Impella Versus Intra-Aortic Balloon Pump For Treatment Of Cardiogenic Shock: A Meta-Analysis of Randomized Controlled Trials

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1 Accepted Manuscript Impella Versus Intra-Aortic Balloon Pump For Treatment Of Cardiogenic Shock: A Meta-Analysis of Randomized Controlled Trials Dagmar M. Ouweneel, MSc, Erlend Eriksen, MD, Melchior Seyfarth, MD, José P.S. Henriques, MD, PhD PII: S (16) DOI: /j.jacc Reference: JAC To appear in: Journal of the American College of Cardiology Received Date: 15 September 2016 Accepted Date: 20 October 2016 Please cite this article as: Ouweneel DM, Eriksen E, Seyfarth M, Henriques JPS, Impella Versus Intra- Aortic Balloon Pump For Treatment Of Cardiogenic Shock: A Meta-Analysis of Randomized Controlled Trials, Journal of the American College of Cardiology (2016), doi: /j.jacc This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Impella Versus Intra-Aortic Balloon Pump For Treatment Of Cardiogenic Shock: A Meta-Analysis of Randomized Controlled Trials Dagmar M. Ouweneel, MSc a ; Erlend Eriksen, MD b ; Melchior Seyfarth, MD c ; José P.S. Henriques, MD, PhD a a Academic Medical Center Heart Center, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands b Department of Cardiology, Helse-Bergen - Haukeland universitetssjukehus, Bergen, Norway c HELIOS Universitätsklinikum Wuppertal, Witten/Herdecke University, Germany Brief title: Meta-analysis on Impella versus IABP in cardiogenic shock Conflicts of interest: The Academic Medical Center has received research grants and speaker honoraria from Abiomed Inc. Address for correspondence: José P.S. Henriques, MD, PhD Academic Medical Center University of Amsterdam AMC Heart Center Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Telephone: Fax: j.p.henriques@amc.uva.nl 1

3 In patients with cardiogenic shock after acute myocardial infarction (AMI), mortality remains high despite advances in treatment. Short-term percutaneous circulatory support devices provide superior hemodynamic support compared with the intra-aortic balloon pump (IABP). The guidelines have downgraded the recommendation for usage of the IABP from a class I to a class IIa, and class III in Europe (1,2). Both American and European guidelines endorse usage of other mechanical assist devices providing more hemodynamic support (1,2). The Impella platform is a frequently used percutaneous circulatory support device providing from L/min depending on the model used. A few randomized, controlled trials have compared the Impella device with IABP. All trials were underpowered to adequately evaluate mortality. Therefore, we pooled the data from these trials to compare Impella with IABP on 30 days and 6 months all-cause mortality and left ventricular ejection fraction (LVEF) during follow-up. If the endpoint was not available in the original manuscript, the data was provided by the investigators. All measurements of LVEF, closest to 6 months were included, independent of the imaging modality. There were 3 randomized controlled trials comparing Impella with IABP in cardiogenic shock after AMI (3). Inclusion criteria of the 3 trials were slightly different as the definition of cardiogenic shock was different in each trial. One trial aimed for inclusion of pre-shock patients, excluding full-blown cardiogenic shock (4), 1 trial used the generally used SHOCK-trial criteria including while the other aimed for inclusion of mechanically ventilated severe shock patients (3). Two trials compared IABP with the Impella 2.5 (2.5 L/min) and 1 trial with the Impella CP (3.5 L/min). A total of 95 patients were randomized to either Impella (n = 49) or IABP (n = 46). As reported in Figure 1, there was no difference in all-cause mortality between the patients treated with Impella or IABP at 30 days (relative risk (RR) 0.99; 95% confidence interval (CI) ; p = 0.95) and at 6 months (RR 1.15; 95% CI ; p = 0.53). Data on LVEF 2

4 during follow-up was available in 47 patients. Seyfarth et al. measured LVEF by angiography at 6 months (not previously published), Ouweneel et al (2016a) reported MRI measurements at 4 months and Ouweneel et al (2016b) reported echocardiography after 2 month. There was no difference in LVEF between Impella and IABP treated patients during follow-up (mean difference -2.6%; 95% CI ; p = 0.42). This meta-analysis of 3 randomized controlled trials comparing Impella with IABP shows no difference in 30 day and 6 months all-cause mortality. Also, no difference was observed in LVEF in survivors between IABP and Impella supported patients. Although the Impella has repeatedly shown to provide more hemodynamic support than the IABP, this did not translate in improved clinical outcome in these very sick patients at a high mortality risk. Our finding should be interpreted with caution. One of the reasons being the relatively unselected patients included in the studies. To some extent, this may result in an almost allcomer shock population with the risk of underestimating the impact of increased circulatory support in patients that may benefit more than the relatively high number of resuscitated patients in all trials. It is possible that a subgroup of patients may benefit from support with the Impella device. Cohort studies have shown that earlier initiation of Impella support, even before revascularization of the occluded artery, is associated with reduced mortality (4), which is supported by experimental studies who have shown that pre-revascularization Impella initiation is associated with reduced infarct size in improved left ventricular function (5). It is therefore important to note that the vast majority of patients enrolled in the studies were treated with mechanical support therapy after revascularization. However, large randomized, controlled trials or large-scale observational studies are needed to show which patients may benefit from this therapy. Another contributing factor is the fact that cardiogenic shock after AMI is complex and patients do not only suffer from cardiac ischemia but also from diminished organ perfusion, anoxic brain damage and systemic inflammatory responses. 3

5 Therefore, providing more hemodynamic support only may not be enough to save these very ill patients and other additional therapies may yield better outcomes. This meta-analysis is limited by the relatively small number of included studies and patients and by the inclusion of studies with different inclusion criteria for the severity of the cardiogenic shock (from pre-shock to severe shock). Also, the studies differed in the usage of the kind of Impella device (Impella 2.5 and Impella CP). The Impella 2.5 has gone through several improvements and recently received FDA approval on the basis of data from the USpella registry (4). In conclusion, although there is only limited data available, this meta-analysis shows no difference in mortality or LVEF in cardiogenic shock patients treated with Impella compared with IABP. A pooled analysis comprising undersized studies may mitigate true effect but in the absence of large-scale, sufficiently sized trials, pooled data are the next best source of evidence. 4

6 References 1. Windecker S, Kolh P, Alfonso F et al ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2014;35: O'Gara PT, Kushner FG, Ascheim DD et al 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. J Am Coll Cardiol 2013;61:e Ouweneel DM, Eriksen E, Sjauw KD et al. Impella CP versus intra-aortic balloon pump support in acute myocardial infarction complicated by cardiogenic shock. The IMPRESS in Severe Shock trial. J Am Coll Cardiol 2016b. 4. O'Neill WW, Schreiber T, Wohns DH et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. Journal of interventional cardiology 2014;27:1-11. Meyns B, Stolinski J, Leunens V, et al. Left ventricular support by catheter-mounted axial flow pump reduces infarct size. J Am Coll Cardiol 2003;41:

7 Figure Legend Figure 1: Meta-analysis showing the relative risk of 30-day (upper panel) and 6 months (middle panel) all-cause mortality with the use of Impella and IABP. Relative risks and 95% confidence intervals are presented of the individual trials as well as the pooled analysis. The lower panel shows the difference in left ventricular ejection fraction with 95% confidence intervals. 6

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