Timing of veno‐arterial extracorporeal membrane oxygenation support in patients with cardiogenic shock
Cardiogenic shock (CS) represents a critical condition marked by a sudden decline in cardiac output resulting in a life‐threatening hypoperfusion of end‐organs. , Even with progress in medical treatment, the early mortality rate for CS remains high at about 30–50%. , , In cases of CS with higher severity, conservative treatment strategies such as vasopressors and inotropes are frequently limited in efficacy. In such patients, mechanical circulatory support (MCS) could potentially enhance outcomes by providing temporary support until native heart recovery or as a bridge to more advanced heart failure therapies. , , Recent data from the DanGer Shock trial revealed lower all‐cause mortality with microaxial flow pump use in highly selected ST‐elevation myocardial infarction‐related CS compared to standard care alone. Moreover, veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO), with the capability of compensatory support for cardiac output and gas exchange, is increasingly employed in patients with severe or refractory CS. Nonetheless, VA‐ECMO therapy is burdened by significant complications and lacks conclusive evidence of efficacy from randomized controlled trials. , , , , One crucial aspect that remains insufficiently understood and is subject to controversial debate is the optimal timing for initiating MCS. , , Some advocate for earlier or proactive MCS utilization to improve perfusion before the onset of refractory CS with irreversible multiorgan failure. In retrospective studies, the earlier initiation of MCS has been associated with improved survival rates. , , Conversely, MCS can be seen as a bail‐out strategy at later CS stages, aiming to avoid overtreatment with associated complications in these patients. In a recent multicentre randomized trial (ECMO‐CS), comparing immediate VA‐ECMO implementation to an initial conservative strategy (with potential subsequent VA‐ECMO implementation) in patients with higher Society for Cardiovascular Angiography and Interventions (SCAI) CS stages D and E, no significant difference in the primary outcome at 30 days was observed. Thus, there is a gap in targeted strategies regarding appropriate timing and patient characteristics, signalling the necessity for MCS intervention, indicating the need for further research efforts. The objective of this study was to evaluate patient characteristics and outcome associated with the timing of VA‐ECMO or ECMELLA (VA‐ECMO plus Impella) implementation in patients with CS within a multicentre, international study cohort. 

Data source and setting This analysis was conducted in a large, anonymized multicentre data set of patients treated either with VA‐ECMO alone or with ECMELLA, from 15 tertiary care centres in three countries (online supplementary Table ). Data on patients treated with other MCS devices, e.g. intra‐aortic balloon pump (IABP), were not collected. Detailed information regarding data entry, the definition of CS and inclusion/exclusion criteria of this registry have been previously reported (NCT03313687). This study examined data from adult patients aged 18 years and older, enrolled in this registry between 2006 and 2021. In this registry, post‐cardiotomy CS was an exclusion criterion. The index event was defined as first MCS device implantation, onset of CS before the initial device implantation was assessed based on incidence of first CS symptoms (e.g. chest pain for patients with ischaemic CS, severe dyspnoea for patients with non‐ischaemic CS). Demographic characteristics, laboratory measurements and medical history were captured at the index event. The management of enrolled patients was determined by local investigators and followed local guidelines. Patients who received extracorporeal cardiopulmonary resuscitation (eCPR) and those with missing data on the time from CS onset to MCS implementation were excluded. Additionally, patients with MCS implementation more than 24 h after the onset of CS were excluded due to heterogeneity in clinical trajectories. This analysis adheres to the principles outlined in the Declaration of Helsinki and received approval from the local ethics committees. The lead ethics committee waived the need for informed consent due to the retrospective nature of the study and its reliance on fully anonymized data. Access to the primary data underlying the study findings can be obtained from the corresponding author upon reasonable request. The authors conceived and designed the study, collected, and analysed the data, drafted the manuscript, and decided to publish. Definition of study groups Participants with an eligible time interval from the onset of CS to the initial implementation of the first MCS device (VA‐ECMO or ECMELLA), defined as CS‐to‐MCS time in h, were stratified into three groups using clinically relevant cutoffs: early, <2 h; intermediate, 2 to ≤12 h; delayed, ≥12 to 24 h. Outcome The primary outcome of the study was the cumulative mortality at 30 days. Safety endpoints were recorded as in‐hospital events, retrospectively obtained by local investigators, and defined as follows: bleeding complications as either severe/moderate bleeding (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries criteria), intracerebral bleeding and haemorrhagic stroke (on computed tomography), interventions due to bleeding events (bleeding requiring surgical or catheter‐based procedures); ischaemic complications such as ischaemic stroke (on computed tomography), interventions necessitated by access site‐related ischaemia, and laparotomies performed due to abdominal compartment syndrome or bowel ischaemia; haemolysis (lactate dehydrogenase levels >1000 U/L and haptoglobin levels <0.3 g/L in two consecutive samples within 24 h); hypoxic brain injury (on computed tomography); renal replacement therapy; sepsis (defined by meeting systemic inflammatory response syndrome criteria and having >2 positive blood cultures). Statistical analyses Continuous variables were described using the median (25th–75th percentile) and analysed using the Mann–Whitney test. Binary variables were presented as absolute and relative frequencies, and comparisons were conducted using Fisher's exact test. To investigate differences in clinical characteristics during the index event, as well as complications during the hospital course between patients with early/intermediate versus delayed CS‐to‐MCS time, multivariable mixed effects logistic regression models were fitted, adjusted for age, sex, lactate (before MCS implementation), cause of CS (acute myocardial infarction‐related vs. heart failure‐related CS) and cardiopulmonary resuscitation (CPR). The crude 30‐day mortality rates were estimated for patients with early, intermediate, and delayed CS‐to‐MCS time during the index event, using the Kaplan–Meier method, with the number of individuals at risk reported. Group comparisons were conducted utilizing the log‐rank test. To assess the association between various CS‐to‐MCS time intervals and 30‐day mortality, cohort‐stratified Cox proportional hazard regression models were fitted, adjusted for age, sex, lactate levels (prior to MCS implementation), the cause of CS (acute myocardial infarction‐related vs. heart failure‐related CS), and CPR. To account for potential non‐linear association between CS‐to‐MCS time and hazard ratio (HR) of 30‐day mortality, natural cubic splines were fitted, and plots were generated to examine the shape of the association. A p ‐value < 0.05 was considered as statistically significant. All analyses were performed with R statistical software version 4.3.1. 

This analysis was conducted in a large, anonymized multicentre data set of patients treated either with VA‐ECMO alone or with ECMELLA, from 15 tertiary care centres in three countries (online supplementary Table ). Data on patients treated with other MCS devices, e.g. intra‐aortic balloon pump (IABP), were not collected. Detailed information regarding data entry, the definition of CS and inclusion/exclusion criteria of this registry have been previously reported (NCT03313687). This study examined data from adult patients aged 18 years and older, enrolled in this registry between 2006 and 2021. In this registry, post‐cardiotomy CS was an exclusion criterion. The index event was defined as first MCS device implantation, onset of CS before the initial device implantation was assessed based on incidence of first CS symptoms (e.g. chest pain for patients with ischaemic CS, severe dyspnoea for patients with non‐ischaemic CS). Demographic characteristics, laboratory measurements and medical history were captured at the index event. The management of enrolled patients was determined by local investigators and followed local guidelines. Patients who received extracorporeal cardiopulmonary resuscitation (eCPR) and those with missing data on the time from CS onset to MCS implementation were excluded. Additionally, patients with MCS implementation more than 24 h after the onset of CS were excluded due to heterogeneity in clinical trajectories. This analysis adheres to the principles outlined in the Declaration of Helsinki and received approval from the local ethics committees. The lead ethics committee waived the need for informed consent due to the retrospective nature of the study and its reliance on fully anonymized data. Access to the primary data underlying the study findings can be obtained from the corresponding author upon reasonable request. The authors conceived and designed the study, collected, and analysed the data, drafted the manuscript, and decided to publish. 

Participants with an eligible time interval from the onset of CS to the initial implementation of the first MCS device (VA‐ECMO or ECMELLA), defined as CS‐to‐MCS time in h, were stratified into three groups using clinically relevant cutoffs: early, <2 h; intermediate, 2 to ≤12 h; delayed, ≥12 to 24 h. 

The primary outcome of the study was the cumulative mortality at 30 days. Safety endpoints were recorded as in‐hospital events, retrospectively obtained by local investigators, and defined as follows: bleeding complications as either severe/moderate bleeding (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries criteria), intracerebral bleeding and haemorrhagic stroke (on computed tomography), interventions due to bleeding events (bleeding requiring surgical or catheter‐based procedures); ischaemic complications such as ischaemic stroke (on computed tomography), interventions necessitated by access site‐related ischaemia, and laparotomies performed due to abdominal compartment syndrome or bowel ischaemia; haemolysis (lactate dehydrogenase levels >1000 U/L and haptoglobin levels <0.3 g/L in two consecutive samples within 24 h); hypoxic brain injury (on computed tomography); renal replacement therapy; sepsis (defined by meeting systemic inflammatory response syndrome criteria and having >2 positive blood cultures). 

Continuous variables were described using the median (25th–75th percentile) and analysed using the Mann–Whitney test. Binary variables were presented as absolute and relative frequencies, and comparisons were conducted using Fisher's exact test. To investigate differences in clinical characteristics during the index event, as well as complications during the hospital course between patients with early/intermediate versus delayed CS‐to‐MCS time, multivariable mixed effects logistic regression models were fitted, adjusted for age, sex, lactate (before MCS implementation), cause of CS (acute myocardial infarction‐related vs. heart failure‐related CS) and cardiopulmonary resuscitation (CPR). The crude 30‐day mortality rates were estimated for patients with early, intermediate, and delayed CS‐to‐MCS time during the index event, using the Kaplan–Meier method, with the number of individuals at risk reported. Group comparisons were conducted utilizing the log‐rank test. To assess the association between various CS‐to‐MCS time intervals and 30‐day mortality, cohort‐stratified Cox proportional hazard regression models were fitted, adjusted for age, sex, lactate levels (prior to MCS implementation), the cause of CS (acute myocardial infarction‐related vs. heart failure‐related CS), and CPR. To account for potential non‐linear association between CS‐to‐MCS time and hazard ratio (HR) of 30‐day mortality, natural cubic splines were fitted, and plots were generated to examine the shape of the association. A p ‐value < 0.05 was considered as statistically significant. All analyses were performed with R statistical software version 4.3.1. 

Study cohort Of 716 patients with CS treated with either VA‐ECMO or ECMELLA in the registry, 330 patients met the inclusion criteria for this study ( Figure ). Baseline characteristics for the overall cohort stratified by early (<2 h) versus intermediate (2–12 h) versus delayed (≥12–24 h) CS‐to‐MCS time interval are shown in Table . The median age of the study population was 57 years (interquartile range [IQR] 49–66), with 249 (75.5%) being male. Among these patients, 202 (61.2%) had an acute myocardial infarction (AMI) as the underlying cause of CS (AMI‐CS). Although there were no significant differences in age and sex distribution across the early, intermediate, and delayed CS‐to‐MCS time intervals, variations in clinical presentation were observed. Patients with early and intermediate CS‐to‐MCS intervals had higher rates of AMI‐CS (65.2% vs. 65.2% vs. 48.1%) and prior CPR (54.8% vs. 51.6% vs. 32.9%), compared to those with delayed CS‐to‐MCS intervals. Furthermore, patients with early and intermediate MCS implementation demonstrated higher creatinine clearance compared to those with delayed MCS implementation (38 ml/min vs. 47 ml/min vs. 37 ml/min). However, no significant disparities were observed in lactate levels, arterial blood pressure, heart rate, haemoglobin, Survival After Veno‐Arterial ECMO (SAVE) score or Simplified Acute Physiology Score (SAPS) II score measured prior to MCS implementation during the index event ( Table ). The median time from the onset of CS to the initiation of the first MCS device was 4 h (IQR 2.0–10.4). Among these patients, 69 (20.9%) received early MCS implementation (median timing interval 1 h, IQR 0.5–1.0), 184 (55.8%) received intermediate MCS implementation (median timing interval 4 h, IQR 3.0–6.0), and 77 (23.3%) received delayed MCS implementation (median timing interval 16 h, IQR 12.8–23.0), as illustrated in the Graphical Abstract . The thoroughly examined use of MCS devices during the hospital course was as follows: in patients with early MCS implementation, VA‐ECMO only was implemented in 34 (49.3%) patients, VA‐ECMO plus Impella 2.5 in 6 (8.7%), and VA‐ECMO plus Impella CP in 24 (34.8%, no Impella 5.0 use in the early group). For those with an intermediate MCS implementation, VA‐ECMO only was utilized in 110 (59.8%) patients, VA‐ECMO plus Impella 2.5 in 20 (10.9%), plus Impella CP in 51 (27.7%), and plus Impella 5.0 in 2 (1.1%). Among patients with a delayed MCS implementation, VA‐ECMO only was used in 43 (55.8%) patients, VA‐ECMO plus Impella 2.5 in 8 (10.4%), plus Impella CP in 22 (28.6%), and plus Impella 5.0 in 3 (3.9%). Regarding the timing between device implantations in ECMELLA strategy, 42% of cases received simultaneous implementation of Impella and VA‐ECMO, while 21% had Impella‐first and 37% VA‐ECMO‐first approaches (detailed in online supplementary Table ). The use of distal perfusion cannula was not different between groups ( Table ). Association between timing of mechanical circulatory support implementation and patient characteristics Differences in clinical characteristics during the index event between patients with earlier (<12 h, early plus intermediate group) versus delayed (≥12–24 h) CS‐to‐MCS time were analysed. Patients with CPR (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.26–0.96, p = 0.039), CPR lasting over 30 min (OR 0.31, 95% CI 0.11–0.89, p = 0.029) and a higher SAVE score (OR 0.94, 95% CI 0.89–0.99, p = 0.026) had a higher likelihood of early MCS implementation ( Figure ). Conversely, patients with a lower pH were more likely to receive delayed MCS therapy (OR 1.31, 95% CI 1.12–1.55, p = 0.001). However, when comparing the crucial index event parameters of CS between patients with early versus delayed MCS implementation, similar mean blood pressure, heart rate, and lactate measurements were observed ( Figure ). Association between timing of mechanical circulatory support implementation, complications, and 30‐day all‐cause mortality In the overall study cohort, 206 patients died during a 30‐day follow‐up period, resulting in a crude 30‐day mortality rate of 63.3%. Patients with early MCS implementation exhibited a slightly lower 30‐day mortality rate of 58.1%, compared to those with intermediate MCS implementation (64.7%) and delayed MCS implementation (64.3%) ( Figure ). Unadjusted and adjusted analysis showed no significant association between timing of MCS implantation and 30‐day all‐cause mortality (adjusted HR for intermediate vs. early MCS: 0.93, 95% CI 0.59–1.46, p = 0.74; adjusted HR for delayed vs. early MCS: 1.29, 95% CI 0.78–2.13, p = 0.33). Additionally, the HR for 30‐day mortality across the CS‐to‐MCS timing continuum, adjusted for age, sex, lactate (before MCS implementation), cause of CS, and CPR, did not show significant effects ( Figure ). The point estimator suggests that a small effect may exist, indicating a potential outcome improvement with early MCS implementation. The overall 30‐day mortality rate in patients with early, intermediate, and delayed CS‐to‐MCS time intervals, stratified by CPR, MCS device (ECMO vs. ECMELLA), median SAPS II, and SAVE score, is illustrated in Figure . Among both resuscitated and non‐resuscitated patients (excluding eCPR), no significant differences in outcomes were observed based on the timing of MCS implantation. Patients who received early VA‐ECMO only treatment exhibited the highest 30‐day mortality, whereas those undergoing early ECMELLA support had a notably lower mortality rate (42.9% vs. 73.5%, p = 0.015) ( Figure ). Moreover, compared to patients with delayed ECMELLA implementation, those with early ECMELLA support had lower mortality rates (42.9% vs. 51.4% vs. 58.8%). Patients with a SAPS II score ≥ the median (60) exhibited higher 30‐day mortality compared to those with lower SAPS II scores, with the highest mortality observed in the delayed CS‐to‐MCS time group ( Figure ). In patients with a SAVE score < the median (−7.5, lower scores indicate worse outcome), mortality was overall higher, with a slight increase in the delayed CS‐to‐MCS time groups ( Figure ). Similarly, there were no significant differences observed when comparing patients with early versus delayed CS‐to‐MCS time intervals, stratified by a median time interval of 4 h, or stratified by < versus ≥12 h, as illustrated in the Kaplan–Meier curves of online supplementary Figure . In patients with early and intermediate CS‐to‐MCS time, haemolysis was less frequently observed (25.9% and 24.2% vs. 42.9%). Numerically, there were slightly fewer rates of renal replacement therapy in the early and intermediate groups (46.2% and 43.7% vs. 59.7%). Event rates of other CS and MCS device‐associated complications did not differ between groups ( Table ). Even after adjustment for relevant confounders, only haemolysis was found to be significantly associated with a higher likelihood of delayed compared to earlier MCS implementation (OR 2.49, 95% CI 1.25–4.96, p = 0.010) ( Figure ). 

Of 716 patients with CS treated with either VA‐ECMO or ECMELLA in the registry, 330 patients met the inclusion criteria for this study ( Figure ). Baseline characteristics for the overall cohort stratified by early (<2 h) versus intermediate (2–12 h) versus delayed (≥12–24 h) CS‐to‐MCS time interval are shown in Table . The median age of the study population was 57 years (interquartile range [IQR] 49–66), with 249 (75.5%) being male. Among these patients, 202 (61.2%) had an acute myocardial infarction (AMI) as the underlying cause of CS (AMI‐CS). Although there were no significant differences in age and sex distribution across the early, intermediate, and delayed CS‐to‐MCS time intervals, variations in clinical presentation were observed. Patients with early and intermediate CS‐to‐MCS intervals had higher rates of AMI‐CS (65.2% vs. 65.2% vs. 48.1%) and prior CPR (54.8% vs. 51.6% vs. 32.9%), compared to those with delayed CS‐to‐MCS intervals. Furthermore, patients with early and intermediate MCS implementation demonstrated higher creatinine clearance compared to those with delayed MCS implementation (38 ml/min vs. 47 ml/min vs. 37 ml/min). However, no significant disparities were observed in lactate levels, arterial blood pressure, heart rate, haemoglobin, Survival After Veno‐Arterial ECMO (SAVE) score or Simplified Acute Physiology Score (SAPS) II score measured prior to MCS implementation during the index event ( Table ). The median time from the onset of CS to the initiation of the first MCS device was 4 h (IQR 2.0–10.4). Among these patients, 69 (20.9%) received early MCS implementation (median timing interval 1 h, IQR 0.5–1.0), 184 (55.8%) received intermediate MCS implementation (median timing interval 4 h, IQR 3.0–6.0), and 77 (23.3%) received delayed MCS implementation (median timing interval 16 h, IQR 12.8–23.0), as illustrated in the Graphical Abstract . The thoroughly examined use of MCS devices during the hospital course was as follows: in patients with early MCS implementation, VA‐ECMO only was implemented in 34 (49.3%) patients, VA‐ECMO plus Impella 2.5 in 6 (8.7%), and VA‐ECMO plus Impella CP in 24 (34.8%, no Impella 5.0 use in the early group). For those with an intermediate MCS implementation, VA‐ECMO only was utilized in 110 (59.8%) patients, VA‐ECMO plus Impella 2.5 in 20 (10.9%), plus Impella CP in 51 (27.7%), and plus Impella 5.0 in 2 (1.1%). Among patients with a delayed MCS implementation, VA‐ECMO only was used in 43 (55.8%) patients, VA‐ECMO plus Impella 2.5 in 8 (10.4%), plus Impella CP in 22 (28.6%), and plus Impella 5.0 in 3 (3.9%). Regarding the timing between device implantations in ECMELLA strategy, 42% of cases received simultaneous implementation of Impella and VA‐ECMO, while 21% had Impella‐first and 37% VA‐ECMO‐first approaches (detailed in online supplementary Table ). The use of distal perfusion cannula was not different between groups ( Table ). 

Differences in clinical characteristics during the index event between patients with earlier (<12 h, early plus intermediate group) versus delayed (≥12–24 h) CS‐to‐MCS time were analysed. Patients with CPR (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.26–0.96, p = 0.039), CPR lasting over 30 min (OR 0.31, 95% CI 0.11–0.89, p = 0.029) and a higher SAVE score (OR 0.94, 95% CI 0.89–0.99, p = 0.026) had a higher likelihood of early MCS implementation ( Figure ). Conversely, patients with a lower pH were more likely to receive delayed MCS therapy (OR 1.31, 95% CI 1.12–1.55, p = 0.001). However, when comparing the crucial index event parameters of CS between patients with early versus delayed MCS implementation, similar mean blood pressure, heart rate, and lactate measurements were observed ( Figure ). 

In the overall study cohort, 206 patients died during a 30‐day follow‐up period, resulting in a crude 30‐day mortality rate of 63.3%. Patients with early MCS implementation exhibited a slightly lower 30‐day mortality rate of 58.1%, compared to those with intermediate MCS implementation (64.7%) and delayed MCS implementation (64.3%) ( Figure ). Unadjusted and adjusted analysis showed no significant association between timing of MCS implantation and 30‐day all‐cause mortality (adjusted HR for intermediate vs. early MCS: 0.93, 95% CI 0.59–1.46, p = 0.74; adjusted HR for delayed vs. early MCS: 1.29, 95% CI 0.78–2.13, p = 0.33). Additionally, the HR for 30‐day mortality across the CS‐to‐MCS timing continuum, adjusted for age, sex, lactate (before MCS implementation), cause of CS, and CPR, did not show significant effects ( Figure ). The point estimator suggests that a small effect may exist, indicating a potential outcome improvement with early MCS implementation. The overall 30‐day mortality rate in patients with early, intermediate, and delayed CS‐to‐MCS time intervals, stratified by CPR, MCS device (ECMO vs. ECMELLA), median SAPS II, and SAVE score, is illustrated in Figure . Among both resuscitated and non‐resuscitated patients (excluding eCPR), no significant differences in outcomes were observed based on the timing of MCS implantation. Patients who received early VA‐ECMO only treatment exhibited the highest 30‐day mortality, whereas those undergoing early ECMELLA support had a notably lower mortality rate (42.9% vs. 73.5%, p = 0.015) ( Figure ). Moreover, compared to patients with delayed ECMELLA implementation, those with early ECMELLA support had lower mortality rates (42.9% vs. 51.4% vs. 58.8%). Patients with a SAPS II score ≥ the median (60) exhibited higher 30‐day mortality compared to those with lower SAPS II scores, with the highest mortality observed in the delayed CS‐to‐MCS time group ( Figure ). In patients with a SAVE score < the median (−7.5, lower scores indicate worse outcome), mortality was overall higher, with a slight increase in the delayed CS‐to‐MCS time groups ( Figure ). Similarly, there were no significant differences observed when comparing patients with early versus delayed CS‐to‐MCS time intervals, stratified by a median time interval of 4 h, or stratified by < versus ≥12 h, as illustrated in the Kaplan–Meier curves of online supplementary Figure . In patients with early and intermediate CS‐to‐MCS time, haemolysis was less frequently observed (25.9% and 24.2% vs. 42.9%). Numerically, there were slightly fewer rates of renal replacement therapy in the early and intermediate groups (46.2% and 43.7% vs. 59.7%). Event rates of other CS and MCS device‐associated complications did not differ between groups ( Table ). Even after adjustment for relevant confounders, only haemolysis was found to be significantly associated with a higher likelihood of delayed compared to earlier MCS implementation (OR 2.49, 95% CI 1.25–4.96, p = 0.010) ( Figure ). 

In this retrospective, multicentre, international study of patients with CS treated with MCS, the timing of device implantation was not associated with 30‐day all‐cause mortality. While the point estimator suggests a potential small effect favouring early MCS implementation, no significant differences were observed when comparing early (<2 h) versus intermediate (2–12 h) and delayed (≥12–24 h) CS‐to‐MCS time intervals. Additionally, the incidence of device‐associated complications during the hospital course, including bleeding, ischaemic or stroke events, did not significantly differ among groups. These findings suggest the non‐inferiority of an initial restrictive MCS approach, which reserves MCS application only for patients experiencing CS deterioration despite conventional therapy. However, these findings warrant validation in larger, better‐characterized cohorts. Association between timing of mechanical circulatory support implementation and outcome In patients with higher CS severity, conservative treatment approaches such as vasopressors and inotropes often fall short in effectiveness emphasizing the potential of MCS to enhance outcomes by providing temporary support. , , Recent findings from the DanGer Shock trial underscore the potential of microaxial flow pumps in reducing all‐cause mortality in a selected group of AMI‐CS compared to standard care alone. Despite the increasing use of VA‐ECMO in CS over the past decade, evidence supporting its mortality benefit remains elusive. , , The ECLS‐SHOCK (Extracorporeal Life Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock) trial demonstrated no mortality benefit among patients with AMI‐CS (SCAI stages C, D, and E) treated with VA‐ECMO compared to those receiving conventional medical therapy. The timing of MCS implementation may significantly impact device efficacy. Early or proactive MCS use aims to enhance perfusion before transitioning to refractory CS and irreversible multiorgan failure, while later implementation as a bail‐out strategy seeks to prevent overtreatment and serious complications. , , , , However, the crucial aspect of timing in MCS implementation remains unclear, warrants research effort, and was therefore further investigated in this study. In this study, patients with CS treated with MCS (VA‐ECMO or ECMELLA) within a shorter timeframe (early and intermediate median CS‐to‐MCS time of 1 and 4 h) did not experience a mortality benefit compared to those with a longer time intervals (delayed median CS‐to‐MCS time of 16 h). Among these patients, nearly half underwent resuscitation prior to MCS (eCPR excluded), with a median lactate level of 7.6 mmol/L before device implementation, indicative of a heightened CS severity. In ECMO‐CS trial, 122 patients with rapidly deteriorating or severe CS were randomized for immediate implementation of VA‐ECMO versus an initially conservative strategy, which allowed downstream use of VA‐ECMO in case of worsening CS. In patients managed initially with conservative CS treatment, VA‐ECMO was utilized in 39% due to subsequent CS deterioration, without outcome differences between groups. These findings are in line with our results, demonstrating no benefit from early implementation of VA‐ECMO. Instead, a multidisciplinary shock team approach evaluating individual patent characteristics as early lactate kinetics, meticulous changes in haemodynamic assessment, and considering the underlying aetiology of CS with its pathophysiological peculiarities, and based on this, individual decision regarding the timing of MCS, could be superior to an early VA‐ECMO approach in general. , , , Our findings contradict the limited prior retrospective analyses examining the impact of MCS timing in CS. , , A multicentre study by Lee et al . found that in patients with refractory CS, earlier VA‐ECMO support was associated with improved clinical outcomes. Patients with early and intermediate median CS‐to‐ECMO times of 0.6 and 1.4 h, respectively, exhibited reduced risks for in‐hospital mortality, ECMO weaning failure, and the composite of all‐cause mortality compared to those with later MCS implantation (CS‐to‐ECMO time 5.1 h). In addition, observational studies have demonstrated that early ECMO‐assisted percutaneous coronary intervention reduces the risk of adverse clinical outcomes in patients with AMI complicated by refractory CS. , , Moreover, observational meta‐analyses of AMI‐CS have shown that VA‐ECMO initiation prior to percutaneous intervention could reduce mortality. However, these results were not confirmed in the ECLS‐SHOCK trial or in the related individual patient data meta‐analysis. , In a recently published study, which included 8619 patients from the Extracorporeal Life Support Organization (ELSO) registry, a key finding revealed that delayed initiation of ECMO beyond 24 h from hospital admission was associated with a higher in‐hospital mortality rate. Nonetheless, among patients with more advanced CS (SCAI C, D, E) and cardiac arrest before admission, no significant differences in in‐hospital mortality were observed when comparing early versus delayed VA‐ECMO initiation. This observation reinforces our findings, as patients in our study also exhibited pronounced hypoperfusion markers, indicating higher CS stages, yet did not demonstrate a significant difference in mortality with early VA‐ECMO implementation. However, whether patients would have derived benefit from early VA‐ECMO implementation in a less severe CS stages (e.g. SCAI B) cannot be answered with this study. Interestingly, patients undergoing ECMELLA therapy within 2 h after CS onset showed lower 30‐day mortality compared to those with delayed ECMELLA implementation intervals – and significantly lower mortality rates than patients who received VA‐ECMO only therapy (42.9% vs. 73.5%). The increase in left ventricular afterload induced by VA‐ECMO may impede myocardial recovery and adversely affect outcomes in CS. A prior study has shown that left ventricular unloading on VA‐ECMO could improve outcome, albeit with a higher incidence of complications. Furthermore, exploratory study results support the earliest possible active left ventricular unloading with Impella on VA‐ECMO in patients with CS. However, it remains ambiguous whether and in which CS subset left ventricular unloading approach should be implemented on VA‐ECMO as a targeted therapeutic strategy. To further investigate these findings recently initiated randomized controlled trials as the UNLOAD‐ECMO trial (NCT05577195) for Impella and the REMAP–ECMO trial (NCT05913622) for IABP unloading are enrolling first participants. The findings of our study, along with prior research, underscore the complex relationship between the timing of MCS implementation and outcomes in CS, highlighting potential overuse without benefit in a larger subgroup of CS patients. In contrast to prevalent trends advocating for early and proactive VA‐ECMO adoption across the heterogeneous spectrum of CS, our results highlight a possible non‐inferiority of an initially conservative CS management approach. Timing of MCS represents only one facet among numerous critical considerations in the management of CS. Other pivotal factors include unique patient characteristics, their potential for recovery, and the feasibility of MCS use as a bridge to left ventricular assist device implantation or heart transplantation. Significant gaps persist in both identifying the appropriate MCS device and determining the optimal timing for MCS implementation, highlighting the urgent need for further research efforts to support an individualized MCS approach. Limitations This study faces several limitations that should be acknowledged. Firstly, due to its non‐randomized design, causal conclusions between CS‐to‐MCS time and outcomes cannot be inferred. Additionally, the assessment of patient characteristics may be influenced by subjective factors related to the examiners and the clinical settings in which evaluations took place, particularly under challenging conditions in intensive care units, emergency departments or catheterization laboratories. Additionally, crucial data on procedural characteristics, invasive haemodynamic parameters, and echocardiography measures were not available in the registry, potentially impacting the study's findings. Furthermore, all safety endpoints were limited to in‐hospital events, and potential late complications post‐discharge were not captured, affecting outcome assessment. While data were gathered from various hospitals across four countries, they were primarily large tertiary care centres with extensive experience in managing CS and utilizing MCS devices. This may introduce bias toward a higher prevalence of severe CS and increased utilization of MCS devices. Given the paucity of evidence over the past two decades, the selection of MCS devices and the timing of their implementation in CS settings remain highly individualized and heterogeneous decisions for clinicians. This registry does not fully capture the entirety of individual factors influencing the decision for early or late device implantation, so that we cannot exactly describe which factors influenced the decision to use the respective device early or delayed. Additionally, due to a lack of data on the use of the IABP in this patient registry, we cannot extend our findings to this patient population. Also, the registry does not provide data on patients who deceased before MCS implantation, so that we cannot make conclusions about this relevant group of patients. Therefore, the generalizability of these data may be limited, necessitating comprehensive exploration of individual patient factors that impact the timing of MCS implementation in larger, more comprehensively characterized patient cohorts. 

In patients with higher CS severity, conservative treatment approaches such as vasopressors and inotropes often fall short in effectiveness emphasizing the potential of MCS to enhance outcomes by providing temporary support. , , Recent findings from the DanGer Shock trial underscore the potential of microaxial flow pumps in reducing all‐cause mortality in a selected group of AMI‐CS compared to standard care alone. Despite the increasing use of VA‐ECMO in CS over the past decade, evidence supporting its mortality benefit remains elusive. , , The ECLS‐SHOCK (Extracorporeal Life Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock) trial demonstrated no mortality benefit among patients with AMI‐CS (SCAI stages C, D, and E) treated with VA‐ECMO compared to those receiving conventional medical therapy. The timing of MCS implementation may significantly impact device efficacy. Early or proactive MCS use aims to enhance perfusion before transitioning to refractory CS and irreversible multiorgan failure, while later implementation as a bail‐out strategy seeks to prevent overtreatment and serious complications. , , , , However, the crucial aspect of timing in MCS implementation remains unclear, warrants research effort, and was therefore further investigated in this study. In this study, patients with CS treated with MCS (VA‐ECMO or ECMELLA) within a shorter timeframe (early and intermediate median CS‐to‐MCS time of 1 and 4 h) did not experience a mortality benefit compared to those with a longer time intervals (delayed median CS‐to‐MCS time of 16 h). Among these patients, nearly half underwent resuscitation prior to MCS (eCPR excluded), with a median lactate level of 7.6 mmol/L before device implementation, indicative of a heightened CS severity. In ECMO‐CS trial, 122 patients with rapidly deteriorating or severe CS were randomized for immediate implementation of VA‐ECMO versus an initially conservative strategy, which allowed downstream use of VA‐ECMO in case of worsening CS. In patients managed initially with conservative CS treatment, VA‐ECMO was utilized in 39% due to subsequent CS deterioration, without outcome differences between groups. These findings are in line with our results, demonstrating no benefit from early implementation of VA‐ECMO. Instead, a multidisciplinary shock team approach evaluating individual patent characteristics as early lactate kinetics, meticulous changes in haemodynamic assessment, and considering the underlying aetiology of CS with its pathophysiological peculiarities, and based on this, individual decision regarding the timing of MCS, could be superior to an early VA‐ECMO approach in general. , , , Our findings contradict the limited prior retrospective analyses examining the impact of MCS timing in CS. , , A multicentre study by Lee et al . found that in patients with refractory CS, earlier VA‐ECMO support was associated with improved clinical outcomes. Patients with early and intermediate median CS‐to‐ECMO times of 0.6 and 1.4 h, respectively, exhibited reduced risks for in‐hospital mortality, ECMO weaning failure, and the composite of all‐cause mortality compared to those with later MCS implantation (CS‐to‐ECMO time 5.1 h). In addition, observational studies have demonstrated that early ECMO‐assisted percutaneous coronary intervention reduces the risk of adverse clinical outcomes in patients with AMI complicated by refractory CS. , , Moreover, observational meta‐analyses of AMI‐CS have shown that VA‐ECMO initiation prior to percutaneous intervention could reduce mortality. However, these results were not confirmed in the ECLS‐SHOCK trial or in the related individual patient data meta‐analysis. , In a recently published study, which included 8619 patients from the Extracorporeal Life Support Organization (ELSO) registry, a key finding revealed that delayed initiation of ECMO beyond 24 h from hospital admission was associated with a higher in‐hospital mortality rate. Nonetheless, among patients with more advanced CS (SCAI C, D, E) and cardiac arrest before admission, no significant differences in in‐hospital mortality were observed when comparing early versus delayed VA‐ECMO initiation. This observation reinforces our findings, as patients in our study also exhibited pronounced hypoperfusion markers, indicating higher CS stages, yet did not demonstrate a significant difference in mortality with early VA‐ECMO implementation. However, whether patients would have derived benefit from early VA‐ECMO implementation in a less severe CS stages (e.g. SCAI B) cannot be answered with this study. Interestingly, patients undergoing ECMELLA therapy within 2 h after CS onset showed lower 30‐day mortality compared to those with delayed ECMELLA implementation intervals – and significantly lower mortality rates than patients who received VA‐ECMO only therapy (42.9% vs. 73.5%). The increase in left ventricular afterload induced by VA‐ECMO may impede myocardial recovery and adversely affect outcomes in CS. A prior study has shown that left ventricular unloading on VA‐ECMO could improve outcome, albeit with a higher incidence of complications. Furthermore, exploratory study results support the earliest possible active left ventricular unloading with Impella on VA‐ECMO in patients with CS. However, it remains ambiguous whether and in which CS subset left ventricular unloading approach should be implemented on VA‐ECMO as a targeted therapeutic strategy. To further investigate these findings recently initiated randomized controlled trials as the UNLOAD‐ECMO trial (NCT05577195) for Impella and the REMAP–ECMO trial (NCT05913622) for IABP unloading are enrolling first participants. The findings of our study, along with prior research, underscore the complex relationship between the timing of MCS implementation and outcomes in CS, highlighting potential overuse without benefit in a larger subgroup of CS patients. In contrast to prevalent trends advocating for early and proactive VA‐ECMO adoption across the heterogeneous spectrum of CS, our results highlight a possible non‐inferiority of an initially conservative CS management approach. Timing of MCS represents only one facet among numerous critical considerations in the management of CS. Other pivotal factors include unique patient characteristics, their potential for recovery, and the feasibility of MCS use as a bridge to left ventricular assist device implantation or heart transplantation. Significant gaps persist in both identifying the appropriate MCS device and determining the optimal timing for MCS implementation, highlighting the urgent need for further research efforts to support an individualized MCS approach. 

This study faces several limitations that should be acknowledged. Firstly, due to its non‐randomized design, causal conclusions between CS‐to‐MCS time and outcomes cannot be inferred. Additionally, the assessment of patient characteristics may be influenced by subjective factors related to the examiners and the clinical settings in which evaluations took place, particularly under challenging conditions in intensive care units, emergency departments or catheterization laboratories. Additionally, crucial data on procedural characteristics, invasive haemodynamic parameters, and echocardiography measures were not available in the registry, potentially impacting the study's findings. Furthermore, all safety endpoints were limited to in‐hospital events, and potential late complications post‐discharge were not captured, affecting outcome assessment. While data were gathered from various hospitals across four countries, they were primarily large tertiary care centres with extensive experience in managing CS and utilizing MCS devices. This may introduce bias toward a higher prevalence of severe CS and increased utilization of MCS devices. Given the paucity of evidence over the past two decades, the selection of MCS devices and the timing of their implementation in CS settings remain highly individualized and heterogeneous decisions for clinicians. This registry does not fully capture the entirety of individual factors influencing the decision for early or late device implantation, so that we cannot exactly describe which factors influenced the decision to use the respective device early or delayed. Additionally, due to a lack of data on the use of the IABP in this patient registry, we cannot extend our findings to this patient population. Also, the registry does not provide data on patients who deceased before MCS implantation, so that we cannot make conclusions about this relevant group of patients. Therefore, the generalizability of these data may be limited, necessitating comprehensive exploration of individual patient factors that impact the timing of MCS implementation in larger, more comprehensively characterized patient cohorts. 

Determining the optimal timing for MCS initiation remains unknown and controversial. In this retrospective, multicentre, international study of patients with CS undergoing VA‐ECMO or ECMELLA therapy, the timing of device implementation within 24 h did not correlate with 30‐day all‐cause mortality. While the data hint at a potential slight benefit for early MCS implementation based on the point estimate, no significant differences were evident between subgroups. Moreover, the occurrence of device‐related complications during the hospital course did not significant differ among groups. These findings support a restrictive VA‐ECMO approach, reserving its application for patients experiencing CS deterioration despite conventional therapy. Individual timing of MCS implementation and escalation in patients with higher CS severity, guided by a multidisciplinary CS team approach, based on individual patient characteristics, may not be inferior to a routine earlier MCS application. Herein, early active left ventricular unloading could be beneficial for CS patients on VA‐ECMO. These findings need to be explored in larger, more comprehensively characterized patient cohorts. 

Appendix S1. Supporting Information. 

