CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ECMO-CS Trial.

Table of contents for the ECMO-CS Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

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

Petr Ostadal, Richard Rokyta, Jiri Karasek, Andreas Kruger, Dagmar Vondrakova, Marek Janotka, Jan Naar, Jana Smalcova, Marketa Hubatova, Milan Hromadka, Stefan Volovar, Miroslava Seyfrydova, Jiri Jarkovsky, Michal Svoboda, Ales Linhart and Jan Belohlavek and for the ECMO-CS Investigators

LINK: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.062949

Relevant Literature – ECMO-CS Trial

• Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a means of mechanical circulatory support (MCS) for patients with cardiogenic shock (SCAI stages D-E) that has become widely adopted internationally. There is limited evidence comparing early VA-ECMO with a more conservative strategy in patients with cardiogenic shock. The current role of ECMO includes complete hemodynamic support to reverse the deleterious effects of organ hypoperfusion in cardiogenic shock and hopeful recovery of intrinsic cardiac function or as a bridge to more durable left ventricular assist devices or heart transplants.¹

• To date, MCS options, including intra-aortic balloon pumps (IABP) and Impella used for cardiogenic shock, have not been shown to have mortality benefits. In the IABP-SHOCK II trial, no difference in all-cause mortality was seen at 30 days for patients in cardiogenic shock from acute MI treated with IABP when compared to the control group.² Furthermore, in the IMPRESS trial, all-cause mortality was the same between Impella and IABP for patients with cardiogenic shock from STEMI undergoing primary PCI.³ For patients with worsening cardiogenic shock, particularly worsening biventricular function refractory to inotropes or other MCS options mentioned above (transition from SCAI stage D to E, see Figure 1), VA-ECMO is a feasible option.

Relevant Guidelines – ECMO-CS Trial

• There are currently no standardized guidelines for choosing MCS in cardiogenic shock. The European Society of Cardiology (ESC) for Heart Failure (2021) recommends that for early hemodynamic stabilization for cardiogenic shock, ventilatory support is a class IIA recommendation, considering inotropes/vasopressors is a class IIB recommendation, and short-term MCS is a class IIA recommendation.⁴ 

Study Rationale – ECMO-CS Trial

• There is limited evidence comparing early VA-ECMO with a more conservative strategy in patients with cardiogenic shock.
• A meta-analysis of cohort studies has shown that ECMO is effective in patients with severe cardiogenic shock and may have a higher 30-day survival rate when compared to the use of IABP alone.³

Objective – ECMO-CS Trial

The aim of the ECMO-CS trial was to compare early conservative therapy with the use of inotropes and vasopressors for hemodynamic stabilization and immediate insertion of ECMO in the setting of rapidly deteriorating cardiogenic shock.

Trial: – ECMO-CS Trial

• Randomized, multicenter, investigator-initiated clinical trial without industry involvement.
• Conducted in four centers in the Czech Republic.

Hypothesis

• Immediate ECMO insertion in the case of severe cardiogenic shock would be associated with improved outcomes in the primary composite endpoint.

Intervention

• 1:1 randomization of 117 patients into immediate VA-ECMO therapy (N = 58) vs early conservative therapy (N = 59).
• In the early conservative group, VA-ECMO could be used downstream in case of a further worsening of hemodynamic status, defined as a rise of serum lactate by 3 mmol/L in comparison with the lowest value during the past 24 hours.

Enrollment Criteria

Outcomes

• Primary
  • Composite: Death from any cause, resuscitated cardiac arrest, and implantation of another MCS device
• Secondary
  • Composite: All-cause mortality or resuscitated cardiac arrest
  • Bleeding, leg ischemia, or stroke

Statistical Analysis

• All analyses were performed with intention-to-treat with all patients and events occurring until 30 days from randomization
• Categorical variables: Pearson Chi-Squared or Fisher’s exact test
• Continuous variables: T-test or Mann-Whitney test
• Time to occurrence of primary composite endpoint: Kaplan-Meier method and compared using a log-rank test
• 95% Confidence intervals and hazard ratios were calculated with the cumulative risk function and Cox proportional hazard model, respectively.

Participant Characteristics:

Outcomes

• Composite Endpoint: 63.8% vs. 71.2% [HR] 0.72, 95% CI 0.46-1.12)
  • All-cause mortality: 50% vs. 47.5% (HR 1.11, 95% CI 0.66-1.87)
  • Another MCS: 17.2% vs. 42.4% (HR 0.38, 95% CI 0.18-0.79)
  • Resuscitated circulatory arrest: 10.3% vs. 13.6% (HR 0.79, 95% CI 0.27-2.28)

Secondary Outcomes

• Composite: All-cause mortality or resuscitated cardiac arrest: 53.4% vs. 54.2% (p > 0.05)
• Bleeding, leg ischemia, or stroke: 37.9% vs. 23.7% (p = 0.10)

Adverse Events

Conclusions

• The immediate insertion of VA-ECMO in patients with SCAI stage D or E cardiogenic shock was not associated with improved outcomes in comparison with early conservative therapy. The study was limited by a high crossover rate of 39%, open-label status, and low rates of left ventricular venting. Further trials are necessary to elucidate the optimal management strategy in patients with cardiogenic shock.

Limitations & Considerations

• The study population was homogeneously white and mostly male, which limits the generalizability of results to other racial or ethnic groups.
• The average age of patients was 66 years old, and therefore, younger patients may be more likely to survive the cardiogenic shock.
• The sample size of 122 patients was too small for subgroup analyses.
• This study was done only in the Czech Republic, and the results may not be generalizable beyond the study population.
• Patients in the conservative arm could be crashed onto ECMO if clinically indicated. The high crossover rate makes interpretation of the primary outcome difficult.
• Patients who were only in stage D and stage E cardiogenic shock were studied; therefore, data can not be extrapolated to any other stages of cardiogenic shock.
• Since there was a large proportion of patients who crossed over from the conservative group (39% of patients) to the VA-ECMO group with a similar mortality rate compared to prior studies that have investigated the mortality rate on ECMO (~50%), the delay of escalation to ECMO until inotropes and other MCS options are attempted may be plausible and much of the mortality on ECMO may be attributed to its complications.
• Left ventricular venting during ECMO support was not standardized or defined in the protocol leading to varying use of other mechanical support in the ECMO arm; this may impair the results of the trial. In turn, the use of a left ventricular venting strategy increased the number of patients meeting the primary outcome in the ECMO arm, which could confound the interpretation of results as left ventricular venting is an optimal strategy to unload the left ventricle to promote myocardial recovery.
• There was an early separation of the Kaplan-Meier curves between both groups before converging at the 15-day mark from randomization; therefore, if there was no crossover, then there may have been a statistically significant mortality benefit of ECMO over conservative therapy.
• The stratification of patients into the etiology of cardiogenic shock (MI vs. acute on chronic heart failure vs. valvular disease vs. myocarditis vs. cardiac tamponade vs. arrhythmias etc.) could make the results more applicable in practice tailored more to each patient (albeit, limited by sample size when designing a randomized controlled trial).

1. Chakaramakkil, M. J., & Sivathasan, C. (2018). ECMO and short-term support for cardiogenic shock in heart failure. Current cardiology reports, 20(10), 1-8.
2. Thiele, H., Zeymer, U., Neumann, F. J., Ferenc, M., Olbrich, H. G., Hausleiter, J., et al. (2012). Intraaortic balloon support for myocardial infarction with cardiogenic shock. New England Journal of Medicine, 367(14), 1287-1296.
3. Ouweneel, D. M., Schotborgh, J. V., Limpens, J., Sjauw, K. D., Engström, A. E., Lagrand, W. K., et al. (2016). Extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis. Intensive care medicine, 42(12), 1922-1934.
4. McDonagh, T. A., Metra, M., Adamo, M., Gardner, R. S., Baumbach, A., Böhm, M., et al. (2021). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. European heart journal, 42(36), 3599-3726.

The published archive features curated twitter highlights from the journal club event.