The strategy of left ventricular assist device (LVAD) implantation as bridge-to-transplant (BTT) has become more common for patients with end-stage heart failure who are not immediately able to undergo heart transplantation.1 Initial reports, that focused on earlier generation LVADs, raised concerns about the impact that a device may have on survival following heart transplantation.2 The basis for this notion was that the duration of mechanical support increased rate of humoral sensitization3,4 as well as post-transplantation mortality.5 Technological advancements in combination with a better understanding and management of heart failure pathophysiology has allowed for better contemporary outcomes in patients receiving LVAD therapy. The duration of mechanical support does not have a direct effect of post-transplantation survival6 and there is no difference between two of the most commonly used devices.7 Continuous-flow pumps have been broadly used for the past decade with over 17,000 implants worldwide.8 The aim of this study was to examine long-term survival and functional status of patients who were BTT with an LVAD in comparison to patients undergoing de novo heart transplantation.
Materials and Methods
Patient Population and Data Sources
Adult patients (age ≥18 years) who underwent isolated heart transplantation between January 1, 2007, and September 30, 2017 were included in this study. We focused on patients bridged-to-transplant with an LVAD (Heartmate II [HMII] or HeartWare Ventricular Assist System [HVAD] only). This group was compared against patients undergoing de novo heart transplantation—defined as a patient without a prior sternotomy or LVAD implantation. Patients supported with extracorporeal or percutaneous LVADs, right ventricular assist devices, biventricular assist devices, and total artificial hearts were excluded. The Organ Procurement and Transplantation Network (OPTN) provided the publicly available Standard Transplant Analysis and Research files with follow-up available until December 1, 2017. These files comprise a prospectively collected dataset of all thoracic transplantation in the United States. This study was approved by the Johns Hopkins Medicine Institutional Review Board (reference IRB00159748).
Study End-Points and Variable Definitions
The primary outcome of interest was overall survival 1, 2, and 5 years after transplantation. Conditional survival estimates were examined to determine whether mortality hazards changed over time for either cohort. Survival was conditioned on 90 day survival (for 1 year survival estimates) and 1 year survival (for 2 and 5 year survival estimates). Secondary outcomes were functional status, return to work, hospital readmission, and graft rejection requiring treatment. Secondary outcomes were examined at the same intervals (1, 2, and 5 years). Functional status was characterized using the Karnofsky Performance Scale (KPS), which assigns a score ranging between 10% and 100%.9 Patients with a KPS score ≤40% are deemed to require complete assistance to manage daily tasks, those between 50% and 70% require partial assistance, and between 80% and 100% require no assistance. The KPS has been previously validated in heart transplantation.10 Postoperative outcomes were identified by crosslinking the index hospitalization to postoperative follow-up encounters for each subject. Data collection and variable definitions for the OPTN data set have been described previously.11,12
Data Presentation and Analysis
Continuous variables are presented as median [25th, 75th percentile] or mean ± standard deviation and categorical variables as count of patient (percentage). Descriptive comparisons were conducted with Kruskal-Wallis rank sum test or one-way analysis of variance for continuous variables and Pearson’s χ2 for categorical variables, as appropriate. Statistical significance was determined at a p value <0.05 (two sided). Analyses were performed using R version 3.4.313 with the following packages: rms,14survival,15 and survminer.16
Recipient-, donor-, and transplant-specific characteristics were compared between BTT and de novo cohorts. These characteristics were systematically collected at the time of transplant. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation17 with the pretransplant creatinine level and pertinent patient characteristics. The Model for End-Stage Liver Disease Excluding INR (MELD-XI) score was calculated as follows:
According to convention, serum creatinine was imputed to 4 mg/dl for patients with chronic renal failure requiring renal replacement therapy. The lower limit of serum creatinine and bilirubin was set to 1 mg/dl. The prognostic utility of the MELD-XI has been previously validated in heart transplantation.18
To examine differences on mortality, actuarial survival estimates were generated using the Kaplan-Meier method. Pairwise comparisons were made using the log-rank test and p values were adjusted with the Benjamini-Hochberg procedure.19 The impact of BTT on risk-adjusted mortality was examined using Cox proportional hazards models. Covariates for each model were only considered if they were collected by OPTN during the study period and selected through bootstrap aggregation.20 In brief, 250 samples were generated through random sampling with replacement. Each bootstrap sample containing 17,879 observations was used to construct a parsimonious model through automated stepwise regression and backward elimination. The retention criterion for covariates was set at a p value <0.05. The results of each bootstrap model were stored and counted. Covariates that entered >50% of the bootstrap models were chosen for the final model. Once covariates were selected, group identity (i.e., BTT or de novo) was forced into the model to evaluate independent association with risk-adjusted mortality. All covariates considered as candidates for model development are listed in Table 1 (Supplemental Digital Content, http://links.lww.com/ASAIO/A332). Separate models were developed for each individual outcome with this method. Estimates are presented as coefficients and hazard ratios (HR) with 95% CI. Strength of association between covariates and risk-adjusted mortality was determined using Wald’s χ2 statistic.
Over the study period, 5,584 patients were successfully BTT using isolated left ventricular support and 12,295 received a de novo heart transplant. Within the BTT cohort, 75% (4,201/5,584) were bridged using a HMII device and 25% (1,383/5,584) with a HVAD device. Additionally, 56% (3,139/5,584) underwent LVAD implantation before registration for heart transplantation and 44% (2,445/5,584) underwent implantation while listed. Follow-up had a mean duration of 3.68 years ± 2.91 and a maximal duration of 10 years and 8 months.
Recipient, Donor, and Transplant Characteristics
There were notable differences between both recipient populations (see Table 2 Supplemental Digital Content, http://links.lww.com/ASAIO/A333). Bridge-to-transplant patients were more commonly male (82% vs. 70%; p < 0.001), African American (24% vs. 20%; p < 0.001), blood group O (46% vs. 34%; p < 0.001), had a higher body mass index (BMI; 28.4 vs. 26.3 kg/m2; p < 0.001), had a higher prevalence of tobacco use (52% vs. 44%; p < 0.001), and diabetes mellitus (32% vs. 27%; p < 0.001), and were less frequently hospitalized at the time of transplant (82% vs. 42%; p < 0.001). De novo patients had a higher MELD-XI score (12.5 vs. 12.1 points; p < 0.001), a lower estimated glomerular filtration rate (65 vs. 68 ml/min/1.73 m2; p < 0.001), a larger proportion required an intraaortic balloon pump at the time of transplant (10% vs. 1%; p < 0.001), and required care at an intensive care unit more frequently (41% vs. 7%; p < 0.001). The total waitlist time (220 vs. 56 days; p < 0.001) and status 1A time (31 vs. 2 days; p < 0.001) was longer for BTT patients.
A higher proportion of donors accepted for BTT patients were male (77% vs. 66%; p < 0.001), blood group O (55% vs. 48%; p < 0.001), and had slightly higher BMI (26.8 vs. 25.9 kg/m2; p < 0.001; see Table 3 Supplemental Digital Content, http://links.lww.com/ASAIO/A334). The median recipient–donor BMI ratio, utilized as a surrogate for size mismatch, was slightly higher for BTT patients (1.05 vs. 1.00; p < 0.001). A higher proportion of de novo patients received an ABO compatible organ (17% vs. 12%; p < 0.001) versus receiving a heart from an ABO identical donor. The median distance between donor hospital and transplant center was longer for the de novo group (150 vs. 139 km; p < 0.001). Yet, the median organ ischemic time was slightly longer for the BTT group (3.2 vs. 3.1 hours; p = 0.019).
Impact of Support on Survival
Unconditional survival estimates were lower for BTT patients at 1 year (90% vs. 91%; p < 0.001), 2 years (86% vs. 88%; p < 0.001), and 5 years (77% vs. 79%; p = 0.003) (Figure 1 and Table 1). One year survival, conditional on 90 day survival, was similar between groups (96% vs. 96%; p = 0.054). Two and 5 year survival, conditional on 1 year survival, were also similar between groups (Table 2). Bridge-to-transplant was independently associated with unconditional, risk-adjusted mortality at 1 (HR: 1.33, 95% CI: 1.19–1.49; Table 3 and see Table 4, Supplemental Digital Content, http://links.lww.com/ASAIO/A335) and 5 years (HR: 1.72, 95% CI: 1.57–1.87; Table 3 and see Table 5, Supplemental Digital Content, http://links.lww.com/ASAIO/A336). This association was also evident for conditional, risk-adjusted mortality at 1 (HR: 1.26, 95% CI: 1.04–1.51; see Table 6, Supplemental Digital Content, http://links.lww.com/ASAIO/A337) and 5 years (HR: 1.39, 95% CI: 1.22–1.59; see Table 7, Supplemental Digital Content, http://links.lww.com/ASAIO/A338).
The impact of LVAD implantation era and transplantation era on post-transplantation survival was examined by clustering patients by years of implantation (2005–2009, 2010–2013, and 2014–2017) or by year of transplantation (2007–2010, 2011–2013, and 2014–2017; Figure 2). Left ventricular assist device implantation in the 2005–2009 was associated with lower survival estimates at 1 (87.0%, 95% CI: 84.9%–89.2%) and 2 years (83.4%, 95% CI: 81.0%–85.7%) after transplantation than the 2010–2013 era (p = 0.014). Survival estimates were similar across all eras of transplantation (all p values >0.05; Figure 2B).
Functional status was examined by stratifying performance according to the KPS categories described previously. At the time of listing, close to 40% required complete assistance in both groups and only 15% required no assistance. These proportions shifted by the time of transplantation with a larger proportion of BTT patients requiring no assistance (23% vs. 12%; p < 0.001) and a smaller proportion requiring complete assistance (33% vs. 58%; p < 0.001; Figure 3). From there on, functional status of both groups was similar. The proportion of patients requiring no assistance to manage daily tasks for BTT and de novo groups was 86% vs. 86%, 89% vs. 90%, and 87% vs. 90% at 1, 2, and 5 years, respectively.
Employment rate was low at the time of listing, but relatively higher for de novo patients (13% vs. 10%; p < 0.001), and remained low at the time of transplantation for both groups (~8%; Figure 4). The proportion of patients returning to work 1 year after transplantation doubled and was relatively higher in the de novo group (23% vs. 19%; p = 0.004). Rates of employment continued to improve over time and were similar between groups at 2 (21%) and 5 years (26%).
Rates of hospital readmission were similar between groups at every time point. Readmission estimates at 1, 2, and 5 years were 40%, 55%, and 73%, respectively. These estimates only account for the interval between transplantation and the first subsequent hospital admission. Iterative events were not examined (Table 4). Rates of graft rejection requiring treatment were also similar between groups at every time point. Rejection estimates at 1, 2, and 5 years were 25%, 33%, and 41%, respectively. Iterative events were not examined.
Bridge-to-transplant using isolated left ventricular support with newer generation, continuous-flow pumps provides comparable long-term post-transplantation survival to de novo transplantation. Bridge-to-transplant incurs an up-front mortality that is 2% higher in the first 3 months from the surgical risk of redo sternotomy with device explantation; however, long-term survival conditional on 90 day survival is similar between groups. Hence, BTT patients who survive the early postoperative phase experience similar hazards of mortality over time to those of de novo patients.
Overall, patients had adequate post-transplantation functional performance with the majority of patients (>80%) requiring no assistance to manage daily tasks (Figure 3). Both groups had similar function at the time of listing but the de novo group suffered a decrease in functionality between registration and transplant, in contrast with the BTT group, which experienced an increase in functionality. The proportion of patients who were employed (Figure 4) decreased for de novo patients between the time of waitlist registration (13%) and transplantation (7%), while the proportion of BTT patients who remained employed did not suffer a similar decrease. These findings serve as indirect evidence for superior rehabilitation and conditioning in patients receiving left ventricular support while waiting for transplantation. It is congruent with the small fraction of BTT patients who required care within a hospital or intensive care unit, preferable preoperative hepato-renal function (examined with estimated glomerular filtration rate and MELD-XI score), and being able to survive longer periods waiting for a heart (see Table 2, Supplemental Digital Content, http://links.lww.com/ASAIO/A333).
Left ventricular assist device implantation during the early era (2005–2009), during which clinical trials for these devices were being conducted, was associated to a 3.6% decrease in 2 year survival (Figure 2A). Perhaps within this era, transplantation was more frequently done in the setting of pump complications and at the outset of widespread use of continuous-flow LVAD’s the outcomes of BTT improved from optimized management and device familiarity.
Prolonged mechanical support with LVAD has been associated with an increased rate of humoral sensitization in observational studies from previous decades.3,4 However, in neither of these has BTT with an LVAD been associated with an increased rate of graft rejection requiring treatment. Arnaoutakis et al.4 described an association with a higher rate of primary graft dysfunction with no negative effects on survival. In the current study, there was no difference in the rates of graft rejection requiring treatment nor hospital readmission at 1, 2, or 5 years between de novo and BTT patients (Table 4). Future studies should examine the extent of humoral sensitization with current generation devices.
Risks and Benefits of Mechanical Support
The use of LVAD as BTT represents a cost-effective alternative to “non-bridge” heart transplantation for intermediate- and high-risk patients,21 particularly for those who are young, have prolonged expected waiting times, or renal dysfunction.22 A comparative, cost-effectiveness analysis estimated that BTT-LVADs offer 3.8 additional life-years to patients who are expected to wait for longer than 6 months.23
Continuous-flow devices provide increased durability and lower rates of infections than those of earlier generations. However, offering BTT with LVAD poses significant challenges to patients who are constantly enduring longer periods of mechanical support. Stroke continues to be the major cause of death for patients on LVAD, closely followed by infection, which is the most common adverse event.8 The hemodynamics of continuous-flow devices have been associated to acquired von Willebrand syndrome24 and aortic insufficiency.25 Additionally, prolonged support is associated to increased risk for gastrointestinal bleeding, pump thrombosis,26 and adverse neurologic events.27 An observational study that compared bridging strategies (LVAD versus inotropic agents) concluded that patients bridged with inotropes who decompensated and required subsequent LVAD implantation acquired a twofold increase in mortality.28 Previous observational studies compared both devices and found no significant differences in pretransplantation end-organ function or post-transplantation patient survival.7,29 Selecting an appropriate bridging strategy for patients who are unlikely to undergo expeditious transplantation requires thoughtful consideration.
The Food and Drug Administration approved HMII and HVAD devices as BTT therapies in 2008 and 2012, respectively. The study period incorporates patients enrolled in regulatory clinical trials and patients who underwent commercial implantation; we could not identify nor adjust for this factor. The volume of LVADs implanted at each center on a yearly basis, a fitting surrogate for center experience, was not available within in the OPTN dataset. National databases may experience inherent variability in data collection. The fields used in these analyses had a low proportion of missing values (all <10%); furthermore, those used for regression modeling had <1% of missing values. This study focused solely on patients who were successfully bridged-to-transplant and these findings should not be extrapolated to BTT patients waiting for a heart. The physiology and clinical management of de novo and BTT patients are categorically different; hence, certain factors may impart different effects to patient outcomes. Future studies should examine the interactions between these groups and predictors for post-transplantation survival.
Bridge-to-transplant with LVAD provides excellent survival and similar quality of life to that of patients undergoing de novo heart transplantation. Bridge-to-transplant patients experience a slightly higher mortality rate within 90 days of transplantation. This difference in survival is offset by the live-years gained during mechanical support. BTT with LVADs may provide a means for pretransplantation rehabilitation and conditioning for otherwise moribund patients.
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