SPECIAL FEATURE.

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1 SPECIAL FEATURE Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device David L. S. Morales, MD, a Christopher S. D. Almond, MD, b Robert D. B. Jaquiss, MD, c David N. Rosenthal, MD, d David C. Naftel, PhD, e M. Patricia Massicotte, MD, f Tilman Humpl, MD, PhD, g Mark W. Turrentine, MD, h James S. Tweddell, MD, i Gordon A. Cohen, MD, PhD, j Robert Kroslowitz, BS, CCP, k Eric J. Devaney, MD, l Charles E. Canter, MD, m Francis Fynn-Thompson, MD, n Olaf Reinhartz, MD, o Michiaki Imamura, MD, PhD, c Nancy S. Ghanayem, MD, p Holger Buchholz, MD, q Sarah Furness, RN, r Robert Mazor, MD, s Sanjiv K. Gandhi, MD, t and Charles D. Fraser Jr, MD a From a Congenital Heart Surgery Division, Texas Children s Hospital, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas; b Department of Cardiology, Children s Hospital Boston, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; c Congenital Thoracic Surgery Division, Arkansas Children s Hospital, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas; d Division of Pediatric Cardiology, Stanford University, Stanford, CA and Lucile Packard Children s Hospital; e Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; f Department of Pediatrics, Stollery Children s Hospital, University of Alberta, Edmonton, Alberta, Canada; g Department of Paediatrics, Division of Cardiology, Department of Critical Care Medicine, Division of Cardiac Critical Care, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; h Pediatric Cardiovascular Surgery Division, Riley Hospital for Children, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; i Cardiothoracic Surgery, Children s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin; j Pediatrics Cardiothoracic Surgery Division, Seattle Children s Hospital, University of Washington School of Medicine, Seattle, Washington; k Berlin Heart Inc, The Woodlands, Texas; l Pediatric Cardiovascular Surgery Division in the Department of Surgery, C.S. Mott Children s Hospital, University of Michigan Medical School, Ann Arbor, Michigan; and m Department of Pediatric Cardiology, St. Louis Children s Hospital, Washington University School of Medicine, St. Louis, Missouri; n Department of Cardiac Surgery, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts; o Pediatric Cardiac Surgery Division in the Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, California; p Pediatric Intensive Care Unit, Children s Hospital of Wisconsin, Department of Pediatrics at Medical College of Wisconsin, Milwaukee, Wisconsin; q Cardiac Surgery Division, Department of Surgery, Stollery Children s Hospital, University of Alberta, Edmonton, Alberta, Canada; r Department of Critical Care Medicine, Division of Cardiac Critical Care, The Hospital for Sick Children, Toronto, Ontario; s Critical Care Medicine Division, Seattle Children s Hospital, Department of Pediatrics, the University of Washington School of Medicine, Seattle, Washington; t Cardiothoracic Surgery Division, St. Louis Children s Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri. BACKGROUND: Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. METHODS: Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. RESULTS: Median age and weight at VAD implant were 2.1years (range, 12 days 17.8 years) and 11 kg (range, kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices /$ -see front matter 2011 International Society for Heart and Lung Transplantation. All rights reserved. doi: /j.healun

2 2 The Journal of Heart and Lung Transplantation, Vol 30, No 1, January 2011 KEY WORDS: heart-assist device; extracorporeal circulation; transplantation; pediatrics (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% (n 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients (p 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. CONCLUSIONS: This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation. J Heart Lung Transplant 2011;30: International Society for Heart and Lung Transplantation. All rights reserved. Reprint requests: David L. S. Morales, MD, Division of Congenital Heart Surgery, Texas Children s Hospital, 6621 Fannin St, WT19345H, Houston, TX Telephone: Fax: address: dlmorale@texaschildrens.org Although heart transplantation has been established as definitive therapy for end-stage cardiac failure in children, there continues to be significant mortality during the waiting interval between listing and transplantation. 1 Several adultsized ventricular assist devices (VADs) are available and have been shown to effectively support larger children and adolescents to transplantation, a process described as bridge to transplant. 2,3 In the United States, the DeBakey VAD Child (MicroMed Technology Inc, Houston, TX) is currently the only Food and Drug Administration-approved VAD designed for use in children, but its approval is limited to children aged older than 5 years and with a body surface area (BSA) greater than 0.7 m 2. 4 The Debakey VAD is able to support the left ventricle effectively but has not been widely applied due to thromboembolic issues. Thus, extracorporeal membrane oxygenation (ECMO) remains the predominant technology for mechanically bridging neonates, infants, and children to cardiac transplantation. ECMO has substantial associated morbidity and mortality, particularly if the duration of support extends beyond 2 weeks. 5 There has been significant frustration over the lack of a suitable device to bridge children with heart failure to transplant. To better support small children awaiting heart transplantation, a pneumatically driven pediatric-specific VAD, the EXCOR, was developed in Germany by Berlin Heart GmBH. 6 The Berlin Heart device is designed to support one or both ventricles and is available in a variety of sizes suitable for children between 3 kg and adult-size. The EXCOR was first implanted in North America in June 2000 but did not gain widespread use until Since then, encouraging preliminary experiences have been reported, but these have been limited to small single-center experiences. 7 9 Because of this rapidly growing interest and application of the EXCOR in North America, Berlin Heart Inc applied for an investigational device exemption (IDE) trial, which was approved and started in May Unfortunately, no collective information or outcomes data are available on the nearly 100 pediatric applications of the EXCOR that occurred before the start of the IDE study. Therefore, we sought to aggregate and analyze the pre-ide Berlin Heart EXCOR experience from multiple centers across North America to give a broader-based and fundamental overview of its efficacy as a bridge to transplant. Methods Before the approval of the FDA IDE Study of the Berlin Heart EXCOR for children from 3 kg to a BSA of 1.5 m 2, the EXCOR was implanted in 97 patients in North America under compassionate use regulations. Limited data from 73 of these patients were entered into a Web-based data entry system replicating the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database for FDA-approved VADs, after local Institutional Review Board approval at each implanting institution. 10,11 The 24 patients not included in this study were at 12 institutions that were unable to enter their data secondary to logistic reasons despite multiple solicitations by Berlin Heart and the authors. The data analyzed in the present study represent a sub-set of the INTERMACS database, which captured the major outcomes of VAD support. Because there was no mechanism for adjudication of certain adverse events such as stroke or bleeding during the period represented in this study, these end points could not be evaluated in the present study. The ongoing IDE trial includes a robust mechanism for recording, adjudicating, and analyzing such morbidity in a prospective fashion. The data collected and available for analysis in the present study were limited to descriptive demographic variables such as cardiac diagnosis, age, sex, race, pre-implant clinical condition, length of VAD support, and final outcome (transplantation, recovery, or death). Statistical analysis Data were summarized using standard statistical descriptors such as means, medians, standard deviations, ranges, and percentages. Time-related event data, such as death, were analyzed using the Kaplan-Meier method. Survival statistics for sub-groups were compared using the log-rank test. The simultaneous estimation of the time-related occurrence of mutually exclusive events (ie, death before transplant, transplant, and explant due to recovery) was analyzed using competing outcomes methods. Risk factors for death were detected by the parametric analog to Cox proportional hazard regression. 12,13 The first step in this process is to estimate the underlying parametric hazard function for death. Once this hazard function is estimated, risk factors are determined by proportional hazard regression based on this spec-

3 Morales et al. North American Experience with the Berlin Heart EXCOR 3 (73%), and ECMO was used as a bridge to EXCOR in 22 patients (30%). All patients not supported with ECMO were receiving continuous inotropic medications (data not available for 3 patients). Device strategy Figure 1 Number of Berlin Heart EXCOR North American implants per year prior to IDE trial. ified parametric hazard function. This procedure detects those risk factors, which are significantly (p.05) associated with an increased risk of death and therefore a shorter time of survival. The resultant estimates are hazard ratios that modify the underlying hazard function. Log transformation was used to analyze age due to the non-linear relationship of age and the risk of death. Results Cohort Between June 2000 and May 2007, 97 patients underwent Berlin Heart EXCOR VAD implantation in North America at 29 institutions. Of these, 73 patients (75% of the total cohort), who received implants at 17 different institutions, had sufficient data and comprised the primary study cohort. The annual number of implants during the period of study is shown in Figure 1. Demographics The cohort consisted of 40 girls (55%; Table 1). Median age at the time of implant was 2.1 years (range, 12 days 17.8 years), and median weight was 11 kg (range, kg). Race and ethnicity distribution consisted of 33 white (45%) 23 African American (32%), 8 Hispanic (11%), 3 Asian (4%), and 6 patients (8%) of other ethnic groups. Pre-implant characteristics The primary cardiac diagnoses were congenital heart disease in 19 (26%), dilated cardiomyopathy in 42 (58%), myocarditis in 7 (10%), and other cardiomyopathies in 5 patients (7%; Table 1). Pre-implant clinical condition was defined according to the 2007 INTERMACS Profile Status criteria as critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), stable but inotrope-dependent in 1 (1%), and recurrent advanced heart failure in 1 patient (1%). 14 Ventilatory support was required in 53 patients The EXCOR was placed as a bridge to transplant in 69 patients (94%) and was implanted as a bridge-to-recovery strategy in 2 patients (3%; Table 1). The pre-implant strategy was not recorded for 2 (3%) patients. A left VAD (LVAD) was used in 42 patients (57%), whereas bi-ventricular assist devices (BiVAD) were applied in 31 patients (43%) at the initial procedure. Outcomes The EXCOR served as a bridge to transplant in 51 patients (70%), with a median support time of 1.6 months (range, 1 day 7.7 months). The EXCOR served as a bridge to recovery in 5 patients (7%), with a median support time of 3.1 months (range, 19 days 5.5 months). Mortality while on the device was 23% (17 patients), with death occurring at a median support time of 1.8 months (range, months). A successful outcome (bridge to transplant or recovery) was achieved in 56 patients (77%). At 6 months after implant, a competing outcomes analysis demonstrated that 67% of patients had received a transplant, 4% continued on support, 7% had been weaned from the EXCOR, and 22% had died (Figure 2A). Multivariable analysis revealed that younger age and use of BiVAD support were significant risk factors for death while being supported on the EXCOR (Table 2). Competing outcomes analyses for LVAD and BiVAD strategies are shown in Figures 2B and 2C, respectively. Mortality in patients with BiVAD support was 36% (11 of 31) compared with 12% (5 of 42) in patients with only LVAD support (p 0.003), and this difference seemed most apparent in younger children (Table 3). Discussion This study presents the clinical outcomes for a retrospective series of 73 children supported with the Berlin Heart EXCOR as a bridge to transplantation at 17 North American centers. This is the largest single-device experience of VAD use in children reported from North America and is similar in scope to the series reported by Hetzer et al 15 from the Berlin Heart Institute. In contrast to the Hetzer study, which represented the outcomes of a single, highly experienced center over 15 years, the current report captures the early application of the device in more than a dozen pediatric centers across North America who were just beginning to gain clinical experience with the EXCOR. The current series demonstrates that the Berlin Heart EXCOR appears effective (77%) in supporting children to transplantation or recovery. Although the 23% mortality rate in this study cohort is substantial, this must be inter-

4 4 The Journal of Heart and Lung Transplantation, Vol 30, No 1, January 2011 Table 1 Baseline Characteristics of the Study Cohort a Variable b Total LVAD BiVAD p-value c Patients, No Age, median (range) years 2.1 (12 d 18 yrs) 2 (36 d 18 yrs) 3.9 (12 d 17 yrs) (30) 14 (33) 8 (26) (38) 16 (38) 12 (39) (15) 5 (12) 6 (19) (17) 7 (17) 5 (16) Weight, median (range), kg 11 (3 87.6) 10.7 (3 49) 11.0 (3 87.6) (29) 13 (31) 8 (26) (56) 23 (55) 18 (58) (15) 6 (14) 5 (16) Female gender 40 (55) 20 (48) 20 (65) 0.15 White race d 33 (45) 18 (43) 15 (48) 0.55 Diagnosis Dilated cardiomyopathy 42 (58) 25 (60) 17 (55) 0.60 Myocarditis 7 (10) 4 (10) 3 (10) 0.99 Congenital heart disease 19 (26) 11 (26) 8 (26) 0.92 Other cardiomyopathies 5 (7) 2 (5) 3 (10) 0.41 INTERMACS profile 1. Critical cardiogenic shock 38 (52) 22 (52) 16 (52) Progressive decline 33 (45) 18 (43) 15 (48) Stable but inotrope dependent 1 (1) 1 (2) 0 (0) Recurrent advanced heart failure 1 (1) 1 (2) 0 (0) 0.39 Ventilator dependant 53 (73) 29 (69) 24 (77) 0.43 ECMO 22 (31) 9 (21) 13 (42) 0.06 Inotropes e 70 (100) 41 (100) 29 (100) 0.99 Strategy for VAD support f Bridge to transplant 69 (94) 39 (93) 30 (97) 0.29 Bridge to recovery 2 (3) 2 (4) 0 (0) 0.22 BiVAD, biventricular assist device; ECMO, extracorporeal membrane oxygenation; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVAD, left ventricular assist device; VAD, ventricular assist device. a As recorded by implanting institution. b Categoric data are reported as No (%). c LVAD compared with BiVAD. d Race was not specified for 6 patients. e Inotrope therapy was not specified for 3 patients. f VAD strategy was not recorded for 2 patients. preted within the context of the high acuity level of the patient cohort at the time of implant. Indeed, more than 50% of the children were in cardiogenic shock (survival expected to be less than 24 hours), and 48% were in progressive decline (worsening end-organ function) despite the use of inotropic or ventilatory therapy. 14 In addition, approximately 33% of patients were already supported with ECMO at the time EXCOR support was initiated. A recent series by Imamura et al 16 found ECMO was associated with 43% mortality when used to bridge pediatric patients to heart transplantation. The Extra-corporeal Life Support Organization (ELSO) international data demonstrate that mortality is 51% for patients aged younger than 16 years being bridged to cardiac transplantation on ECMO. 5 Comparison of such historical data to the present series is difficult to make due to powerful confounders such as patient selection and era as well as incomplete data entry from the various implanting centers. However, the 77% success rate at bridging children to a positive outcome with the EXCOR in this study compares favorably with the 39% to 64% success rate in bridging children to transplant with ECMO previously reported in single-center ECMO bridge experiences Beyond information about whether the Berlin Heart is an effective bridge, the present study is also informative about what sort of duration of support may be expected when mechanically bridging a child to transplant in North America. It is generally accepted that ECMO is effective for only 10 to 14 days, beyond which time the rate of transplantdisqualifying complications rises dramatically. It is therefore noteworthy that the median time of support in the present report was 1.6 months, or at least 3 times as long as could reasonably be expected with ECMO. In addition, some patients were supported with EXCOR for more than 6 months, a duration that is simply not feasible with ECMO. Also 33% of the patients in the present report were on ECMO before Berlin Heart VAD implantation, which may be termed a bridge-to-bridge approach, meaning that the overall mechanical support time for these patients is even longer. This possibility of extended support is particularly

5 Morales et al. North American Experience with the Berlin Heart EXCOR 5 Figure 2 (A) Competing outcomes analysis for the entire cohort. (B) Competing outcomes analysis for left ventricular assist device strategy. (C) Competing outcomes analysis for biventricular assist device strategy. important given the decade-long plateau in the number of pediatric heart donors in North America. 25 The potential ability for extended support time would also be of great value in the case of a sensitized recipient for whom a prospective or virtual cross-match may be desired. Risk factors for mortality in this series included younger age and use of BiVAD support. Interestingly, neither bridging patients to the EXCOR with ECMO nor congenital heart disease had a significant association with overall mortality. We must acknowledge that the small cohort size and relatively low number of total deaths in this study may have left it underpowered to assess all risk factors. Therefore, risk factors analyzed that were not significantly associated with death do not exclude the possibility that such an association exits. The influence of young age on mortality risk may be highlighting the present lack of understanding in how to anti-coagulate and measure the effectiveness of anticoagulation in small children with cardiac devices. Some of the difficulty in anti-coagulating this cohort is undoubtedly due to age-related maturation of the coagulation and fibrinolytic systems as well as the more complex requirements for medication administration. The increased risk of death with BiVAD support is consistent with previous reports of adult and pediatric VAD patients. 15,26 Many believe that patients requiring BiVAD support are a different patient population with more endorgan compromise and perhaps more advanced heart failure. This was not observed in the present series, however, where pre-operative characteristics and demographics were similar between the LVAD and BiVAD cohorts (Table 1). It may be speculated that having 2 devices in a small child, irrespective of the pre-implantation clinical state, increases the morbidity profile, especially the thromboembolic rate. It is important to note, however, that outstanding results with the EXCOR have been reported with a strategy using BiVAD implantation in all patients. 8 Advocates for this strategy suggest that this aggressive approach eliminates the risk of right heart failure after LVAD implantation, allowing faster recovery, enhanced mobilization, and earlier intensive care unit discharge. 8 Support for this viewpoint has been drawn from some adult VAD experience in which poorer outcomes documented with BiVAD support are skewed by the patients who first undergo LVAD placement and then undergo later right ventricular assist device placement because of right ventricular failure. In this series, by contrast, all BiVAD implantations were simultaneous, suggesting that the poorer outcomes in BiVAD patients were not a timing issue. The prospective study should provide more insight into this important issue. The overall 7% rate of explantation or bridge to recovery in the current series is consistent with the described device strategy at the time of implantation, which was bridge to transplantation in 94% of patients and bridge to recovery in 3%. The 14% bridge to recovery and explant rate described by Hetzer et al 15 is higher, but this is most likely due to the use of the Berlin Heart EXCOR to support children with acute myocarditis, which comprised 13% of their EXCOR patient population. In North America, patients with etiologies known to cause temporary periods of heart failure (ie, myocarditis, cardiac graft failure) have been more commonly supported with short-term devices, such as Levitronix (Waltham, MA), RotaFlow (Maquet Inc, Wayne, NJ), and Tandem Heart (CardiacAssist Inc, Pittsburgh, PA), or ECMO because of the expectation of recovery. In the present series, nearly all patients received a VAD with intention to transplant. This study has several limitations related to the retrospective study design. First, because only 73 of 97 children (75%) implanted with an EXCOR Pediatric VAD in North America before May 2007 were captured in this analysis,

6 6 The Journal of Heart and Lung Transplantation, Vol 30, No 1, January 2011 Table 2 Univariate and Multivariable Predictors of Death While on Berlin Heart EXCOR Ventricular Assist Device Support Univariate Multivariable Risk factors examined HR (95% CI) p-value HR (95% CI) p-value Age at implant a 0.53 ( ) ( ) Height, lower 0.98 ( ) ( ) 0.83 Weight, lower 0.96 ( ) ( ) 0.59 Body surface area, smaller 0.19 ( ) ( ) 0.68 Female gender 1.26 ( ) ( ) 0.46 White race 1.95 ( ) ( ) 0.56 INTERMACS patient profile 1. Cardiogenic shock 0.68 ( ) ( ) 0.44 Ventilatory support 2.28 ( ) ( ) 0.20 ECMO 1.21 ( ) ( ) 0.95 Biventricular assist device 4.82 ( ) ( ) Congenital diagnosis 2.56 ( ) ( ) 0.48 CI, confidence interval; ECMO, extracorporeal membrane oxygenation; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; HR, hazard ratio. a The natural logarithm of age (years) was used in the analysis; younger age was risk factor for death. selection bias could skew the current results if certain patients were differentially excluded, particularly if the non-analyzed patients had poorer outcomes. However, secondary analysis of records from Berlin Heart Inc (Woodlands, TX), which includes the outcomes (ie, death, transplant, recovery) of the 24 patients for whom data were not entered into the voluntary INTERMACS registry, suggests that reporting bias did not play a major role in the present study. This analysis of all 97 pre-ide patients who received EXCOR implants demonstrates that 64% received a transplant, 10% recovered, and 26% died on the device, making the probability of a positive outcome (transplanted or recovered) 74% vs 77% in the study cohort of 73 patients. Second, because the sample size was fixed at 73 patients, there was limited statistical power to discriminate multivariable risk factors for death while on VAD support. Nevertheless, this report represents the largest pediatric VAD experience to date involving a single pediatric device and was successful in isolating at least 2 factors independently associated with death. Third, the analysis was restricted to a limited data set of clinical covariates where complete data were available. As such, data on adverse events most notably stroke, thromboembolism, infection, and device malfunction were not available, precluding any formal assessment of the device safety as part of this report. Formal assessment of the safety profile of the EXCOR is the primary motivation behind the current Berlin Heart EXCOR IDE clinical trial, which has been designed to acquire sufficient safety data to meet FDA criteria for approval under the humanitarian device exemption regulation. Lastly, because information on potential confounders such as pump size, prior neurologic injury, or end-organ dysfunction were not collected, it is difficult to exclude the role of residual or unmeasured confounding. However, as the total number of children supported with the EXCOR grows over time and patients are routinely enrolled in a broad standardized data collection protocol such as INTERMACS, opportunities to resolve and adjust for potential confounding will improve. The current Berlin Heart EXCOR Pediatric IDE trial seeks to address many of these limitations. This multicenter trial seeks to examine systematically the safety and efficacy of the Berlin Heart EXCOR Pediatric VAD used as a bridge Table 3 Left Ventricular Assist Device and Biventricular Assist Device Outcomes in Different Age Groups a Age groups, No. (%) 1 year 1 5 years 5 years Outcome LVAD BiVAD LVAD b BiVAD LVAD BiVAD Received HTx 10 (71) 3 (38) 12 (80) 8 (67) 9 (69) 9 (82) Death (pre-htx) 3 (22) 5 (62) 2 (13) 4 (33) 1 (8) 2 (18) Recovery 1 (7) 0 (0) 1 (7) 0 (0) 3 (23) 0 (0) Total 14 (100) 8 (100) 15 (100) 12 (100) 13 (100) 11 (100) BiVAD, Biventricular Assist Device; HTx, heart transplant; LVAD, Left Ventricular Assist Device. LVADs: N 42; BiVADs: N 31. a Statistical comparison between BiVAD and LVAD outcomes at all ages are not significant p 0.05.

7 Morales et al. North American Experience with the Berlin Heart EXCOR 7 his duties as the National PI. He receives no personal compensation for his role with Berlin Heart Inc. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The authors acknowledge Shands Hospital at the University of Florida, The Children s Hospital of Philadelphia, and the Children s Medical Center in Dallas for contributing patients and their data to this retrospective cohort. Figure 3 Flow chart shows Berlin Heart EXCOR Pediatric Ventricular Assist Device Food and Drug Administration (FDA) investigational device exemption (IDE) trial. BSA, body surface area. to heart transplantation in a select population of children with severe heart failure refractory to optimal medical therapy. Children who weighed 3 to 50 kg actively listed for heart transplantation, requiring either left heart or BiVAD support, are eligible for inclusion in the study and are divided in 2 cohorts according to BSA (Figure 3). All patients enrolled in the study are managed according to a uniform anti-coagulation and anti-platelet protocol. Adverse events are defined and adjudicated according to consensus criteria established by the Pediatric INTERMACS. Standardized protocols have also been developed for detection of neurologic adverse events, which include pre-implant brain imaging and a neurologic assessment 1 year after explant. In conclusion, this limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The planned prospective IDE trial presently underway, will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation. Disclosure statement This study was supported in part by a grant from the FDA, Office of Orphan Product Development (R01 FD ). Dr Almond is supported by Orphan Product Grant (R01 FD 03557) by the FDA s Office of Orphan Product Development. The Berlin Heart EXCOR IDE Clinical Trial is supported by the same grant (R01 FD-03557). Dr Morales serves as the director of the North American Reference and Training Center established by Berlin Heart Inc. Berlin Heart Inc provides compensation to Baylor College of Medicine for Dr Morales s services as a Reference and Training Center Faculty Member. He receives no direct personal compensation. Dr Almond is a non-paid consultant to Berlin Heart Inc. Dr Massicotte serves as a consultant for Astellas, Sanofi Aventis, Bristol Myers Squibb, Bayer, Berlin Heart Inc, Daichii Sankyo, and Levitronix. Dr Fraser is the National Principal Investigator (PI) for the Berlin Heart Pediatric EXCOR VAD Clinical Trial in the United States and provides leadership and clinical guidance for the trial. Berlin Heart Inc provides administrative support for Dr Fraser s role as the National PI and offsets travel expenses for Dr Fraser related to References 1. Almond CS, Thiagarajan RR, Piercey GE, et al. Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009;119: Reinhartz O, Stiller B, Eilers R, Farrar DJ. Current clinical status of pulsatile pediatric circulatory support. ASAIO J 2002;48: Blume ED, Naftel DC, Bastardi HJ, Duncan BW, Kirklin JK, Webber SA. Outcomes of children bridged to heart transplantation with ventricular assist devices: a multi-institutional study. 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8 8 The Journal of Heart and Lung Transplantation, Vol 30, No 1, January Levi D, Marelli D, Plunkett M, et al. Use of assist devices and ECMO to bridge pediatric patients with cardiomyopathy to transplantation. J Heart Lung Transplant 2002;21: Kirshbom PM, Bridges ND, Myung RJ, Gaynor JW, Clark BJ, Spray TL. Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation. J Thorac Cardiovasc Surg 2002; 123: Fiser WP, Yetman AT, Gunselman RJ, et al. Pediatric arte- riovenous extracorporeal membrane oxygenation (ECMO) as a bridge to cardiac transplantation. J Heart Lung Transplant 2003;22: Gajarski RJ, Mosca RS, Ohye RG, et al. Use of extracorporeal life support as a bridge to pediatric cardiac transplantation. J Heart Lung Transplant 2003;22: Bae JO, Frischer JS, Waich M, Addonizio LJ, Lazar EL, Stolar CJ. Extracorporeal membrane oxygenation in pediatric cardiac transplantation. J Pediatr Surg 2005;40: BarZiv SM, McCrindle BW, West LJ, et ai. Outcomes of pediatric patients bridged to heart transplantation from extracorporeal membrane oxygenation support. ASAIO J 2007;53: Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation:Twelfth official pediatric heart transplantation report J Heart Lung Transplant 2009;28: Holman WL, Komos RL, Naftel DC, et al. Predictors of dearth and transplant in patients with a mechanical circulatory support device: a multi-institutional study. J Heart Lung Transplant 2009;28:44-50.