, or destination such as transplant)
• The role of VA ECMO in patients in earlier cardiogenic shock (before they have started to develop the cardio metabolic syndrome) remains of interest, especially if the trajectory can be predicted- further studies will help define this

External Links

• Article– Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial
• Further reading: Extracorporeal membrane oxygenation for cardiogenic shock: A meta analysis of mortality and complications
• Further watching:  Radcliffe & CardioNerds @AHA22: The ECMO-CS Trial

Metadata

Summary author: Alastair Brown
Summary date: 29th December 2022
Peer-review editor: Segun Olusanya

Picture by: Wavelength by Luan Rezende (Courtesy of PEXELS)