Implanted in patients with biventricular failure, the Syncardia TAH has over time asserted itself as a reliable bridge to transplantation,1–6 and in 2004, it was approved by the United States Food and Drug Administration (FDA) and by the Centers for Medicare & Medicaid Service in 2008.7 In recent years, the number of centers worldwide accredited for TAH implantation has increased dramatically with 93 implanting centers between Europe, Australia, and the United States in 2013.8 An additional 35 centers are in the process of being credentialed.8
The approval of a portable external device (Freedom Driver) in March 2010 for the SynCardia TAH now allows patients to be discharged from the hospital.9 This portability has improved the quality of life for patients with a TAH and opened the possibility for its use as a long-term or permanent implantation device.9 Although not published, the longest survivor known with a TAH lived 1,374 days (almost 4 years) and subsequently went on to successful heart transplantation. These developments led to the FDA approval of the Syncardia TAH in April 2012 to be used as a destination therapy (DT) for humanitarian use device.8
Recently, the short-term quality of life of patients discharged home and supported with a SynCardia have been reported.9 However, a paucity of published experience on the long-term use of the TAH leaves questions regarding its safety and utility as a DT. In an effort to investigate the use of SynCardia TAH as a long-term support device, we collected the outcomes of all patients supported for more than 1 year worldwide.
Patient Selection and Inclusion Criteria
All patients who received a SynCardia TAH between 1989 and December 2011 and had the device implanted for more than 1 year were included in the study. After the study period and at time of publication, an additional 29 patients had the SynCardia TAH implanted for more than 1 year (Figure 1A). SynCardia Systems Inc. provided the date of birth, date of implant, time of support, and center of implant of patients fitting this criteria. The individual institutions were then contacted to acquire the data. During this time period, a total of 13 centers had at least one patient with a SynCardia TAH implanted for more than 1 year. An online database was prepared to acquire each institutions data. The single centers were responsible to upload the database and verify the accuracy of the data inserted. SynCardia Systems Inc. did not receive access to the database. Patients were excluded if data were not complete or partially available.
Data Collection and Data Analysis
A review of the medical records and computerized hospital data was approved by the Clinical Investigation Committee of the University Hospital of Padua, and the procedures followed were in accordance to the institutional guidelines for retrospective record review and protection of patient confidentiality. Individual consent was not required for this study. Patients were not identified, and the chairperson of the Ethics Committee of each institution consented to send data for publication. The data reviewed were relative to the hospital course and to the follow-up clinical controls of patients supported with a Syncardia TAH for more than 1 year. Variables analyzed included demographics, preoperative clinical data, and postoperative data. Data were collected on survival, thromboembolic (TE) events, hemorrhagic events, device failure, and the antithrombotic therapy regimen. Definitions of these variables were in agreement with the INTERMACS registry.10
Because quantitative variables are not normally distributed, comparisons among groups were carried out by the Wilcoxon signed-rank test. The difference between proportions was assessed by Fisher exact test. Data were analyzed with SAS software, release 9.1.3 (SAS Stat 9.1, SAS Institute Inc, Cary, NC), and values of p < 0.05 were considered significant.
A total of 1,075 patients received a SynCardia TAH during the study period (Figure 1A, B). The majority of these patients had the device implanted for less than 1 year. Fifty-three patients from 13 centers met the study criteria for enrolment. Six patients from three centers were then excluded from the study because of incomplete data. The remaining 47 patients from 10 centers worldwide who received a TAH for more than 1 year between 1989 and 2011 were included in the analysis. This composed of three centers from the United States and seven centers from Europe with each center entering between 1 and 23 patients into the database (median of four patients per center).
Patient demographics and preoperative data are stratified by preoperative diagnosis and presented in Table 1. There were 41 males (87%). Median age was 49 years (range 19–69 years); median weight was 85 kg (range 62.5–128 kg), median height 180 cm (range 155–202 cm). The median body surface area (BSA) was 2.02 square meters (range 1.64–2.4 square meters) with 11 patients (23%) having a BSA value below 1.8 m2. Twenty-three (49%) patients had an initial diagnosis of dilated cardiomyopathy, 18 patients (32%) ischemic cardiomyopathy, and 9 patients (19%) were classified as having other causes for heart failure.
Thirty-three of 47 patients (70.2%) were ascribable to an INTERMACS class: 23 patients were in INTERMACS class I (crash and burn), 7 were in class II (sliding on inotropes), and 3 were on class III.
The median support time was 554 days (1.5 years) (range 365–1,374 days) and cumulative support time was 79.8 years.
Differences in the surgical implantation technique adopted in the centers enrolled were not recorded and we assumed all patients received the TAH according to a standard surgical technique.11
Of the 47 patients included in the series, 12 patients (25%) died supported with SynCardia TAH (within a median time of 525 days—range 381–971 days) (Table 2), 34 patients (72%) underwent cardiac transplantation, and one patient remain supported with the device.
Of the 34 patients who underwent cardiac transplantation, three patients died at a median time of 145 days (range 50–328 days); graft rejection was the cause of death in all of them.
Mean intensive care unit (ICU) length of stay was 28 days (range 5–467). Delayed sternal closure occurred in 11 patients (23%) with a median time to delayed closure of 4 days (range 1–6 days). A wound infection occurred in two patients. New renal replacement therapy (RRT) was necessary in 12 patients (26%), while an additional 18 (60%) patients who required RRT preoperatively continued to require it postoperatively. Of all 30 patients requiring postoperative RRT, recovery of renal function occurred in 22 (73%), whereas persistent RRT was required in 8 (17%) at 1 year.
Forty patients (85%) were discharged home: 39 received an Excor drive support (available only in Europe), and 11 of them were then switched to a Freedom device. One patient was discharged with Freedom driver as the primary portable driver unit.
Of the seven patients who remained in-hospital, five were from the United States where, at the time of their TAH support, a portable driver was not available yet.
Anticoagulation/Thrombotic Complications and Infections
All patients received warfarin with a target INR range between 2.5 and 3.5. Thromboelastogram (TEG) was available and routinely used to set the antithrombotic therapy in 7 of 10 centers enrolled in the study.
Anticoagulation strategies are shown in Figure 2. Forty-two patients (89%) received antiplatelet therapy in addition to warfarin. Thromboembolic events complicated the postoperative course of nine patients (19%) and they occurred after a median time of 500 days from TAH implantation (range 159–815 days). Six patients (12.7 %) experienced a transitory ischemic attack, whereas three patients (6.3 %) suffered a major cerebrovascular accident with hemiparesis or aphasia (Table 3).
Hemorrhagic events occurred in seven patients (14%) after a median time of 249 days (range 174–598 days). A cerebral hemorrhage occurred in three patients, a subarachnoid hemorrhage in another two, and other two patients experienced a gastrointestinal tract bleeding (Table 3). Thus, eight strokes (three embolic and five hemorrhagic) or 0.083 strokes per patient year were observed.
Twenty-six patients (55%) used an antihypertensive treatment during their support, with one (15 patients) or more drugs (11 patients) per day.
Systemic infection requiring intravenous antibiotics occurred in 25 patients (53%). Driveline infections occurred in 13 patients (27%); in 11 patients, the infection was superficial and did not ascend to the mediastinum, in 2 patients, the infection was deep (4%) (mediastinitis) and it was the cause of death for one of them. Five patients died of sepsis with multiorgan failure. This is the most common cause of death in between our cohort of patients.
Five patients (10%) experienced a major device-related technical problem. Two patients died because of a device failure: in both cases, a membrane rupture occurred; one at 801 and the other at 971 days,. The three nonfatal events were 1) an Excor unit patient was observed to have a lower than usual left pump output 400 days after implantation with a right pump output higher than the left and increasing signs of pulmonary congestion. He was urgently admitted to the hospital and switched to a new Excor Unit with complete recovery. He was successfully transplanted 197 days after this event; 2) another patient reported a membrane rupture at 694 days postimplantation. The rupture was identified on a computed tomography scan of the chest and the patient was successfully transplanted; and 3) the last patient reported an air-hole in the driveline: no major changes in the pump output had been recorded, but he was admitted urgently and successfully transplanted 69 days after this event (Table 4).
When we stratified patients by BSA, we found important differences. Patients with a BSA < 1.8m2 were found to have a increased incidence of death (p = 0.0045), hemorrhagic events (p = 0.009), and systemic infections (p = 0.008) (Table 5) (Figure 3).
The 47 patients were entered in a Kaplan–Meier survival curve. Kaplan–Meier estimate of the overall survival according to BSA resulted statistically significant (p = 0.002). No differences in freedom from device failure, freedom from transplant survival, and freedom from TE events were recorded when patients were tested for BSA < 1.8 m2 and BSA >1.8 m2 (Figures 4–6).
According to the fifth INTERMACS annual report, DT represents an increasing application of continuous flow-left ventricular assist device and currently accounts for nearly one-third of overall mechanical circulatory support (MCS) activity in the United States.12
Despite these success in the treatment of left ventricle failure, refractory biventricular failure remains a major clinical and surgical challenge especially in long-term support.13
In the fourth INTERMACS report, survival at 3 and 6 months of patients with biventricular dysfunction supported with a TAH appeared to be higher than for patients supported with a BiVAD.14 Despite this statistics, there is a paucity of data available on the outcomes of long-term support with a TAH.
We collected the entire international experience of patients assisted with a Syncardia TAH for more than 1 year to investigate the long-term application of this device.
In long-term support, the use of TAH was safe with only two deaths (4%) occurring secondary to device failure and over 70% of patients being successfully transplanted with a median time of TAH support of 554 days (1.5 years).
Infections and hemorrhagic events were the leading cause of death in this series.
Role of Body Surface Area
One striking observation of this series is the role of BSA as a risk factor for death, infections, and hemorrhagic events. BSA is undoubtedly a marker for “fit complications” that have been noted since the introduction of the Jarvik-7 (100 ml) in the 1980s.13 In fact, the United States FDA clinical protocol stipulates patients with a BSA of less than 1.7 m2 should be excluded from receiving the Syncardia.15
The preliminary experience at LaPitiè-Salpetriere Hospital during the 1980s reported that a BSA < 1.7 was an independent risk factor for death with a TAH.16 Clinically, the BSA is rarely used as a selection criterion in the algorithm for device selection. Instead, the SynCardia TAH is implanted as long as the patient is in INTERMACS class I or II and the anterior–posterior diameter of the mediastinum (by chest computed tomography) is least 10 cm to accommodate the device. The same French group reported in their most recent series a survival rate that reached 75% in patients with a BSA < 1.7m2. This result was achieved with short-term support with a median implantation time of 40 ± 50 days17 and is because of more accurate surgical techniques used to implant the CardioWest TAH inside small chests.10,17
Our data show patients with a BSA < 1.8m2 have an increased risk of death with long-term support (p = 0.0045). Indeed a benchmark of 1.8 m2 or less is a risk factor for hemorrhagic (p = 0.009) and infection complications (p = 0.008), both representing 75% of the causes of death in our cohort. The increased incidence of intracranial hemorrhagic complications in these patients may be caused by the stroke volume mismatch and high blood pressure secondary to high cardiac output generated by the TAH.
The association of infection with the smaller BSA patients in our series is unclear. The majority of infections had a pulmonary source. Placing the TAH in a small chest could lead surgeons to laterally displace one of the artificial left ventricle into the left chest cavity17 compromising normal lung physiology leading to a higher risk of pulmonary atelectasis and pneumonia. However, infections still represent a major cause of morbidity in all MCS patients. All of these devices have external drivelines, increasing the risk of ascending infection in the chest cavity.
A totally internally implantable MCS is in the process of being developed and would likely significantly decrease device-related infections.
To evaluate the use of TAH as a long-term strategy, an analysis of its safety is crucial. We recorded a total of five episodes (10%) of device malfunction and for two patients, it was the leading cause of death (Table 4). Including these three patients, six overall episodes of membrane rupture have been reported5,18 (Table 6). It is difficult to assess the true incidence of this complication considering the only current data available about the safety of the internal membrane of TAH is provided by the Syncardia itself. Nevertheless, device malfunctions are generally referred to as a rare complication with the TAH, especially when used for short- to mid-term length support.19–21 Interestingly, a recent study that included home discharged SynCardia TAH recipients recorded a 21% rate of device malfunction with no device dysfunction-related deaths.9 In this subset of patients discharged home, an air leak in the pneumatic driveline was described. In our series, we also recorded an air leak from the driveline in a patient discharged home. After sealing the leak, this patient survived uneventfully for 69 days until he was transplanted. As patients regain mobility, thanks to the portable driver, the possibility for air leaks on the pneumatic pipeline has to be more closely monitored. This complication seems to be safely manageable by sealing the air leak while awaiting for a high priority organ allocation.9
Outcome and Heart Transplantation
Even after 1 year of support, the vast majority (72%) of patients with a TAH included in our series underwent successful cardiac transplantation within a median support time of 563 days. Despite the long-term presence of the TAH, no intraoperative mortality is reported at the time of the cardiac transplantation when the device is removed from the chest.
The outcome of heart transplantation in patients supported for long term with a TAH should be discussed cautiously using our data: a selection bias is present in our cohort because of the exclusion of all the patients supported for less than 1 year. Despite this, according to our results, patients who survive with a TAH for greater than a year still have a high rate of successful heart transplantation. Nevertheless in the experience of Copeland et al,7 with 100 TAH implants (mean support time 87 ± 94.8 days), 70% of deaths occurred in the first 14 days and 90% occurred within the first 40 days after implantation, underlining a substantial stabilization of patient death events over time. These data are confirmed also in the most recent experience in France where the actuarial estimates of survival under TAH support is constant between 120 and 360 days.22
If the patient survives the initial surgery and complications of multiorgan failure experienced at the time of TAH placement, focusing on avoiding subsequent infections seems to play a major role in the survival of these patients. Six of 12 deaths in our cohort are ascribable to multiorgan failure secondary to an infectious origin. A bulky device with external connections tunnelized under the skin is more prone to develop in long-term potential lethal infections. Nevertheless, in patients supported with TAH death generally arrive after a long-term period of ICU where the hemodynamic conditions are guaranteed by the mechanical device and infections superimposed a clinical scenario of multiorgan failure. These data highlight the need for maintaining an extremely high index of suspicion for infection in patients supported long term with a SynCardia TAH.
Hemorrhagic and Thromboembolic Events
In our study, we recorded an incidence of 0.083 TE events per patient month comparable with the previous international experience achieved within 1 year of support (Table 7). Interestingly, this data show that long-term TAH support does not increase the risk of TE events. Moreover, a variety of anticoagulation protocols and monitoring were used in the centers enrolled in our study; however, these differences did not impact the rate of TE events. Even the recent experience at La Pitie-Salpetriere Hospital in Paris illustrates that a simplification of the anticoagulation protocol of Szefner did not result in an increase in neurologic complications or thrombotic events.22,23 Furthermore, the recent report from GRAM (Groupe de Relexion sur l’Assistance Mecanique) registry showed that Syncardia recipients experienced significantly fewer neurologic events compared with BiVAD recipients. There are likely elements to the design of this device, which may be responsible for reduced TE events.24 Moreover, TE events had a more favorable clinical course (only 1/9 deaths) compared with hemorrhagic episodes (5/7 deaths). This data should be considered when addressing the anticoagulation strategy for patients supported with a TAH.
Our cohort of patients represent only the 4% of the entire populations of patients supported with a Syncardia TAH. Up to now, this device is more extensively used as BTT in short-term support (<6 months) (Figure 1B). One of the major limitations of our study is the exclusion of the patients supported for less than 1 year by selection criteria. This choice was made to focus the attention on the outcomes of the few patients with long-term survival using a SynCardia TAH. Patient included in this study received a TAH within a broad time period (1988–2012) with different expertise and technologies available in the respective eras. Furthermore, the reason why these patients were supported for more than 1 year was not always specified by the included centers. It is likely that complications experienced while under the use of TAH caused prolonged support times and represent a selection bias of our population.
The current iteration of the TAH is far from ideal given the large size, external drivelines tunneled under the skin, the weight of the back pack, the high incidence of infections, and the noise associated with the device (75 dB)—all which impact the quality of life of patients. However, the SynCardia TAH has emerged as a robust form of mechanical circulatory support for patients with biventricular failure. This study illustrates that support using the Syncardia TAH beyond 1 year has acceptable outcomes, but further improvements in the device, patient selection, and long-term patient management need to be achieved to further reduce the major complications of infection, TE, and hemorrhagic events.
The future promises of new technologies will potentially overcome the current drawbacks and limitations and hence improve the quality of life and survival in patients.
The author is grateful to Dr Analechi Anyanwu for his thoughtful assistance in editing the manuscript.
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