Clinical Evidence of Impella in AMICS
Cardiogenic shock (CS) is a state of critical hypoperfusion of end-organs due to reduced cardiac output1. The incidence of CS is about 7% of patients with acute myocardial infarction (AMI)2. The landmark SHOCK trial and subsequent post-hoc analyses reported improved long-term survival in patients with AMI and CS following early revascularization compared to initial medical stabilization with delayed revascularization3,4. Mechanical circulatory devices (MCS) are used during high-risk revascularization procedure in patients with CS to maintain adequate perfusion and prevent irreversible end-organ damage. IABP is the most widely used MCS device5. However, based on the results of IABP-SHOCK II trial reporting similar mortality rates at 30 days and 1 year with or without IABP, the current guidelines in the US do not recommend routine use of IABP in CS6-8. In addition, European guidelines downgraded routine use of IABP in CS to a class IIIB recommendation (evidence of harm in some cases) with similar reports from Germany and Japan9,10.
Given the potential cardiotoxicity associated with the use of catecholamines to improve cardiac output and systemic perfusion, currently available percutaneous MCS such as Impella devices, TandemHeart, and extracorporeal membrane oxygenation (ECMO) represent viable options for circulatory support in patients with AMI and CS11. However, limited clinical evidence evaluating the efficacy and safety of percutaneous MCS in CS is available. In a recent meta-analysis by Thiele et al, only 4 randomized trials comparing percutaneous MCS vs. IABP was identified1. Of the 4 randomized trials, TandemHeart device was used in 2 trials and Impella device was used in 2 trials.
Impella is a percutaneous, transcatheter, micro-axial flow MCS. The FDA indication for use of Impella in AMICS includes the entire platform of left-side devices, Impella 2.5®, Impella CP®, Impella 5.0® and Impella LD®. The right-side Impella RP® heart pump is also FDA approved for cardiogenic shock. Impella devices are the first and only MCS devices that are FDA-approved as safe and effective for the cardiogenic shock indication. In the setting of CS, the Impella heart pumps stabilize the patient's hemodynamics, unload the left ventricle, perfuse the end organs and allow for recovery of the native heart. The company’s FDA PMA labeling for cardiogenic shock specifically states ‘heart recovery’: “The intent of the Impella system therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.”
Impella in CS: Evidence from Clinical Studies so far
The FRENCH trial, was a multicenter randomized trial comparing standard treatment to standard treatment plus ECLS or Impella 2.5 in patients with AMI and CS12. Standard treatment included use of 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 CS requiring LVAD device. 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 trial, a prospective randomized 2-center trial was conducted to compare the hemodynamic effects of Impella with that of IABP. Over the course of 19 months, 26 patients with AMI for less than 48 hours and CS were randomized to IABP or Impella 2.5 support after PCI2. At baseline, median LVEF was 27.5%, 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 mins 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 mm Hg vs. -8.0 ± 13.1 mm Hg, p = 0.002). The secondary endpoint of all-cause mortality at 30 days was 46% in both groups. Higher rates of hemolysis was 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 towards more rapid reversal of serum lactate levels were observed in patients with Impella than with IABP. ISAR-SHOCK was the first randomized trial to report on the safety and hemodynamic benefits with Impella in patients with AMI and CS. However, an independent audit of the trial data found multiple methodologic problems, including randomization violations and a lack of equipoise (personal communication, ABIOMED on file, March 28, 2018).
IMPRESS in STEMI Trial
The purpose of this multicenter, international randomized trial was to compare IABP and Impella 2.5 after PCI in the setting of cardiogenic pre-shock anterior STEMI13,14. Cardiogenic pre-shock was defined as heart rate > 100 beats/min and/or systolic blood pressure < 100 mm Hg with clinical signs of cold extremities, cyanosis, oliguria, and decreased mental status. The primary endpoint was 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 small number of patients enrolled, the trial was stopped prematurely precluding an appropriate assessment of clinical outcomes.
RECOVER II FDA Trial
This multicenter, open-label, randomized trial was initiated to compare clinical outcomes with Impella 2.5 and IABP in patients with AMI and CS15. 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 58 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).
DAN Shock Trial
This ongoing, open-label randomized trial is being carried out in in patients with AMICS in Denmark with planned expansion in Germany16. A total of 360 patients are planned to be enrolled to assess the primary outcome of death from all causes at 6 months with Impella CP compared to standard care. Inclusion criteria of study participants include: STEMI for < 36 hours, CS for < 24 hours confirmed based on arterial blood lactate ≥2.5mmol/l and/or SvO2 <55% with a normal PaO2 and systolic BP < 100 mm Hg and/or need to vasopressor therapy, and LV ejection fraction < 45%. Since the study initiation in December 2012, about 90 patients have been enrolled through the end of 2017.
IMPRESS in Cardiac Arrest
This open-label trial was initiated to determine whether Impella can decrease 30-day all-cause mortality compared to IABP in patients with severe shock complicating acute myocardial infarction23. Based on the assumption that survival in severe shock is less than 10%, 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 total enrolled patients had cardiac arrest with 48% having ROSC longer than 20 mins. 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% patients had traumatic injuries due to cardiac arrest, disproportionately higher rates were observed in Impella group than in IABP group (21% vs. 8%). The main cause of death was brain damage and refractory CS in 46% and 29% respectively. Many shortcomings is identified in conduct of the trial. The definition used for severe CS is unclear and patients were deemed to have CS based on operator’s discretion. As per protocol, crossover between treatments were 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 Impella arm compared to 8% in IABP arm. Given the disproportionately higher rates of traumatic injuries at admission in patients receiving Impella, higher rates of bleeding events is not unexpected. In fact, device-related bleeding events was not different between groups, 3 events in the Impella group and 1 event in the IABP group. In the combined analysis of entire study population, a trend towards lower mortality at 30 days was observed if MCS was used pre-PCI (25% vs. 53%, p = 0.16). Similar trends of lower mortality was observed in patients with ROSC < 20 mins and lactate levels lower than 7.5mmol/l at admission. Given the high rates of post-anoxic neurological damage, use of any MCS 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 use of Impella in AMICS. Hence, it is better to describe this trial as ‘IMPRESS in Cardiac Arrest’.
Table 1. Prospective Trials of Impella in AMICS
Meta-analysis of Clinical Studies on the Use of Impella Pre-PCI in Patients with AMICS
Flaherty et al performed a meta-analysis by including studies providing clinical outcomes following early (pre-PCI) and late (post-PCI) implantation of Impella in patients with AMI and CS17. The primary outcome of this meta-analysis was in-hospital mortality or 30-day mortality. Based on the inclusion criteria, three studies were identified (IMPRESS-Severe Shock randomized controlled trial, observational study of 287 patients from the global catheter-based ventricular assist device (cVAD) registry, and 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).
In addition to the above clinical studies, Lauten et al. evaluated the real world evidence of efficacy and safety of Impella in 120 patients with AMICS in the EUROSHOCK registry18. Patients in this registry had profound CS at baseline with low mean arterial pressure (68.3 ± 17.3 mm Hg), elevated plasma lactate (5.8 ± 5.0 mmol/L) and severely reduced LV ejection fraction (0.27±0.11). In addition, 102 (85%) patients received vasopressors and inotropics, 35 patients (29.0%) were on 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 is likely due to the profound severity of CS of the study participants with higher risk of imminent death. Essentially, this study evaluated effect of salvage therapy with Impella in patients with AMICS.
Detroit Cardiogenic Shock Initiative
This multicenter observational study was conducted to assess the feasibility and effects of a shock protocol emphasizing early initiation of support with Impella along with invasive hemodynamic monitoring to achieve rapid door to support times in 41 patients with AMICS19. 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 implantation. 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 67% increase in cardiac power output 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% and achievement of TIMI III flow after PCI in 87%.
Lessons Learned from Clinical Studies with Impella Devices
Low and Slow Enrollment
Choice of Comparator
In a randomized trial, the choice of the comparator affects both the conduct and the interpretation of results. IABP is the most widely used comparator intervention in randomized trials of MCS in cardiogenic shock mainly due to relative ease and familiarity of use by interventional cardiologists. However, randomization of patients to IABP despite clinical evidence of lack of mortality and hemodynamic benefit 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 that continue to deteriorate clinically and hemodynamically to comparator arm. Such crossovers may affect the trial outcomes and the effect sizes of the interventions.
Definition of CS and Inclusion Criteria
CS represents a continuum of patient condition ranging from hypotension after AMI to out of hospital cardiac arrest requiring multiple inotropes19. So it is challenging to identify patients with CS 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 Impella 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 the eligible patient in the trial during emergency situation presents a significant challenge.
Due to the life-threatening nature of CS and the correlation of hemodynamic parameters with clinical outcomes, it is expected that MCS may affect the prognosis. Accordingly, the primary outcome of most randomized trials have been long- or short-term mortality (Table 1). Based on the ability of Impella to improve hemodynamic parameters, it is a possibility that Impella or other MCS 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 Impella2,19. Consensus on which outcomes are best assessed, when and how they should be measured is needed for randomized control trials in patients with CS.
Timing of Impella Support
Given the importance of rapid revascularization, historically MCS devices were implanted after PCI. Contrary to established clinical practice, results of clinical studies with Impella to date suggest early support with Impella prior to PCI and escalating doses of inotropes is associated with better clinical outcomes19,20. 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 has helped identify the optimal timing for implantation of Impella devices and has demonstrated that patients with shorter “shock to support” times are most likely to benefit with Impella use20.
Randomized trials play an important role in assessment of cardiovascular and medical device innovations, albeit pose many logistic and methodological challenges. Consequently, evidence on the impact of MCS in CS based on randomized controlled trials is limited.
Clinical results from registries of MCS devices provide valuable real world evidence of efficacy and safety. The results from registries of Impella (cVAD, IQ database) have consistently demonstrated good clinical outcome and safety in patients with AMICS and informed the clinical community on best practices.
Abiomed is committed to providing the best possible clinical care and evidence of beneficial effect of Impella in critically ill patients with cardiogenic shock and clearly sees the value of a well-conducted randomized trial. Taking into consideration the lessons learned, the following strategies could be employed to overcome these challenges.
- A standardized best practice algorithm for the treatment of patients with AMICS has been recently established19. Adoption of this framework will reduce significant care variability regarding the optimal timing of Impella support, use of additional diagnostic adjuvants such as invasive hemodynamic monitoring, duration of support, and strategy for treatment escalations.
- Exception from prospective informed consent in emergency situation such as AMI and CS could help overcome the low enrollment and improve the speed of trial conduct21. In addition, it might also aid in early identification and initiation of Impella support. The “delayed consent” model has been previously successfully used in the setting of AMI in the HEAT-PPCI trial conducted in UK22 and IMPRESS in Severe Shock trial conducted in Netherlands23.
- Use of stepped wedge design of randomization instead of parallel design could help reduce the number of patients required to determine an effect of the intervention24. Stepped wedge design can be used to compare Impella with ECMO with an opportunity to crossover uni-directionally from one intervention to the other. Comparison of studies with Impella first therapy vs. ECMO first therapy will also help clarify the best first therapy, thus improving clinical outcomes for patients.
- Given the hemodynamic benefits of Impella, outcomes assessed should include clinical outcomes such as survival with native heart recovery, metabolic parameters such as lactate levels in addition to composites of adverse events.
The lessons learned from years of clinical research has demonstrated that management of these extremely high risk patients involves complex interplay of systems of care in addition to the MCS device used. Through our ongoing initiatives with academic and clinical research partners, we will continue to fill the knowledge gaps with use of Impella devices.
Physicians must make the best decision based on all the available data to counsel patients and choose the best options for management. RCTs are valuable, but are not the sole source for informed decision making. If physicians choose to only use drugs and devices for which efficacy and safety has been demonstrated in randomized trials, there would be few options for many patients and no options for patients in cardiogenic shock. Pressors, ECMO, and all other MCS devices have not been studied in RCTs and IABP has been studied but failed to demonstrate a benefit. The database for Impella is by far the largest of any MCS device and much of this data has been reviewed and audited by the FDA who deemed it safe and effective for use in patients with cardiogenic shock.
- Thiele H, Jobs A, Ouweneel DM, Henriques JPS, Seyfarth M, Desch S, et al. Percutaneous short-term active mechanical support devices in cardiogenic shock: a systematic review and collaborative meta-analysis of randomized trials. European Heart Journal. 2017.
- Seyfarth M, Sibbing D, Bauer I, Frohlich G, Bott-Flugel L, Byrne R, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol. 2008;52(19):1584-8.
- Hochman JS, Sleeper LA, Webb JG, Dzavik V, Buller CE, Aylward P, et al. Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA. 2006;295(21):2511-5.
- Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341(9):625-34.
- Rihal C, Naidu S, Givertz M, Szeto W, JA B, NK K, et al. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care. Journal of American College of Cardiology. 2015;65(19):e7-26.
- O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-425.
- Thiele H, Zeymer U, Neumann F-J, Ferenc M, Olbrich H-G, Hausleiter J, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. New England Journal of Medicine. 2012;367(14):1287-96.
- Thiele H, Zeymer U, Neumann F-J, Ferenc M, Olbrich H-G, Hausleiter J, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. The Lancet. 2013;382(9905):1638-45.
- Werdan K, Russ M, Buerke M, Delle-Karth G, Geppert A, Schondube FA, et al. Cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment: a German-Austrian S3 Guideline. Dtsch Arztebl Int. 2012;109(19):343-51.
- Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure (JCS 2017/JHFS 2017) 2018 [Available from: http://www.asas.or.jp/jhfs/pdf/topics20180323.pdf. (Article in Japanese)
- Chera HH, Nagar M, Chang NL, Morales-Mangual C, Dous G, Marmur JD, et al. Overview of Impella and mechanical devices in cardiogenic shock. Expert Rev Med Devices. 2018:1-7.
- Massetti M. Comparison of Standard Treatment Versus Standard Treatment Plus Extracorporeal Life Support (ECLS) in Myocardial Infarction Complicated With Cardiogenic Shock 2006 [Available from: https://clinicaltrials.gov/ct2/show/NCT00314847?term=NCT00314847&rank=1.
- Ouweneel DM, Engstrom AE, Sjauw KD, Hirsch A, Hill JM, Gockel B, et al. Experience from a randomized controlled trial with Impella 2.5 versus IABP in STEMI patients with cardiogenic pre-shock. Lessons learned from the IMPRESS in STEMI trial. Int J Cardiol. 2016;202:894-6.
- Henriques JP. IMPRESS in STEMI 2007 [Available from: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1079.
- O'Neill W. Trial Using Impella LP 2.5 System in Patients With Acute Myocardial Infarction Induced Hemodynamic Instability (RECOVER II) 2008 [Available from: https://clinicaltrials.gov/ct2/show/NCT00972270?term=NCT00972270&rank=1.
- Moller JE. Danish Cardiogenic Shock Trial (DanShock) 2012 [Available from: https://clinicaltrials.gov/ct2/show/NCT01633502?term=NCT01633502&rank=1.
- Flaherty MP, Khan AR, O'Neill WW. Early Initiation of Impella in Acute Myocardial Infarction Complicated by Cardiogenic Shock Improves Survival: A Meta-Analysis. JACC Cardiovasc Interv. 2017;10(17):1805-6.
- Lauten A, Engstrom AE, Jung C, Empen K, Erne P, Cook S, et al. Percutaneous left-ventricular support with the Impella-2.5-assist device in acute cardiogenic shock: results of the Impella-EUROSHOCK-registry. Circ Heart Fail. 2013;6(1):23-30.
- Basir MB, Schreiber T, Dixon S, Alaswad K, Patel K, Almany S, et al. Feasibility of early mechanical circulatory support in acute myocardial infarction complicated by cardiogenic shock: The Detroit cardiogenic shock initiative. Catheter Cardiovasc Interv. 2017.
- Basir MB, Schreiber TL, Grines CL, Dixon SR, Moses JW, Maini BS, et al. Effect of early initiation of mechanical circulatory support on survival in cardiogenic shock. The American journal of cardiology. 2017;119(6):845-51.
- Cook JA. The challenges faced in the design, conduct and analysis of surgical randomised controlled trials. Trials. 2009;10:9.
- Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384(9957):1849-58.
- Ouweneel DM, Eriksen E, Sjauw KD, van Dongen IM, Hirsch A, Packer EJ, et al. Percutaneous Mechanical Circulatory Support Versus Intra-Aortic Balloon Pump in Cardiogenic Shock After Acute Myocardial Infarction. J Am Coll Cardiol. 2017;69(3):278-287.
- Hughes JP, Granston TS, Heagerty PJ. Current issues in the design and analysis of stepped wedge trials. Contemp Clin Trials. 2015;45(Pt A):55-60.