Secondary Logo

Journal Logo

Postapproval Outcomes: The Berlin Heart EXCOR Pediatric in North America

Jaquiss, Robert D. B.; Humpl, Tilman; Canter, Charles E.; Morales, David L. S.; Rosenthal, David N.; Fraser, Charles D. Jr

doi: 10.1097/MAT.0000000000000454
Pediatric Circulatory Support
Free

The Berlin Heart EXCOR Pediatric Ventricular Assist Device (BH) was approved for use in the United States in December 2011, based on a prospective investigational device exemption (IDE) trial. Strict exclusion criteria for the trial selected a low-risk “ideal” cohort. We sought to determine whether postapproval usage of the BH in a “real world” cohort of recipients would result in similar outcomes. Preimplant diagnostic information was collected for all patients. Efficacy was evaluated by comparison of all children (efficacy group, n = 247) implanted between FDA approval and April 2015 to those in the IDE trial (IDE, n = 48), with regard to achievement of one of four end-states: transplanted, successful weaning, death/unsuccessful weaning, or still-on-device. Safety outcomes were compared between IDE patients and a subset of postapproval patients (safety group, n = 39) for whom adjudicated adverse events were tracked in a regulator-mandated dataset. Diagnostic categories were similar between groups: IDE (congenital 19%, dilated cardiomyopathy/myocarditis/other 81%) versus Efficacy Group (congenital 24%, dilated cardiomyopathy/myocarditis/other 75%). Patients in the IDE cohort were larger (median 14.8 kg, range 3.6–58.1 kg vs. 10.7 kg, 2.9–112.0 kg, p = 0.02). More IDE patients were successfully supported than in the efficacy group cohort (90% vs. 77%, p = 0.05). Proportions with bleeding and stroke were similar between the IDE and safety group cohorts (46% vs. 41%, p = 0.65; 29% vs. 33%, p = 0.68, respectively). With usage of the BH in a less-ideal population, rates of bridge to transplant and weaning have declined slightly, but remain encouragingly high. Bleeding and neurologic event rates have not increased.

From the *Duke Children’s Hospital, Durham, North Carolina; The Hospital for Sick Children, Toronto, Ontario, Canada; St. Louis Children’s Hospital, St. Louis, Missouri; §Cincinnati Children’s Hospital, Cincinnati, Ohio; Stanford University, Palo Alto, California; and Texas Children’s Hospital, Houston, Texas.

Submitted for consideration June 2016; accepted for publication in revised form September 2016.

Disclosures: The authors have no conflicts of interest to report.

Presented at International Society for Heart Lung Transplantation Meeting 2015, Nice, France.

Correspondence: Robert D. B. Jaquiss, DUMC 3474, Durham, NC 27110. Email robert.jaquiss@duke.edu.

After its development and initial use in Europe, the Berlin Heart EXCOR Pediatric (EXCOR) was first implanted in North America more than 10 years ago.1 With favorable initial experience and lack of suitable alternatives, the use of the device increased rapidly, but implantations could only be performed under compassionate use regulation.2 Because of the embrace of the device by the medical community and the cumbersome nature of the application for compassionate use implant, a prospective trial was undertaken with an investigational device exemption (IDE),3 with the intent of achieving a Humanitarian Use Device (HUD) approval.4 In December 2011, the Food and Drug Administration (FDA) formally approved the use of the EXCOR as an HUD device, with the requirement that Berlin Heart perform a postapproval study with specific focus on safety end-points including the incidence of stroke and bleeding, which had been the subject of much interest during the IDE trial. In this study, we sought to describe the results of that postapproval experience and to further describe the efficacy outcomes of postapproval use outside the confines of the original pivotal trial.

Back to Top | Article Outline

Methods

Safety Outcomes

To address the safety of the device in the postapproval market, at the direction of the FDA, Berlin Heart established a database designed to prospectively record all information including serious adverse events for a nonselected cohort of patients (n = 39) who were implanted after FDA approval of the device. The definitions of serious adverse events were the same as those used in the pivotal trial,3,4 and major adverse events (bleeding, infection, and neurological dysfunction) were adjudicated by an independent Clinical Events Committee. The study protocol was approved by the institutional review board at each center, and written informed consent was obtained for all patients. The safety outcomes for this cohort of patients were compared with the outcomes for the patients reported in the original study cohort (n = 48). Baseline and descriptive characteristics of the two cohorts are shown in Table 1. Because the time-related hazard function for various adverse events is not constant, adverse events were expressed for the cohorts as both the number of patients with a particular adverse event and the number of particular adverse events per 100 patient-months of support. Comparisons between the cohorts were made using χ2 or Fisher exact test for categorical data, Kruskal–Wallis test for continuous variables, and the mid-p exact test for the linearized rates.

Table 1

Table 1

Back to Top | Article Outline

Efficacy Outcomes

For all patients implanted with an EXCOR device, the company maintains a simple efficacy database which tracks date of implant and the final disposition of the patient, including the date of outcome. This database does not include any information on adverse events, and simply contains the current state of the patient—transplanted, dead, or still on-device. The collection of implant outcome data was approved by the institutional review board at each center, and written informed consent was obtained for all patients. Outcomes for all patients implanted between device approval in December 2011 and April 2015 (efficacy group, n = 247) were compared with the outcomes for the IDE cohort (n = 48) in the original pivotal study. Baseline and descriptive characteristics of the two cohorts are shown in Table 2. For each cohort, a comparison was made for the occurrence of several mutually exclusive end-points: bridge to transplant, successful wean from device, death on device or unsuccessful wean from device, or remaining on device. Patients who were bridged to transplant or weaned from device and survived were considered successes. Because the time on device was quite different between the cohorts, a competing outcomes analysis is also presented.

Table 2

Table 2

Back to Top | Article Outline

Results

Safety

Although the postapproval study (safety group) cohort was nonselected (no exclusion criteria), and indeed represents only the first 39 patients for whom data were voluntarily submitted and evaluable, there was no statistically significant difference between them and the comparator IDE cohort in any important clinical variable, including the median duration of support. Among the major adverse outcomes of interest, including stroke, major bleeding, infection, and pump changes, there were no differences in the proportion of patients with each type of event, as shown in Table 3. When examined as a function of time (events per 100 patient-months on device), the rates of bleeding, stroke, infection, and pump changes were all lower in the safety group cohort. The difference in stroke rate was not significantly statistically different as shown in Table 4.

Table 3

Table 3

Table 4

Table 4

Back to Top | Article Outline

Efficacy Outcomes

The patients implanted after device approval were younger and smaller (both by weight and body surface area) than their IDE counterparts, and more likely to receive a small volume pump (10 or 15 ml), as demonstrated in Table 2. (The 15 ml device was not available during the IDE trial.) The cohorts did not differ in support strategy (proportion receiving left ventricular assist device or biventricular assist device), or etiology of heart failure. In the efficacy group, 11% of patients had univentricular congenital heart disease, as compared with none in the IDE group, as this was an exclusion criterion in the IDE trial. The median duration of support was longer in the efficacy group, but this difference (55.0 vs. 38.0 days) was not statistically significant. Of those reaching a definitive end-point by April 1, 2015, a smaller fraction of those in the efficacy group were supported successfully compared with the IDE group (77% vs. 90%, p = 0.0495), as shown in Table 5. The time-related achievement of the various end-points is shown in Figure 1.

Table 5

Table 5

Figure 1

Figure 1

Back to Top | Article Outline

Discussion

After approval of durable mechanical circulatory support devices used in adults, results in postapproval studies may actually be better than those achieved in pivotal trials.5,6 In part, this may occur because the population in the pivotal approval study is very closely mirrored by the postapproval study population so that lessons learned are relatively easily applied. Because of the relatively strict inclusion and exclusion criteria in the Berlin Heart IDE population, and the anticipated extension of use into much higher risk populations (single ventricle physiology, smaller patients),7,8 there was concern that postapproval outcomes for the EXCOR might be significantly worse than in the IDE trial. On that score, the present report contains both good news and bad news.

An important positive finding in this analysis is that the proportion of patients experiencing all major classes of adverse events has not increased, despite extension of use into higher risk subpopulations. This is similar to results reported in an analysis of a cohort of patients implanted coincident with but outside of the IDE trial, under compassionate use regulations.9 Furthermore, as function of time on device, the rate of certain events (bleeding, infection, and pump changes) has actually significantly decreased. This is particularly important because the waiting times on device seem very unlikely to decrease. That the median time on device in the safety group (63 days) was not statistically significantly different than the support time for the IDE group (38 days) is almost certainly a reflection of small sample size. The reduction in events per 100 days for those nonstroke outcomes is encouraging. The mechanism for this may be related to increased experience and expertise with pediatric mechanical circulatory support and specifically with the EXCOR. Alternatively, it may simply reflect the fact that the hazard function is likely highest immediately after device implantation, so longer durations of support will inevitably be accompanied by lower events per duration of support.10

A particularly disappointing finding is the observation that the rate of stroke does not seem to have decreased, whether assessed by the proportion of patients experiencing the event or the event rate per 100 days of support. The reason for the persistence of stroke as a problem is not clear or particularly revealed by the data in this report. There may be some hint about what the mechanism of stroke is not related to, in the observation that the stroke rate is unchanged while the number of pump changes has been reduced significantly. It may be reasonable to offer the conjecture that there may actually be less visible debris within the pumps in the safety group (hence fewer pump changes) but no lower incidence of stroke. A logical conclusion is that the source thrombi responsible for embolic stroke may come from within the left atrium or left ventricle, and therefore not be visible. This might suggest even more rigorous anticoagulation would be helpful in reducing the rate of stroke. Furthermore, the reduction in bleeding reported in the safety group implies there may be safety margin to permit this even more intense anticoagulation. A recent single center report described a reduction in stroke rate with increasing experience and pointed out a fourfold reduction in stroke rate after the target anticoagulation was achieved compared with before it was achieved.11 Experience with enhanced anticoagulation from another large center has demonstrated a reduction in stroke rate as well (C. Almond, personal communication, July 25, 2016), but clearly there is a need for a much larger and more systematic approach to study this problem, perhaps with a prospective trial of enhanced versus standard anticoagulation. Overall, the higher rate of adverse events with the pulsatile Berlin Heart as compared with continuous flow devices has led to increasing use of continuous flow ventricular assist devices in ever-smaller children.12,13

An area in which the good news/bad news verdict is perhaps less clear is in the assessment of efficacy. The bad news is that a smaller proportion of EXCOR patients were successfully supported in the efficacy group than in the IDE cohort. The efficacy group rate of successful support (77%) was much better than the 55% success rate reported by Almond et al.9 in the preapproval non-IDE compassionate use group. The good news is that patients in the efficacy group cohort were at significantly higher risk than the IDE cohort, in that efficacy group patients were smaller and younger. It is notable that the efficacy group included a substantial number of patients with single ventricle congenital heart malformations, a group at particularly high risk.8 Furthermore, the safety group cohort had a median support time that was nearly 3 weeks longer than in the IDE population, although this difference was barely beyond statistical significance (p = 0.06). It must be recalled that before the availability of the EXCOR device, the only available modality was extracorporeal membrane oxygenation, with safe support times that rarely exceeded 7–10 days, far shorter than the median support time of nearly 8 weeks recorded in the efficacy group cohort.

Back to Top | Article Outline

Limitations

Perhaps the most important limitation of this study is the relative paucity of information contained in the efficacy group cohort database maintained by the company. Most importantly, only baseline descriptors of age, weight, and fundamental diagnosis are known, along with the final postsupport outcome. No safety information (adverse events) is available for this group, nor is other important risk stratification (ventilatory support, prior mechanical circulatory support status, etc.). This circumstance is unlikely to change until mandatory reporting for all pediatric mechanical circulatory support is required. Recent publications suggest a growing participation in PediMACS, but enrollment is still far from universal.12–15

Back to Top | Article Outline

Conclusion

In the postapproval time frame, the incidence of stroke remains unchanged. However, the Berlin Heart EXCOR Pediatric continues to provide durable, efficacious support for small children with severe heart failure awaiting transplant, with an overall improving safety profile.

Back to Top | Article Outline

References

1. Arabía FA, Tsau PH, Smith RG, et al. Pediatric bridge to heart transplantation: application of the Berlin Heart, Medos and Thoratec ventricular assist devices. J Heart Lung Transplant. 2006.25: 16–21.
2. Morales DLS, Almond CSD, Jaquiss RDB, 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. 2011.30: 1–8.
3. 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. 2011.162: 425–435.e6.
4. 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. 2012.367: 532–541.
5. Jorde UP, Kushwaha SS, Tatooles AJ, et al; HeartMate II Clinical Investigators. Results of the destination therapy post-Food and Drug Administration approval study with a continuous flow left ventricular assist device: A prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol. 2014.63: 1751–1757.
6. John R, Naka Y, Smedira NG, et al. Continuous flow left ventricular assist device outcomes in commercial use compared with the prior clinical trial. Ann Thorac Surg. 2011.92: 1406–1413.
7. Conway J, St Louis J, Morales DL, Law S, Tjossem C, Humpl T. Delineating survival outcomes in children <10 kg bridged to transplant or recovery with the Berlin Heart EXCOR Ventricular Assist Device. JACC Heart Fail. 2015.3: 70–77.
8. Weinstein S, Bello R, Pizarro C, et al. The use of the Berlin Heart EXCOR in patients with functional single ventricle. J Thorac Cardiovasc Surg. 2014.147: 697–704; discussion 704.
9. Almond CS, Morales DL, Blackstone EH, et al. Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation. 2013.127: 1702–1711.
10. Jordan LC, Ichord RN, Reinhartz O, et al. Neurological complications and outcomes in the Berlin Heart EXCOR® pediatric investigational device exemption trial. J Am Heart Assoc. 2015.4: e001429.
11. Byrnes JW, Prodhan P, Williams BA, et al. Incremental reduction in the incidence of stroke in children supported with the Berlin EXCOR ventricular assist device. Ann Thorac Surg. 2013.96: 1727–1733.
12. Rosenthal DN, Almond CS, Jaquiss RD, et al. Adverse events in children implanted with ventricular assist devices in the United States: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS). J Heart Lung Transplant. 2016.35: 569–577.
13. Rossano JW, Lorts A, VanderPluym CJ, et al. Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: A report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS). J Heart Lung Transplant. 2016.35: 585–590.
14. Blume ED, Rosenthal DN, Rossano JW, et al; PediMACS Investigators. Outcomes of children implanted with ventricular assist devices in the United States: First analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS). J Heart Lung Transplant. 2016.35: 578–584.
15. Burns KM. Paediatric heart failure research: Role of the National Heart, Lung, and Blood Institute. Cardiol Young. 2015.25suppl 2167–171.
Keywords:

Berlin Heart; pediatric; ventricular assist device

Copyright © 2017 by the American Society for Artificial Internal Organs