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Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices
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http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices Michael Yaoyao Yin, MD,a Omar Wever-Pinzon, MD,a Mandeep R. Mehra, MD, MSc,b Craig H. Selzman, MD,c Alice E. Toll, MS,d Wida S. Cherikh, PhD,d Jose Nativi-Nicolau, MD,a James C. Fang, MD,a Abdallah G. Kfoury, MD,e Edward M. Gilbert, MD,a Line Kemeyou, MD,c Stephen H. McKellar, MD,c Antigone Koliopoulou, MD,c Muthiah Vaduganathan, MD, MPH,b Stavros G. Drakos, MD, PhD,a and Josef Stehlik, MD, MPHa From the aDivision of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah; bBrigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts; cDivision of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah; dUnited Network for Organ Sharing, Richmond, Virginia; and the eIntermountain Medical Center, Murray, Utah.
KEYWORDS: heart allocation; heart transplant; mechanical circulatory support; outcome; risk prediction; survival
BACKGROUND: The new heart allocation system in the United States prioritizes patients supported by temporary mechanical circulatory support (TMCS) devices over those with uncomplicated durable continuous-flow left ventricular assist devices (CF-LVADs), which may increase the number of patients bridged to transplant with TMCS. Limited data are available in guiding post-transplant outcomes with various TMCS devices. We sought to describe post-transplant outcome and identify clinical variables associated with post-transplant outcome in patients bridged to transplant with TMCS. METHODS: Using data from the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, we included subjects who underwent transplantation between 2005 and 2016 with known use of mechanical circulatory support. Pre-transplant recipient, donor, and transplant-specific variables were abstracted. The primary outcome was patient survival at 1-year post-transplant. Outcomes of patients bridged to transplant with TMCS were compared with those of patients bridged with CF-LVADs. Cox regression analyses were performed to identify clinical variables associated with the outcomes. RESULTS: There were 6,528 patients bridged to transplant with the following types of mechanical circulatory support: durable CF-LVADs (n = 6,206), extracorporeal membrane oxygenation (ECMO, n = 134), percutaneous temporary CF-LVADs (n = 75), surgically implanted temporary CF-LVADs (n = 38) or surgically implanted temporary BiVAD (n = 75). Bridging with ECMO (hazard ratio 3.79, 95% confidence interval [CI] 2.69−5.34, p < 0.001) or percutaneous temporary CF-LVADs (hazard ratio 1.83, 95% CI 1.09−3.08, p = 0.02) was independently associated with higher risk of mortality.
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiovascular Medicine, University of Utah, 50 N Medical Dr, Salt Lake City, Utah 84132. Telephone: 801-585-2340. Fax: 801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.04.003
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Additional risk factors included older donor age, female/male donor-recipient match, older recipient age, higher recipient body mass index, higher recipient creatinine, and prolonged ischemic time. CONCLUSIONS: This analysis of a large international cohort of patients bridged to transplant with mechanical circulatory support identified ECMO and percutaneous temporary CF-LVADs as predictors of mortality after transplant, along with additional donor and recipient clinical characteristics. These findings may provide guidance to clinicians in decisions on mechanical circulatory support device selection, transplant eligibility, and timing of transplant. J Heart Lung Transplant 000;000:1−12 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.
The rising incidence and prevalence of heart failure has resulted in an increase in the number of patients listed for heart transplantation in the last decade, yet the number of transplants has risen only modestly.1,2 This discrepancy between the number of transplant candidates and the number of available donors is the principal reason for continuous attention of regulatory transplant bodies worldwide to the appropriateness of their organ allocation algorithms. In the United States, the United Network for Organ Sharing has, over the years, implemented a number of policy changes aimed at preserving a fair and equitable allocation of donor hearts. Such changes have focused mainly on prioritizing patients with the highest waitlist mortality.3 Despite these policy changes, the mortality of patients on the waitlist remains considerable both in the United States and elsewhere.4−12 The introduction of durable left ventricular assist devices (LVADs) to clinical care has increased the numbers of patients successfully bridged to transplant.1,13−15 The first generation of pulsatile continuous flow left ventricular assist devices (CF-LVADs) suffered from an excessive early mortality, prompting an allocation policy in 1999 to allow highest urgency status for patients within the first 30 days of device implantation. Once improvement in post-operative care ensued, this policy was modified in 2002 to allow for the 30-day highest urgency status to be used at the discretion of the clinical team.3,16 The advent of CF-LVADs has reduced the morbidity and mortality of these patients awaiting transplantation without adversely affecting post-transplant survival. In the current era, patients bridged to transplant with durable CF-LVADs have lower rates of death and of deactivation from the list and higher rates of transplantation when compared with patients on dual inotropes or temporary mechanical circulatory support (TMCS) devices.17,18 Thus, a new policy has been introduced to address concerns of a disproportionate advantage for patients listed with durable CFLVADs in relation to the high waitlist mortality for patients awaiting transplantation while supported with TMCS.3,17,18 The United Network for Organ Sharing implemented the most recent revision to the heart allocation system in October of 2018, at which time the priority of uncomplicated patients supported with durable CF-LVADs was lowered and that of patients supported by various TMCS moved to the highest priority. These TMCS modalities include the following: (1) veno-arterial extracorporeal membrane oxygenation (ECMO), (2) non-dischargeable,
surgically implanted biventricular support systems (TBiVADs), (3) non-dischargeable, surgically implanted left ventricular support systems (T-LVADs), and (4) percutaneous ventricular support devices (P-VADs).19 Considering that prior experiences have suggested that patients supported with TMCS are at a greatest risk of waitlist and early post-transplant morbidity and mortality, it is paramount that post-transplant survival be accurately described and clinical variables associated with outcome in such patients be identified.8,20−24 Thus, the principal aim of this study was to describe post-transplant survival in patients bridged to transplant with TMCS and identify recipient, donor, and transplant process characteristics associated with post-transplant outcome.
Methods Study population We examined data in the Thoracic Transplant Registry of the International Society for Heart and Lung Transplantation (ISHLT Registry).1 We included subjects transplanted between January 1, 2005 and June 30, 2016. The study cohort included adult recipients (aged ≥18 years) bridged to transplant with known types of CF-LVADs and TMCS devices including the following: (1) CF-LVADs (HeartMate II, Abbott, Lake Bluff, IL; HeartMate 3, Abbott; HeartWare, Medtronic, Minneapolis, MN; and Jarvik 2000, Jarvik Heart, New York, NY), (2) ECMO, (3) P-VADs (Impella 2.5, Impella CP, and Impella 5.0, Abiomed, Danvers, MA; TandemHeart, Kardia, Italy), (4) TBiVADs (CentriMag Bi-VADs, Abbott), and (5) T-LVADs (CentriMag LVADs, Abbott). The study excluded the following groups of patients: heterotopic transplants, retransplants, multiorgan transplants, recipients bridged with a total artificial heart, recipients bridged with both ECMO and other type of TMCS, and recipients with no follow-up reported after transplant (Figure 1).
Study data Pre-transplant recipient, donor, and transplant-specific variables were abstracted from patient data collected in the ISHLT Registry at the time of transplant. Pre-transplant recipient variables included age, sex, body mass index, heart failure etiology, serum creatinine, history of diabetes, hypertension, and blood type. Donor variables included age, body mass index, history of diabetes mellitus, hypertension, smoking, and cause of death. Transplant-specific variables included ischemic time and donor/ recipient sex.
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Figure 1 Study population. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
Primary and secondary outcomes The primary outcome was patient survival at 1 year after transplant. The secondary outcomes included treated acute rejection; severe renal dysfunction defined as creatinine >2.5 mg/dl, dialysis or renal transplant at the time of follow-up; cardiac allograft vasculopathy; and recipient cause of death (multiorgan failure, graft failure, infection, cerebrovascular accident, cardiac allograft vasculopathy, acute rejection, or other) for those who died within 1 year of transplant.
Statistical analysis Baseline characteristics and outcomes of patients bridged to transplant with TMCS were compared with patients bridged with CFLVADs. Continuous variables were compared with Kruskal −Wallis tests and categorical variables were compared with chisquare tests. Unadjusted patient survival rates, freedom from acute rejection, cardiac allograft vasculopathy, and severe renal dysfunction within 1 year were estimated using the Kaplan−Meier method, by bridging strategy (TMCS vs CF-LVADs) and compared using log-rank tests. The Benjamin-Hochberg procedure was used to adjust pairwise log-rank tests for multiple comparisons.25 Cox proportional hazards analyses were used to examine the association between bridging strategy and 1-year post-transplant mortality. The model was initially built with all of the variables listed in Table 1. Backwards selection was used to determine variables to retain in the final model (p < 0.05). Missing values for risk factors were imputed using multiple imputation methods. Continuous variables were included in the model using a restricted cubic spline to allow for the most flexible fit of the functional form. Model validation was performed using the bootstrap method (without data splitting) and bias corrected index of concordance (c-statistic) was calculated as a measure of discrimination. Continuous calibration to assess the agreement between observed and
predicted risk of graft failure was performed using the bootstrap method.26 The regression coefficients in the final model were used to construct a patient 1-year survival calculator. In the current analyses, p < 0.05 was considered statistically significant. Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC), and R, version 3.3.2 (R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org/).
Results Patient characteristics There were 23,265 heart transplants with known mechanical circulatory support device status and types recorded by the ISHLT Registry during the study period, of which 6,528 patients were bridged to transplant with known types of CF-LVADs or TMCS devices. Most data were submitted by centers from North America (98%), followed by Europe (1%) and other regions (1%). The cohort was further stratified into the following study groups based on the type of devices used for bridging: (1) CF-LVADs (n = 6,206), (2) ECMO (n = 134), (3) P-VAD (n = 75), (4) T-BiVAD (n = 75), and (5) T-LVADs (n = 38). Baseline recipient, donor, and transplant characteristics are displayed in Table 1.
Survival by mechanical circulatory support device type There were 710 deaths in the study cohort at 1 year posttransplant, of which 643 occurred in the CF-LVADs group, 38 in the ECMO group, 15 in the P-VAD group, 10 in the
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Table 1
Recipient, Donor, and Transplant Process Characteristics by Mechanical Circulatory Support Bridging Strategy
Characteristics
P-VAD (n = 75)
ECMO (n = 134)
T-LVAD (n = 38)
T-BiVAD (n = 75)
CF-LVAD (control) (n= 6206)
Total (N = 6528)
53.3 (12.1)
44.9 (15.3)
48.0 (15.7)
45.1 (14.0)
53.4 (12.1)
53.1 (12.3)
25.6 (4.1)
25.5 (4.8)
26.7 (4.6)
25.8 (4.5)
28.4 (5.0)
28.3 (5.0)
35 (0.6) 56 (0.9) 2,559 (41.2) 3,394 (54.7) 65 (1.0) 63 (1.0) 34 (0.5)
47 (0.7) 67 (1.0) 2,659 (40.7) 3,563 (54.6) 72 (1.1) 76 (1.2) 43 (0.7)
1.2 (0.4)
1.2 (0.4)
p-value <0.0001 <0.0001 <0.0001
10 (7.5) 7 (5.3) 44 (33.1) 62 (46.6) 2 (1.5) 6 (4.5) 2 (1.5)
0 (0.0) 1 (2.6) 16 (42.1) 19 (50.0) 0 (0.0) 2 (5.3) 0 (0.0)
0 (0.0) 1 (1.3) 18 (24.0) 47 (62.7) 0 (0.0) 3 (4.0) 6 (8.0)
1.4 (0.6)
1.2 (0.5)
1.1 (0.5)
1.1 (0.5)
19 (25.3)
15 (11.3)
7 (18.4)
20 (27.0)
1890 (30.5)
1951 (29.9)
24 (40.7)
20 (18.2)
10 (33.3)
29 (46.8)
2,573 (55.3)
2,656 (54.0)
22 (29.3) 5 (6.7) 12 (16.0) 36 (48.0)
62 (46.3) 10 (7.5) 12 (9.0) 50 (37.3)
12 (31.6) 6 (15.8) 1 (2.6) 19 (50.0)
35 (46.7) 2 (2.7) 11 (14.7) 27 (36.0)
2,324 (37.4) 237 (3.8) 838 (13.5) 2,807 (45.2)
2,455 (37.6) 260 (4.0) 874 (13.4) 2,939 (45.0)
34.0 (13.0)
35.3 (13.7)
38.3 (9.2)
32.0 (12.8)
31.5 (11.0)
31.7 (11.2)
27.7 (7.1)
26.8 (5.6)
29.5 (5.8)
26.9 (6.1)
27.6 (5.7)
27.6 (5.7)
4 (5.4)
3 (2.4)
1 (2.6)
3 (4.2)
202 (3.3)
213 (3.3)
8 (10.8)
18 (14.6)
10 (26.3)
15 (20.8)
917 (15.0)
968 (15.0)
19 (25.3) 21 (28.0) 32 (42.7) 3 (4.0) 0 (0.0)
23 (17.6) 32 (24.4) 63 (48.1) 0 (0.0) 13 (9.9)
11 (29.7) 13 (35.1) 12 (32.4) 0 (0.0) 1 (2.7)
22 (30.1) 14 (19.2) 32 (43.8) 0 (0.0) 5 (6.8)
1,447 (23.3) 1,171 (18.9) 3,403 (54.9) 36 (0.6) 144 (2.3)
1,522 (23.4) 1,251 (19.2) 3,542 (54.4) 39 (0.6) 163 (2.5)
0.0004 <0.0001 <0.0001 0.0005
Donor characteristics Donor age (years) Mean (SD) Donor body mass index Mean (SD) Donor diabetes mellitus, n (%) Yes Donor hypertension, n (%) Yes Donor cause of death, n (%) Anoxia Cerebrovascular/stroke Head trauma Brain tumor Other
<0.0001 0.0217 0.8158 0.1491 <0.0001
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2 (2.7) 2 (2.7) 22 (29.3) 41 (54.7) 5 (6.7) 2 (2.7) 1 (1.3)
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Recipient characteristics Recipient age (years) Mean (SD) Recipient body mass index Mean (SD) Recipient diagnosis, n (%) Congenital heart disease Hypertrophic cardiomyopathy Ischemic cardiomyopathy Non-ischemic cardiomyopathy Restrictive cardiomyopathy Valvular cardiomyopathy Other Recipient serum creatinine (mg/dl) Mean (SD) Recipient diabetes mellitus, n (%) Yes Recipient hypertension, n (%) Yes Recipient ABO, n (%) A AB B O
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726 (11.1) 816 (12.5) 566 (8.7) 4,420 (67.7)
1,503 (100) 5,025 (100)
673 (10.8) 757 (12.2) 523 (8.4) 4,253 (68.5)
1,403 (93.3) 4,803 (95.6)
12 (16.0) 7 (9.3) 9 (12.0) 47 (62.7)
14 (0.9) 61 (1.2) 7 (0.5) 31 (0.6) 57 (3.7) 77 (1.5) 22 (1.5) 53 (1.1) 2005−2010 2011−2016
Transplant era, n (%)
20 (14.9) 29 (21.6) 21 (15.7) 64 (47.8) 14 (18.7) 15 (20.0) 9 (12.0) 37 (49.3)
CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems. Continuous variables are expressed as mean (SD); categorical variables are expressed as n (%).
3.2 (1.1) 3.2 (1.1) 3.5 (1.2) 3.7 (1.3)
Allograft ischemic time (hours) Mean (SD) Donor/recipient sex, n (%) Donor female/recipient female Donor female/recipient male Donor male/recipient female Donor male/recipient male
Transplant characteristics
3.5 (1.3)
3.9 (1.2)
10 (27.0) 28 (23.5) 11 (15.1)
7 (18.4) 8 (21.1) 4 (10.5) 19 (50.0)
827 (12.9) 7 (9.7)
771 (12.7)
<0.0001
<0.0001
<0.0001
0.0006
Post-transplant outcome in patients bridged to transplant
Donor history of smoking, n (%) Yes
Characteristics
Table 1 (Continued)
P-VAD (n = 75)
ECMO (n = 134)
T-LVAD (n = 38)
T-BiVAD (n = 75)
CF-LVAD (control) (n= 6206)
Total (N = 6528)
p-value
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T-BiVAD group, and 4 in the T-LVADs group. Survival at 1 year was lowest in the ECMO group (71.2%), followed by the P-VAD group (79.9%), T-BiVAD group (86.2%), T-LVADs group (89.5%), and CF-LVADs group (89.6%; Figure 1). The Kaplan−Meier estimates for patient survival within 1 year of transplant are displayed in Figure 2. In pairwise log-rank comparison of survival at 1 year, ECMObridged patients had lower survival than those bridged with T-LVADs (p = 0.048), T-BiVAD (p = 0.025), and CFLVADs (p ≤ 0.001). P-VAD was associated with lower survival compared with CF-LVADs (p = 0.019). There were no significant differences in pairwise survival comparisons between the other mechanical circulatory support bridging strategies. There were no significant differences in distribution of causes of death by mechanical circulatory support bridging strategy among subjects who died within 1 year of transplant (Table 2).
Acute rejection, cardiac allograft vasculopathy, and severe renal dysfunction by mechanical circulatory support device type There were no significant differences in the rates of treatment for acute rejection, cardiac allograft vasculopathy, or severe renal dysfunction within 1 year by mechanical circulatory support bridging strategy (Figure 3 and Table 3).
Risk factors for 1-year mortality Multivariable Cox regression analyses identified the following independent risk factors for 1-year post-transplant mortality: donor age, donor/recipient sex mismatch, recipient age, recipient body mass index, recipient serum creatinine, allograft ischemic time, and bridging with ECMO and P-VAD vs bridging with CF-LVADs (Figure 4, and Table S1 and Figures S1−5 in the Supplementary Material available online at www.jhltonline.org/). The goodness of the fit of the model was assessed with a calibration plot and showed that the model accurately estimates mortality for high-risk patients and slightly underestimates the risk of mortality for low-risk patients. The model had a c-index of 0.64 for performance in discrimination (Figure S6 online). To better illustrate the survival outcomes in patients bridged to transplant with different types of mechanical circulatory support, we constructed a calculator for estimated 1-year post-transplant survival—https://unos.shinyapps.io/ Yin_Heart_Mortality/ (Figure 5, Table S2). This calculator is not intended for immediate clinical use. Rather, it is a first step example in developing a clinical decision aid that should be refined and updated as more data on TMCS bridging to heart transplant accumulate.
Discussion The latest revision to the US adult heart allocation system prioritizes patients supported by TMCS devices over those with uncomplicated durable CF-LVADs. This, in
ARTICLE IN PRESS CAV, cardiac allograft vasculopathy; CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; NA, not applicable; P-VAD, percutaneous ventricular support devices; TBiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems.
38 (5.8) 11 (1.7) 56 (8.5) 144 (22.0) 173 (26.4) 114 (17.4) 119 (18.2) 55 (.%) 35 (5.9) 10 (1.7) 49 (8.2) 136 (22.9) 153 (25.8) 99 (16.7) 112 (18.9) 49 (.%) 1 (11.1) 1 (11.1) 1 (11.1) 1 (11.1) 3 (33.3) 2 (22.2) 0 (0.0) 1 (.%) 0 (0.0) 0 (0.0) 1 (25.0) 1 (25.0) 1 (25.0) 0 (0.0) 1 (25.0) 0 (.%) 2 (5.6) 0 (0.0) 4 (11.1) 3 (8.3) 13 (36.1) 9 (25.0) 5 (13.9) 2 (.%) 0 (0.0) 0 (0.0) 1 (8.3) 3 (25.0) 3 (25.0) 4 (33.3) 1 (8.3) 3 (.%) Recipient cause of death, n (%) Acute rejection CAV Cerebrovascular Infection Graft failure Multiple organ failure Other Missing
Total (N = 710) CF-LVAD (control) (n = 643) T-BiVAD (n = 10) T-LVAD (n = 4) ECMO (n = 38) P-VAD (n = 15)
Recipient Causes of Death at 1 Year Table 2
0.7493 0.2874 0.4202 0.2287 0.6314 0.2727 0.5385 N/A
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combination with increased access to TMCS in transplant centers worldwide, is likely to result in an increase in the number of patients bridged to transplant with TMCS.19 In this study, we identified donor, recipient, and transplant characteristics associated with 1-year post-transplant mortality in patients bridged to transplant with various types of mechanical circulatory support and specifically examined the differences between those implanted with a durable CFLVAD compared with other TMCS devices using patientlevel data from a large, international registry. Bridging with TMCS directly to transplant has been relatively rare in the past because these patients did not have a significant advantage compared with patients with durable mechanical circulatory support in access to donor allografts. Therefore, most patients on TMCS required transition to some other form of more durable support before transplant could take place. Yet, given the recent change in the allocation scheme, a more expedited transplantation of TMCS can be expected. Representative and contemporary data regarding expected survival after transplant under different mechanical circulatory support scenarios are thus needed. In our cohort, patients bridged to transplant with ECMO had the highest mortality at 1 year despite being younger and having less comorbidities at the time of transplantation compared with a number of the other mechanical circulatory support groups. A recent study by Ouyang et al23 using the National Inpatient Sample found that patients who were bridged with ECMO had longer length of hospital stay post-transplant. Another recent study of a Spanish national registry by Barge-Caballero et al8 reported that patients bridged with ECMO had higher in-hospital and 1-year mortality post-transplant compared with patients bridged with other strategies. We extended these findings by examining an international cohort of patients and provided additional information on the timing of mortality risk. The mortality risk was highest early after transplant as survival declined to 76.0% within 1 month post-transplant. In recipients who survived past 1 month post-transplant, the rate of death decreased and approximated that of the other groups between 1 and 12 months after transplant (76.0% survival at 1 month and 71.2% at 12 months post-transplant). It must be noted that the distribution of the cause of death in the ECMO group is not different from the other study groups. The duration of mechanical circulatory support before transplant was not available in our study. Barge-Caballero et al8 reported that the duration of support was the shortest in patients bridged to transplant with ECMO, and despite that, their 1-year survival was the lowest among the mechanical circulatory support groups. It is therefore likely that patients with refractory cardiogenic shock who remained on ECMO support at transplant were more likely to experience multiorgan failure and had more adverse events associated with the surgery and post-transplant immunosuppression. Previously, only single-center studies have investigated the outcome of patients bridged to transplant with P-VAD, and the results have been inconclusive.27,28 In our cohort,
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Figure 2 Kaplan−Meier estimates for patient survival within 1 year. Pairwise survival was compared with log-rank tests. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; PVAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; TLVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
patients bridged with P-VAD had lower survival at 1 year compared with patients bridged with CF-LVADs. The mechanisms of this unfavorable outcome are again uncertain but could reflect the frequent use of P-VAD in acute heart failure resulting from acute coronary events or cardiogenic shock during severe decompensation of chronic heart failure.29 Further investigation is warranted as the number of patients bridged to transplant with P-VAD is expected to increase with the approval of a newer generation of P-VAD to be used for up to 30 days.30 While temporary surgically implanted LVADs and BiVADs have been shown to improve hemodynamics in patients with refractory cardiogenic shock, overall survival of this cohort of patients has not been favorable, with only 57% of these patients surviving to hospital discharge without a more definitive therapy.31 Our study shows that survival of patients with T-LVADs or T-BiVAD who received transplant was excellent, reaching close to 90% at 1 year after transplant. Although survival appears similar for patients bridged to transplant with T-LVADs and T-BiVAD compared with CF-LVADs, the sample sizes are small, comprising only 38 patients in the T-LVADs group and 75 patients in the T-BiVAD group. A number of unmeasured variables have likely contributed to the selection of TMCS in these patients, and therefore, this survival comparison should be interpreted in the context of this limitation. In patients with refractory cardiogenic shock resulting from biventricular failure, both ECMO and T-BiVADs are
reasonable choices for temporary support. From the perspective of post-transplant outcome, there appears to be a significant survival advantage in patients bridged to transplant with T-BiVAD compared with patients bridged with ECMO. Even though both support strategies provide a similar degree of hemodynamic support, they each have a unique adverse event profile.32,33 The rapidity of deployment of ECMO offers advantages over the surgically implanted T-BiVAD, as early hemodynamic support in patients with cardiogenic shock confers improved survival.34,35 However, the early stabilization benefit offered by ECMO does not seem to translate to the post-transplant period in patients where a decision is made to proceed to transplant while on ECMO. Ultimately, randomized controlled trials of mechanical circulatory support bridging strategies are needed to guide clinical decision making. This is especially important since the allocation change may result in markedly different time to transplant under different statuses. Therefore, whether the time spent on TMCS will modify post-transplant outcomes needs to be better determined. No differences in the risk of rejection, cardiac allograft vasculopathy, or renal failure were detected within 1 year post-transplant between patients bridged with TMCS and CF-LVADs. Durable mechanical circulatory support devices are known to result in allosensitization, which has been associated with increased rates of post-transplant rejection. Yet, the mechanism of CF-LVADs-induced
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Figure 3 Kaplan−Meier estimates of freedom from cardiac allograft vasculopathy (CAV) (panel A) and freedom from severe renal failure (panel B) within 1 year of transplant. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
allosensitization remains unclear.36−38 In addition, exposure to TMCS resulted in the same rate of rejection as in patients who were supported with durable CF-LVADs. Further investigation on the allosensitization and rejection in
patients bridged to transplant with TMCS is warranted. Ouyang et al23 reported high rates of acute renal failure of up to 64% immediately post-transplant in patients bridged with TMCS using the National Inpatient Sampling
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Treated Acute Rejection Within 1 Year of Transplant
Study group
Patients with known rejection status (n)
Patients with treated acute rejection (n)
Treated acute rejection rate (%)
p-value
CF-LVAD (control) P-VAD ECMO T-LVAD T-BiVAD Overall
5,607 54 78 34 66 5,839
759 5 11 6 8 789
14 9 14 18 12 14
0.832
CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems.
database. Our results show that by 1 year after transplant, the rate of renal failure is <10% across most TMCS groups. This indicates long-term recovery of renal function in most transplant recipients bridged with TMCS.39−41 We believe our findings are relevant and timely as transplant centers across the United States adapt to the new national heart allocation algorithm and as various TMCS are being increasingly used internationally.42 Argument can be made based on our findings that listing of patients with ECMO and P-VAD for transplant should be highly selective, even though these patients now have the highest priority in the allocation scheme. The improved access to transplant for patients with TMCS who suffer high waitlist mortality should be balanced with the potential risk of lower post-transplant survival.1,29,43−47 In this context, we described the overall post-transplant survival for each TMCS bridge to transplant group. In addition, we identified
a number of pre-transplant clinical variables related to the donor, the recipient, and the transplant procedure that can influence expected survival in patients bridged to transplant with TMCS. Some of the clinical characteristics, such as recipient renal function, donor cause of death, and ischemic time have been reported by previous studies to be associated with post-transplant outcome.39−41 Our results can be interpreted and integrated with discretion by clinicians and potentially provide guidance on the types of TMCS to choose for hemodynamically unstable patients who are transplant candidates and on whether proceeding with transplantation for patients already on TMCS can result in an acceptable outcome based on individual patient profiles.48 We recognize that there are important limitations to our study. This was a registry-based retrospective analysis and is subject to limitations related to the study design. The
Figure 4 Risk factors for patient death at 1 year after transplant. Hazard ratios for continuous risk factors are shown for third quartile value compared with first quartile value. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
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Figure 5 Patient predicted survival calculator. Live version is available at https://unos.shinyapps.io/Yin_Heart_Mortality/. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
results of our study have to be interpreted with caution. The number of patients in the TMCS study groups is relatively small, and as such the outcome of each TMCS group as well as the risk factors identified in this study should not be used as the sole decision factor but in the context of the patient factors that may not have been captured by our study. Our analysis only included centers that reported types and brands of support devices, potentially introducing selection bias. As this is an international cohort, it would be interesting to study the waitlist time and survival under different allocation systems. However, most data (98%) were submitted by the centers from North America, and countryspecific data were not available because of data-sharing agreements. By examining registry data that only included patients who received a transplant, we did not address the likelihood of different bridging strategies to result in a transplant. In addition, we excluded patients with multiple or sequential devices; however, the numbers of these were small. Although clinically relevant pre-transplant characteristics captured by the pre-transplant form were included in the predictive model, other potential clinical characteristics not captured in the registry may be responsible for residual confounding. It would be of interest to know the duration of mechanical circulatory support before transplant; however, these data were not available. It is also important to note that the predictive model is derived from a rather small cohort and that its c-statistic is modest, and as such, it may not be accounting for other potential important factors affecting survival. Therefore, external validation of our model would be important. As the clinical profiles of
patients receiving TMCS may change with time, our results will need to be updated. This information could then be used to refine and validate a survival calculator that may at that point be examined as a decision aid tool. We did not include intra-aortic balloon pump as a mechanical circulatory support bridging strategy because the aim of the study was to evaluate the outcome of patients bridged to transplant with support devices with active mode of circulatory support. Although the c index for our model is 0.64, it is similar to the performance of other clinical prediction models used in advanced heart failure and transplant.49−51 While validation of our predictive model in an independent cohort would be desirable, internal validation using robust statistical methods supports its performance.
Conclusion The recent heart allocation policy change in the United States will likely result in an increase in the number of patients bridged to transplant with TMCS. By analyzing a large international database, we found that post-transplant survival is lower in patients bridged to transplant with ECMO and P-VAD; however, the individual patient survival is also influenced by other donor and recipient characteristics. The risk factors identified in this study can assist clinicians in mechanical circulatory support device selection, transplant eligibility, and timing of transplant. Further research is required to prospectively evaluate the changing patterns of mechanical circulatory support bridging strategies as the new heart donor allocation system is adopted.
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Disclosure statement MV is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/ NCATS Award UL 1TR002541) and serves on advisory boards for AstraZeneca, Bayer AG, and Baxter Healthcare. JS reports personal fees from Medtronic and Abbott during the conduct of the study. This work was supported by the ISHLT Transplant Registry Early Career Award to MJY.
Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.hea lun.2019.04.003.
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15. Slaughter MS, Pagani FD, McGee EC, et al. HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2013;32:675-83. 16. Moazami N, Sun B, Feldman D. Stable patients on left ventricular assist device support have a disproportionate advantage: time to reevaluate the current UNOS policy. J Heart Lung Transplant 2011;30:971-4. 17. Dardas T, Mokadam NA, Pagani F, Aaronson K, Levy WC. Transplant registrants with implanted left ventricular assist devices have insufficient risk to justify elective organ procurement and transplantation network status 1A time. J Am Coll Cardiol 2012;60:36-43. 18. Wever-Pinzon O, Drakos SG, Kfoury AG, et al. Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United Network for Organ Sharing thoracic organ allocation policy justified? Circulation 2013;127:452-62. 19. United Network for Organ Sharing, Organ Procurement and Transplantation Network. Adult heart allocation changes; 2018. https://optn. transplant.hrsa.gov/media/2413/adult_heart_criteria.pdf. 20. DePasquale EC, Cheng RK, Baas A, et al. Outcomes of heart transplant (HT) recipients bridged with ECMO. J Heart Lung Transplant 2013;32:S141. 21. Grimm JC, Sciortino CM, Magruder JT, et al. Outcomes in patients bridged with univentricular and biventricular devices in the modern era of heart transplantation. Ann Thorac Surg 2016;102:102-8. 22. Karamlou T, Gelow J, Diggs BS, et al. Mechanical circulatory support pathways that maximize post-heart transplant survival. Ann Thorac Surg 2013;95:480-5. discussion 485. 23. Ouyang D, Gulati G, Ha R, Banerjee D. Incidence of temporary mechanical circulatory support before heart transplantation and impact on post-transplant outcomes. J Heart Lung Transplant 2018;37:1060-6. 24. Chung JC, Tsai PR, Chou NK, Chi NH, Wang SS, Ko WJ. Extracorporeal membrane oxygenation bridge to adult heart transplantation. Clin Transpl 2010;24:375-80. 25. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 update: a report from the American Heart Association. Circulation 2017;135:e146-603. 26. Harrel FE Jr. Regression modeling strategies. 2nd ed. New York, NY: Springer-Verlag; 2015. 27. Hall SA, Lima B, Kale P, et al. Impella 5.0 as a bridge to cardiac transplantation or durable left ventricular assist device. J Heart Lung Transplant 2015;34:S231. 28. Lima B, Kale P, Gonzalez-Stawinski GV, Kuiper JJ, Carey S, Hall SA. Effectiveness and safety of the Impella 5.0 as a bridge to cardiac transplantation or durable left ventricular assist device. Am J Cardiol 2016;117:1622-8. 29. O’Neill WW, Grines C, Schreiber T, et al. Analysis of outcomes for 15,259 US patients with acute myocardial infarction cardiogenic shock (AMICS) supported with the Impella device. Am Heart J 2018;202:33-8. 30. Bernhardt AM, Hakmi S, Sinning C, Lubos E, Reichenspurner H. A newly developed transaortic axial flow ventricular assist device: early clinical experience. J Heart Lung Transplant 2019;38:466-7. 31. Takayama H, Soni L, Kalesan B, et al. Bridge-to-decision therapy with a continuous-flow external ventricular assist device in refractory cardiogenic shock of various causes. Circ Heart Fail 2014;7:799-806. 32. Miller PE, Solomon MA, McAreavey D. Advanced percutaneous mechanical circulatory support devices for cardiogenic shock. Crit Care Med 2017;45:1922-9. 33. Saffarzadeh A, Bonde P. Options for temporary mechanical circulatory support. J Thorac Dis 2015;7:2102-11. 34. Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. J Am Coll Cardiol 2014;63:2769-78. 35. Rihal CS, Naidu SS, Givertz MM, et al. SCAI/ACC/HFSA/STS clinical expert consensus statement on the use of percutaneous mechanical circulatory support devices in cardiovascular care: endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia
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Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiol 2015;65:e7-e26. Chiu P, Schaffer JM, Oyer PE, et al. Influence of durable mechanical circulatory support and allosensitization on mortality after heart transplantation. J Heart Lung Transplant 2016;35: 731-42. Drakos SG, Kfoury AG, Kotter JR, et al. Prior human leukocyte antigen-allosensitization and left ventricular assist device type affect degree of post-implantation human leukocyte antigen-allosensitization. J Heart Lung Transplant 2009;28:838-42. Ko BS, Drakos S, Kfoury AG, et al. Immunologic effects of continuous-flow left ventricular assist devices before and after heart transplant. J Heart Lung Transplant 2016;35:1024-30. Foroutan F, Alba AC, Guyatt G, et al. Predictors of 1-year mortality in heart transplant recipients: a systematic review and meta-analysis. Heart 2018;104:151-60. Marasco SF, Kras A, Schulberg E, Vale M, Lee GA. Impact of warm ischemia time on survival after heart transplantation. Transplant Proc 2012;44:1385-9. Singhal AK, Sheng X, Drakos SG, Stehlik J. Impact of donor cause of death on transplant outcomes: UNOS registry analysis. Transplant Proc 2009;41:3539-44. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J 2014;35:156-67. Grady KL, Naftel DC, Kobashigawa J, et al. Patterns and predictors of quality of life at 5 to 10 years after heart transplantation. J Heart Lung Transplant 2007;26:535-43.
44. Keebler ME, Haddad EV, Choi CW, et al. Venoarterial extracorporeal membrane oxygenation in cardiogenic shock. JACC Heart Fail 2018;6:503-16. 45. Stehlik J, Kobashigawa J, Hunt SA, Reichenspurner H, Kirklin JK. Honoring 50 years of clinical heart transplantation in circulation: indepth state-of-the-art review. Circulation 2018;137:71-87. 46. Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Ann Thorac Surg 2014;97:610-6. 47. United Network for Organ Sharing, Organ Procurement and Transplantation Network. Modify adult heart allocation 2016 2nd round; 2016. https://optn.transplant.hrsa.gov/governance/public-comment/ modify-adult-heart-allocation-2016-2nd-round/. 48. Shah P, Pagani FD, Desai SS, et al. Outcomes of patients receiving temporary circulatory support Before durable ventricular assist device. Ann Thorac Surg 2017;103:106-12. 49. Alba AC, Agoritsas T, Jankowski M, et al. Risk prediction models for mortality in ambulatory patients with heart failure: a systematic review. Circ Heart Fail 2013;6:881-9. 50. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009;88:231-6. 51. United Network for Organ Sharing, Organ Procurement and Transplantation Network. A guide to calculating and interpreting the estimated post-transplant survival (EPTS) score used in the kidney allocation system (KAS); 2018.
http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices Michael Yaoyao Yin, MD,a Omar Wever-Pinzon, MD,a Mandeep R. Mehra, MD, MSc,b Craig H. Selzman, MD,c Alice E. Toll, MS,d Wida S. Cherikh, PhD,d Jose Nativi-Nicolau, MD,a James C. Fang, MD,a Abdallah G. Kfoury, MD,e Edward M. Gilbert, MD,a Line Kemeyou, MD,c Stephen H. McKellar, MD,c Antigone Koliopoulou, MD,c Muthiah Vaduganathan, MD, MPH,b Stavros G. Drakos, MD, PhD,a and Josef Stehlik, MD, MPHa From the aDivision of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah; bBrigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts; cDivision of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah; dUnited Network for Organ Sharing, Richmond, Virginia; and the eIntermountain Medical Center, Murray, Utah.
KEYWORDS: heart allocation; heart transplant; mechanical circulatory support; outcome; risk prediction; survival
BACKGROUND: The new heart allocation system in the United States prioritizes patients supported by temporary mechanical circulatory support (TMCS) devices over those with uncomplicated durable continuous-flow left ventricular assist devices (CF-LVADs), which may increase the number of patients bridged to transplant with TMCS. Limited data are available in guiding post-transplant outcomes with various TMCS devices. We sought to describe post-transplant outcome and identify clinical variables associated with post-transplant outcome in patients bridged to transplant with TMCS. METHODS: Using data from the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, we included subjects who underwent transplantation between 2005 and 2016 with known use of mechanical circulatory support. Pre-transplant recipient, donor, and transplant-specific variables were abstracted. The primary outcome was patient survival at 1-year post-transplant. Outcomes of patients bridged to transplant with TMCS were compared with those of patients bridged with CF-LVADs. Cox regression analyses were performed to identify clinical variables associated with the outcomes. RESULTS: There were 6,528 patients bridged to transplant with the following types of mechanical circulatory support: durable CF-LVADs (n = 6,206), extracorporeal membrane oxygenation (ECMO, n = 134), percutaneous temporary CF-LVADs (n = 75), surgically implanted temporary CF-LVADs (n = 38) or surgically implanted temporary BiVAD (n = 75). Bridging with ECMO (hazard ratio 3.79, 95% confidence interval [CI] 2.69−5.34, p < 0.001) or percutaneous temporary CF-LVADs (hazard ratio 1.83, 95% CI 1.09−3.08, p = 0.02) was independently associated with higher risk of mortality.
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiovascular Medicine, University of Utah, 50 N Medical Dr, Salt Lake City, Utah 84132. Telephone: 801-585-2340. Fax: 801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.04.003
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Additional risk factors included older donor age, female/male donor-recipient match, older recipient age, higher recipient body mass index, higher recipient creatinine, and prolonged ischemic time. CONCLUSIONS: This analysis of a large international cohort of patients bridged to transplant with mechanical circulatory support identified ECMO and percutaneous temporary CF-LVADs as predictors of mortality after transplant, along with additional donor and recipient clinical characteristics. These findings may provide guidance to clinicians in decisions on mechanical circulatory support device selection, transplant eligibility, and timing of transplant. J Heart Lung Transplant 000;000:1−12 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.
The rising incidence and prevalence of heart failure has resulted in an increase in the number of patients listed for heart transplantation in the last decade, yet the number of transplants has risen only modestly.1,2 This discrepancy between the number of transplant candidates and the number of available donors is the principal reason for continuous attention of regulatory transplant bodies worldwide to the appropriateness of their organ allocation algorithms. In the United States, the United Network for Organ Sharing has, over the years, implemented a number of policy changes aimed at preserving a fair and equitable allocation of donor hearts. Such changes have focused mainly on prioritizing patients with the highest waitlist mortality.3 Despite these policy changes, the mortality of patients on the waitlist remains considerable both in the United States and elsewhere.4−12 The introduction of durable left ventricular assist devices (LVADs) to clinical care has increased the numbers of patients successfully bridged to transplant.1,13−15 The first generation of pulsatile continuous flow left ventricular assist devices (CF-LVADs) suffered from an excessive early mortality, prompting an allocation policy in 1999 to allow highest urgency status for patients within the first 30 days of device implantation. Once improvement in post-operative care ensued, this policy was modified in 2002 to allow for the 30-day highest urgency status to be used at the discretion of the clinical team.3,16 The advent of CF-LVADs has reduced the morbidity and mortality of these patients awaiting transplantation without adversely affecting post-transplant survival. In the current era, patients bridged to transplant with durable CF-LVADs have lower rates of death and of deactivation from the list and higher rates of transplantation when compared with patients on dual inotropes or temporary mechanical circulatory support (TMCS) devices.17,18 Thus, a new policy has been introduced to address concerns of a disproportionate advantage for patients listed with durable CFLVADs in relation to the high waitlist mortality for patients awaiting transplantation while supported with TMCS.3,17,18 The United Network for Organ Sharing implemented the most recent revision to the heart allocation system in October of 2018, at which time the priority of uncomplicated patients supported with durable CF-LVADs was lowered and that of patients supported by various TMCS moved to the highest priority. These TMCS modalities include the following: (1) veno-arterial extracorporeal membrane oxygenation (ECMO), (2) non-dischargeable,
surgically implanted biventricular support systems (TBiVADs), (3) non-dischargeable, surgically implanted left ventricular support systems (T-LVADs), and (4) percutaneous ventricular support devices (P-VADs).19 Considering that prior experiences have suggested that patients supported with TMCS are at a greatest risk of waitlist and early post-transplant morbidity and mortality, it is paramount that post-transplant survival be accurately described and clinical variables associated with outcome in such patients be identified.8,20−24 Thus, the principal aim of this study was to describe post-transplant survival in patients bridged to transplant with TMCS and identify recipient, donor, and transplant process characteristics associated with post-transplant outcome.
Methods Study population We examined data in the Thoracic Transplant Registry of the International Society for Heart and Lung Transplantation (ISHLT Registry).1 We included subjects transplanted between January 1, 2005 and June 30, 2016. The study cohort included adult recipients (aged ≥18 years) bridged to transplant with known types of CF-LVADs and TMCS devices including the following: (1) CF-LVADs (HeartMate II, Abbott, Lake Bluff, IL; HeartMate 3, Abbott; HeartWare, Medtronic, Minneapolis, MN; and Jarvik 2000, Jarvik Heart, New York, NY), (2) ECMO, (3) P-VADs (Impella 2.5, Impella CP, and Impella 5.0, Abiomed, Danvers, MA; TandemHeart, Kardia, Italy), (4) TBiVADs (CentriMag Bi-VADs, Abbott), and (5) T-LVADs (CentriMag LVADs, Abbott). The study excluded the following groups of patients: heterotopic transplants, retransplants, multiorgan transplants, recipients bridged with a total artificial heart, recipients bridged with both ECMO and other type of TMCS, and recipients with no follow-up reported after transplant (Figure 1).
Study data Pre-transplant recipient, donor, and transplant-specific variables were abstracted from patient data collected in the ISHLT Registry at the time of transplant. Pre-transplant recipient variables included age, sex, body mass index, heart failure etiology, serum creatinine, history of diabetes, hypertension, and blood type. Donor variables included age, body mass index, history of diabetes mellitus, hypertension, smoking, and cause of death. Transplant-specific variables included ischemic time and donor/ recipient sex.
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Figure 1 Study population. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
Primary and secondary outcomes The primary outcome was patient survival at 1 year after transplant. The secondary outcomes included treated acute rejection; severe renal dysfunction defined as creatinine >2.5 mg/dl, dialysis or renal transplant at the time of follow-up; cardiac allograft vasculopathy; and recipient cause of death (multiorgan failure, graft failure, infection, cerebrovascular accident, cardiac allograft vasculopathy, acute rejection, or other) for those who died within 1 year of transplant.
Statistical analysis Baseline characteristics and outcomes of patients bridged to transplant with TMCS were compared with patients bridged with CFLVADs. Continuous variables were compared with Kruskal −Wallis tests and categorical variables were compared with chisquare tests. Unadjusted patient survival rates, freedom from acute rejection, cardiac allograft vasculopathy, and severe renal dysfunction within 1 year were estimated using the Kaplan−Meier method, by bridging strategy (TMCS vs CF-LVADs) and compared using log-rank tests. The Benjamin-Hochberg procedure was used to adjust pairwise log-rank tests for multiple comparisons.25 Cox proportional hazards analyses were used to examine the association between bridging strategy and 1-year post-transplant mortality. The model was initially built with all of the variables listed in Table 1. Backwards selection was used to determine variables to retain in the final model (p < 0.05). Missing values for risk factors were imputed using multiple imputation methods. Continuous variables were included in the model using a restricted cubic spline to allow for the most flexible fit of the functional form. Model validation was performed using the bootstrap method (without data splitting) and bias corrected index of concordance (c-statistic) was calculated as a measure of discrimination. Continuous calibration to assess the agreement between observed and
predicted risk of graft failure was performed using the bootstrap method.26 The regression coefficients in the final model were used to construct a patient 1-year survival calculator. In the current analyses, p < 0.05 was considered statistically significant. Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC), and R, version 3.3.2 (R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org/).
Results Patient characteristics There were 23,265 heart transplants with known mechanical circulatory support device status and types recorded by the ISHLT Registry during the study period, of which 6,528 patients were bridged to transplant with known types of CF-LVADs or TMCS devices. Most data were submitted by centers from North America (98%), followed by Europe (1%) and other regions (1%). The cohort was further stratified into the following study groups based on the type of devices used for bridging: (1) CF-LVADs (n = 6,206), (2) ECMO (n = 134), (3) P-VAD (n = 75), (4) T-BiVAD (n = 75), and (5) T-LVADs (n = 38). Baseline recipient, donor, and transplant characteristics are displayed in Table 1.
Survival by mechanical circulatory support device type There were 710 deaths in the study cohort at 1 year posttransplant, of which 643 occurred in the CF-LVADs group, 38 in the ECMO group, 15 in the P-VAD group, 10 in the
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Table 1
Recipient, Donor, and Transplant Process Characteristics by Mechanical Circulatory Support Bridging Strategy
Characteristics
P-VAD (n = 75)
ECMO (n = 134)
T-LVAD (n = 38)
T-BiVAD (n = 75)
CF-LVAD (control) (n= 6206)
Total (N = 6528)
53.3 (12.1)
44.9 (15.3)
48.0 (15.7)
45.1 (14.0)
53.4 (12.1)
53.1 (12.3)
25.6 (4.1)
25.5 (4.8)
26.7 (4.6)
25.8 (4.5)
28.4 (5.0)
28.3 (5.0)
35 (0.6) 56 (0.9) 2,559 (41.2) 3,394 (54.7) 65 (1.0) 63 (1.0) 34 (0.5)
47 (0.7) 67 (1.0) 2,659 (40.7) 3,563 (54.6) 72 (1.1) 76 (1.2) 43 (0.7)
1.2 (0.4)
1.2 (0.4)
p-value <0.0001 <0.0001 <0.0001
10 (7.5) 7 (5.3) 44 (33.1) 62 (46.6) 2 (1.5) 6 (4.5) 2 (1.5)
0 (0.0) 1 (2.6) 16 (42.1) 19 (50.0) 0 (0.0) 2 (5.3) 0 (0.0)
0 (0.0) 1 (1.3) 18 (24.0) 47 (62.7) 0 (0.0) 3 (4.0) 6 (8.0)
1.4 (0.6)
1.2 (0.5)
1.1 (0.5)
1.1 (0.5)
19 (25.3)
15 (11.3)
7 (18.4)
20 (27.0)
1890 (30.5)
1951 (29.9)
24 (40.7)
20 (18.2)
10 (33.3)
29 (46.8)
2,573 (55.3)
2,656 (54.0)
22 (29.3) 5 (6.7) 12 (16.0) 36 (48.0)
62 (46.3) 10 (7.5) 12 (9.0) 50 (37.3)
12 (31.6) 6 (15.8) 1 (2.6) 19 (50.0)
35 (46.7) 2 (2.7) 11 (14.7) 27 (36.0)
2,324 (37.4) 237 (3.8) 838 (13.5) 2,807 (45.2)
2,455 (37.6) 260 (4.0) 874 (13.4) 2,939 (45.0)
34.0 (13.0)
35.3 (13.7)
38.3 (9.2)
32.0 (12.8)
31.5 (11.0)
31.7 (11.2)
27.7 (7.1)
26.8 (5.6)
29.5 (5.8)
26.9 (6.1)
27.6 (5.7)
27.6 (5.7)
4 (5.4)
3 (2.4)
1 (2.6)
3 (4.2)
202 (3.3)
213 (3.3)
8 (10.8)
18 (14.6)
10 (26.3)
15 (20.8)
917 (15.0)
968 (15.0)
19 (25.3) 21 (28.0) 32 (42.7) 3 (4.0) 0 (0.0)
23 (17.6) 32 (24.4) 63 (48.1) 0 (0.0) 13 (9.9)
11 (29.7) 13 (35.1) 12 (32.4) 0 (0.0) 1 (2.7)
22 (30.1) 14 (19.2) 32 (43.8) 0 (0.0) 5 (6.8)
1,447 (23.3) 1,171 (18.9) 3,403 (54.9) 36 (0.6) 144 (2.3)
1,522 (23.4) 1,251 (19.2) 3,542 (54.4) 39 (0.6) 163 (2.5)
0.0004 <0.0001 <0.0001 0.0005
Donor characteristics Donor age (years) Mean (SD) Donor body mass index Mean (SD) Donor diabetes mellitus, n (%) Yes Donor hypertension, n (%) Yes Donor cause of death, n (%) Anoxia Cerebrovascular/stroke Head trauma Brain tumor Other
<0.0001 0.0217 0.8158 0.1491 <0.0001
(continued on next page)
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2 (2.7) 2 (2.7) 22 (29.3) 41 (54.7) 5 (6.7) 2 (2.7) 1 (1.3)
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Recipient characteristics Recipient age (years) Mean (SD) Recipient body mass index Mean (SD) Recipient diagnosis, n (%) Congenital heart disease Hypertrophic cardiomyopathy Ischemic cardiomyopathy Non-ischemic cardiomyopathy Restrictive cardiomyopathy Valvular cardiomyopathy Other Recipient serum creatinine (mg/dl) Mean (SD) Recipient diabetes mellitus, n (%) Yes Recipient hypertension, n (%) Yes Recipient ABO, n (%) A AB B O
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726 (11.1) 816 (12.5) 566 (8.7) 4,420 (67.7)
1,503 (100) 5,025 (100)
673 (10.8) 757 (12.2) 523 (8.4) 4,253 (68.5)
1,403 (93.3) 4,803 (95.6)
12 (16.0) 7 (9.3) 9 (12.0) 47 (62.7)
14 (0.9) 61 (1.2) 7 (0.5) 31 (0.6) 57 (3.7) 77 (1.5) 22 (1.5) 53 (1.1) 2005−2010 2011−2016
Transplant era, n (%)
20 (14.9) 29 (21.6) 21 (15.7) 64 (47.8) 14 (18.7) 15 (20.0) 9 (12.0) 37 (49.3)
CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems. Continuous variables are expressed as mean (SD); categorical variables are expressed as n (%).
3.2 (1.1) 3.2 (1.1) 3.5 (1.2) 3.7 (1.3)
Allograft ischemic time (hours) Mean (SD) Donor/recipient sex, n (%) Donor female/recipient female Donor female/recipient male Donor male/recipient female Donor male/recipient male
Transplant characteristics
3.5 (1.3)
3.9 (1.2)
10 (27.0) 28 (23.5) 11 (15.1)
7 (18.4) 8 (21.1) 4 (10.5) 19 (50.0)
827 (12.9) 7 (9.7)
771 (12.7)
<0.0001
<0.0001
<0.0001
0.0006
Post-transplant outcome in patients bridged to transplant
Donor history of smoking, n (%) Yes
Characteristics
Table 1 (Continued)
P-VAD (n = 75)
ECMO (n = 134)
T-LVAD (n = 38)
T-BiVAD (n = 75)
CF-LVAD (control) (n= 6206)
Total (N = 6528)
p-value
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5
T-BiVAD group, and 4 in the T-LVADs group. Survival at 1 year was lowest in the ECMO group (71.2%), followed by the P-VAD group (79.9%), T-BiVAD group (86.2%), T-LVADs group (89.5%), and CF-LVADs group (89.6%; Figure 1). The Kaplan−Meier estimates for patient survival within 1 year of transplant are displayed in Figure 2. In pairwise log-rank comparison of survival at 1 year, ECMObridged patients had lower survival than those bridged with T-LVADs (p = 0.048), T-BiVAD (p = 0.025), and CFLVADs (p ≤ 0.001). P-VAD was associated with lower survival compared with CF-LVADs (p = 0.019). There were no significant differences in pairwise survival comparisons between the other mechanical circulatory support bridging strategies. There were no significant differences in distribution of causes of death by mechanical circulatory support bridging strategy among subjects who died within 1 year of transplant (Table 2).
Acute rejection, cardiac allograft vasculopathy, and severe renal dysfunction by mechanical circulatory support device type There were no significant differences in the rates of treatment for acute rejection, cardiac allograft vasculopathy, or severe renal dysfunction within 1 year by mechanical circulatory support bridging strategy (Figure 3 and Table 3).
Risk factors for 1-year mortality Multivariable Cox regression analyses identified the following independent risk factors for 1-year post-transplant mortality: donor age, donor/recipient sex mismatch, recipient age, recipient body mass index, recipient serum creatinine, allograft ischemic time, and bridging with ECMO and P-VAD vs bridging with CF-LVADs (Figure 4, and Table S1 and Figures S1−5 in the Supplementary Material available online at www.jhltonline.org/). The goodness of the fit of the model was assessed with a calibration plot and showed that the model accurately estimates mortality for high-risk patients and slightly underestimates the risk of mortality for low-risk patients. The model had a c-index of 0.64 for performance in discrimination (Figure S6 online). To better illustrate the survival outcomes in patients bridged to transplant with different types of mechanical circulatory support, we constructed a calculator for estimated 1-year post-transplant survival—https://unos.shinyapps.io/ Yin_Heart_Mortality/ (Figure 5, Table S2). This calculator is not intended for immediate clinical use. Rather, it is a first step example in developing a clinical decision aid that should be refined and updated as more data on TMCS bridging to heart transplant accumulate.
Discussion The latest revision to the US adult heart allocation system prioritizes patients supported by TMCS devices over those with uncomplicated durable CF-LVADs. This, in
ARTICLE IN PRESS CAV, cardiac allograft vasculopathy; CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; NA, not applicable; P-VAD, percutaneous ventricular support devices; TBiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems.
38 (5.8) 11 (1.7) 56 (8.5) 144 (22.0) 173 (26.4) 114 (17.4) 119 (18.2) 55 (.%) 35 (5.9) 10 (1.7) 49 (8.2) 136 (22.9) 153 (25.8) 99 (16.7) 112 (18.9) 49 (.%) 1 (11.1) 1 (11.1) 1 (11.1) 1 (11.1) 3 (33.3) 2 (22.2) 0 (0.0) 1 (.%) 0 (0.0) 0 (0.0) 1 (25.0) 1 (25.0) 1 (25.0) 0 (0.0) 1 (25.0) 0 (.%) 2 (5.6) 0 (0.0) 4 (11.1) 3 (8.3) 13 (36.1) 9 (25.0) 5 (13.9) 2 (.%) 0 (0.0) 0 (0.0) 1 (8.3) 3 (25.0) 3 (25.0) 4 (33.3) 1 (8.3) 3 (.%) Recipient cause of death, n (%) Acute rejection CAV Cerebrovascular Infection Graft failure Multiple organ failure Other Missing
Total (N = 710) CF-LVAD (control) (n = 643) T-BiVAD (n = 10) T-LVAD (n = 4) ECMO (n = 38) P-VAD (n = 15)
Recipient Causes of Death at 1 Year Table 2
0.7493 0.2874 0.4202 0.2287 0.6314 0.2727 0.5385 N/A
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p-value
6
combination with increased access to TMCS in transplant centers worldwide, is likely to result in an increase in the number of patients bridged to transplant with TMCS.19 In this study, we identified donor, recipient, and transplant characteristics associated with 1-year post-transplant mortality in patients bridged to transplant with various types of mechanical circulatory support and specifically examined the differences between those implanted with a durable CFLVAD compared with other TMCS devices using patientlevel data from a large, international registry. Bridging with TMCS directly to transplant has been relatively rare in the past because these patients did not have a significant advantage compared with patients with durable mechanical circulatory support in access to donor allografts. Therefore, most patients on TMCS required transition to some other form of more durable support before transplant could take place. Yet, given the recent change in the allocation scheme, a more expedited transplantation of TMCS can be expected. Representative and contemporary data regarding expected survival after transplant under different mechanical circulatory support scenarios are thus needed. In our cohort, patients bridged to transplant with ECMO had the highest mortality at 1 year despite being younger and having less comorbidities at the time of transplantation compared with a number of the other mechanical circulatory support groups. A recent study by Ouyang et al23 using the National Inpatient Sample found that patients who were bridged with ECMO had longer length of hospital stay post-transplant. Another recent study of a Spanish national registry by Barge-Caballero et al8 reported that patients bridged with ECMO had higher in-hospital and 1-year mortality post-transplant compared with patients bridged with other strategies. We extended these findings by examining an international cohort of patients and provided additional information on the timing of mortality risk. The mortality risk was highest early after transplant as survival declined to 76.0% within 1 month post-transplant. In recipients who survived past 1 month post-transplant, the rate of death decreased and approximated that of the other groups between 1 and 12 months after transplant (76.0% survival at 1 month and 71.2% at 12 months post-transplant). It must be noted that the distribution of the cause of death in the ECMO group is not different from the other study groups. The duration of mechanical circulatory support before transplant was not available in our study. Barge-Caballero et al8 reported that the duration of support was the shortest in patients bridged to transplant with ECMO, and despite that, their 1-year survival was the lowest among the mechanical circulatory support groups. It is therefore likely that patients with refractory cardiogenic shock who remained on ECMO support at transplant were more likely to experience multiorgan failure and had more adverse events associated with the surgery and post-transplant immunosuppression. Previously, only single-center studies have investigated the outcome of patients bridged to transplant with P-VAD, and the results have been inconclusive.27,28 In our cohort,
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Figure 2 Kaplan−Meier estimates for patient survival within 1 year. Pairwise survival was compared with log-rank tests. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; PVAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; TLVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
patients bridged with P-VAD had lower survival at 1 year compared with patients bridged with CF-LVADs. The mechanisms of this unfavorable outcome are again uncertain but could reflect the frequent use of P-VAD in acute heart failure resulting from acute coronary events or cardiogenic shock during severe decompensation of chronic heart failure.29 Further investigation is warranted as the number of patients bridged to transplant with P-VAD is expected to increase with the approval of a newer generation of P-VAD to be used for up to 30 days.30 While temporary surgically implanted LVADs and BiVADs have been shown to improve hemodynamics in patients with refractory cardiogenic shock, overall survival of this cohort of patients has not been favorable, with only 57% of these patients surviving to hospital discharge without a more definitive therapy.31 Our study shows that survival of patients with T-LVADs or T-BiVAD who received transplant was excellent, reaching close to 90% at 1 year after transplant. Although survival appears similar for patients bridged to transplant with T-LVADs and T-BiVAD compared with CF-LVADs, the sample sizes are small, comprising only 38 patients in the T-LVADs group and 75 patients in the T-BiVAD group. A number of unmeasured variables have likely contributed to the selection of TMCS in these patients, and therefore, this survival comparison should be interpreted in the context of this limitation. In patients with refractory cardiogenic shock resulting from biventricular failure, both ECMO and T-BiVADs are
reasonable choices for temporary support. From the perspective of post-transplant outcome, there appears to be a significant survival advantage in patients bridged to transplant with T-BiVAD compared with patients bridged with ECMO. Even though both support strategies provide a similar degree of hemodynamic support, they each have a unique adverse event profile.32,33 The rapidity of deployment of ECMO offers advantages over the surgically implanted T-BiVAD, as early hemodynamic support in patients with cardiogenic shock confers improved survival.34,35 However, the early stabilization benefit offered by ECMO does not seem to translate to the post-transplant period in patients where a decision is made to proceed to transplant while on ECMO. Ultimately, randomized controlled trials of mechanical circulatory support bridging strategies are needed to guide clinical decision making. This is especially important since the allocation change may result in markedly different time to transplant under different statuses. Therefore, whether the time spent on TMCS will modify post-transplant outcomes needs to be better determined. No differences in the risk of rejection, cardiac allograft vasculopathy, or renal failure were detected within 1 year post-transplant between patients bridged with TMCS and CF-LVADs. Durable mechanical circulatory support devices are known to result in allosensitization, which has been associated with increased rates of post-transplant rejection. Yet, the mechanism of CF-LVADs-induced
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Figure 3 Kaplan−Meier estimates of freedom from cardiac allograft vasculopathy (CAV) (panel A) and freedom from severe renal failure (panel B) within 1 year of transplant. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
allosensitization remains unclear.36−38 In addition, exposure to TMCS resulted in the same rate of rejection as in patients who were supported with durable CF-LVADs. Further investigation on the allosensitization and rejection in
patients bridged to transplant with TMCS is warranted. Ouyang et al23 reported high rates of acute renal failure of up to 64% immediately post-transplant in patients bridged with TMCS using the National Inpatient Sampling
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Treated Acute Rejection Within 1 Year of Transplant
Study group
Patients with known rejection status (n)
Patients with treated acute rejection (n)
Treated acute rejection rate (%)
p-value
CF-LVAD (control) P-VAD ECMO T-LVAD T-BiVAD Overall
5,607 54 78 34 66 5,839
759 5 11 6 8 789
14 9 14 18 12 14
0.832
CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems.
database. Our results show that by 1 year after transplant, the rate of renal failure is <10% across most TMCS groups. This indicates long-term recovery of renal function in most transplant recipients bridged with TMCS.39−41 We believe our findings are relevant and timely as transplant centers across the United States adapt to the new national heart allocation algorithm and as various TMCS are being increasingly used internationally.42 Argument can be made based on our findings that listing of patients with ECMO and P-VAD for transplant should be highly selective, even though these patients now have the highest priority in the allocation scheme. The improved access to transplant for patients with TMCS who suffer high waitlist mortality should be balanced with the potential risk of lower post-transplant survival.1,29,43−47 In this context, we described the overall post-transplant survival for each TMCS bridge to transplant group. In addition, we identified
a number of pre-transplant clinical variables related to the donor, the recipient, and the transplant procedure that can influence expected survival in patients bridged to transplant with TMCS. Some of the clinical characteristics, such as recipient renal function, donor cause of death, and ischemic time have been reported by previous studies to be associated with post-transplant outcome.39−41 Our results can be interpreted and integrated with discretion by clinicians and potentially provide guidance on the types of TMCS to choose for hemodynamically unstable patients who are transplant candidates and on whether proceeding with transplantation for patients already on TMCS can result in an acceptable outcome based on individual patient profiles.48 We recognize that there are important limitations to our study. This was a registry-based retrospective analysis and is subject to limitations related to the study design. The
Figure 4 Risk factors for patient death at 1 year after transplant. Hazard ratios for continuous risk factors are shown for third quartile value compared with first quartile value. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
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Figure 5 Patient predicted survival calculator. Live version is available at https://unos.shinyapps.io/Yin_Heart_Mortality/. CF-LVAD, continuous-flow left ventricular assist devices; ECMO, extracorporeal membrane oxygenation; MCS, mechanical circulatory support; P-VAD, percutaneous ventricular support devices; T-BiVAD, non-dischargeable, surgically implanted biventricular support system; T-LVAD, non-dischargeable, surgically implanted left ventricular support systems; VAD, ventricular assist device.
results of our study have to be interpreted with caution. The number of patients in the TMCS study groups is relatively small, and as such the outcome of each TMCS group as well as the risk factors identified in this study should not be used as the sole decision factor but in the context of the patient factors that may not have been captured by our study. Our analysis only included centers that reported types and brands of support devices, potentially introducing selection bias. As this is an international cohort, it would be interesting to study the waitlist time and survival under different allocation systems. However, most data (98%) were submitted by the centers from North America, and countryspecific data were not available because of data-sharing agreements. By examining registry data that only included patients who received a transplant, we did not address the likelihood of different bridging strategies to result in a transplant. In addition, we excluded patients with multiple or sequential devices; however, the numbers of these were small. Although clinically relevant pre-transplant characteristics captured by the pre-transplant form were included in the predictive model, other potential clinical characteristics not captured in the registry may be responsible for residual confounding. It would be of interest to know the duration of mechanical circulatory support before transplant; however, these data were not available. It is also important to note that the predictive model is derived from a rather small cohort and that its c-statistic is modest, and as such, it may not be accounting for other potential important factors affecting survival. Therefore, external validation of our model would be important. As the clinical profiles of
patients receiving TMCS may change with time, our results will need to be updated. This information could then be used to refine and validate a survival calculator that may at that point be examined as a decision aid tool. We did not include intra-aortic balloon pump as a mechanical circulatory support bridging strategy because the aim of the study was to evaluate the outcome of patients bridged to transplant with support devices with active mode of circulatory support. Although the c index for our model is 0.64, it is similar to the performance of other clinical prediction models used in advanced heart failure and transplant.49−51 While validation of our predictive model in an independent cohort would be desirable, internal validation using robust statistical methods supports its performance.
Conclusion The recent heart allocation policy change in the United States will likely result in an increase in the number of patients bridged to transplant with TMCS. By analyzing a large international database, we found that post-transplant survival is lower in patients bridged to transplant with ECMO and P-VAD; however, the individual patient survival is also influenced by other donor and recipient characteristics. The risk factors identified in this study can assist clinicians in mechanical circulatory support device selection, transplant eligibility, and timing of transplant. Further research is required to prospectively evaluate the changing patterns of mechanical circulatory support bridging strategies as the new heart donor allocation system is adopted.
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Disclosure statement MV is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/ NCATS Award UL 1TR002541) and serves on advisory boards for AstraZeneca, Bayer AG, and Baxter Healthcare. JS reports personal fees from Medtronic and Abbott during the conduct of the study. This work was supported by the ISHLT Transplant Registry Early Career Award to MJY.
Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.hea lun.2019.04.003.
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