Utilization and outcomes in biventricular assist device support in pediatrics

Journal Pre-proof Utilization and Outcomes in Bi-Ventricular Assist Device Support in Pediatrics Nathanya Baez Hernandez, MD, Richard Kirk, MA FRCP, David Sutcliffe, MD, Ryan Davies, Robert Jaquiss, Ang Gao, MS, Song Zhang, PhD, Ryan J. Butts, MD PII:

S0022-5223(19)36113-6

DOI:

https://doi.org/10.1016/j.jtcvs.2019.11.068

Reference:

YMTC 15438

To appear in:

The Journal of Thoracic and Cardiovascular Surgery

Received Date: 20 December 2018 Revised Date:

18 November 2019

Accepted Date: 23 November 2019

Please cite this article as: Hernandez NB, Kirk R, Sutcliffe D, Davies R, Jaquiss R, Gao A, Zhang S, Butts RJ, Utilization and Outcomes in Bi-Ventricular Assist Device Support in Pediatrics, The Journal of Thoracic and Cardiovascular Surgery (2020), doi: https://doi.org/10.1016/j.jtcvs.2019.11.068. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. Copyright © 2019 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery

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Title: Utilization and Outcomes in Bi-Ventricular Assist Device Support in Pediatrics

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Authors: Nathanya Baez Hernandez, MD 1; Richard Kirk, MA FRCP1; David Sutcliffe, MD1;

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Ryan Davies2; Robert Jaquiss2; Ang Gao, MS3; Song Zhang, PhD3; Ryan J Butts, MD1

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University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, TX

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University of Texas Southwestern Medical Center, Department of Cardiothoracic Surgery,

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Dallas, TX

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University of Texas Southwestern Medical Center, Department of Clinical Science, Dallas, TX

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Disclosure: Early financial support for this analysis was provided by The National Heart, Lung

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and Blood Institute, National Institutes of Health, Department of Health and Human Services

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under Contract No. HHSN268201100025C. The analysis was completed with funding from The

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Society of Thoracic Surgeons.

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Conflict of interest: Dr. David Sutcliffe received <$1000 in travel funds for leadership/planning

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meetings for multicenter quality improvement network (Action Learning Network). (No relevant

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to this study). The rest of the authors have no affiliations with or involvement in any

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organization or entity with any financial or non-financial interest in the subject matter or

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materials discussed in this manuscript.

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Corresponding Author:

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Nathanya Baez Hernandez, MD

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Children’s Medical Center of Dallas

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1935 Medical District Drive, B3.09

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Dallas, TX 75235

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Phone: 214-456-582

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[email protected]

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Keywords: Biventricular Assist Device, Pediatrics

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Word Count: 2071

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Glossary of Abbreviations

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BiVAD: Biventricular assist device

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LVAD: Left ventricular assist device

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Pedimacs: Pediatric Interagency Registry for Mechanical Circulatory Support

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BUN: Blood urea nitrogen

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DCM: Dilated cardiomyopathy

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RCM: Restrictive cardiomyopathy

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LV: Left ventricle

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CENTRAL MESSAGE

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Differences in unmatched patient outcomes between biventricular assist device vs left

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ventricular assist device cohorts likely represent differences in severity of illness rather

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than device strategy

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PERSPECTIVE STATEMENT

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The use of ventricular assist device has increased in the pediatric population. The

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differences in biventricular assist device (BiVAD) vs left ventricular assist device

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(LVAD) outcomes are likely driven by patient characteristics. The choice of BiVAD vs

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LVAD strategy should be dictated by the clinical situation and not by a perceived

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adverse outcome profile of BiVAD support.

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CENTRAL PICTURE LEGEND Similar survival after propensity score matching between BiVAD and LVAD patients.

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GRAPHICAL ABSTRACT LEGEND

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Similar post implant survival between BiVAD and LVAD patients after propensity score

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matching.

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Abstract

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Objective: Biventricular assist device (BiVAD) patients have worse outcomes than left

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ventricular assist device (LVAD) patients. It is unclear whether these outcomes are due to device

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selection or patient factors. We used propensity score matching to reduce patient heterogeneity

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and compare outcomes in pediatric patients supported with BiVADs to a similar LVAD cohort.

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Methods: The Pedimacs registry was queried for patients who were supported with BiVAD or

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LVAD. Patients were analyzed by BiVAD or LVAD at primary implant and the two groups

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were compared prior to and after utilizing propensity score matching.

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Results: Of 363 patients that met inclusion criteria, 63 (17%) underwent primary BiVAD

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support. After propensity score matching, differences between cohorts were reduced. Six

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months after implant, in the BiVAD cohort (LVAD cohort) 52.5% (42.5%) had been

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transplanted; 32.5% (40%) were alive with device and 15% (10%) had died. Survival was similar

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between cohorts (p=0.31, log-rank) but BiVAD patients were more likely to experience a major

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adverse event in the form of bleeding (p=0.04, log-rank). At one week, one and three months

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post-implant the percentage of patients on mechanical ventilation, on dialysis, or with elevated

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bilirubin was similar between the two groups.

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Conclusion: When propensity scores were utilized to reduce differences in patient characteristics,

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there were no differences in survival but more major adverse events in the BiVAD patients,

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particularly bleeding. Differences in unmatched patient outcomes between LVAD and BiVAD

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cohorts likely represent differences in severity of illness rather than mode of support.

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Introduction There have been many changes in the usage of pediatric mechanical circulatory support

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since the original reports in BiVAD support which described extracorporeal, pulsatile support in

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children with predominantly cardiomyopathy. Trends in device utilization have shown increasing

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deployment of continuous flow and intracorporeal pumps that are utilized in smaller patients

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(BSA <1m2) as well as to provide LVAD and BiVAD support.1-3

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Use of biventricular assist device (BiVAD) support has been associated with increased

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mortality compared to left ventricular assist device (LVAD) in the initial North American

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experience with the Berlin Heart EXCOR.4-6 Improved outcomes for LVAD patients compared

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to BiVAD patients have also been demonstrated in the adult population.7 However, there were

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significant differences in the patient characteristics between the BiVAD and LVAD groups in

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these publications - both adult and pediatric BiVAD patients were more critically ill.6, 8 These

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reports have contributed to a decreasing amount of BiVAD use in adult heart failure.

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The aim of this study is to analyze outcomes after primary LVAD versus BiVAD implant

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in the current era and includes patients supported with continuous flow devices or pulsatile

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devices. Propensity score matching is used to reduce differences in patient characteristics that

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might influence outcomes.

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Methods

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The Interagency Registry of Mechanical Circulatory Support (INTERMACS) is a North

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American registry sponsored originally by the National Heart, Lung and Blood Institute and now

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by the Society of Thoracic Surgeons. It contains data on >15,000 patients supported on FDA-

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approved ventricular assist devices. The pediatric component of INTERMACS, Pedimacs

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(Pediatric Interagency Registry for Mechanical Circulatory Support), collects data on pediatric

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patients supported with temporary or durable ventricular assist devices. All pediatric patients

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receiving LVAD or BiVAD support between September 19, 2012 and March 31, 2017 were

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included. Patients were excluded if they were supported with a RVAD alone, total artificial

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heart, or single ventricle VAD. Patients were classified based upon their initial implant strategy,

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i.e. LVAD vs. BiVAD at first VAD operation.

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Clinical and demographic data is reported with descriptive statistics, continuous variables

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reported as median, interquartile range. Comparisons between LVAD and BiVAD cohort were

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performed with Wilcoxon rank sum or Chi-Square. Propensity score matching was utilized to

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reduce differences between the BiVAD and LVAD cohorts. Variables used in calculating

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propensity scores were: age, total bilirubin at implant, creatinine, cardiac diagnosis

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(cardiomyopathy vs. biventricular congenital heart disease vs. transplant vs. other), gender,

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height, implant year, mechanical ventilation, continuous vs. pulsatile device in the left ventricle

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(LV) position, Pedimacs profile (1 vs. all-others), sodium at implant, and weight. Dichotomizing

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Pedimacs profile was based upon previous reports showing significantly different survival for

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Pedimacs profile 1 versus Pedimacs profile 2/3.9 LVADs were matched 2:1 to BiVADs using a

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propensity score algorithm.10 Acceptable matches were defined as VAD recipients that had a

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difference between propensity scores of less than 0.2 times the standard deviation of propensity

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scores for the entire cohort.

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Survival was estimated by Kaplan-Meier curves with censoring at transplant or device

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removal for recovery and compared with log-rank test. Multivariable Cox regression was

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performed with the covariates [age, total bilirubin at implant, cardiac diagnosis (cardiomyopathy

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vs. biventricular congenital heart disease vs. transplant vs. other), gender, height, implant year,

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mechanical ventilation, continuous vs. pulsatile device in the LV position, Pedimacs profile (1

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vs. all-others), sodium at implant, and weight] to assess the association between survival and

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device strategy with censoring at transplant or device removal for recovery. Freedom from

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major adverse events was analyzed using Kaplan-Meier curves and log-rank test. Major adverse

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events were classified by Pedimacs definitions and included: infection, major bleeding,

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neurologic dysfunction and device malfunction post device implantation. Device malfunction

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included pump exchanges on pulsatile devices performed for thrombosis. Follow-up data after

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implant included use of dialysis, use of mechanical ventilation, or elevated bilirubin (>1.2

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mg/dL).4 Time points analyzed for follow-up data were; 1-week, 1 month, and 3-months post

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implant.

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Results Between September 19, 2012 and March 31, 2017, a total of 456 patients were entered

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into Pedimacs from 45 different institutions with a mean follow-up of 4.4 months. Of those 456

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patients, 376 (82.4%) met study inclusion criteria. Of the 80 patients who were excluded, 63 had

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single ventricle heart disease, 8 had total artificial hearts and 9 had RVAD alone. Of the study

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patients 63 (16.8%) had BiVADs and 313 (83.2%) had LVAD alone. Median follow-up for the

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LVAD patients was 2.3 months (IQR 0.89-5.2) and 1.6 months (IQR 0.46-4.0) for the BiVAD

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patients. The percentage of patients who had a BiVAD peaked in 2012 at 23.5% and has

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declined since (Figure 1).

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Unmatched BiVAD vs. LVAD

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Table 1 compares patients who had a BiVAD versus LVAD. Patients with BiVADs were more

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likely to be on mechanical ventilation and have Pedimacs 1 profile, more likely to have

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congenital heart disease, and less likely to have continuous flow device in the LV position.

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Survival was better for LVAD group (Online-Only Data Supplemental Figure 1). Factors

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associated with survival included cardiac diagnosis (HR 1.6 95% CI 1.2-2.0, p<0.001), Pedimacs

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profile (HR 1.8 95%CI 1.3-2.6, p=0.013 Pedimacs 1 vs. all others), implant year HR 1.2. (95%

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CI 1.0-1.3, p<0.01). The 23 unmatched BiVAD patients were older and predominantly female,

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had worse renal and liver function and majority corresponded to Pedimacs profile1 at implant

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(Online-Only data Supplemental Table 1). The LVAD group had better freedom from major

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adverse events compared to the BiVAD group; however, the only difference in major adverse

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events when analyzed individually was a lower freedom from bleeding events among BiVAD

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patients. One week after implant, the LVAD cohort had less patients on mechanical ventilation

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(23.2% vs. 64.3%), and on dialysis (4.4% vs. 16.7%); but not significant difference in the

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percentage of patients with elevated bilirubin level (32.4 % vs 47.2%). These differences in

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patients on mechanical ventilation or dialysis were not evident by 1-month post-implant.

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LVAD vs. BiVAD Propensity Matched Analysis

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After propensity score matching, differences between the LVAD and BiVAD cohorts

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were eliminated (Table 1). Overall survival after implant was similar between the matched

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cohorts (p=0.31, log-rank, Figure 2, multivariable Cox regression, HR=1.2, 0.5-1.9 95% CI,

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p=0.9). Six months after implant, in the BiVAD cohort (LVAD cohort) 52.5% (42.5%) had been

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transplanted, 32.5% (40%) were alive with device and 15% (10%) had died. The BiVAD group

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was more likely to experience a major adverse event (p=0.05, log-rank, Figure 3). When

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analyzed individually, the BiVAD cohort was more likely to have bleeding (p=0.04, Figure 4),

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but no difference in device malfunction (p=0.74), infection (p=0.16) or central nervous system

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dysfunction (p=0.74). At 1-week post-implant the number of patients with elevated bilirubin was

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(LVAD 21% vs. BiVAD 37%, p=0.11), patients requiring mechanical ventilation (LVAD 42%

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vs. BiVAD 63%, p=0.06) or patients on dialysis (LVAD 6.6% vs. BiVAD 13.3%, p=0.22). No

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differences were seen at 1 and 3 months.

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Discussion

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Over the entirety of the study duration approximately 17% of pediatric patients required

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BiVAD support, though there was a downward trend over the final three years. This trend likely

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relates to the recognition that pediatric patients supported by BiVADs have worse survival

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outcomes and experience more adverse events compared to patients supported with LVADs, a

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finding recapitulated in this study.4 However, when comparing more homogenous patient

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populations following propensity matching, apparent differences in support outcomes were

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minimized and likely due to patient characteristics. BiVADs were more likely to be used in

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pediatric patients with congenital heart disease, presenting with cardiogenic shock and requiring

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mechanical ventilation as compared to patients supported with LVADs. Propensity score

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matching eliminated these differences in patient characteristics and revealed similar survival

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outcomes despite a higher frequency of major bleeding adverse events in BiVAD patients

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(Figure 5. See Graphical Abstract).

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In the Berlin Heart IDE trial, approximately 35% of patients were supported with

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BiVADs, decreasing to 28% of implants in the Berlin post-approval study. 4, 11, 12 The IDE trial

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spanned from 2007 to 2010 with the post-approval study running from 2011 to 2015. In our

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study only 17% of patients were supported with BiVADs, and the percentage of BiVAD

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implants has continued to decrease each year since 2014. A similar downtrend in utilization

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rates of BiVADs has also been seen in the adult VAD population.7 Early reports of worse

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outcomes after BiVAD support compared to LVAD alone has led the field to improve patient

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selection and adopt earlier implantation when feasible.4, 5, 9 This is evidenced by 57% of the

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patients in the Berlin Heart IDE trial being in cardiogenic shock (Pedimacs-1) at time of implants

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versus only 30% of the patients implanted in this analysis.11

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The use of BiVADs in pediatrics remains higher than in the adult population, consisting

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of 17% of pediatric implants in all years of this study as compared to 3% of all adult implants

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according to Intermacs reporting.13 The higher percentage of pediatric patients having congenital

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heart disease versus adults (8% of pediatric VADs versus <1% of adult VADs) combined with

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increased use of BiVAD support in congenital heart disease indicates that the use of BiVADs in

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pediatric VAD population will likely remain higher than in the adult VAD population.9, 14

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Survival after BiVAD implantation appears to be better for children with an estimated 75-80%

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survival at 6 months versus 55-65% in adults.7 However, this is very likely influenced by the

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shorter duration of support in children and the greater likelihood of a pediatric patient to be

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transplanted within 6 months of implant.13

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Late conversion to BiVAD support from initial LVAD placement has been associated

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with worse outcomes compared to initial BiVAD support in the adult VAD population.15 Due to

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small numbers, we were unable to investigate the outcomes in late conversion to BiVAD

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support. Risk factors for RV failure after LVAD placement have been studied extensively in the

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adult VAD population, but little is known in children.16-20 As the pediatric VAD experience

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grows, identifying risk factors for RV failure post-VAD will help identify which children would

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benefit from BiVAD support at implant vs. LVAD alone; as we have demonstrated that when

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comparing similar patient profiles LVAD and BiVAD support have similar outcomes. As the

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number of patients entered into Pedimacs continues to grow, future analyses of the Pedimacs

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database should investigate outcomes in late conversion to BiVAD in pediatric patients to

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address these clear gaps in our clinical knowledge.

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Adverse events were still more common in BiVAD patients compared to LVAD patients

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after propensity score matching. The difference in adverse events was driven by BiVAD patients

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being more likely to suffer from bleeding. There was no difference in the use of dialysis,

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mechanical ventilation or presence of elevated bilirubin 1-week, 1-month or 3-months after

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implant. Therefore, it appears the extra risk that BiVAD support incurs compared to LVAD

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alone when comparing similar patients, is bleeding.

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Limitations

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The data analyzed is from a multi-institutional registry; therefore, accuracy of data is

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dependent on correct data entry of reporting institutions. Unrecorded variables may have

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influenced the decision of utilizing BiVAD vs. LVAD support and therefore not been adjusted

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for in the propensity score analysis. Pre-operative heart failure management, anticoagulation

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strategies plus other post-operative management strategies (use of mechanical ventilation and

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renal replacement therapies) were determined by individual institutions and not recorded in the

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registry database and may have influenced patient outcomes. The propensity score matched

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cohorts have significant differences from other patients in the Pedimacs database in terms of age,

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cardiac diagnosis, Pedimacs profile and use of mechanical ventilation. Therefore, the results of

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the propensity score matched cohorts may not be generalizable to the entire Pedimacs

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population. The small number of patients in the propensity score matched cohorts prevented

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analyzing the associations between device type (pulsatile vs. continuous flow) and outcomes.

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The small number of patients in the propensity score may have resulted in differences not being

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statistically significant due to reduced statistical power (i.e. the percentage of patients intubated

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at 1week post implant). The de-identified dataset did not include brand of VAD and therefore

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was not included in the study. Given the low number of patients that were able to be propensity

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score matched a Type II error could be present.

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Conclusion

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This analysis demonstrates that the differences in BiVAD vs LVAD outcomes are likely

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significantly impacted by difference in patient characteristics. BiVAD patients are more likely to

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have a bleeding event but had similar survival when matched to similar LVAD patients. The

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choice of BiVAD vs LVAD strategy should be dictated by risks for severe and persistent RV

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failure after VAD placement.

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References

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395 396 Table 1. LVAD versus BiVAD patients at initial implant before and after propensity score matching LVAD vs. BiVAD Prior to Propensity Score Matching LVAD BiVAD Standardized (n=313) (n=63) Difference

LVAD vs. BiVAD after Propensity Score Matching LVAD BiVAD Standardized (n=80) (n=40) Difference

Patient Characteristics Age (y) Female

11 (2-16) 124 (39.6%)

8 (3-14) 30 (47.6%)

0.74 -0.13

7 (1-15) 21 (47%)

6 (1-15) 11 (46%)

-0.11 0.016

Weight (kg)

44.2 ±3 2.2

32.7 ± 30.5

0.86

20 (7.1-59)

21 (8.4-46)

0.29

Height (cm) Bilirubin at Implant (mg/dL)

144 (92-168) 1.0 (0.6-1.5)

129 (88-160) 1.4 (0.7-2.7)

1.3 -0.33

118 (70-163) 0.81 (0.5-1.5)

120 (72-160) 1.2 (0.6-1.6)

-0.086 -0.16

Sodium (mEq/L)

136 (133-140)

138 (134-142)

-0.92

137 (134-142)

138 (133-142)

-0.36

Intubated Prior to Implant Sinus Rhythm

117 (37%) 237 (76%)

38 (60%) 41 (65%)

-0.39 0.21

46 (58%) 57 (71%)

24 (60%) 27 (68%)

-0.03 0.05

BUN (mg/dL)

20 (15-29)

23 (18-41)

-0.48

21 (14-31)

21 (16-35)

-0.19

PediMACS Profile 1 at Implant

83 (27%)

31 (49%)

-0.39

31 (39%)

16 (40%)

-0.017

Cardiac Diagnosis Congenital Heart Disease

25 (8%)

8 (13%)

-0.14

15 (19%)

8 (23%)

-0.081

DCM RCM

258 (86%) 9 (3%)

42 (71%) 4 (7%)

0.32

60 (75%) 3 (4%)

26 (65%) 2 (5%)

0.18

Post-Transplant

8 (3%)

5 (8%)

2 (2%)

3 (7%)

Device Strategy Bridge to Transplant

274 (88%)

55 (87%)

71 (89%)

38 (95%)

Bridge to Recovery

31 (10%)

7 (11%)

0.02 -0.03

7 (9%)

2 (5%)

0

2 (2%) 37 (46%)

0 (0%) 20 (50%)

Destination Therapy Continuous Flow Device in LV

8 (2%) 228 (74%)

1 (2%) 31 (49%)

-0.16 -0.19

0.44

397 398 LVAD= left ventricular assist device, BiVAD= biventricular assist device, BUN=blood urea nitrogen, DCM=dilated 399 cardiomyopathy, RCM=restrictive cardiomyopathy, LV=left ventricle. Continuous variables are shown as median, interquartile 400 range; categorical data is displayed as n (%) 401 402 403 404 405 406 407

-0.04 -0.22 -0.17 0.12 0.14 -0.065

21

408 409

Figure Legends

410

Figure 1. Patient Cohort. Bar graph depicting the percent of VAD implants that made study

411

inclusion/exclusion criteria that were BiVADs (red) versus LVADs (blue) by year. VAD:

412

ventricular assist device, BiVAD: biventricular assist device, LVAD: left ventricular assist

413

device.

414 415

Figure 2. Survival in the Matched Cohort. Kaplan-Meier curve depicting survival after VAD

416

implant for propensity score matched patients, with LVAD patients depicted by blue curve,

417

BiVAD in red curve. No difference was seen in survival between cohorts. Patients censored at

418

time of transplant and/or at device explant for recovery. Shaded areas indicate 95% confidence

419

intervals for each group. VAD: ventricular assist device, LVAD: left ventricular assist device,

420

BiVAD: biventricular assist device

421 422

Figure 3. Adverse Events in the Matched Cohort. Kaplan-Meier curve depicting freedom

423

from any major adverse event after VAD implant for propensity score matched patients, with

424

LVAD patients depicted by blue curve, BiVAD in red curve. Patients censored at time of

425

transplant and/or at device explant for recovery. Shaded areas indicate 95% confidence intervals

426

for each group. VAD: ventricular assist device, LVAD: left ventricular assist device, BiVAD:

427

biventricular assist device

428 429

Figure 4. Freedom from Adverse Events in the Matched Cohort. Kaplan-Meier curve

430

depicting freedom from each individual major adverse event after VAD implant for propensity

431

score matched patients, with LVAD patients depicted by blue line, BiVAD in red curve. Patients

432

censored at time of transplant and/or at device explant for recovery. Shaded areas indicate 95%

433

confidence intervals for each group. VAD: ventricular assist device, LVAD: left ventricular

434

assist device, BiVAD: biventricular assist device

435

22

436

Figure 5. Post Implant Survival Before and After Propensity Matching. Kaplan-Meier curve

437

depicting post VAD implant survival before and after propensity score matched patients, with

438

LVAD patients depicted by blue curve, BiVAD in red curve. No difference was seen in survival

439

between cohorts after propensity matching. Patients censored at time of transplant and/or at

440

device explant for recovery. Shaded areas indicate 95% confidence intervals for each group.

441

VAD: ventricular assist device, LVAD: left ventricular assist device, BiVAD: biventricular assist

442

device

443 444

Video. Ventricular assist device in the pediatric population

445 446 447 448

Supplemental Material

449 450

Due to the fact that unmatched cohort had significant differences, p-values for comparisons were

451

removed. Survival curve for the unmatched groups is here included. Here we present the data of

452

the unmatched cohort as well as the data on the 23 BiVAD patients that were removed during the

453

propensity score matching.

454 455 456

Unmatched Cohort Comparison

As shown in Supplemental Figure 1, survival was better for LVAD group (p=0.001). In

457

multivariate Cox regression analysis, device support (BiVAD vs LAVD) was not associated with

458

survival (HR=1.4, 95% CI 0.6-2.4p=0.87). Factors associated with survival included cardiac

459

diagnosis (p<0.01, Pedimacs profile p=0.013, and implant year (p<0.01). The LVAD group had

460

better freedom from major adverse events compared to the BiVAD group (p=0.03, log-rank);

461

however, the only difference in major adverse events when analyzed individually was a lower

23

462

freedom from bleeding events among BiVAD patients p <0.01, log-rank. One week after implant

463

the LVAD cohort had less patients on mechanical ventilation (23.2% vs. 64.3%, p<0.01), and on

464

dialysis (4.4% vs. 16.7% p<0.01), but no significant difference in the percentage of patients with

465

elevated bilirubin (32.4% vs. 47.2%, p=0.16). These differences in patients on mechanical

466

ventilation or dialysis were not evident by 1-month post-implant (p=0.89 & 0.65, respectively).

467

BiVAD Patients Removed After Propensity Score Matching Supplemental Table 1 shows the demographic, device strategy and cardiac diagnosis of

468 469

the 23 BiVAD patients eliminated after propensity score matching.

470

471

Figure 1. Survival in the Unmatched Cohort. Kaplan-Meier curve depicting survival after

472

VAD implant in the unmatched cohort. LVAD patients depicted by blue line, BiVAD in red line.

473

LVAD patients had better survival. Patients censored at time of transplant and/or at device

474

explant for recovery. Shaded areas indicate 95% confidence intervals for each group. VAD:

475

ventricular assist device, LVAD: left ventricular assist device, BIVAD: biventricular assist

476

device

477

478

Supplemental Figure 2. Kaplan-Meier curve depicting survival of the 23 patients unmatched

479

BiVAD patients. Shaded areas indicate 95% confidence intervals. BIVAD: biventricular assist

480

device

481

Supplemental Figure 3. Kaplan-Meier curve depicting freedom from major adverse events after

482

VAD implant of the 23 patients unmatched BiVAD patients. Shaded areas indicate 95%

483

confidence intervals. VAD: ventricular assist device, BIVAD: biventricular assist device

24

484

Supplemental Figure 4. shows freedom from each individual major adverse event after VAD

485

implant of the 23 patients unmatched BiVAD patients. Shaded areas indicate 95% confidence

486

intervals. VAD: ventricular assist device, BIVAD: biventricular assist device

487

488

489 490

1

Table 1. LVAD versus BiVAD patients at initial implant before and after propensity score matching LVAD vs. BiVAD Prior to Propensity Score Matching LVAD BiVAD Standardized (n=313) (n=63) Difference

LVAD vs. BiVAD after Propensity Score Matching LVAD BiVAD Standardized (n=80) (n=40) Difference

Patient Characteristics Age (y) Female

11 (2-16) 124 (39.6%)

8 (3-14) 30 (47.6%)

0.74 -0.13

7 (1-15) 21 (47%)

6 (1-15) 11 (46%)

-0.11 0.016

Weight (kg)

44.2 ±3 2.2

32.7 ± 30.5

0.86

20 (7.1-59)

21 (8.4-46)

0.29

Height (cm) Bilirubin at Implant (mg/dL)

144 (92-168) 1.0 (0.6-1.5)

129 (88-160) 1.4 (0.7-2.7)

1.3 -0.33

118 (70-163) 0.81 (0.5-1.5)

120 (72-160) 1.2 (0.6-1.6)

-0.086 -0.16

Sodium (mEq/L)

136 (133-140)

138 (134-142)

-0.92

137 (134-142)

138 (133-142)

-0.36

Intubated Prior to Implant Sinus Rhythm

117 (37%) 237 (76%)

38 (60%) 41 (65%)

-0.39 0.21

46 (58%) 57 (71%)

24 (60%) 27 (68%)

-0.03 0.05

BUN (mg/dL)

20 (15-29)

23 (18-41)

-0.48

21 (14-31)

21 (16-35)

-0.19

Pedimacs Profile 1 at Implant

83 (27%)

31 (49%)

-0.39

31 (39%)

16 (40%)

-0.017

Cardiac Diagnosis Congenital Heart Disease

25 (8%)

8 (13%)

-0.14

15 (19%)

8 (23%)

-0.081

DCM RCM

258 (86%) 9 (3%)

42 (71%) 4 (7%)

0.32

60 (75%) 3 (4%)

26 (65%) 2 (5%)

0.18

Post-Transplant

8 (3%)

5 (8%)

2 (2%)

3 (7%)

Device Strategy Bridge to Transplant

274 (88%)

55 (87%)

71 (89%)

38 (95%)

Bridge to Recovery

31 (10%)

7 (11%)

0.02 -0.03

7 (9%)

2 (5%)

0

2 (2%) 37 (46%)

0 (0%) 20 (50%)

Destination Therapy Continuous Flow Device in LV

8 (2%) 228 (74%)

1 (2%) 31 (49%)

-0.16 -0.19

0.44

LVAD= left ventricular assist device, BiVAD= biventricular assist device, BUN=blood urea nitrogen, DCM=dilated cardiomyopathy, RCM=restrictive cardiomyopathy, LV=left ventricle. Continuous variables are shown as median, interquartile range; categorical data is displayed as n (%)

-0.04 -0.22 -0.17 0.12 0.14 -0.065

Supplemental Table 1. Patient Characteristics Age (y) Female Weight (kg) Height (cm) Bilirubin at Implant (mg/dL) Sodium (mEq/L) Intubated Prior to Implant Sinus Rhythm BUN (mg/dL) PediMACS Profile 1 at Implant Cardiac Diagnosis Congenital Heart Disease DCM RCM Post-Transplant Device Strategy Bridge to Transplant Bridge to Recovery Destination Therapy Continuous Flow Device in LV

BiVAD patients (n=23) 11 (5-14) 19 (83%) 36.3 (17-69) 131 (105-159) 1.6 (0.8-2.9) 140 (137-142 14 (61%) 14 (61%) 40 (20-47) 15 (65%) 1 (4%) 16 (70%) 3 (13%) 3 (13%) 17 (74%) 5 (22%) 1 (4%) 11 (48%)

Demographic, device strategy and cardiac diagnosis of the 23 BiVAD patients eliminated after propensity score matching. Biventricular Assist Device

Supplemental Material

Due to the fact that unmatched cohort had significant differences, p-values for comparisons were removed. Survival curve for the unmatched groups is here included. Here we present the data of the unmatched cohort as well as the data on the 23 BiVAD patients that were removed during the propensity score matching.

Unmatched Cohort Comparison

As shown in Supplemental Figure 1, survival was better for LVAD group (p=0.001). In multivariate Cox regression analysis, device support (BiVAD vs LAVD) was not associated with survival (HR=1.4, 95% CI 0.6-2.4p=0.87). Factors associated with survival included cardiac diagnosis (p<0.01, Pedimacs profile p=0.013, and implant year (p<0.01). The LVAD group had better freedom from major adverse events compared to the BiVAD group (p=0.03, log-rank); however, the only difference in major adverse events when analyzed individually was a lower freedom from bleeding events among BiVAD patients p <0.01, log-rank. One week after implant the LVAD cohort had less patients on mechanical ventilation (23.2% vs. 64.3%, p<0.01), and on dialysis (4.4% vs. 16.7% p<0.01), but no significant difference in the percentage of patients with elevated bilirubin (32.4% vs. 47.2%, p=0.16). These differences in patients on mechanical ventilation or dialysis were not evident by 1-month post-implant (p=0.89 & 0.65, respectively). BiVAD Patients Removed After Propensity Score Matching Supplemental Table 1 shows the demographic, device strategy and cardiac diagnosis of the 23 BiVAD patients eliminated after propensity score matching.

Figure 1. Survival in the Unmatched Cohort. Kaplan-Meier curve depicting survival after VAD implant in the unmatched cohort. LVAD patients depicted by blue line, BiVAD in red line. LVAD patients had better survival. Patients censored at time of transplant and/or at device explant for recovery. Shaded areas indicate 95% confidence intervals for each group. VAD: ventricular assist device, LVAD: left ventricular assist device, BiVAD: biventricular assist device

Supplemental Figure 2. Kaplan-Meier curve depicting survival of the 23 patients unmatched BiVAD patients. Shaded areas indicate 95% confidence intervals. BiVAD: biventricular assist device Supplemental Figure 3. Kaplan-Meier curve depicting freedom from major adverse events after VAD implant of the 23 patients unmatched BiVAD patients. Shaded areas indicate 95% confidence intervals. VAD: ventricular assist device, BiVAD: biventricular assist device Supplemental Figure 4. shows freedom from each individual major adverse event after VAD implant of the 23 patients unmatched BiVAD patients. Shaded areas indicate 95% confidence intervals. VAD: ventricular assist device, BiVAD: biventricular assist device