NEWS AND VIEWS

Berlin Heart EXCOR Food and Drug Administration Investigational Device Exemption Trial Iki Adachi, MD, and Charles D. Fraser Jr, MD INTRODUCTION The history of ventricular assist device (VAD) development spans nearly 50 years, starting at the initial attempt of VAD implantation by Hall in 1963.1 Owing to continuing improvement, VAD has become an integral part of the standard care for adult patients with end-stage heart failure. In contrast, VAD use for children has significantly lagged behind the adult counterpart.2 Upon successful completion of the so-called Berlin Heart investigational device exemption (IDE) trial,3 the U.S. Food and Drug Administration granted Humanitarian Device Exemption approval of the Berlin Heart EXCOR Pediatric VAD on December 16, 2011. The EXCOR has become the first pediatric-specific VAD that has gained widespread acceptance in North America. This is truly a landmark event for children suffering from terminal heart failure. This study aims to summarize the data from the IDE trial and to provide more updated information with this device by reviewing recent publications and several important abstracts presented at the annual meeting of International Society for Heart and Lung Transplantation (ISHLT) held in April 2013. SUMMARY OF THE BERLIN HEART TRIAL Study Design When looking into the data from the Berlin Heart IDE trial, it is important to have a good understanding of its unique study design. The details of the study design have been described previously.4 This trial was Division of Congenital Heart Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas. The authors of this manuscript report Texas Children’s received financial support from TBD for the clinical IDE trial. Permission attached. Address reprint requests to Charles D. Fraser Jr, MD, Division of Congenital Heart Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 6621 Fannin St, 19345H, Houston, Texas 77030. E-mail: cdfraser@texaschildrens. org

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a prospective, multicenter, single-group cohort study involving 14 pediatric centers in the United States and Canada (IDE study sites). Children who underwent implantation of the EXCOR at the IDE study sites as a bridge to transplantation were included in this study when they met study inclusion criteria. It is noteworthy that children who did not meet the study inclusion criteria at the IDE sites and those who were treated at non-IDE sites also had access to the EXCOR during the study period on a compassionate-use basis. Study participants were divided into 2 cohorts based on body surface area [(BSA); cohort 1, o0.7 m2 and cohort 2, 0.7-1.5 m2)], with 24 participants in each cohort. The outcome of each cohort was compared with that of historical control group of children who were supported with extracorporeal membrane oxygenation (ECMO). The control group was selected from the Extracorporeal Life Support Organization (ELSO) registry (Ann Arbor, MI).5 The ELSO registry is an international, multicenter, voluntary database that enrolls patients who undergo ECMO support. A propensity-score analysis was used to match each patient with the EXCOR to 2 children who had received ECMO support. This is perhaps one of the key features of this study. The greatest challenge in study planning was selection of a valid control population. Although a randomized design comparing the EXCOR with ECMO was considered, it was decided to be infeasible because of a lack of clinical equipoise.6 Outcome Overall, approximately 90% of the patients in both cohorts achieved favorable outcome, mostly with heart transplantation. This is despite the critical condition of the study participants (approximately 50% with Interagency Registry for Mechanically Assisted Circulatory Support-level 1 and the remaining with level 2 in both cohorts). For children in cohort 1 (BSA; o0.7 m2), the median duration of support with the VAD was 28 days, as compared with 5 days for the matched ECMO group (P o 0.001). The primary end point in 1043-0679/$-see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2013.07.008

BERLIN HEART EXCOR TRIAL the VAD group (the time to death or weaning from the device with an unacceptable neurologic outcome) had not been reached at 174 days. In contrast, the primary end point in the matched ECMO group (only the time to death) was 13 days (P o 0.001). For children in cohort 2 (BSA; 0.7-o1.5 m2), the median duration of support with the VAD was 43 days, as compared with 5 days for the matched ECMO group (P o 0.001). The primary end point in the VAD group was 144 days. In contrast, the primary end point in the matched ECMO group was 10 days (P o 0.001). Note that primary end points for the VAD and ECMO groups were not exactly the same because data on neurologic status were not available in the ELSO registry. Nonetheless, despite more strict definition of a primary end point in the VAD group, the median durations to the primary end point were significantly longer in the VAD group than in the matched ECMO group, demonstrating survival benefit of VAD irrespective of the patient’s age. Competing-outcome analyses in the ECMO groups were performed, which tracked 3 mutually exclusive outcome events including being alive while still receiving ECMO support. These analyses showed the chances of being alive on ECMO approached 0 at 21 days in cohort 1 and 28 days in cohort 2 (Fig. 1). These data have demonstrated an inability of ECMO to provide stable long-term support that is necessary when aiming to bridge children to heart

transplantation. These data are in stark contrast to those in the VAD groups (Fig. 2). In cohort 1, the chances of being alive on VAD support reached 0 at 174 days, at which point 88% of the patients had undergone successful transplantation and only 12% had poor outcome (death or unacceptable neurologic status). Similarly, in cohort 2, the chance of being alive on VAD support reached 0 at 192 days, at which point 92% had favorable outcome (successful transplant or weaning from VAD) and 8% had poor outcome. These data have demonstrated the efficiency of the VAD to provide a long-term circulatory support during which the patient can be transplanted with reasonably low wait-list mortality. Despite high success rates in both cohorts, morbidity profiles of the VAD were not negligible. The rate of serious adverse events in cohort 1 was 0.07 events per patient-day (95% confidence interval, 0.06-0.08), and in cohort 2, the rate was 0.08 events per patient-day (95% confidence interval, 0.060.09). These adverse events in cohort 1 and cohort 2 included major bleeding in 42% and 50%, infection in 63% and 50%, and stroke in 29% and 29%, respectively.

What Have We Learned? Survival rate of  90% in the IDE trial is seemingly very high compared with Germany experience (60%, 56 of 93 patients; survival either with recovery

Figure 1. Competing-outcomes analysis of the ECMO groups. (Adapted with permission from Fraser et al.3). Three mutually exclusive outcome events were tracked for this analysis: death occurring while the child was receiving circulatory support with ECMO, death within 30 days after weaning from the device, and device removal (without death within 30 days). Children who had not yet had any of these specific outcome events were classified as being alive and receiving circulatory support. (Color version of figure is available online.)

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Figure 2. Competing-outcomes analysis of the ventricular assist cohorts. (Adapted with permission from Fraser et al.3). Four mutually exclusive outcome events were tracked for this analysis: death occurring while the child was receiving circulatory support with the ventricular assist device, heart transplantation, weaning from the device but either dying or having an unacceptable neurologic outcome within 30 days after weaning or before discharge from the hospital (whichever was longer), and weaning from the device without death or an unacceptable neurologic outcome in the period defined above. Children who had not yet had any of these specific outcome events were classified as being alive and receiving circulatory support. (Color version of figure is available online.)

or transplantation)7 and earlier North America experience in the pre-IDE era (77%, 75 of 97 patients; survival either with recovery or transplantation).8 Care must be taken, however, when comparing these figures. The data from the IDE trial are not necessarily representative of the entire North America experience. In fact, study participants of

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the IDE trial represent less than a quarter of all implantations performed during the same period in North America (Fig. 3). Also noteworthy is that even among the IDE trial participants, there was a significant disproportion in case volume as per each participating institution. Large proportions of the patients were operated at certain institutions; the top

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Figure 3. Total experience with the Berlin Heart EXCOR in North America during the IDE trial period (May 2007December 2010). A total of 203 implantations were carried out in the United States and 1 in Canada. Of the 204, 68 (33%) met the IDE trial criteria; 48 were in the original IDE trial cohort and 20 were implanted after trial enrollment was complete. The remaining 136 (67%) patients were implanted on a compassionate-use basis; 41 were implanted at an IDE center and 95 were at a non-IDE center. (Color version of figure is available online.)

4 centers contributed 88% of cohort 1 and 71% of cohort 2 (Fig. 4). In this regard, the IDE trial data should be considered the best possible outcome that could be achieved with the EXCOR in selected patients when used by experienced hands.

What is the Reality? To know the real-world experience in North America, Almond et al.9 analyzed 204 implantations during the IDE trial period (May 2007-December 2010); 203 were in the U.S. and 1 was in Canada. Of the 204 cases, 68 (33%) met the IDE trial criteria; 48 were in the original IDE trial cohort and 20 were implanted after trial enrollment was complete. The

remaining 136 (67%) patients were implanted on a compassionate-use basis; 41 were implanted at an IDE center and 95 were at a non-IDE center (Fig. 3). In this retrospective analysis of entire EXCOR implantation in North America, survival at 12 months on EXCOR support was 75% (64% with transplant, 6% with recovery, and 5% alive with the device), which is very similar to that of pre-IDE era.8 Mortalities were significantly higher in children implanted under compassionate use compared with IDE subjects (34% vs 7%; P o 0.01). This significant difference in mortalities between the 2 cohorts is not surprising given the different baseline characteristics: the compassionate-use cohort is significantly smaller than the IDE cohort (9.4 kg vs 12.1 kg; P ¼ 0.01),

Figure 4. Berlin Heart EXCOR® Pediatric IDE Trial results. the number of implantations performed at each participating center. Cohort 1 represents patients with a body surface area of o0.7 m2. Cohort 2 represents patients with a body surface are of 0.7-1.5 m2. (Color version of figure is available online.)

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BERLIN HEART EXCOR TRIAL congenital cardiac malformation is more frequent (36% vs 15%; P ¼ 0.001), ECMO use is more frequent (48% vs 27%; P value not available for this particular category), and glomerular filtration rate is lower (89 vs 115; P ¼ 0.019). Multivariable analysis identified lower patient weight at implantation, higher serum total bilirubin, and BiVAD support as risk factors for early mortality (o2 months). It is intriguing to see that in this multivariable model, ECMO was not identified as a risk factor for mortality. Although ECMO is generally considered as a risk factor of VAD support, it can be used for temporary resuscitative support to normalize end-organ function before VAD implantation and may even improve VAD candidacy in selected patients. This duality of effect for ECMO on mortality might have been attributed to its absence in the final multivariable model. Another interesting finding of this study is the absence of center EXCOR volume effect on mortality in the multivariable model, despite the center volume being identified as having a very strong effect on mortality in the univariate analysis. Mortality at experienced centers (11%; 410 implants) was significantly (P o 0.001) lower than those of medium-sized centers (28%; 6-10 implants) and low-volume centers (47%; 1-5 implants). Despite there being no clear explanations about these findings, a potential explanation may be that experienced centers have improved outcome over time with maturation of patients selection process and thus by implanting the EXCOR before patients become too sick. As with all interventions, one’s threshold to provide a therapy changes as the confidence in that therapy to produce beneficial and consistent outcomes for patients increases. In this regard, it would be reasonable to consider some sort of certification for implantation of pediatric VADs, as is the case in the adult VAD field.10 Neurologic dysfunction, which was the leading cause of mortality, occurred in 29%, which is very similar to the incidence in the IDE trial. It is noteworthy that the incidences of neurologic complications were identical between the IDE subjects and compassionate-use subjects (28% vs 30%). There were also no differences between the 2 cohorts in the incidences of other adverse events such as major bleeding (43% vs 45%), major infection (50% vs 44%), respiratory failure (25% vs 31%), and right heart failure (10% vs 14%). These findings would suggest that these complications are essentially intrinsic to the device and, although there is a potential room for improvement with fine tuning of management,11 dramatic reduction of complication rates is unlikely to occur. It is noteworthy that the median duration of support in the EXCOR

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patients was 40 days, with the longest being 435 days. This number is not very different from that of the IDE trial (28 days in cohort 1 and 43 days in cohort 2). It is clear that the use of pediatric VAD as a bridge to transplant has been increasing, which was well demonstrated by Almond et al.12 at the 2103 ISHLT annual meeting. Using the Organ Procurement and Transplantation Network (OPTN) database, they demonstrated dramatic increase in the percentage of children supported with a VAD at heart transplant (2% in 2004 to 17% in 2010). As the VAD use increases, average waiting time on transplant list would increase in the setting of static organ supply.13 Given the high complication rates of the EXCOR, which are unlikely to change dramatically, the likelihood of successful outcome may decrease as support duration becomes longer. These considerations should have important clinical implication when determining the optimal timing of EXCOR placement and counseling the family for VAD placement. Although waiting too long to implant the EXCOR sharply increases the risk of mortality, initiating EXCOR support too early can also increase the risk of morbidities. The dilemma for clinicians is the fact that the appropriate time for implantation between “too early” and “too late” for this particular device is slim and difficult to find. It is hoped that emergence of a next-generation device would solve this dilemma, at least in part. The infant Jarvik 2000 (Jarvik Heart, Inc, New York, NY) is currently being tested in an animal model14 and its clinical trial is on the horizon.15 Until the next generation arrives, however, the EXCOR will continue to play an important role in pediatric heart failure, especially for children. While waiting for newer pediatric-specific devices, the use of adult devices in older children is a realistic option for now. At Texas Children’s Hospital, the HVAD (HeartWare, Framingham, MA) is currently the device of choice for patients with a BSA of 0.7o1.3 and the HeartMate II (Thoratec, Pleasanton, CA) for larger patients.16 We also have access to other devices including short-term VADs (Rotaflow [Maquet, Wayne, NJ], TandemHeart [CardiacAssist, Pittsburgh, PA], and Impella [Abiomed, Danvers, MA]) and even total artificial heart (Syncardia, Tucson, AZ). The use of total artificial heart in children is technically challenging especially for those with congenital heart disease.17 Nonetheless, total artificial heart is an indispensable adjunct to the field of pediatric heart failure where VAD therapy is not always the best mode of mechanical circulatory support.18 A smaller system (with 50-ml pump) will become available shortly and would expand the

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Figure 5. Berlin Heart EXCOR® Pediatric IDE Trial results. Comparison of cardiac graft survival. Cardiac graft survival after bridge to transplant with the Berlin Heart EXCOR at Texas Children’s Hospital (TCH) was comparable to a national benchmark of pediatric heart transplant using the Organ Procurement and Transplantation Network (OPTN).

application of total artificial heart in the pediatric population.19 As the pediatric patients are so divergent in terms of size and cardiac status, appropriate device selection is practically impossible without having a fully equipped armamentarium of mechanical circulatory support devices. Having realized that using various devices is a big economical challenge for freestanding pediatric hospitals, centralization of pediatric VAD programs through an appropriate certification process might be necessary.

Post-VAD Treatment Another unanswered question with the EXCOR is whether its use as bridge to transplant affects posttransplant outcome or not. One of the potential downsides of VAD therapy is human leukocyte antigen (HLA) sensitization. Almond et al. also presented the data regarding this at the 2013 ISHLT meeting. Using the OPTN data focusing on dilated cardiomyopathy only, children on VAD support at heart transplant were compared with children who were not on VAD support before transplant.20 They found that the use of VADs for bridge to transplant in children with dilated cardiomyopathy was associated with a 3-fold increase in HLA sensitization, a 2-fold increase in the risk of a positive crossmatch at transplant, and a higher incidence of rejection after transplant. These findings are not surprising given the fact that VAD patients are more likely to be exposed to blood products and therefore have a higher risk of sensitization. It is still unclear, however, whether higher HLA sensitization affects

transplant outcome in the midterm to long-term. We have reviewed our own experience with the EXCOR. Of 30 consecutive EXCOR implantations (left VAD 28 and BiVAD 2) at Texas Children's Hospital, 28 (93%) patients were bridged to transplant. Of the 28, 22 (79%) had cardiomyopathy and 6 (22%) had congenital heart disease. Median age and weight at EXCOR implantation was 1.5 years (69 days-13 years) and 9 kg (3 -28 kg). Support duration was 60 days (2-173 days). Posttransplant outcome of these patients were compared with a national benchmark of pediatric heart transplant using the OPTN data. The 1-year and 3-year survival following transplant was 82% and 75%, respectively, which was comparable to the national benchmark (Fig. 5). Based on these data, the use of the EXCOR does not seem to have a strong negative effect on midterm posttransplant outcome. It remains to be seen, however, if this trend holds true in the long term.

CONCLUSIONS There has been an increasing interest in pediatric VADs. The Berlin Heart EXCOR is currently the only pediatric-specific device that has gained widespread acceptance in North America. Determination of optimal timing to proceed with device implantation is critical for a successful outcome. When deciding the operative timing, various factors need to be taken into account, which include both patient-specific factors (eg. body size, cardiac diagnosis, and HLA sensitization) and nonspecific factors (eg, donor availability in that particular region and center

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BERLIN HEART EXCOR TRIAL experience with pediatric VAD), as all these factors affect expected waiting time on the device and hence risk of the device support. Thorough understanding

1. Hall CW: When did artificial heart implants begin? J Am Med Assoc 259:1650, 1988 2. Adachi I, Fraser CD Jr: Mechanical circulatory support for infants and small children. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 14:38-44, 2011 3. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al: Berlin Heart Study Investigators. Prospective trial of a pediatric ventricular assist device. N Engl J Med 367:532-541, 2012 4. Almond CS, Buchholz H, Massicotte P, et al: Berlin Heart EXCOR Pediatric ventricular assist device investigational device exemption study: Study design and rationale. Am Heart J 162:425-435, 2011 5. Extracorporeal Life Support Organization. Available at: http://www.elso.med.umich.edu. Accessed May 20, 2013 6. US Food and Drug Administration. Public workshop—optimizing clinical trial design for the development of pediatric cardiovascular devices, September 30, 2010, San Francisco, CA (jointly sponsored by the American Academy of Pediatrics and the American College of Cardiology). Available at: www.fda.gov/MedicalDevices/News Events/WorkshopsConferences/ucm221439. Accessed May 20, 2013 7. Hetzer R, Potapov EV, Alexi-Meskishvili V, et al: Single-center experience with treatment of cardiogenic shock in children by pediatric

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of these important considerations is an absolute prerequisite to make the best decision for each individual patient.

ventricular assist devices. J Thorac Cardiovasc Surg 141:616-623, 2011 Morales DL, Almond CS, Jaquiss RD, et al: Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device. J Heart Lung Transplant 30:1-8, 2011 Almond CS, Morales DL, Blackstone EH, et al: Berlin Heart EXCOR Pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation 127:1702-1711, 2013 Pagani FD, Kormos RL, Calhoon JH, et al: Certification for implantation of durable, implantable ventricular assist devices in the United States: The need for clarification of the process. Ann Thorac Surg 95:1520-1522, 2013 Orr Y, Jeewa A, McGarry MC, et al: Upsizing of a Berlin Heart Excor Paediatric LVAD to achieve adequate flow requirement. J Heart Lung Transplant (in press) Almond CS, Yarlagadda V, VanderPluym C, et al: Trends in pediatric VAD utilization: Analysis of organ procurement and transplant network data. J Heart Lung Transplant 32:S289, 2013 Colvin-Adams M, Smith JM, Heubner BM, et al: OPTN/SRTR 2011 Annual Data Report: Heart. Am J Transplant 13(suppl 1):119-148, 2013 Wei X, Li T, Li S, et al: Pre-clinical evaluation of the infant Jarvik 2000 heart in a neonate

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piglet model. J Heart Lung Transplant 32: 112-119, 2013 Baldwin JT, Borovetz HS, Duncan BW, et al: The National Heart, Lung, and Blood Institute Pediatric Circulatory Support Program: A summary of the 5-year experience. Circulation 123: 1233-1240, 2011 Stiller B, Adachi I, Fraser CD: Pediatric ventricular assist devices. Pediatr Crit Care Med (in press) Morales DL, Khan MS, Gottlieb EA, et al: Implantation of total artificial heart in congenital heart disease. Semin Thorac Cardiovasc Surg 24:142-143, 2012 Adachi I, Khan MS, McKenzie ED, et al: Is ventricular assist device an effective tool to support children with a failing cardiac graft? J Heart Lung Transplant 32:S288, 2013 Syncardia, Inc. Available at: http://www.syncar dia.com/2013-Press-Releases/syncardias-50cctotal-artificial-heart-receives-two-hud-designa tions-from-the-fda-for-destination-thera py-and-pediatric-bridge-to-transplant.html. Accessed May 20, 2013. Almond CS, Daly KP, Singh TP, et al: Effect of VAD use on HLA sensitization and risk of rejection post-heart transplant in US children with dilated cardiomyopathy. J Heart Lung Transplant 32:S108, 2013

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Berlin Heart EXCOR Food and Drug Administration Investigational Device Exemption Trial.

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