Clinical trial NCT06645990: Early Left Ventricular unLoading by Impella vs Intra-aortic Balloon Pump
Official title: Early Left Ventricular unLoading by Impella (ECMELLA) or Intra-aortic Balloon Pump for Cardiogenic Shock in Patients on VA-ECMO
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cardiogenic Shock
Keywords: ECMO
ECLS
Impella
IABP
pVAD
mortality
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2024-10-17
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All Adult patients (more than or =18 years) admitted for Cardiogenic Shock supported by ECMO+ IABP or ECMELLA between January 1, 2010, and December 31, 2023

Brief summary: Over the past decade, VA-ECMO has become the main mechanical support for cardiogenic shock (CS) unresponsive to medical therapy. However, recent studies failed to show any significant survival benefit at 30 days compared to medical treatment for myocardial infarction-related CS. This could be due to the complications of VA-ECMO, such as LV overload and increased LV distension, which can hinder heart recovery.

To address this, early LV unloading using devices like IABP or Impella (ECMELLA) may help by reducing LV wall stress and oxygen consumption. However, these techniques carry risks, and their benefit is still unclear. A randomized trial is needed to compare these approaches, but observational studies are also contributing to understanding the best strategies

Detailed description: Over the last decade, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has become the mechanical circulatory support of choice for cardiogenic shock (CS) refractory to medical treatment. VA-ECMO allows to supplement cardiac function until myocardium recovers, or in bridge to long-term left ventricular assist device (LVAD) or to heart transplant. However, recent randomized controlled trials (RCT) and meta-analysis have failed to demonstrate any benefit of VA-ECMO in terms of 30-day survival compared with optimal medical treatment in CS related to myocardial infarction.

Reasons for these disappointing results are multifactorial. The associated risk of temporary mechanical circulatory support (t-MCS)-related complications might counterbalance any hemodynamic benefit. In addition to hemorrhagic and ischemic complications, the significant myocardial impact due to VA-ECMO drawbacks should not be overlooked. Indeed, while VA-ECMO restores systemic perfusion, it can also lead to an increase in left ventricle (LV) loading conditions. Although LV distension is not consistently observed, recent publications strongly suggest that the origin of LV overload seems to be multifactorial and contributes partially to cardiac remodeling through the modulation of cardioprotective cellular pathways, resulting in reduced cardiomyocyte apoptosis. Furthermore, peripheral VA-ECMO affects myocardial contractility and increases myocardial work (potential energy, stroke work, and pressure-volume area), particularly at native low blood flow.

Thus, cardiac recovery may be compromised and weaning from VA-ECMO delayed. This vicious cycle affects the patients overall prognosis, as delayed and possibly failure of VA-ECMO weaning and may convert the initial medical strategy of recovery towards heart transplantation or LVAD. To optimize the chance of VA-ECMO weaning, early LV unloading may be a good therapeutic option. It aims at increasing coronary flow directly and, indirectly, by improving sub-endocardial myocardial perfusion through decreasing LV wall stress and myocardial oxygen consumption. Currently, 2 techniques are mainly used, the intra-aortic balloon pump (IABP) and the microaxial flow pump as Impella device familly (ECMELLA). These invasive techniques carry risks of bleeding and thromboembolic complications, and the benefit/risk ratio of their use for myocardial recovery is not clearly established.

A few retrospective studies suggest that early left ventricular unloading during VA-ECMO could improve prognosis. In the absence of RCT, the choice of the technique (Impella or IABP) is mainly driven by center practice. A multicenter randomized clinical trial would be the best choice to address this question. However, due to the acute poor prognosis of these patients (50% of early deaths), reliable preliminary data about the expected effect size are necessary to design the most efficient clinical trial. Recent epidemiologic developments of observational studies, the emulated trials, allow a better control of immortal time bias and indication bias.

This innovative multicenter study will compare the effectiveness and safety of LV unloading by Impella (ECMELLA) versus IABP in terms of survival with myocardial recovery in patients with refractory CS

Eligibility criteria: Inclusion Criteria:

* Adult patients (more than or =18 years) admitted for cardiogenic shock supported by ECMO+ IABP or ECMELLA between January 1, 2010, and December 31, 2023

Exclusion Criteria:

* Ongoing extra-corporeal CardioPulmonary Resuscitation (eCPR) at time of ECMO implantation
* Cardiogenic shock with previous prolonged continuous cardiopulmonary resuscitation (CPR) more than 30 minutes
* Acute irreversible neurological injury
* Previous known severe chronic cardiomyopathy (LVEF less than 25%) or awaiting heart transplantation or LVAD implantation
* Contraindication to the implantation of an Impella or IABP
* Mechanical complications of myocardial infarction
* Moribund patient (SAPS more than 90)
* Previous known severe chronic renal or hepatic failure
* Age less than18 years

Primary outcomes:
measure: Myocardial recovery
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
Secondary outcomes:
measure: Early mortality
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
measure: Adverse events related to LV unloading technics
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
measure: Duration of mechanical ventilation
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
measure: Duration of temporary MCS support
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
measure: Lengh of stay
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
measure: Cardiac long-term project
timeFrame: from start of hospitalization until hospital discharge assessed up to 3 month
Other outcomes:
Locations:
city: Montpellier
country: France
facility: CHU Arnaud de Villeneuve
Study officials:
affiliation: Montpellier University Hospital, France
name: Aurore UGHETTO, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Authors/Task Force Members:; McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022 Jan;24(1):4-131. doi: 10.1002/ejhf.2333.
citation: Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012 Jan;33(2):176-82. doi: 10.1093/eurheartj/ehr352. Epub 2011 Sep 6.
citation: Hernan MA, Sauer BC, Hernandez-Diaz S, Platt R, Shrier I. Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses. J Clin Epidemiol. 2016 Nov;79:70-75. doi: 10.1016/j.jclinepi.2016.04.014. Epub 2016 May 27.
citation: Hernan MA, Robins JM. Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available. Am J Epidemiol. 2016 Apr 15;183(8):758-64. doi: 10.1093/aje/kwv254. Epub 2016 Mar 18.
citation: Ezad SM, Ryan M, Donker DW, Pappalardo F, Barrett N, Camporota L, Price S, Kapur NK, Perera D. Unloading the Left Ventricle in Venoarterial ECMO: In Whom, When, and How? Circulation. 2023 Apr 18;147(16):1237-1250. doi: 10.1161/CIRCULATIONAHA.122.062371. Epub 2023 Apr 17.
citation: Bernhardt AM, Copeland H, Deswal A, Gluck J, Givertz MM; Chairs:; Co-Chairs:; Contributing Writers:; Chair:; Co-Chair:; Contributing Writers:; Chair:; Co-Chairs:; Contributing Writers:; Chair:; Co-Chair:; Contributing Writers:. The International Society for Heart and Lung Transplantation/Heart Failure Society of America Guideline on Acute Mechanical Circulatory Support. J Heart Lung Transplant. 2023 Apr;42(4):e1-e64. doi: 10.1016/j.healun.2022.10.028. Epub 2023 Feb 6. No abstract available.
citation: Ostadal P, Rokyta R, Karasek J, Kruger A, Vondrakova D, Janotka M, Naar J, Smalcova J, Hubatova M, Hromadka M, Volovar S, Seyfrydova M, Jarkovsky J, Svoboda M, Linhart A, Belohlavek J; ECMO-CS Investigators. Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial. Circulation. 2023 Feb 7;147(6):454-464. doi: 10.1161/CIRCULATIONAHA.122.062949. Epub 2022 Nov 6.
citation: Banning AS, Sabate M, Orban M, Gracey J, Lopez-Sobrino T, Massberg S, Kastrati A, Bogaerts K, Adriaenssens T, Berry C, Erglis A, Haine S, Myrmel T, Patel S, Buera I, Sionis A, Vilalta V, Yusuff H, Vrints C, Adlam D, Flather M, Gershlick AH. Venoarterial extracorporeal membrane oxygenation or standard care in patients with cardiogenic shock complicating acute myocardial infarction: the multicentre, randomised EURO SHOCK trial. EuroIntervention. 2023 Aug 21;19(6):482-492. doi: 10.4244/EIJ-D-23-00204.
citation: Thiele H, Zeymer U, Akin I, Behnes M, Rassaf T, Mahabadi AA, Lehmann R, Eitel I, Graf T, Seidler T, Schuster A, Skurk C, Duerschmied D, Clemmensen P, Hennersdorf M, Fichtlscherer S, Voigt I, Seyfarth M, John S, Ewen S, Linke A, Tigges E, Nordbeck P, Bruch L, Jung C, Franz J, Lauten P, Goslar T, Feistritzer HJ, Poss J, Kirchhof E, Ouarrak T, Schneider S, Desch S, Freund A; ECLS-SHOCK Investigators. Extracorporeal Life Support in Infarct-Related Cardiogenic Shock. N Engl J Med. 2023 Oct 5;389(14):1286-1297. doi: 10.1056/NEJMoa2307227. Epub 2023 Aug 26.
citation: Schmidt M, Burrell A, Roberts L, Bailey M, Sheldrake J, Rycus PT, Hodgson C, Scheinkestel C, Cooper DJ, Thiagarajan RR, Brodie D, Pellegrino V, Pilcher D. Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J. 2015 Sep 1;36(33):2246-56. doi: 10.1093/eurheartj/ehv194. Epub 2015 Jun 1.
citation: Muller G, Flecher E, Lebreton G, Luyt CE, Trouillet JL, Brechot N, Schmidt M, Mastroianni C, Chastre J, Leprince P, Anselmi A, Combes A. The ENCOURAGE mortality risk score and analysis of long-term outcomes after VA-ECMO for acute myocardial infarction with cardiogenic shock. Intensive Care Med. 2016 Mar;42(3):370-378. doi: 10.1007/s00134-016-4223-9. Epub 2016 Jan 29.
citation: Dickerman BA, Garcia-Albeniz X, Logan RW, Denaxas S, Hernan MA. Avoidable flaws in observational analyses: an application to statins and cancer. Nat Med. 2019 Oct;25(10):1601-1606. doi: 10.1038/s41591-019-0597-x. Epub 2019 Oct 7.
citation: Meuwese CL, Koudstaal S, Braithwaite S, Hermens JAJ, Donker DW. Left Ventricular Unloading During Extracorporeal Membrane Oxygenation: Insights From Meta-Analyzed Observational Data Corrected for Confounders. J Am Coll Cardiol. 2019 Jun 18;73(23):3034-3035. doi: 10.1016/j.jacc.2019.03.505. No abstract available.
citation: Beurton A, Michot M, Herion FX, Rienzo M, Oddos C, Couffinhal T, Imbault J, Ouattara A. Systemic Hemodynamics, Cardiac Mechanics, and Signaling Pathways Induced by Extracorporeal Membrane Oxygenation in a Cardiogenic Shock Model. ASAIO J. 2024 Mar 1;70(3):177-184. doi: 10.1097/MAT.0000000000002139. Epub 2024 Jan 23.
citation: Ughetto A, Eliet J, Nagot N, David H, Bazalgette F, Marin G, Kollen S, Mourad M, Zeroual N, Muller L, Gaudard P, Colson P. Early temporary mechanical circulatory support for cardiogenic shock: Real-life data from a regional cardiac assistance network. J Heart Lung Transplant. 2024 Jun;43(6):911-919. doi: 10.1016/j.healun.2024.02.009. Epub 2024 Feb 15.