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.
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
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.
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