Clinical Research & Data, Safety & Efficacy, AMI Cardiogenic Shock
FAQ: Is There Randomized Controlled Trial Data Available for Impella® Heart Pump Use in Cardiogenic Shock?
Randomized controlled trials are considered the “gold standard” for evaluating the efficacy and safety of medical interventions. Abiomed is committed to providing the best possible clinical care and evidence of beneficial effect of Impella in critically ill patients with cardiogenic shock. To date, 7 randomized trials have been attempted with Impella and 5 were discontinued following inadequate enrollment to evaluate primary outcome of survival benefit with Impella compared to control intervention. The ISAR-SHOCK trial comparing the hemodynamic effects of Impella with IABP in acute myocardial infarction and cardiogenic shock (AMICS) was completed. The RECOVER II trial planned to evaluate patients with AMICS but was discontinued after 18 months following enrollment of only 1 patient from 50 IRB approved sites. The DANSHOCK trial enrolled 100 patients with AMICS in Denmark in its initial 5 years and was recently expanded to enroll patients from Germany and renamed to DanGer Shock trial.
The FRENCH trial was a multicenter randomized trial comparing standard treatment to standard treatment plus extracorporeal life support (ECLS) or the Impella 2.5® heart pump in patients with AMI cardiogenic shock (AMICS).1 Standard treatment included use of intra-aortic balloon pump (IABP), inotropic drugs and antiplatelet agents based on the recommended treatment at the study hospital. The primary endpoint was all-cause mortality at 30 days or evolution to refractory cardiogenic shock requiring 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 discontinuation of the study due to low enrollment rate. The results of this trial are not publicly available.
ISAR-SHOCK, a prospective randomized two-center trial, was conducted to compare the hemodynamic effects of the Impella heart pump with the effects of the intra-aortic balloon pump (IABP).2 Over the course of 19 months, 26 patients with AMI for less than 48 hours and cardiogenic shock were randomized to IABP or Impella 2.5 support after percutaneous coronary intervention (PCI). At baseline, median left ventricular ejection fraction (LVEF) was 27.5% and time from AMI onset was 4.5 hours with no significant difference in baseline characteristics observed between groups. The primary endpoint was improvement in cardiac index 30 minutes after device implantation. IABP was safely placed in 13 patients and Impella 2.5 in 12 patients. One patient randomized to Impella 2.5 died before implantation. The cardiac index after 30 minutes of support increased significantly with Impella 2.5 compared to IABP (0.49 ± 0.46 L/min/m2 vs. 0.11 ± 0.31 L/min/m2, p = 0.02). In addition, the diastolic arterial pressure increased with Impella compared to reduction with IABP support (9.2 ± 12.1 mmHg vs. -8.0 ± 13.1 mmHg, p = 0.002). The secondary endpoint of all-cause mortality at 30 days was 46% in both groups. Higher rates of hemolysis were observed in patients with Impella in the first 24 hours requiring more transfusion. No device-related malfunction, major bleeding or ischemic events were reported during support with Impella or IABP. A trend toward more rapid reversal of serum lactate levels was observed in patients with Impella compared to IABP. ISAR-SHOCK was the first randomized trial to report on the safety and hemodynamic benefits with Impella in patients with AMI and cardiogenic shock.
IMPRESS in STEMI trial
The purpose of this multicenter, international randomized trial was to compare intra-aortic balloon pump (IABP) and the Impella 2.5 heart pump after percutaneous coronary intervention (PCI) in the setting of cardiogenic pre-shock anterior STEMI.3,4 Cardiogenic pre-shock was defined as heart rate >100 beats/min and/or systolic blood pressure <100 mmHg with clinical signs of cold extremities, cyanosis, oliguria, and decreased mental status. The primary endpoint was left ventricular ejection fraction (LVEF) assessed by MRI at 4 months follow-up. The target number of participants to assess the primary outcome of this study was 130 patients; however, only 21 patients were randomized to Impella (n = 12) or IABP (n = 9) in 5 centers over 42 months. Due to the small number of patients enrolled, the trial was stopped prematurely, precluding an appropriate assessment of clinical outcomes.
RECOVER I FDA trial
The RECOVER I study was a prospective, single-arm, feasibility trial to investigate the safety and feasibility of the Impella 5.0® heart pump in patients experiencing cardiogenic shock after cardiac surgery.5 Impella 5.0 was successfully placed in all of the 16 patients. Hemodynamic parameters improved immediately after device placement leading to an increase in mean cardiac index from 1.4 to 2.5 L/min/m2 and MAP from 71 mmHg to 83 mmHg. Hemodynamics improved in conjunction with a decreased need for inotropic medications. The primary efficacy endpoint of native heart function recovery occurred in 93% of patients who were discharged and 7% were bridged to other therapy. Survival at 1 month, 6 months, and 1 year was 94%, 81%, and 75%, respectively.
RECOVER II FDA trial
The RECOVER II study 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 1 patient was enrolled in the study between July 2008 and August 2010, resulting in discontinuation of the trial due to low enrollment (personal communication, Abiomed on file, March 28, 2018).
DanGer Shock trial
The DanGer Shock trial is an ongoing, open-label randomized trial initiated in patients with AMI cardiogenic shock (AMICS) in Denmark7 and given the name DanGer Shock trial when it was expanded to enroll patients from Germany. A total of 360 patients are planned to be enrolled to assess the primary outcome of death from all causes at 6 months with the Impella CP® heart pump compared to standard care. 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%. Since the study initiation in December 2012, >150 patients have been enrolled.
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 the intra-aortic balloon pump (IABP) in patients with severe shock complicating acute myocardial infarction.8 Based on the assumption that survival in severe shock is less than 10%, the sample size needed to determine significant differences in mortality between groups was initially determined to be 48 (24 patients in each group). At the interim analysis, it was evident that the mortality in the control group was much lower than original assumption of 90%. Since >100 patients would be required to determine a difference in mortality between Impella and IABP, it was decided to complete the study with 48 patients as an exploratory analysis. 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 6 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 conduct of the trial. The definition used for severe cardiogenic shock is unclear and patients were deemed to have cardiogenic shock based on operator’s discretion. As per protocol, crossover between treatments was not allowed; however, 3 patients in the IABP group crossed over to Impella group. Among the patients in the Impella group, 1 patient received Impella 5.0 after Impella CP, 1 patient received IABP before Impella thus constituting a protocol violation, and 1 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 3 events in the Impella group and 1 event in the IABP group. In the combined analysis of 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, use of any mechanical circulatory support device may be of limited utility. While this study offers an insight on 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).’
What are the challenges with conduct of randomized trials in cardiogenic shock?
Randomized trials play an important role in assessment of 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 outcomes of the Impella® heart pump in AMICS based on randomized controlled trials is limited.
Variable definition of cardiogenic shock
Cardiogenic shock represents a continuum of patient condition 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. Moreover, the adaptation of treatment options depending on the severity of shock affects both the inclusion criteria as well the clinical outcomes of the trial. While broadening inclusion criteria may increase the inclusion of patients in the trial, it might also mask the specific effect of the Impella® heart pump in a subset of responder patient population. On the other hand, narrowing the inclusion criteria to exclude patients such as those with severe brain injury may help assess the impact of Impella but requires implementation of uniform protocols. Depending on the inclusion criteria, early identification and subsequent enrollment of eligible patients in the trial during emergency situations presents a significant challenge.
Low and slow enrollment
Despite repeated attempts at conducting randomized control trials with the Impella heart pump in patients with cardiogenic shock, the recurrent theme observed is both low and slow enrollment rates. Given the low incidence rate of cardiogenic shock of <10% of patients with AMI, the slower enrollment has been observed in randomized trials of mechanical assist devices.3 Moreover, patients with cardiogenic shock have high mortality and procedural risks due to presence of multiple comorbidities and extensive coronary disease and thus are not readily enrolled in clinical trials.10 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 availability of trained surgeons and individual preferences of treating physicians.
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. However, randomization of patients to IABP despite clinical evidence pointing to lack of hemodynamic or mortality benefits poses an ethical dilemma and highlights the lack of clinical equipoise. The additional challenge encountered with management of patients randomized to “usual care” is crossover of patients who continue to deteriorate clinically and hemodynamically to the comparator arm. Such crossovers may affect the trial outcomes and the effect sizes of the interventions.
Due to the life-threatening nature of cardiogenic shock and the correlation of hemodynamic parameters with clinical outcomes, it is expected that mechanical circulatory support devices may affect the prognosis. Accordingly, the primary outcome of most randomized trials has been long- or short-term mortality. Based on the ability of the Impella heart pump to improve hemodynamic parameters, it is a possibility that Impella or other mechanical circulatory support devices may likely only affect the hemodynamic parameters. Hence, calculating the sample size of the trials to detect significant difference in mortality outcomes likely contributes to underpowered study designs and inconclusive study results. A plethora of surrogate outcomes such as cardiac index, mean arterial pressure, lactate levels, and length of intensive care unit treatment have been previously assessed. Not surprisingly, studies assessing hemodynamic benefits have reported significant improvements with Impella.2,9 Consensus on which outcomes are best assessed, when 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 use of Impella. 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.
Timing of Impella support
Given the importance of rapid revascularization, historically mechanical circulatory support devices were implanted after PCI. Contrary to established clinical practice, results of clinical studies with the Impella heart pump to date suggest early support with Impella prior to PCI and escalating doses of inotropes is associated with better clinical outcomes.9,11 In addition, beneficial effect of Impella in patients with futile situations such as severe brain injury appears to be unlikely. The years of clinical research have helped identify the optimal timing for implantation of Impella devices and have demonstrated that patients with shorter “shock to support” times are most likely to benefit with Impella use.11
What is the published clinical evidence for Impella use in cardiogenic shock?
Given the challenges with conduct of randomized trials in cardiogenic shock, the clinical outcomes after Impella heart pump 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 outcome 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
Lauten et al. evaluated the real-world evidence of efficacy and safety of the Impella heart pump in 120 patients with AMICS in the EUROSHOCK registry.12 Patients in this registry had profound cardiogenic shock at baseline with low mean arterial pressure (68.3 ± 17.3 mmHg), elevated plasma lactate (5.8 ± 5.0 mmol/L) and severely reduced left ventricular (LV) ejection fraction (0.27 ± 0.11). In addition, 102 (85%) patients received vasopressors and inotropes, 35 patients (29.0%) were on intra-aortic balloon pump (IABP) support, and 49 patients (41%) had been resuscitated for out-of-hospital cardiac arrest. The overall mortality at 30 days, primary outcome, was 64.2%. Patients who were resuscitated within 72 hours prior to Impella had lower survival at 30 days compared to those not requiring resuscitation (24.5% vs. 43.7%, p = 0.002). Use of Impella resulted in significant decrease in lactate levels at 48 hours. Further, age >65 years and lactate levels >3.8 mmol/L at admission were identified as independent predictors of mortality at 30 days. The authors concluded that the poor survival observed in this study was likely due to the profound severity of cardiogenic shock of the study participants with higher risk of imminent death. Essentially, this study evaluated effect of salvage therapy with Impella in patients with AMICS.
cVAD Study/USpella registry
O’Neill et al. evaluated the clinical outcomes of Impella 2.5 in 154 patients with AMI cardiogenic shock (AMICS) in the USpella registry.13 A total of 63 patients receiving Impella 2.5 support pre-PCI were compared with 91 patients receiving Impella support post-PCI. The primary endpoint was survival to discharge. Baseline characteristics were comparable between the groups except for higher prevalence of diabetes, peripheral vascular disease, chronic obstructive pulmonary disease, and prior stroke in the pre-PCI group. Patients presenting with STEMI were more likely to receive Impella after PCI (87.9% vs. 55.6%, p < 0.0001). Hemodynamics improved significantly after initiation of Impella support with no difference between groups. Survival to discharge was higher in the pre-PCI group compared with post-PCI group (65.1% vs. 40.7%, p = 0.003). In addition, patients in the pre-PCI group had extensive revascularization with more lesions and vessels treated than post-PCI group. In a multivariate analysis, initiation of Impella support prior to PCI was an independent predictor of in-hospital survival (OR 0.37, 95% CI 0.17-0.79). The rates of in-hospital adverse events were similar between the groups. The results of this study demonstrated that early initiation of hemodynamic support with Impella 2.5 is associated with improved survival and complete revascularization in patients with AMICS.
Meta-analysis of clinical studies on the use of Impella pre-PCI in patients with AMICS
The interesting finding of lower mortality with early initiation of the Impella heart pump in AMI cardiogenic shock (AMICS) was further strengthened by the results of a meta-analysis performed in the setting of AMICS. Flaherty et al. performed a meta-analysis by including studies providing clinical outcomes following early (pre-PCI) and late (post-PCI) use of Impella in patients with AMICS.14 The primary outcome of this meta-analysis was in-hospital mortality or 30-day mortality. Based on the inclusion criteria, 3 studies were identified (the IMPRESS-Severe Shock randomized controlled trial, the observational study of 287 patients from the global catheter-based ventricular assist device (cVAD) registry, and the observational study of 68 patients from a single-center.) Of the 379 patients in the pooled analysis at baseline, 49% had cardiac arrest, 82% received inotropes, and 81% required mechanical ventilation. The results of the pooled analysis of 3 studies showed lower in-hospital/30-day mortality with use of Impella pre-PCI vs. Impella post-PCI (RR 0.52, 95% CI 0.31-0.88).
Analysis of Impella Quality (IQ) Database
This study was a retrospective analysis of 15,259 patients with AMI cardiogenic shock (AMICS) from 1,010 U.S. hospitals receiving Impella heart pumps between 2009 and 2016 in the Impella Quality registry.15 Impella CP was used in 61% patients. Survival to explantation in the overall cohort was 53%. Survival was higher in men compared to women (56% vs. 52%, p < 0.001). Wide variability in survival rates was observed between hospital sites. Survival was lower at low volume sites (< 4 Impella cases/year) compared to high volume sites (> 4 Impella cases/year) (52% vs. 56%, p < 0.001). Two other variables associated with improved survival included timing of Impella use and hemodynamic monitoring. Survival among patients with Impella use pre-PCI was 59% compared to 52% with Impella use as salvage strategy (p < 0.001). In addition, survival rate was 63% in patients receiving hemodynamic monitoring compared with 49% in patients without hemodynamic monitoring (p < 0.0001). In multivariate analysis, PA catheter use (OR 1.66, 95% CI 1.48-1.87) and Impella use pre-PCI (OR 1.34, 95% CI 1.2-1.5) were associated with better survival. Also, use of Impella CP was associated with better survival than use of Impella 2.5® (OR 1.28, 95% CI 1.12-1.47). The results of this study highlight the modifiable treatment patterns associated with higher survival following use of Impella support in patients with AMICS.
Detroit Cardiogenic Shock Initiative (DCSI)
Based on the consistent finding of good survival outcomes with early hemodynamic support with the Impella heart pump, collaborators of DCSI established a best practices algorithm for the treatment of patients with AMI cardiogenic shock (AMICS). They assessed the feasibility and effects of the best practices algorithm in achieving rapid door to support times in 41 patients with AMICS.9 Before initiation of Impella support, 93% of patients received vasopressors or inotropes, 15% had out of hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 17% were under active cardiopulmonary resuscitation during Impella insertion. In accordance with the adoption of a uniform shock protocol, 66% of patients had Impella inserted pre-PCI, 83% of patients had right heart catheterization and hemodynamic monitoring. The study reported average door to support times of 83 minutes and reduction in doses of inotropes and vasopressors within the first 24 hours in 71% of patients. A 66% increase in cardiac power output (CPO) was observed. Survival to explant for the entire cohort was 85% compared to 51% with institutional historical controls (p < 0.001). The study also reported a survival to discharge of 76% with native heart recovery in 100% of patients who survived and achievement of TIMI III flow after PCI in 87% of cases. In conclusion, this pilot study conducted in 4 metro Detroit hospital sites demonstrated that systematic use of a shock protocol emphasizing early initiation of Impella with invasive hemodynamic monitoring is feasible and may improve survival in AMICS. Based on the encouraging findings of this study, a national, multicenter, quality initiative titled the National Cardiogenic Shock Initiative (NCSI) Study has been launched.16
- Massetti, M. (2006). Comparison of Standard Treatment Versus Standard Treatment Plus Extracorporeal Life Support (ECLS) in Myocardial Infarction Complicated With Cardiogenic Shock. https://clinicaltrials.gov/ct2/show/NCT0314847?term=nct00314847&rank=1
- Seyfarth, M., et al. (2008). J Am Coll Cardiol, 52(19), 1584-1588.
- Ouweneel, D.M., et al. (2016). Int J Cardiol, 202, 894-896.
- Henriques, J.P. (2007). IMPRESS in STEMI. https://www.trialregister.nl/trialreg/admin/rctview.asp?tc=1079
- Griffith, B.P., et al. (2013). J Thorac Cardiovasc Surg, 145(2), 548-554.
- O'Neill, W.W. (2008). Trial Using Impella LP 2.5 System in Patients With Acute Myocardial Infarction Induced Hemodynamic Instability (RECOVER II). https://clinicaltrials.gov/ct2/show/nct00972270?term=nct00972270&rank=1
- Møller, J.E. (2012). Danish Cardiogenic Shock Trial (DanShock). https://clinicaltrials.gov/ct2/show/nct01633502?term=nct01633502&rank=1
- Ouweneel, D.M., et al. (2017). J Am Coll Cardiol, 69(3), 278-287.
- Basir, M.B., et al. (2018). Catheter Cardiovasc Interv, 91(3), 454-461.
- Rihal, C.S., et al. (2015). J Am Coll Cardiol, 65(19), e7-e26.
- Basir, M.B., et al. (2017). Am J Cardiol, 119(6), 845-851.
- Lauten, A., et al. (2013). Circ Heart Fail, 6(1), 23-30.
- O'Neill, W.W., et al. (2014). J Interv Cardiol, 27(1), 1-11.
- Flaherty, M.P., et al. (2017). JACC Cardiovasc Interv, 10(17), 1805-1806.
- O'Neill, W.W., et al. (2018). Am Heart J, 202, 33-38.
- O’Neill, W.W. (2016). National Cardiogenic Shock Initiative. https://www.henryford.com/cardiogenicshock