FAQ: Is There Randomized Controlled Trial Data Available for Impella® Heart Pump Use in Cardiogenic Shock?

​​Randomized controlled trials (RCTs) are considered the “gold standard” for evaluating the efficacy and safety of medical interventions.​ ​​The​​ ​​​DanGer Shock RCT, published in the New England Journal of Medicine, is a landmark study confirming that the Impella CP® heart pump improves survival by 12.7% compared to standard treatment without Impella in patients experiencing cardiogenic shock following a heart attack or Acute Myocardial Infarction-related Cardiogenic Shock (AMICS) due to STEMI​​​ (ST-Elevation Myocardial Infarction),​ undergoing emergency PCI (Percutaneous Coronary Intervention). ​​ 

​​​This is the first RCT in AMICS trial history to successfully complete enrollment and meet its primary endpoint, and notably, the first RCT among mechanical circulatory support (MCS) device trials to demonstrate a clear survival benefit in this high-risk population.​​ 

​At J&J MedTech, we are committed to advancing clinical evidence and improving outcomes for critically ill patients with cardiogenic shock. While seven RCTs have been initiated to study Impella, five were discontinued due to challenges with patient enrollment. The success of DanGer Shock marks a significant milestone in both the MCS field and the care of patients with AMICS.​​

​​​The ISAR-SHOCK trial compared the hemodynamic effects of the Impella device with the intra-aortic balloon pump (IABP) in patients experiencing acute myocardial infarction-related cardiogenic shock (AMICS) and was completed.​​ 

Following that, the RECOVER II trial was launched to evaluate the impact of Impella in AMICS patients but was discontinued after 18 months due to low enrollment—only one patient was enrolled across 50 IRB-approved sites.​​ 

​​​The DANSHOCK trial began in Denmark, enrolling 100 AMICS patients over its first five years. It was later expanded to include sites in Germany and renamed the DanGer Shock trial. This became the largest randomized controlled trial (RCT) in cardiogenic shock, conducted over 10 years. ​​ 

The study assessed the efficacy of Impella CP®, with or without SmartAssist®, in treating patients with cardiogenic shock caused by STEMI who were undergoing emergency PCI. The final results of the DanGer Shock trial were published in the New England Journal of Medicine (NEJM) and presented at ACC 2024.​​ 

​​​In September 2022, Abiomed announced FDA approval for the RECOVER IV randomized controlled trial (RCT), designed to compare outcomes in AMICS patients receiving Impella support before PCI versus those receiving conventional therapies, including other forms of mechanical circulatory support. However, the trial has since been halted following a recommendation by the Data and Safety Monitoring Board (DSMB).​​ 

​​​This decision was made because the DanGer Shock trial showed a clear survival advantage with the Impella CP® heart pump in STEMI patients with cardiogenic shock, making it unethical to continue assigning patients to treatments that are now known to be less effective.​​ 

FRENCH Trial

​​​The FRENCH trial was a multicenter, randomized study that compared standard treatment alone to standard treatment plus either extracorporeal life support (ECLS) or the Impella 2.5® heart pump in patients experiencing acute myocardial infarction-related cardiogenic shock (AMICS).​​ 

​​​​Standard treatment included the use of intra-aortic balloon pumps (IABP), inotropic medications (which help the heart pump more effectively), and antiplatelet drugs, all based on the standard protocols of each participating hospital.​​​ 

​​​​The primary endpoint was a combination of all-cause mortality at 30 days or progression to refractory cardiogenic shock requiring a left ventricular assist device (LVAD).​​​ 

The sample size required to detect differences in the primary outcome was 200 patients​;​ ​however, only 19 patients were enrolled over 52 months​,​ resulting in the discontinuation of the study due to ​a ​low enrollment rate. The results of this trial are not publicly available.

ISAR-SHOCK

​​​The ISAR-SHOCK trial was initially designed as a prospective, randomized study to compare the hemodynamic effects of the Impella 2.5® heart pump with the intra-aortic balloon pump (IABP) in patients with AMICS. However, the final execution was non-randomized.​​ 

​​​Over a 19-month period, the study enrolled 26 patients who had experienced an AMI within 48 hours and were in cardiogenic shock. After undergoing PCI, patients were assigned to receive either IABP (13 patients) or Impella 2.5 (12 patients). One patient randomized to the Impella group died before the device could be implanted.​​ 

​​​At baseline, the median left ventricular ejection fraction (LVEF) was 27.5%, and the average time from AMI onset to enrollment was 4.5 hours. There were no significant differences in baseline characteristics between the two groups.​​ 

​​​The primary endpoint was the change in cardiac index 30 minutes after device implantation. The Impella 2.5 group showed a significantly greater improvement in cardiac index compared to the IABP group (0.49 ± 0.46 L/min/m² vs. 0.11 ± 0.31 L/min/m², p = 0.02). Additionally, diastolic arterial pressure increased in the Impella group and decreased in the IABP group (+9.2 ± 12.1 mmHg vs. -8.0 ± 13.1 mmHg, p = 0.002).​​ 

​​​The secondary endpoint, 30-day all-cause mortality, was 46% in both groups. Patients in the Impella group experienced higher rates of hemolysis within the first 24 hours, leading to an increased need for blood transfusions. ​​ 

​​​However, neither group had any device-related malfunctions, major bleeding, or ischemic events during support. Notably, there was also a trend toward faster reversal of elevated serum lactate levels in the Impella group, suggesting potentially improved tissue perfusion.​​ 

​​​The ISAR-SHOCK trial was initially designed as a prospective, randomized study to compare the hemodynamic effects of the Impella 2.5® heart pump with the intra-aortic balloon pump (IABP) in patients with AMICS. However, the final execution was non-randomized.​​ 

​​​Over a 19-month period, the study enrolled 26 patients who had experienced an AMI within 48 hours and were in cardiogenic shock. After undergoing PCI, patients were assigned to receive either IABP (13 patients) or Impella 2.5 (12 patients). One patient randomized to the Impella group died before the device could be implanted.​​ 

​​​At baseline, the median left ventricular ejection fraction (LVEF) was 27.5%, and the average time from AMI onset to enrollment was 4.5 hours. There were no significant differences in baseline characteristics between the two groups.​​ 

​​​The primary endpoint was the change in cardiac index 30 minutes after device implantation. The Impella 2.5 group showed a significantly greater improvement in cardiac index compared to the IABP group (0.49 ± 0.46 L/min/m² vs. 0.11 ± 0.31 L/min/m², p = 0.02). Additionally, diastolic arterial pressure increased in the Impella group and decreased in the IABP group (+9.2 ± 12.1 mmHg vs. -8.0 ± 13.1 mmHg, p = 0.002).​​ 

​​​The secondary endpoint, 30-day all-cause mortality, was 46% in both groups. Patients in the Impella group experienced higher rates of hemolysis within the first 24 hours, leading to an increased need for blood transfusions. ​​ 

​​​However, neither group had any device-related malfunctions, major bleeding, or ischemic events during support. Notably, there was also a trend toward faster reversal of elevated serum lactate levels in the Impella group, suggesting potentially improved tissue perfusion.​​ 

IMPRESS in STEMI Trial

​​​This multicenter, international randomized trial aimed to compare the effectiveness of the Impella 2.5® heart pump versus the intra-aortic balloon pump (IABP) following percutaneous coronary intervention (PCI) in patients with cardiogenic pre-shock due to anterior ST-elevation myocardial infarction (STEMI).​​ 

​​​Cardiogenic pre-shock was defined by a heart rate over 100 beats per minute and/or systolic blood pressure below 100 mmHg, accompanied by clinical signs such as cold extremities, cyanosis, low urine output (oliguria), and altered mental status.​​ 

​​​The study’s primary endpoint was left ventricular ejection fraction (LVEF) measured by MRI at four months post-intervention.​​ 

​​​The trial originally aimed to enroll 130 patients to properly assess this outcome. However, over 42 months, only 21 patients were randomized across five centers; 12 to Impella and 9 to IABP. Due to the low enrollment, the study was discontinued, preventing a meaningful evaluation of clinical outcomes.​​

RECOVER II FDA Trial

RECOVER II  was a multicenter, open-label, randomized trial initiated to compare clinical outcomes with the Impella 2.5 heart pump and the intra-aortic balloon pump (IABP) in patients with AMI cardiogenic shock (AMICS).6 The primary outcome was composite rate of major adverse events within 30 days or at hospital discharge and the secondary outcome was maximum increase in cardiac power output from baseline. The sample size needed to determine significant differences between groups in major adverse events was 384.

Despite 50 sites with IRB approval in the US, only one patient was enrolled in the study between July 2008 and August 2010, resulting in the discontinuation of the trial due to low enrollment.

IMPRESS Trial

​​The IMPRESS trial was an open-label trial initiated to determine whether the Impella heart pump can decrease 30-day all-cause mortality compared to IABP in patients with severe shock complicating acute myocardial infarction.⁸ 

​​​​The study originally estimated that 48 patients (24 in each group) would be needed to detect a significant difference in mortality between the Impella and IABP groups, based on the assumption that survival in severe cardiogenic shock would be less than 10%.​​ 

​​​However, during an interim analysis, it became clear that the mortality rate in the control (IABP) group was much lower than the expected 90%, significantly impacting the study's statistical power. To reliably detect a mortality difference at this lower rate, more than 100 patients would have been required.​​ 

​​​Given this new information, the investigators chose to complete the study with the originally planned 48 patients, but as an exploratory analysis rather than one powered to determine definitive differences in mortality.​​ 

​​Given that the trial was statistically underpowered, no difference in mortality was observed between groups at 30 days and 6 months. Mortality at 30 days was 46% in patients treated with Impella compared to 50% with IABP (p = 0.92).​​ 

​​At six months, mortality rate was 50% in both treatment groups (p = 0.92). Importantly, about 92% of the enrolled patients had cardiac arrest​,​ with 48% having return of spontaneous circulation (ROSC) longer than 20 minutes.

All patients were treated with catecholamines before randomization and 75% received therapeutic hypothermia. Of the 24 patients in either intervention group, about 84% had device placement after revascularization. In addition, overall, 15% of patients had traumatic injuries due to cardiac arrest​,​ with disproportionately higher rates observed in the Impella group compared to the IABP group (21% vs. 8%). The main cause of death was brain damage and refractory cardiogenic shock in 46% and 29%, respectively. 

Many shortcomings are identified in the conduct of the trial, which had non-randomized or sequential execution. The definition used for severe cardiogenic shock is unclear and patients were deemed to have cardiogenic shock based on operator discretion. As per protocol, crossover between treatments was not allowed; however, three patients in the IABP group crossed over to Impella group. Among the patients in the Impella group, one patient received Impella 5.0® after Impella CP®, one patient received IABP before Impella thus constituting a protocol violation, and one patient did not receive Impella after randomization. 

Major bleeding was reported in 33% of patients in the Impella arm compared to 8% in the IABP arm. Given the disproportionately higher rates of traumatic injuries at admission in patients receiving Impella, higher rates of bleeding events are not unexpected. In fact, device-related bleeding events were not different between groups with three events in the Impella group and one event in the IABP group. 

In the combined analysis of the entire study population, a trend toward lower mortality at 30 days was observed if the mechanical circulatory support device was used pre-PCI (25% vs 53%, p = 0.16). Similar trends of lower mortality were observed in patients with ROSC <20 minutes and lactate levels lower than 7.5mmol/L at admission. Given the high rates of post-anoxic neurological damage, the use of any mechanical circulatory support device may be of limited utility. 

While this study offers insight into the use of Impella in patients with cardiac arrest, it does not address the survival outcome associated with the use of Impella in AMICS. Hence, it is better to describe this trial as ‘IMPRESS in Cardiac Arrest (CA).' 

DanGer Shock Trial

The DanGer Shock trial is an open-label, randomized clinical trial that began in Denmark, enrolling patients with AMICS. When the trial was later expanded to include patients from Germany, it was officially named the DanGer Shock trial.

Inclusion criteria for study participants include STEMI for <36 hours, cardiogenic shock for <24 hours confirmed based on arterial blood lactate ≥2.5mmol/L and/or SvO2 <55% with a normal PaO2 and systolic BP <100 mmHg and/or need for vasopressor therapy, and LV ejection fraction <45%. 

​​The DanGer RCT results have been published in NEJM and were presented at ACC 2024.

​​Randomized trials play an important role in ​assessing cardiovascular and medical device innovations, although they also pose many logistical and methodological challenges, particularly in the emergent setting of acute myocardial infarction and cardiogenic shock (AMICS). Consequently, evidence on the outcomes of the Impella heart pump in AMICS based on randomized controlled trials is limited. 

1. Variable definition of cardiogenic shock

Cardiogenic shock represents a continuum of patient conditions ranging from hypotension after AMI to out-of-hospital cardiac arrest requiring multiple inotropes.9 It is therefore challenging to differentiate patients with cardiogenic shock who have not passed the window of opportunity for treatment from patients in the “hemo-metabolic state” who may have irreversible organ injury despite normalization of hemodynamic parameters such as cardiac arrest with anoxic brain injury.

​​​The way treatment is adapted based on the severity of shock directly impacts both the inclusion criteria and the clinical outcomes of a trial.​​ 

​​​Broadening the inclusion criteria can help enroll more patients, but it may also dilute the observed effect of the Impella heart pump by including individuals less likely to benefit, potentially obscuring its effectiveness in a specific responder subgroup. Conversely, narrowing the criteria—for example, by excluding patients with severe brain injury—can better isolate the impact of Impella, but doing so requires strict, standardized protocols across all study sites.​​ 

​​​Regardless of the approach, the early identification and enrollment of eligible patients during emergency situations remains a significant logistical challenge.​​ 

2. Low and slow enrollment

​​​​Despite multiple efforts to conduct randomized controlled trials (RCTs) evaluating the Impella heart pump in patients with cardiogenic shock, a consistent challenge has been low and slow enrollment rates.​​​ 

​​​​This is partly due to the fact that cardiogenic shock occurs in fewer than 10% of patients with acute myocardial infarction (AMI), making eligible patients relatively rare. Additionally, patients in cardiogenic shock often face high mortality and significant procedural risks due to multiple comorbidities and severe coronary artery disease.​​​ 

​​​​These factors make both clinicians and families more hesitant to enroll such patients in clinical trials, further slowing recruitment in studies involving mechanical circulatory support devices.​​​ 

Obtaining informed consent is a contributing factor to the low enrollment rates. Due to the emergent nature of intervention in the setting of myocardial infarction, seeking informed consent from the patient’s family may either cause additional delay or may not be possible at all. The exclusion of the study candidates most likely to benefit from Impella might also be due to a variety of circumstantial reasons​, such as the availability of trained surgeons and the ​​individual preferences of treating physicians. 

3. Choice of comparator and crossover issues

In a randomized trial, the choice of the comparator affects both the conduct and the interpretation of results. The intra-aortic balloon pump (IABP) is the most widely used comparator intervention in randomized trials of mechanical circulatory support devices in cardiogenic shock​,​ mainly due to relative familiarity and ease of use by interventional cardiologists. 

​​​Randomizing patients to IABP despite existing clinical evidence showing no significant hemodynamic or mortality benefit raises ethical concerns and underscores a lack of clinical equipoise.​​ 

​​​Another challenge arises when patients assigned to "usual care" continue to deteriorate both clinically and hemodynamically, leading to crossovers into the comparator arm (e.g., Impella support). These crossovers can complicate the interpretation of results by diluting the differences between treatment groups and potentially reducing the observed effect size of the intervention.​​ 

4. Outcome assessment

​​​​Cardiogenic shock is a life-threatening condition, and hemodynamic parameters are closely tied to clinical outcomes. As such, ​​mechanical circulatory support (MCS) devices​​ are expected to have a meaningful impact on patient prognosis. Consequently, most randomized trials have used ​​short- or long-term mortality​​ as the primary endpoint.​​​ 

​​​​However, detecting significant differences in mortality typically requires ​​large sample sizes​​, often resulting in ​​underpowered trials​​ and ​​inconclusive findings​​. To supplement these outcomes, researchers have also assessed various ​​surrogate measures​​ such as ​​cardiac index, mean arterial pressure, lactate levels​​, and ​​ICU length of stay​​.​​​ 

Not surprisingly, studies assessing hemodynamic benefits have reported significant improvements with Impella.​2,9 Consensus on which outcomes are best assessed, when they should be measured, and how they should be measured is needed for randomized control trials in patients with cardiogenic shock.​​

Importantly, treatment of high-risk patients with cardiogenic shock involves a complex interplay of ‘systems of care’ in addition to ​the use of Impella. The outcome​​ of survival is dependent not only on the identification and appropriate use of Impella but also on the comprehensive care of patients during and after Impella support, which varies widely based on the patient’s underlying conditions and hospital practices. 

5. Timing of Impella support

​​​​Due to the critical need for rapid revascularization, mechanical circulatory support (MCS) devices like Impella were typically implanted after percutaneous coronary intervention (PCI). However, emerging clinical studies with the Impella heart pump suggest that early implantation, prior to PCI and before high doses of inotropes are required, may​​ lead to better clinical outcomes​​.​​​ 

​​​​Additionally, the use of Impella appears to offer ​​limited benefit in futile clinical situations​​, such as in patients with ​​severe brain injury​​. Years of clinical research have helped clarify the ​​optimal timing for Impella implantation​​, showing that patients with a ​​shorter “shock-to-support” time​​ are more likely to experience positive outcomes.​​​ 

​​​DanGer Shock RCT, published in the New England Journal of Medicine, is a landmark study and the first completed RCT of Impella in AMICS7. Impella is the only MCS shown to increase survival in MCS device trials.⁷  

In the DanGer Shock study, routine use of Impella CP reduced all-cause 180-day mortality [by 12.7%; NNT=8, p=0.04, HR 0.74] vs standard of care in AMICS due to STEMI.⁷ 

In addition to DanGer Shock RCT, the clinical outcomes of Impella support have been analyzed in real-world registries. The results from registries of Impella (cVAD Study, Impella Quality (IQ) Database) have consistently demonstrated good clinical ​outcomes​​ and safety in patients with AMI cardiogenic shock (AMICS) and informed the clinical community on best practices. Importantly, clinical evidence from studies on Impella has helped identify the optimal timing for implantation of Impella and has demonstrated that patients with shorter “shock to support” times are most likely to benefit with Impella use.¹¹ 

Investigator-led studies that demonstrate Impella improves survival and native heart recovery in AMICS patients include: 

BMJ Open Heart, 2020

A cohort study of all consecutive patients (n=903) with AMICS undergoing PCI <24 hours of symptom onset in southeastern Denmark from 2010 to 2017 comparing 30-day mortality between patients receiving early-IABP or early-Impella CP and their respective control group. That data showed that the early application of Impella CP was associated with reduced 30-day mortality compared with a matched control group.¹²

Frontiers Cardiovascular Medicine, 2020

A retrospective analysis of 166 consecutive patients with cardiogenic shock who met IABP-SHOCK II eligibility criteria was conducted across four dedicated shock centers. The findings showed that among patients at highest risk of mortality, those treated with Impella circulatory support had a significantly lower observed mortality than what was predicted. Overall​, 30-day mortality was 42%, and mortality was higher in resuscitated patients (50 vs. 36%) and when Impella was implanted post-PCI (Impella-pre-PCI: 28%, Impella-post-PCI: 51%).¹³ 

Catheterization and Cardiovascular Interventions, 2021

​​ An analysis of data from 365 patients treated with Impella 2.5 or Impella CP across 17 centers participating in the IMP-IT Registry found that implanting Impella before PCI, rather than during or after the procedure, was associated with a survival benefit and lower rates of major bleeding.​ Pre-procedural insertion was associated with an improvement in one-year survival in AMICS patients treated with PCI and HR-PCI​,​ and early Impella support was associated with a lower rate of the composite of mortality, re-hospitalization for heart failure and need for left-ventricular assist device/heart transplantation at ​one year​​.¹⁴ 

International Journal of Cardiology, 2022

This large meta-analysis of 13 studies (6810 patients) suggests that Impella placement prior to PCI in AMICS may have a positive impact on short- and midterm mortality compared with post-PCI, with similar safety outcomes. Short-term mortality was significantly reduced in those receiving pre-PCI vs. during/post-PCI Impella support (37.2% vs 53.6%), and midterm mortality was also lower in the pre-PCI Impella group (47.9% vs 73%).¹⁵

JSCAI, 2022

This study showed women had a 74% relative survival benefit with Impella placement pre-PCI compared to post-PCI highlighting that the benefit of Impella implantation pre-PCI is more prominent in women.¹⁶

National Cardiogenic Shock Initiative (NCSI) Study, 2021

This single-arm trial demonstrated a 71% survival to discharge with greater than 90% native heart recovery when best practices are used, including placement of Impella prior to PCI. The NCSI study evaluated outcomes of 406 patients at 80 community hospitals and academic medical centers in the U.S.

Journal of the American College of Cardiology, 2019

This study of 204 patients in the INOVA Health System showed an increase in survival at 30 days from 44% to 82% when utilizing a standardized team-based approach with a best practice protocol that includes early use of percutaneous MCS.¹⁷

Journal of Artificial Organs, 2022

This three-year interim analysis of all Impella patients treated in Japan found use of Impella was associated with a 77% AMICS survival rate at 30 days among a cohort at 109 hospitals. The study was conducted with oversight by 10 Japanese professional societies, including the Japanese Circulation Society.¹⁸