Role of Early VA-ECMO Implementation in Patients with Rapidly Deteriorating Severe Cardiogenic Shock
March 1, 2023
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By Arnaldo Lopez Ruiz, MD
Attending Physician, Division of Critical Care, AdventHealth Medical Group, AdventHealth Orlando, FL
SYNOPSIS: The ECMO-CS trial found that using early VA-ECMO in patients with rapidly deteriorating or severe cardiogenic shock (Society for Cardiovascular Angiography and Interventions stages D or E) did not result in better patient outcomes compared to initial conservative care.
SOURCE: Ostadal P, Rokyta R, Karasek J, et al. Extracorporeal membrane oxygenation in the therapy of cardiogenic shock: Results of the ECMO-CS randomized clinical trial. Circulation 2023;147:454-464.
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is being used increasingly for mechanical circulatory support in patients with cardiogenic shock (CS). However, the evidence supporting its use in this context remains insufficient, and it has not been shown consistently to improve mortality. The goal of the ECMO-CS trial was to compare the safety and effectiveness of VA-ECMO to usual care in patients with rapidly deteriorating or severe CS.
This was a multicenter, randomized, investigator-initiated, academic clinical trial that included patients with rapidly deteriorating or severe CS based on Society for Cardiovascular Angiography and Interventions (SCAI) classification. Eligible patients with CS were enrolled at four centers in the Czech Republic and randomized in a 1:1 open-label fashion to either immediate VA-ECMO (n = 58) or early conservative therapy (n = 59). The primary endpoint was the composite of death from any cause, resuscitated circulatory arrest, and implementation of another mechanical circulatory support (MCS) device at 30 days.
At the time of randomization, 14% of patients were on an intra-aortic balloon pump (IABP). Patients in the control arm could switch over to VA-ECMO for worsening hemodynamic status at the discretion of the treating physicians. To be included in the study, patients had to meet two criteria: rapidly deteriorating CS (SCAI shock stage D) defined as progressive hemodynamic instability necessitating repeated bolus administration of vasopressors to maintain mean arterial pressure > 50 mmHg; and impaired left ventricular systolic function with a left ventricular ejection fraction (LVEF) < 35% or LVEF 35% to 55% in cases of severe mitral regurgitation or aortic stenosis. Stage D of CS considers hemodynamic (cardiac index [CI] < 2.2 L/min/m2 plus norepinephrine > 0.1 mcg/kg/min plus dobutamine > 5 mcg/kg/min, or systolic blood pressure < 100 mmHg plus norepinephrine dose > 0.2 mcg/kg/min plus dobutamine dose > 5 mcg/kg/min) and metabolic parameters (two consecutive lactate values ≥ 3 mmol/L [with ≥ 30 minutes between samples] or two consecutive venous oxygen saturation [SvO2] values < 50% [with ≥ 30 minutes between measurements]). In addition, hypovolemia should be excluded as defined by a central venous pressure > 7 mmHg or pulmonary capillary wedge pressure > 12 mmHg. The exclusion criteria were age younger than 18 years, life expectancy less than one year, cardiac arrest survivors, hypertrophic cardiomyopathy, and patients with severe peripheral artery disease or aortic dissection.
At the time of randomization, the baseline characteristics of the two study groups were balanced. The median age of patients was 67 years (interquartile range [IQR], 60-74) in the group receiving immediate VA-ECMO and 65 years (IQR, 58-71) in the group receiving early conservative treatment. Median arterial blood lactate level at randomization was 5.3 mmol/L (IQR, 3.1 mmol/L to 8.4 mmol/L) in the immediate VA-ECMO group and 4.7 mmol/L (IQR 3.3 mmol/L to 7.4 mmol/L) in the early conservative group. More than 70% of patients in both groups were receiving mechanical ventilation.
About 86% of subjects in the immediate VA-ECMO group and 84.7% in the early conservative group received norepinephrine, and a substantial and equal proportion of both groups received epinephrine (3.4%), dobutamine (54.7%), milrinone (32.5%), and vasopressin (35%). The vasoactive-inotropic score was 59.9 in the immediate VA-ECMO group compared to 61.0 in the early conservative group. In both arms of the study, the most common cause of CS was ST-segment elevation acute myocardial infarction (STEMI) (50%), followed by decompensation of chronic heart failure (24%). Therapeutic intervention use, including percutaneous coronary intervention and cardiac surgery, did not differ between the two study groups. Patients who previously had undergone cardiac surgery were not excluded, but primarily non-surgical patients were enrolled in the trial, although some of the patients required subsequent cardiac surgery during hospitalization.
The primary outcome, defined as a composite of all-cause mortality, implantation of another MCS device, and resuscitated cardiac arrest, was 68.3% for VA-ECMO compared to 71.2% for early conservative care (hazard ratio, 0.72; 95% confidence interval [CI], 0.46-1.12). Secondary outcomes for VA-ECMO vs. early conservative care all were similarly not statistically significant: composite of all-cause mortality or resuscitated cardiac arrest of 53.4% vs. 54.2% (P > 0.05), and adverse events of bleeding, leg ischemia, or stroke of 37.9% vs. 23.7% (P = 0.10), respectively.
COMMENTARY
This study’s results indicate that the use of early VA-ECMO in patients with SCAI D or E CS did not result in superior outcomes compared to initial conservative care. However, it is very important to consider that 23 (39%) patients in the conservative care arm crossed over to VA-ECMO, of whom 12 (52%) died. This crossover was part of the primary endpoint for the study but did not result in better outcomes or mortality rate in the VA-ECMO arm.
To date, the ECMO-CS trial is one of the few randomized controlled trials comparing VA-ECMO to conservative medical therapy in CS, but it has some important limitations. First, all patients were white and were recruited only in the Czech Republic, which may limit generalizability of the results to other racial, ethnic, or geographic groups. Secondly, the trial design used a sample size that was calculated to find a difference in a composite primary outcome. Therefore, all the other single-outcome results must be considered hypothesis-generating. Third, the trial was not blinded, and the endpoints were not adjudicated. Fourth, the study inclusion criteria were based on shock severity (defined by intensity of vasoactive therapy, hemodynamic or metabolic parameters, and the evidence of cardiac pump failure), but were not based on specific etiologies. Exclusion of certain specific conditions that may cause or influence CS, including pulmonary embolism, cardiac tamponade, refractory arrhythmias, and cardiac arrest survivors, makes the results difficult to generalize to all other etiologies of CS. Finally, the trial did not compare VA-ECMO vs. conservative therapy overall, but instead it compared immediate VA-ECMO with an early conservative strategy allowing a “transition” to VA-ECMO therapy in cases of hemodynamic worsening. Therefore, the results should be interpreted accordingly.
In addition, the definition of shock progression that allowed for VA-ECMO placement in the early conservative arm was based only on refractory lactic acidosis that may be influenced by clearance rather than by hemodynamic parameters. A relevant point for future trials using VA-ECMO in CS is consideration that unloading the left ventricle (LV) with an IABP or Impella may affect the outcomes in the MCS arm. In this study, IABP was used in six patients in the immediate VA-ECMO arm already at randomization, and another seven patients received percutaneous or surgical MCS later.
Most of the data supporting the use of VA-ECMO for MCS in patients with CS come from retrospective or observational studies. Most of these cohort studies suggest that the use of VA-ECMO in CS is associated with improved mortality up to six months compared to no MCS.1,2 This short-term benefit also was observed in a subsequent meta-analysis.3 However, such observational studies are limited by major confounders, such as severity and etiology of CS, duration of medical therapies before implementing VA-ECMO, and by the presence of distant organ complications (e.g., brain, lung, kidney) before or during VA-ECMO. More recently before the ECMO-CS trial, a small randomized controlled trial of 42 patients with CS secondary to myocardial infarction (MI) demonstrated a trend toward improvement in short-term outcomes with VA-ECMO compared to no MCS, but the trial was too small to detect a statistically significant improvement in 30-day mortality.4
Appropriate patient selection, timing, criteria for transitioning to MCS, and markers that predict no response to MCS are crucial issues that remain unresolved. The same authors of this ECMO-CS trial previously have defined refractory CS to include persistent hypotension and/or low cardiac index, high lactate (two consecutive values ≥ 3 mmol/L) and/or low SvO2 levels (two consecutive values < 50%) despite adequate pharmacological treatment (norepinephrine dose > 0.2 mcg/kg/min plus dobutamine dose > 5 mcg/kg/min).5 However, these criteria do not predict poor response to conservative therapy. Therefore, placing a patient on VA-ECMO who would otherwise respond to standard therapy may unnecessarily increase the risk of device-related complications and result in worse outcomes.
At the other end of the spectrum, using VA-ECMO in cases of CS in which reversibility of myocardial damage is improbable and there are no future durable options, such as transplant or LV assist devices, will not change clinical outcome.6 A scoring system (Survival After Veno-Arterial ECMO [SAVE] score) has been developed to support the decision and predict survival on VA-ECMO in patients with CS, but it needs further validation across different CS etiologies.7 However, age, CS etiology, LV function at baseline, and the presence of renal failure are good predictors of survival.8
The potential beneficial role of VA-ECMO in CS will be tested in three upcoming large, randomized trials: EURO-SHOCK (NCT03813134), ECLS-SHOCK (NCT03637205), and ANCHOR (NCT04184635). However, the performance of VA-ECMO compared to other forms of MCS (e.g., IABP, TandemHeart, and Impella) currently is unknown and represents an area that needs further investigation. In addition, the increase in cardiac afterload that often is seen in patients receiving VA-ECMO for CS may improve via methods or devices that can unload the left ventricle. Therefore, combining VA-ECMO with IABP or Impella has been shown in a retrospective study to improve outcomes compared to either one alone.9
Guidelines from both the European Society of Cardiology (ESC) and the American Heart Association (AHA) recommend that VA-ECMO should be considered only in patients with refractory CS and clear evidence of persistent tissue hypoperfusion and/or those who are not responding to medical therapies.9,10 No stringent or specific selection criteria are mentioned, and optimal timing or duration of other supportive measures (namely vasopressors and inotropes) is unspecified, highlighting the necessity for research on the prognostic factors associated with outcomes in patients receiving temporary VA-ECMO for CS. VA-ECMO and other MCS devices do not reverse the etiology of CS, and these interventions should only be considered as methods of support until recovery or as a bridge to durable support or cardiac transplantation.
Currently, VA-ECMO is considered the first-line MCS in refractory CS.11 In cases in which additional LV unloading is needed, the addition of Impella CP represents the best available option. Several ongoing randomized controlled trials will help to establish whether VA-ECMO can improve outcomes in CS. Careful patient selection by a multidisciplinary team, initiation of VA-ECMO before multiorgan failure development, and comprehensive intensive care remain the keys to successful outcomes in patients with CS.
REFERENCES
- Muller G, Flecher E, Lebreton G, et al. The ENCOURAGE mortality risk score and analysis of long-term outcomes after VA-ECMO for acute myocardial infarction with cardiogenic shock. Intensive Care Med 2016;42:370-378.
- Sheu JJ, Tsai TH, Lee FY, et al. Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock. Crit Care Med 2010;38:1810-1817.
- Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest and cardiogenic shock: A systematic review and meta-analysis. Intensive Care Med 2016;42:1922-1934.
- Brunner S, Guenther SPW, Lackermair K, et al. Extracorporeal life support in cardiogenic shock complicating acute myocardial infarction. J Am Coll Cardiol 2019;73:2355-2357.
- Ostadal P, Rokyta R, Kruger A, et al. Extra corporeal membrane oxygenation in the therapy of cardiogenic shock (ECMO-CS): Rationale and design of the multicenter randomized trial. Eur J Heart Fail 2017;19:124-127.
- Combes A, Price S, Slutsky AS, Brodie D. Temporary circulatory support for cardiogenic shock. Lancet 2020;396:199-212.
- Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory cardiogenic shock: The survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J 2015;36:2246-2256.
- Garan AR, Eckhardt C, Takeda K, et al. Predictors of survival and ability to wean from short-term mechanical circulatory support device following acute myocardial infarction complicated by cardiogenic shock. Eur Heart J Acute Cardiovasc Care 2018;7:755-765.
- Russo JJ, Aleksova N, Pitcher I, et al. Left ventricular unloading during extracorporeal membrane oxygenation in patients with cardiogenic shock. J Am Coll Cardiol 2019;73:654-662.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975.
- Peura JL, Colvin-Adams M, Francis GS, et al. Recommendations for the use of mechanical circulatory support: Device strategies and patient selection: A scientific statement from the American Heart Association. Circulation 2012;126:2648-2667.
The ECMO-CS trial found that using early VA-ECMO in patients with rapidly deteriorating or severe cardiogenic shock (Society for Cardiovascular Angiography and Interventions stages D or E) did not result in better patient outcomes compared to initial conservative care.
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