A Contemporary Analysis of Heart Transplantation and Bridge-to-Transplant Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis

Accepted Manuscript Title: A Contemporary Analysis of Heart Transplantation and Bridge-toTransplantation Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis Author: Todd C. Crawford, David R. Okada, J. Trent Magruder, Charles Fraser, Nishant Patel, Brian A. Houston, Glenn J. Whitman, Kaushik Mandal, Kenton J. Zehr, Robert S. Higgins, Edward S. Chen, Hari Tandri, Edward K. Kasper, Ryan J. Tedford, Stuart D. Russell, Nisha A. Gilotra PII: DOI: Reference:

S1071-9164(18)30083-6 https://doi.org/10.1016/j.cardfail.2018.02.009 YJCAF 4106

To appear in:

Journal of Cardiac Failure

Received date: Revised date: Accepted date:

5-6-2017 11-2-2018 13-2-2018

Please cite this article as: Todd C. Crawford, David R. Okada, J. Trent Magruder, Charles Fraser, Nishant Patel, Brian A. Houston, Glenn J. Whitman, Kaushik Mandal, Kenton J. Zehr, Robert S. Higgins, Edward S. Chen, Hari Tandri, Edward K. Kasper, Ryan J. Tedford, Stuart D. Russell, Nisha A. Gilotra, A Contemporary Analysis of Heart Transplantation and Bridge-toTransplantation Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis, Journal of Cardiac Failure (2018), https://doi.org/10.1016/j.cardfail.2018.02.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A Contemporary Analysis of Heart Transplantation and Bridge-to-Transplantation Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis Todd C Crawford, MD1, David R Okada, MD2, J. Trent Magruder, MD1, Charles Fraser, MD1, Nishant Patel, MD1, Brian A Houston, MD3, Glenn J Whitman, MD1, Kaushik Mandal, MD1, Kenton J Zehr, MD1, Robert S Higgins, MD1, Edward S Chen4, MD, Hari Tandri, MD2, Edward K Kasper, MD2, Ryan J Tedford, MD2, Stuart D Russell, MD2, Nisha A Gilotra, MD2 1

Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA 3 Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC USA 4 Division of Pulmonology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA 2

Corresponding Author: Nisha A Gilotra, MD Assistant Professor of Medicine Division of Cardiology, Johns Hopkins University School of Medicine [email protected] Phone: 443-287-6720 Fax: 410-367-2149

Acknowledgements, Conflicts of Interest and Financial Disclosures: The authors have no conflicts of interest or financial relationships to disclose. Dr. Crawford is the Hugh R Sharp, Jr Endowed Cardiac Surgery Research Fellow at Johns Hopkins.

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Highlights for 178267R1   

Heart transplantation for cardiac sarcoidosis is increasing Mechanical support as bridge to transplant is an option in cardiac sarcoid Post-transplant outcomes are favorable in cardiac sarcoid patients

Abstract Background: Patients with end-stage cardiomyopathy due to cardiac sarcoidosis (CS) may be referred for mechanical circulatory support (MCS) and heart transplantation (HT). Here, we describe outcomes of patients with CS undergoing HT, focusing on the use of MCS as a bridge-to-transplant (BTT). Methods: Using the United Network for Organ Sharing (UNOS) Scientific Registry of Transplant Recipients (SRTR), we identified all adult waitlisted patients and isolated HT recipients from 2006-2015. These were divided into those with and without CS, and further divided into those who did or did not receive MCS as BTT. Outcomes included 1- and 5-yr post-transplant freedom from mortality and 5-yr freedom from primary graft failure. Results: Over the study period, 31,528 patients were listed for HT, 148 (0.4%) of whom had CS. Among CS patients, 34 (23%) received MCS as BTT. 18,348 patients (58%) eventually underwent HT, including 67 (0.4%) with CS, 20 (30%) of whom were BTT MCS. Compared to non-CS diagnoses, CS patients had similar 1-yr (91 vs 90%, log rank p=0.88) and 5-yr (83 vs 77%, log rank p=0.46) freedom from mortality. Survival was also comparable between CS BTT and non-CS BTT groups at 1 year (89% vs 89%, log-rank p=0.92) and 5 years (72% vs 75%, log-rank p=0.77). Conclusions: Survival after heart transplantation was similar between CS and non-CS patients out to 5 years, and was additionally similar among CS and non-CS BTT cohorts. Both HT and BTT MCS should be considered in patients with CS. Keywords: Sarcoidosis Heart Transplantation

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Survival Analysis Propensity Score Matching

Introduction Sarcoidosis is an immune-mediated disease that may affect any organ in the body, including the heart [1]. Cardiac sarcoidosis (CS) manifests as heart failure, ventricular arrhythmias, including sudden cardiac death, and conduction system disease [2-5]. While only 5% of patients with systemic sarcoidosis display cardiac symptoms, up to 25% of patients with extracardiac sarcoidosis (ECS) have cardiac involvement at autopsy [6, 7]. Furthermore, up to 25% of patients with CS have isolated cardiac sarcoidosis (ICS), which may carry a worse prognosis than non-isolated CS as patients with ICS more frequently present with left ventricular dysfunction and/or ventricular tachycardia [8]. Around the world, the incidence of cardiac sarcoidosis (CS) appears to be rising [8]. With treatment with corticosteroids and implantable defibrillators, transplantation-free 5-year survival among patients with CS may be > 90% [9]. However, endstage heart failure and refractory ventricular arrhythmias account for the primary drivers of mortality in sarcoidosis. Though consensus statements exist regarding diagnostic imaging and arrhythmia management in this patient cohort, guidance on the management of heart failure, including use of advanced therapies, is lacking [10-12]. The 2016 International Society for Heart and Lung Transplantation (ISHLT) heart transplantation listing criteria do mention CS under the broader category of restrictive cardiomyopathies due to infiltrative/inflammatory disease and highlight the importance of pre-transplant diagnosis in order to assess systemic involvement and post-transplant specific treatment [13]. There have been several older small case series describing transplant outcomes in CS (Table). A previous registry-based report described better 1-year survival (87.7% vs 84.5%, p=0.03) among patients undergoing HT for CS as compared with patients undergoing HT for all other indications [14]. Despite this, concerns about multi-organ involvement and the possibility of recurrence in the allograft have led to hesitancy to pursue HT in patients with CS [15, 16].

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There is limited data from the contemporary HT era regarding outcomes in transplanted CS patients. At the same time, an increasing number of advanced heart failure patients are being referred for mechanical circulatory support (MCS) as bridge-to-transplantation (BTT). Currently, data on the use of MCS as BTT in patients with CS is limited to case reports or small case series [17, 18]. Therefore, the aim of this study was to describe outcomes of patients undergoing HT for CS, with a focus on the use of MCS as BTT.

Methods Patient Population We queried the United Network for Organ Sharing (UNOS) Scientific Registry of Transplant Recipients (SRTR) to identify adult patients (≥18 years) who were listed for or underwent orthotopic HT (OHT) during the period January 1, 2006 to December 31, 2015. We then separated patients into those with and without Sarcoidosis based on the diagnosis at listing. Institutional Review Board approval was waived for this study as the UNOS SRTR contains deidentified data. Outcomes The primary outcomes were freedom from mortality at 1 year and 5 years. We assessed the impact of MCS as BTT, as compared with direct HT, on these outcomes. Finally, we compared primary graft failure between recipients with CS and those with other diagnoses and additionally compared wait-list survival. Statistical Analysis Variables with data missing for greater than 10% of patients were excluded from statistical analysis. Continuous data were reported as mean ± standard deviation for parametric variables and median with interquartile range (IQR) for non-parametric variables and were compared using Student’s t-test and Wilcoxon rank-sum testing, respectively. Categorical variables were reported as n (%) and were compared with Chi-square testing.

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Survival data were analyzed by the method of Kaplan-Meier, and log-rank testing was used to assess differences in freedom from mortality and graft survival. Transplanted patients were propensity scored across 18 variables: age, sex, white race, body mass index, complete dependence (Karnofsky performance status <50), diabetes, baseline GFR, pre-transplant intra-aortic balloon pump requirement, chronic steroid use, MELD-XI score, pulmonary artery (PA) diastolic pressure, pulmonary vascular resistance (PVR), donor age, recipient-donor gender match, donor ejection fraction, number of HLA mismatches, total allograft ischemia time, and average annual volume of transplanting center. The balancing property was satisfied. CS and nonCS groups were then propensity score matched 1:1 without replacement. Variable imbalance was compared between CS and non-CS groups with absolute standardized difference of mean testing. Survival analysis by the method of Kaplan-Meier was then performed and CS and non-CS groups were compared by log-rank testing. STATA 12.0 was used for all statistical analyses (StataCorp, College Station, TX).

Results Between Jan 1, 2006 and Dec 31, 2015, 31,528 patients were listed for HT, including 148 (0.5%) with a list diagnosis of CS. Table 1 compares baseline characteristics of listed patients with and without CS. CS patients were more likely to be female (54/148, 36% vs 8,410 /31,380, 27%, p<0.01), black (62/148, 42% vs 6,641/31,380, 21%, p<0.01), have better renal function (median GFR 60 mL/min CS vs 53 mL/min, p<0.01), and better hemodynamics despite a significantly higher pulmonary vascular resistance (PVR) (Table 1). During the study period, 18,348 (58%) listed patients underwent isolated OHT, including 67/148 (45%) with CS (Figure 1). CS and non-CS heart transplant recipients are subsequently compared in Table 2. CS recipients, as compared to non-CS recipients, were more commonly female (27/67, 40% vs 4706/18,281, 26%, p<0.01) and had a lower prevalence of diabetes (12% vs 27%, p<0.01) despite increased exposure to chronic steroid therapy (58% vs 10%, p<0.01). Median waitlist duration among OHT recipients was 88 days (IQR 23-217) for CS patients versus 80 days (IQR 24-222) for non-CS patients (rank-sum p=0.71).

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Wait-list survival probability at 1 year was 83% in patients with sarcoidosis compared to 86% in patients without CS (log-rank p=0.36). However, a competing risk analysis demonstrated higher probability of transplantation in patients without CS (log-rank p<0.01) (Figure 2). Patients with CS had similar freedom from mortality following HT at 1-year (91% CS vs 90% non-CS, log-rank p=0.88) and 5-years (83% CS vs 77% non-CS, log-rank p=0.46) (Figure 3a). In total, 10 CS patients expired after heart transplantation after a median survival of 200 days. The most common cause of death was infection (n=3, 30%), followed by hemorrhagic complications (n=2, 20%). Acute rejection was the cause of 1 additional mortality (10%). Among the transplanted patients with CS, 3 patients (4.5%) experienced primary graft failure, including 2 patients with acute rejection and 1 patient with an unknown etiology. Median time from transplantation to graft failure in the CS population was 416 days (range 323-1023 days). Similar freedom from primary graft failure at 5 years was noted between CS and non-CS groups (93% vs 92%, respectively, log-rank p=0.76) (Figure 3b). MCS as BTT in Patients with CS During the study period, 10,903 OHT recipients (35%) required MCS as BTT, including 34 patients (0.3%) with CS: 31 patients received a left ventricular assist device (LVAD), 1 patient received a total artificial heart (TAH) and 2 patients received biventricular support (BiVAD). The date of MCS initiation was available for 22 of the 34 CS patients (Figure 1). Of the 34 patients with CS requiring BTT, 16 (47%) received MCS prior to HT listing, and the remaining 18 received MCS while listed. The most commonly implanted MCS devices were HeartMate II (Thoratec, Pleasanton, CA) (n=12, 35%) and HeartWare HVAD (Framingham, MA) (n=8, 24%). Additional LVAD devices included Heartmate XVE (Thoratec, Pleasanton, CA) (n=2, 5.9%), Thoratec (Thoratec, Pleasanton, CA) (n=1, 2.9%). Unspecified LVAD devices were used in an additional 8 patients (24%). Biventricular support was provided by Abiomed BVS 5000 (Abiomed US, Danvers, MA) (n=1, 2.9%) or CentriMag (Thoratec, Pleasanton, CA) (n=1, 2.9%). One patient had a CardioWest Total Artificial Heart (SynCardia Systems, LLC, Tucson, AZ) (n=1, 2.9%).

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Of the 34 waitlisted CS patients who received MCS, 20 (59%) ultimately underwent HT. This proportion was similar to the 6,891/10,869 (63%) MCS patients without CS who were transplanted (p=0.58). Alternatively, patients with CS who did not receive MCS as BTT were less likely than their non-CS counterparts without MCS to be transplanted (41% (47/114) vs 55% (11,390/20,511), p<0.01). CS patients who received MCS included 18 CS patients bridged with LVADs, with 1 patient bridged with a total artificial heart and 1 patient bridged with a BiVAD. BiVAD and TAH therefore constituted 10% of all CS BTT recipients. Comparably, 782 of the 6,891 transplanted non-CS BTT patients (11%) were bridged with either a TAH or BiVAD. In comparing BTT recipients with and without CS, the only notable differences were CS patients were more often female (9/20, 45% vs 1335/6891, 19%, p<0.01) and underwent subsequent HT at lower average transplant volume centers (17 vs 26 transplants, p=0.02) (Table 2). Among CS patients, notable differences in donor and transplant variables emerged between BTT (n=20) and non-bridged (n=47) groups. BTT patients were younger (median age 50 vs 54 years, rank sum p=0.07) and received allografts from younger donors (28 vs 35 years, p=0.02). However, CS BTT patients underwent HT at lower volume centers (17 vs 34 transplants/year, p<0.01) with longer average ischemic times (3.6 vs 2.9 hours, p<0.01) (Table 3). Survival was similar for CS BTT and non-CS BTT groups at 1 year (89% vs 89%, log-rank p=0.92) and 5 years (72% vs 75%, log-rank p=0.77). Additionally, survival probability was comparable between CS BTT and directly transplanted CS patients at 1 year (89% BTT vs 91% non-BTT, log-rank p=0.86) and the survival difference at 5 years also did not reach statistical significance (72% BTT vs 88% non-BTT, log-rank p=0.27). Freedom from primary graft failure was similar at 5 years among all BTT MCS patients, (87% CS vs 92% non-CS patients, log-rank p=0.35). Propensity score matching resulted in 45 well-matched pairs of transplanted CS and non-CS patients. There was minimal imbalance in covariates after successful matching (Supplemental Table 1). Riskadjusted survival analysis revealed nearly identical 1-year (93% CS vs 93% non-CS, log-rank p=1.00) and 5year survival (82% CS vs 79% non-CS, log-rank p=0.97) (Figure 4). Repeat propensity score matching among only BTT patients resulted in 9 well-matched pairs of CS and non-CS recipients. Again, survival at

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both 1 (100% CS vs 89% non-CS, log-rank p=0.32) and 5 years (64% CS vs 53% non-CS, log-rank p=0.90) was similar between groups.

Discussion In this contemporary analysis of patients with end-stage cardiomyopathy due to CS, we demonstrated similar 1-year and 5-year survival after HT between patients with and without CS. After controlling for recipient, donor, and transplant-related confounders, survival remained nearly identical between CS and non-CS HT patients at both 1 and 5 years. Additionally, we showed similar 1-year and 5year survival after BTT MCS between patients with and without CS. Finally, we showed similar 5-year freedom from primary graft failure between patients with and without CS undergoing both BTT and direct HT. The present study is the largest UNOS-based study and the most contemporary to investigate heart transplant outcomes in the CS population, and our data support the findings of previously published smaller institutional and database-driven studies [14, 19]. Furthermore, our study is the first to delve into bridge-totransplantation and the associated heart transplant outcomes among patients with CS. Historical barriers to HT in patients with CS have included concerns about recurrent sarcoidosis in the allograft and multi-organ involvement that might threaten post-HT survival. Case reports have described both histologic [15, 20] and radiologic evidence of CS recurrence in cardiac allografts [21], typically after the tapering off of steroids. In at least 1 report, recurrence was responsive to corticosteroid therapy [22]. As a result, long-term maintenance steroid therapy remains a crucial component of the immunosuppressive regimen in patients with CS who have undergone HT. More contemporary case series have described excellent transplant outcomes in the CS population with no evidence of sarcoidosis recurrence [23-26]. The largest of these single-center studies was performed by Perkel et al and included 19 CS patients with an 83% 5-year post-transplant survival [26]. In a CS pathology-focused study, Sperry, et al demonstrated no recurrence in 19 CS transplant recipients, 5 of whom underwent BTT, at a mean follow-up of 4.2 years [27]. Similarly, in the single-center case series by Theofilogiannakos et al of 12 patients transplanted for CS in

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which they demonstrated 83% 5-year survival, there was no recurrence of cardiac or extra-cardiac sarcoidosis [19]. Our analysis builds on the previous findings from other investigators as it demonstrates comparable 1-year and 5-year survival between patients with and without CS undergoing HT in the contemporary transplant era, during which time there has been increased use of tacrolimus as the preferred calcineurin inhibitor, more rapid steroid tapering and advancements in MCS. Additionally, we found a temporal trend with increased number of patients undergoing HT and MCS over the last decade. The reason for this could be multifold including an increasing incidence of CS whether due to epidemiologic changes or more sensitive diagnostic tools [8], or due to increased comfort of transplant centers in transplanting or bridging CS patients. Previous studies have shown that among BTT patients, functional independence is protective against mortality at 3 years and higher MELD-XI scores are independently associated with increased 3- year mortality [28]. In the present study, functional independence and MELD-XI scores were similar between bridged and non-bridged CS patients. However, two notable characteristics differed between bridged and non-bridged CS patients. First, average ischemic time, which is associated with mortality following HT, was significantly higher in the CS BTT group [18-20]. Second, average center volume, which is also associated with outcomes following HT, was significantly lower in the CS BTT group [29]. It remains unclear why this difference existed and is difficult to make any inferences given the retrospective nature of this study. We anticipated higher volume centers would be performing more complex heart transplants (i.e. patients with pre-transplant MCS support), but that was not observed in this study. Alternatively, perhaps these patients were being bridged with MCS due to long wait times and lack of donor availability at smaller center, and this also explains the longer wait time at status 1A we observed in the CS group as compared to the non-CS group. Though we report that heart transplantation and mechanical circulatory support can be effectively pursued in CS patients, this is within the context of appropriate diagnosis, patient selection and management of these patients perioperatively. As per ISHLT guidelines, a concerted effort should be made to determine heart failure etiology preoperatively as this can have clinical management implications [13]. For cardiac Page 9 of 24

sarcoidosis, this involves appropriate cardiac screening in patients with extracardiac sarcoidosis and cardiac signs or symptoms, including tissue diagnosis when possible [11], imaging in those with suspected isolated CS [10], and thorough assessment of systemic involvement. Advanced therapies should then be considered after failure of immunosuppression to improve cardiac status. At time of transplantation, careful attention should be paid to native heart explant pathology to confirm the diagnosis of CS, and if confirmed, these patients benefit from chronic low dose steroid treatment to avoid recurrence (similar to those with giant cell myocarditis), as opposed to non-CS HT recipients in whom the current practice is to wean steroids off entirely [30]. Additionally, because CS is not necessarily limited to the left ventricle, in those patients being considered for LVAD as a bridge to transplant, thorough hemodynamic assessment should be performed to determine LVAD candidacy and risk of post-LVAD right ventricular failure as per standard guidelines [31]. Post-LVAD these patients likely benefit from ongoing immunosuppressive regimen to treat sarcoidosis in order to avoid recurrent inflammation and control extracardiac manifestations if present. Lastly, CS patients presenting primarily with refractory ventricular arrhythmias that are often driven by granuloma-induced ventricular scar would most likely benefit from direct HT rather than a BTT LVAD approach. More robust retrospective and prospective studies are needed to further explore LVAD patient selection, management and outcomes in the CS population. This retrospective analysis of the UNOS SRTR was subject to several limitations. First, the diagnosis of CS is based on listed diagnosis and does not take into consideration explanted heart pathology as this data was unavailable. Second, the number of CS patients undergoing HT was relatively small. Third, rapid evolution in MCS technology may attenuate the significance of comparisons among patients who underwent BTT at different points in time. Additionally, this analysis did not account for immunosuppression regimens used in the pre-transplant management of sarcoidosis, which may have affected the decision to pursue MCS versus direct transplantation. Finally, we were not able to describe the incidence of sarcoidosis recurrence in cardiac allografts as this outcome is not currently captured in the UNOS database, but we believe this to be a rare event, especially as only 3 cases of primary graft failure were encountered in the CS population at a median follow-up of 968 days. Despite the aforementioned limitations, this is the largest UNOS-based study

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to-date to describe transplant outcomes in the CS population. Furthermore, this is the first study to address outcomes associated with mechanical-circulatory support in CS patients. In conclusion, despite historical concerns about the durability of HT in patients with CS, our study demonstrated equivalent risk-adjusted survival and freedom from primary graft failure out to 5 years between patients with and without CS undergoing both BTT and direct HT. Additionally, our findings suggest that MCS as BTT is efficacious in this unique cohort of heart failure patients, despite increased theoretical risks for MCS complications associated with chronic immunosuppression. As the burden of cardiac sarcoidosis continues to rise, many patients are presenting with the need for advanced mechanical circulatory support and/or heart transplantation, and both MCS and HT should remain part of the treatment paradigm in patients with advanced heart failure due to CS.

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Figure Legend Figure 1. Trends in number of LVADs placed and heart transplants performed in the cardiac sarcoidosis population over the study period Figure 2. Competing risk analysis between sarcoidosis and non-sarcoidosis wait-list populations out to 1 year, comparing probabilities of survival and transplantation. Figure 3 – (a) Kaplan-Meier survival comparison between cardiac sarcoidosis (CS) and non-sarcoidosis heart transplant recipients at 1 and 5 years. (b) Freedom from primary graft failure comparison between CS and non-sarcoidosis patients out to 5 years. Figure 4 - Risk-adjusted post-transplant survival comparison of sarcoidosis and non-sarcoidosis patients out to 5 years.

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Table 1. Comparison of Baseline Characteristics – Sarcoidosis vs Non-Sarcoid Diagnosis

Demographics Age, years Male Gender Race White Black Other BMI, kg/m2 Karnofsky Performance Status Complete Independence (>70) Partial Independence (50-70) Complete Dependence (<50) Diabetes Baseline GFR, mL/min Intubated (at listing) ECMO (at listing) LVAD (at listing) Hemodynamic Measures PA systolic pressure, mmHg PA diastolic pressure, mmHg Pulmonary Capillary Wedge Pressure, mmHg Pulmonary Vascular Resistance, mmHg/L/min Cardiac Index

Sarcoidosis n=148 53 (47-58) 94 (64%)

All Patients Listed Non-Sarcoid Etiology n=31,380 54 (42-61) 22,970 (73%)

p-value 0.46 <0.01 <0.01

83 (56%) 62 (42%) 3 (2.0%)

20,803 (66%) 6,641 (21%) 3,936 (13%)

28±5

27±6

13 (8.8%) 77 (52%) 58 (39%) 35 (24%) 60 (46-80) 3 (2.0%) 1 (0.7%) 5,819 (19%)

5,393 (17%) 12,691 (40%) 13,296 (42%) 8,435 (27%) 53 (39-75) 1,412 (4.5%) 724 (2.3%) 16 (11%)

0.36 <0.01 0.15 0.19 0.02

41±19 19±9 16±8 3.2±3.1 2.1±0.7

44±15 22±9 20±9 2.6±2.3 2.2±0.8

0.02 <0.01 <0.01 <0.01 0.11

0.03 <0.01

Page 16 of 24

Table 2. Comparison of CS and non-CS patients who underwent heart transplant. The left panel compares all transplanted patients over the study period and the right panel compares only patients categorized as bridgeto-transplant. *Bolded p-values indicate statistically significant differences (p<0.05) Sarcoidosi s

Non-Sarcoid Etiology

n=67

n=18,281

Age, years

51 (47-59)

56 (46-62)

Male Sex

40 (60%)

13,575 (71%)

Transplanted Patients pSarcoidosis value BTT

Non-Sarcoid BTT

pvalue

n=20

n=6,891

0.13

50 (46-55)

55 (45-62)

0.06

<0.01

11 (55%)

5,556 (81%)

<0.01

Demographics

Race

0.12

0.70

White

52 (78%)

12,400 (68%)

14 (70%)

4,601 (67%)

Black

12 (18%)

3,660 (20%)

5 (25%)

1,548 (22%)

Other

3 (4.5%)

2,221 (12%)

1 (5%)

742 (11%)

28±5

27±5

29±6

28±5

BMI, kg/m2

0.42

Karnofsky Performance Status

0.26

0.28

0.66

Complete Independence (>70)

7 (10%)

3,265 (18%)

3 (15%)

1,609 (23%)

Partial Independence (50-70)

24 (36%)

6,155 (34%)

8 (40%)

2,646 (38%)

Complete Dependence (<50)

36 (54%)

8,861 (48%)

9 (45%)

2,636 (38%)

a

a

<0.01

3 (15%)

2,019 (29%)a

0.16

53 (41-72)

0.41

Diabetes Baseline GFR, mL/min

8 (12%)

4,945 (27%)

53 (40-72)

53 (40-73)

0.69

44 (38-78)

Previous Transplant

0

539 (3.0%)

0.15

0

47 (0.7%)

0.71

Intubated (at transplant)

0

350 (1.9%)

0.25

0

129 (1.9%)

0.54

ECMO (at transplant)

0

134 (0.7%)

0.48

0

29 (0.4%)

0.77

0.33

0

IABP (at transplant) Chronic Steroid Use

2 (3.0%) 38 (58%)

b

1,053 (5.8%) 1,683 (9.4%)

b

142 (2.1%) b

0.52

<0.01

9 (47%)

MELD-XI Score

10±5.3

10±5.7

0.70

9.3±5.9

9.9±5.6

0.69

Days Status 1a

39±77

27±52

0.05

93±107

48±70

<0.01

Status at Transplantation

545 (8.0%)

b

0.45

0.99

1a

34 (51%)

10,422 (57%)

15 (75%)

5,065 (74%)

1b

26 (39%)

6,538 (36%)

5 (25%)

1,823 (26%)

2

7 (10%)

1,321 (7%)

0

3 (0.04%)

ABO Group

<0.01

0.83

0.82

A

28 (42%)

7,537 (41%)

7 (35%)

2,573 (37%)

B

13 (19%)

2,702 (15%)

4 (20%)

910 (13%)

6 (9%)

1,062 (6%)

0

261 (4%)

20 (30%)

6,980 (38%)

9 (45%)

3,147 (46%)

PA systolic pressure, mmHg

35±14

41±14

<0.01

38±12

39±14

0.57

PA diastolic pressure, mmHg PA Capillary Wedge Pressure, mmHg Pulmonary Vascular Resistance (WU)

17±8

20±9

<0.01

19±7

19±9

0.83

17±8

19±9

0.07

17±9

17±9

0.88

2.0±1.1

2.4±1.8

0.16

2.2±0.6

2.2±1.8

0.88

AB O Hemodynamic Measures

Page 17 of 24

Cardiac Index

2.1±0.7

2.3±0.7

0.11

2.2±0.6

2.3±0.7

0.46

33±12

32±12

0.42

28±12

31±11

0.12

Donor Male Gender

45 (67%)

12,971 (71%)

0.50

13 (65%)

5,284 (77%)

0.22

Donor Gender=Recipient Gender

48 (72%)

13,587 (74%)

0.62

16 (80%)

5,379 (78%)

0.83

Donor Race=Recipient Race

40 (60%)

9,776 (53%)

0.31

12 (60%)

3,649 (53%)

0.53

1.0±0.3

1.0±0.2

1.00

0.9±0.2

1.0±0.2

0.11

63±7

62±7

0.24

61±6

61±7

0.69

4.6±1.0

4.6±1.1

0.85

4.2±0.9

4.6±1.1

0.16

Allograft Ischemic Time

3.1±0.9

3.2±1.1

0.36

3.6±0.9

3.3±1.1

0.23

Average Transplant Center Volume

29±17

28±18

0.88

17±4

26±18

0.02

Donor Variables Donor Age

Donor BMI/Recipient BMI Ratio Donor Ejection Fraction HLA Mismatch Transplant Characteristics

b

out of 66

a

out of 18,233

b

out of 17,991

a b

out of 19

out of 6,869 b

out of 6,768

*BMI-body mass index; GFR–glomerular filtration rate; ECMO–Extracorporeal Membrane Oxygenation; IABP-intraaortic balloon pump; PA-Pulmonary Artery; HLA-Human Leukocyte Antigen

Page 18 of 24

Table 3. Comparison of BTT vs Directly Transplanted Recipients with Cardiac Sarcoidosis Cardiac Sarcoidosis Transplant Recipients BTT

Directly Transplanted

p-value

n=20

n=47

Age, years

50 (46-55)

54 (48-61)

0.07

Female Sex

9 (45%)

18 (38%)

0.61

White

14 (70%)

38 (81%)

Black

5 (25%)

7 (15%)

1 (5%)

2 (4%)

29±6

27±4

Demographics

Race

0.60

Other 2

BMI, kg/m

Karnofsky Performance Status

0.05 0.57

Complete Independence (>70)

3 (15%)

4 (9%)

Partial Independence (50-70)

8 (40%)

16 (34%)

Complete Dependence (<50)

9 (45%)

27 (57%)

3 (15%)

5 (11%)

0.61

44 (38-78)

54 (44-63)

0.41

0

2 (4.3%)

0.35

Diabetes Baseline GFR, mL/min IABP (at transplant)

b

Chronic Steroid Use

9 (47%)

29 (62%)

0.29

MELD-XI Score

9.3±5.9

10.3±5.2

0.53

Days Status 1a

93±107

16±44

<0.01

PA systolic pressure, mmHg

38±12

34±14

0.38

PA diastolic pressure, mmHg

19±7

16±8

0.28

Pulmonary Capillary Wedge Pressure, mmHg

17±9

16±8

0.76

Pulmonary Vascular Resistance, mmHg/L/min

2.2±0.6

2.0±1.3

0.56

Cardiac Index

2.2±0.6

2.1±0.7

0.52

28±12

35±12

0.02

Donor Male Gender

13 (65%)

32 (68%)

0.81

Donor Gender=Recipient Gender

16 (80%)

32 (68%)

0.32

Donor Race=Recipient Race

12 (60%)

28 (60%)

0.97

0.9±0.2

1.1±0.3

0.03

61±6

63±7

0.17

4.2±0.9

4.7±1.0

0.11

3.6±0.9

2.9±0.9

<0.01

17±4

34±19

<0.01

Hemodynamic Measures

Donor Variables Donor Age

Donor BMI/Recipient BMI Ratio Donor Ejection Fraction HLA Mismatch Transplant Characteristics Allograft Ischemic Time Average Transplant Center Volume b

out of 19

Page 19 of 24

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JCF Figure 1.tif

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Revised JCF Figure 2 FEB2018 TC.tif

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Revised JCF Figure 3 FEB2018 TC.tif

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Revised JCF Figure 4 FEB2018 final version.tif

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