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Pages 952-960 (November 2018)
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Vol. 71. Issue 11.
Pages 952-960 (November 2018)
Special article
DOI: 10.1016/j.rec.2018.08.018
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Spanish Heart Transplant Registry. 29th Official Report of the Spanish Society of Cardiology Working Group on Heart Failure
Registro Español de Trasplante Cardiaco. XXIX Informe Oficial de la Sección de Insuficiencia Cardiaca de la Sociedad Española de Cardiología (1984-2017)
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Francisco González-Vílcheza,
Corresponding author
cargvf@gmail.com

Corresponding author: Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla s/n, 39008 Santander, Cantabria, Spain.
, Luis Almenar-Bonetb, María G. Crespo-Leiroc, Luis Alonso-Pulpónd, José González-Costeloe, José Manuel Sobrino-Márquezf, José María Arizón del Pradog, Iago Sousa-Casasnovash, Juan Delgado-Jiménezi, Félix Pérez-Villaj, on behalf of the Spanish Heart Transplant Teams
a Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
b Hospital Universitario y Politécnico La Fe, Valencia, Spain
c Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
d Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
e Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
f Hospital Universitario Virgen del Rocío, Sevilla, Spain
g Hospital Universitario Reina Sofía, Córdoba, Spain
h Hospital Universitario Gregorio Marañón, Madrid, Spain
i Hospital Universitario 12 de Octubre, Madrid, Spain
j Hospital Universitari Clínic de Barcelona, Barcelona, Spain
COLLABORATORS IN THE SPANISH HEART TRANSPLANT REGISTRY, 1984-2017
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Tables (7)
Table 1. Centers Participating in the Spanish Heart Transplant Registry by Order of First Transplant Performed (1984-2017)
Table 2. Spanish Heart Transplant Registry (1984-2017). Procedure Type
Table 3. Recipient Characteristics in the Spanish Heart Transplant Registry (2008-2017)
Table 4. Donor Characteristics and Ischemia Time in the Spanish Heart Transplant Registry (2008-2017)
Table 5. Induction Immunosuppression in the Spanish Heart Transplant Registry (2008-2017)
Table 6. Univariate Survival Analysis by Baseline Characteristics of the Recipient, Donor, and Procedure (2008-2017)
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Abstract
Introduction and objectives

The present report updates the characteristics and results of heart transplantation in Spain, mainly focused in the 2008-2017 period.

Methods

We describe the recipient and donor characteristics, surgical procedures, and outcomes of heart transplants performed in 2017. The 2017 data were compared with those obtained from 2008 to 2016.

Results

A total of 304 cardiac transplants were performed in 2017. Between 1984 and 2017, 8173 procedures were performed, 2689 of them after 2008. Significant temporal trends were observed in recipient characteristics (lower pulmonary vascular resistance, lower use of mechanical ventilation, and a higher percentage of diabetic patients and those with previous cardiac surgery), donor characteristics (older donor age and a higher percentage of female donors and those with a prior cardiac arrest) and procedures (lower ischemia time). In 2017, 27% of patients were transplanted after undergoing mechanical ventricular assistance (P <.001 for trend). In the last decade, there was a trend to better survival.

Conclusions

Around 300 transplants per year were performed in Spain in the last decade. There was a significant increase in the use of pretransplant mechanical circulatory support and a trend to improved survival.

Keywords:
Heart transplant
Registry
Survival
Abbreviations:
ECMO
RETC
Resumen
Introducción y objetivos

Se actualizan las características clínicas y los resultados de los trasplantes cardiacos realizados en España en el periodo 2008-2017.

Métodos

Se describen las características de los receptores, los donantes, los procedimientos quirúrgicos y los resultados de los trasplantes realizados en 2017 y se ponen en contexto respecto a los del periodo 2008-2016.

Resultados

En 2017 se realizaron 304 trasplantes. Desde 1984, se han realizado 8.173 trasplantes, 2.689 de ellos desde 2008. Para el periodo 2008-2017, se observan tendencias temporales significativas en las características del receptor (menores resistencias vasculares pulmonares, menos ventilación mecánica previa al trasplante, mayor tasa de diabéticos y cirugía cardiaca previa), el donante (de más edad, más donantes mujeres y más donantes con parada cardiaca) y el procedimiento (menos tiempo de isquemia). En 2017, el 27% de los trasplantes se realizaron previa asistencia ventricular mecánica (p<0,001 para la tendencia). En la última década, se observa una tendencia a una mejor supervivencia.

Conclusiones

La actividad de trasplante cardiaco se estabiliza en alrededor de 300 procedimientos al año. Se extiende el uso de dispositivos de asistencia ventricular antes del trasplante, con tendencia a la mejora de la supervivencia.

Palabras clave:
Trasplante cardiaco
Registro
Supervivencia
Full Text
INTRODUCTION

In the absence of contraindications, heart transplant is currently the recommended treatment for heart failure patients whose condition remains critical despite optimal medical and device therapy. In 2016, more than 7000 heart transplant procedures were performed worldwide, with more than a third of them in Europe.1 For low prevalence diseases and procedures such as heart transplant, one of the most effective ways to improve quality of care and clinical research is to maintain a clinical registry. These registries are especially valuable if they are comprehensive, like the Spanish Heart Transplant Registry (Registro Español de Trasplante Cardiaco [RETC]).

This annual report provides an update on the RETC, incorporating transplant data from 2017.

METHODSPatients and Procedures

The data analyzed cover the clinical characteristics of recipients and donors, surgical procedures, immunosuppression, and mortality in the 18 active heart transplant programs in Spain (Table 1). Of the participating centers, 6 carry out pediatric heart transplants, 2 of them exclusively, and 2 of the centers carry out combined heart-lung transplants. The numbers of procedures performed since the first use of this therapeutic modality are summarized in Figure 1. Since 1984, 8173 heart transplant procedures have been carried out in Spain. The types of procedures performed in the whole series are summarized in Table 2.

Table 1.

Centers Participating in the Spanish Heart Transplant Registry by Order of First Transplant Performed (1984-2017)

1. Hospital de la Santa Creu i Sant Pau, Barcelona 
2. Clínica Universitaria de Navarra, Pamplona 
3. Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid 
4. Hospital Marqués de Valdecilla, Santander 
5. Hospital Reina Sofía, Córdoba (adults and pediatric) 
6. Hospital Universitario y Politécnico La Fe, Valencia (adults and pediatric) 
7. Hospital Gregorio Marañón, Madrid (adults and pediatric) 
8. Fundación Jiménez Díaz, Madrid (1989-1994) 
9. Hospital Virgen del Rocío, Seville 
10. Hospital 12 de Octubre, Madrid 
11. Hospital Universitario de A Coruña, La Coruña (adults and pediatric) 
12. Hospital Bellvitge, L’Hospitalet de Llobregat, Barcelona 
13. Hospital La Paz, Madrid (pediatric) 
14. Hospital Central de Asturias, Oviedo, Asturias 
15. Hospital Clínic, Barcelona 
16. Hospital Virgen de la Arrixaca, El Palmar, Murcia 
17. Hospital Miguel Servet, Zaragoza 
18. Hospital Clínico, Valladolid 
19. Hospital Vall d’Hebron, Barcelona (pediatric) 
Figure 1.

Yearly number of transplant procedures performed (1984-2017), in the total series and by age group.

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Table 2.

Spanish Heart Transplant Registry (1984-2017). Procedure Type

Procedure  2017  1984-2017 
De novo heart transplant  295  7806 
Retrasplant  193 
Combined retransplant  6a 
Combined transplant  162 
Heart-lung  81 
Heart-kidney  70b 
Heart-liver  11 
Total  304  8161 
a

All were renal transplants.

b

Heart retransplants are included.

The present report analyzes results from the past 10 years (2008-2017). To analyze time trends, most results were grouped into 3-year transplant periods (2008-2010, 2011-2013, and 2014-2016). The percentage of urgent transplants, the type of circulatory support, and donor age were analyzed by year of transplant.

The database structure and RETC practices concerning data collection, data handling, auditing, and data protection have been described previously.2 An effort has been made to present statistical data from before 2017 in a format consistent with previous studies; however, the process of continually updating the registry database may have led to the introduction of minor discrepancies in decimals. Nevertheless, any such minor discrepancies do not significantly affect the trends in proportions shown with this same updating procedure, which reveals large changes in pretransplant circulatory support (Figure 2).

Figure 2.

Type of pretransplant circulatory support used by year (2008-2017). ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.

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Statistical Analysis

Continuous variables are expressed as mean±standard deviation, and categorical variables as as percentages. Between-group differences in categorical variables were analyzed by the Kendall tau nonparametric test for a time series trend, whereas between-group differences in continuous variables were examined by analysis of variance with polynomial adjustment. Survival curves were calculated using the Kaplan-Meier method and were compared by the log-rank test. Differences were considered statistically significant at P <.05.

RESULTSRecipient Characteristics

The main recipient characteristics by 3-year transplant period are summarized in Table 3. In 2017, there were 304 transplant procedures, 23 (7.6%) of them in recipients younger than 16 years. Approximately 3 of every 4 recipients were men, and mean recipient age was 48.5 (range, 0.05-73.0) years. The mean age of adult recipients was 51.8 years. Most procedures were de novo heart-only transplants (97%), with retransplants and combined transplants accounting for less than 3% of the total. Most combined transplant procedures were heart and lung or heart and kidney. These rates have remained largely unaltered since 2008.

Table 3.

Recipient Characteristics in the Spanish Heart Transplant Registry (2008-2017)

  2008-2010 (n=807)  2011-2013 (n=732)  2014-2016 (n=846)  P (trend)  2017 (n=304) 
Age, y  49.8±17.1  49.1±17.1  49.7±16.6  .9  48.5±16.6 
<16 years  7.7  8.1  6.4  .29  7.6 
> 60 years  30.1  27.7  29.2  .69  24.7 
Men  73.0  74.3  75.4  .26  72.4 
BMI  25.0±4.7  24.6±4.8  24.6±4.5  .11  25.0±5.1 
Underlying heart disease        .88   
Dilated nonischemic  35.9  35.8  37.1    38.2 
Ischemic  37.8  35.5  37.0    31.3 
Valvular  6.9  6.3  4.0    3.5 
Other  19.3  22.4  21.9    27.0 
PVR (WU)  2.5±1.7  2.1±1.2  2.2±1.3  .001  2.1±1.2 
Creatinine> 2 mg/dL  5.6  5.0  6.0  .71  6.6 
Bilirubin> 2 mg/dL  15.4  15.8  16.8  .48  19.6 
Insulin-dependent diabetes  15.6  19.4  23.1  < .001  22.6 
Moderate-severe COPD  9.3  8.7  11.7  .1  9.6 
Previous infection  14.0  14.5  15.7  .31  15.8 
Previous cardiac surgery  27.0  32.8  32.1  .025  36.6 
Type of transplant        .85   
Single transplant  96.2  95.8  96.3    97.0 
Retransplant  1.6*  2.2  1.8    1.6 
Combined  2.1  2.0  1.9    1.3 
Heart-lung  1.1  0.9  1.0   
Heart-kidney  0.7*  0.9  0.7    — 
Heart-liver  0.2  0.1  0.2    0.3 
Pretransplant mechanical ventilation  18.4  15.8  14.6  .04  11.8 
Urgent transplant  34.3  41.1  46.3  < .001  44.4 
Prettransplant circulatory support        < .001   
No support  73.6  65.7  61.1    60.9 
Balloon pump  15.2  15.4  11.0    3.9 
ECMO  4.5  8.7  10.8    8.2 
Ventricular assist device  6.7  10.1  17.1    27.0 

BMI, body mass index; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; PVR, pulmonary vascular resistance.

Data are expressed as the percentage or the mean±standard deviation.

*

One patient with a heart retransplant combined with a kidney transplant.

Since 2008, there have been statistically significant trends toward lower pulmonary resistance (P <.001), increased percentages of recipients with diabetes (P <.001) and a history of cardiac surgery before transplant (P <.025), and a lower percentage of recipients receiving mechanical ventilation at the time of transplant (P <.04). Over the same period, there was an appreciable but nonsignificant trend toward an increase in the number of recipients with obstructive pulmonary disease (P <.10).

In 2017, 44% of transplant procedures were urgent (Figure 3), and 39.1% of transplant recipients received pretransplant circulatory support. Compared with previous years, there was a higher use of continuous-flow ventricular assist devices, with a marked reduction in the use of balloon pump counterpulsation. There were no changes in the use of extracorporeal membrane oxygenation (ECMO) and pulsatile-flow ventricular assist devices (Figure 2).

Figure 3.

Percentage of urgent transplant procedures performed by year in the total series (2008-2017).

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Donor Characteristics and Ischemia Time

Donor characteristics for the 3-year transplant periods and for 2017 are summarized in Table 4. The trend toward a higher mean donor age continued in 2017, with donors older than 45 years now accounting for 60% of the total (Figure 4). There was a further increase in the percentage of donors who died due to stroke (54.9%), accompanied by corresponding decreases in the percentage who died due to trauma (17.4%) and in the number of donors with pretransplant cardiac arrest. In contrast, cold ischemia time decreased slightly in 2017, with a decrease in ischemia times >4hours (25.3%) and an increase in times <2hours.

Table 4.

Donor Characteristics and Ischemia Time in the Spanish Heart Transplant Registry (2008-2017)

  2008-2010 (n=807)  2011-2013 (n=732)  2014-2016 (n=846)  P (trend)  2017 (n=304) 
Age, y  37.4±14.4  39.8±15.6  43.3±14.4  < .001  44.7±14.0 
Age> 45 years  35.2  41.8  54.1  < .001  59.9 
Men  66.8  61.2  59  .001  60.9 
Female donor-male recipient  18.3  23.4  24.8  .001  23.0 
Weight, kg  72.7±18.1  72.6±18.6  74.6±17.9  .03  74.7±17.2 
Recipient/donor weight  0.94±0.2  0.94±0.2  0.93±0.2  .14  0.96±0.2 
Recipient/donor weight> 1.2  7.6  8.1  6.3  .27  10.9 
Recipient/donor weight <0.8  20.0  21.1  21.8  .38  21.1 
Causeof death        .016   
Trauma  30.6  30.5  23.2    17.4 
Stroke  44.1  46.4  50.7    54.9 
Other  25.3  23.1  26.1    27.6 
Pretransplant cardiac arresta  10.1  12.4  16.8  < .001  19.4 
Predonation echocardiographyb        .09   
Not done  3.3  3.0  1.0    1.6 
Normal  93.8  94  96.3    95.6 
Mild generalized dysfunction  2.1  3.0  2.7    2.8 
Ischemia time, min  212.4±64.3  211.0±60.1  197.7±72.2  < .001  193.4±71.1 
≤ 120 min  9.8  8.9  16.3  .001  18.8 
120-180 min  21.8  19.4  22.6    20.4 
180-240 min  37.9  42.8  34.3    35.5 
> 240 min  30.5  28.9  26.8    25.3 

Data are expressed as the percentage or the mean±standard deviation.

a

Of 2129 transplant procedures.

b

Of 2066 transplant procedures.

Figure 4.

Yearly changes in donor age and percentage of donors older than 45 years (2008-2017). 95%CI, 95% confidence interval; ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.

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Immunosuppresion

The drugs used for induction immunosuppression during the study period are summarized in Table 5. As in previous years, induction therapy in 2017 mostly consisted of tacrolimus (90.5%), mycophenolate (and to a much lower extent mycophenolic acid) (96.6%), and steroids (98%). Approximately 85% of transplant recipients in 2017 also received antibody-based induction therapy, mostly basiliximab (76.1%).

Table 5.

Induction Immunosuppression in the Spanish Heart Transplant Registry (2008-2017)

  2008-2010 (n=807)  2011-2013 (n=732)  2014-2016 (n=846)  P (trend)  2017 (n=304) 
Calcineurin inhibitors, %
Cyclosporine  35.5  23.6  8.0  < .001  5.8 
Tacrolimus  59.5  72.3  89.2  < .001  90.5 
Antiproliferative agents, %
MMF/MPS  94.6  96.4  96.2  .93  96.6 
Azathioprine  2.5  0.3  0.9  .013  1.4 
m-TOR inhibitors
Sirolimus  0.4  0.5  0.3  .58  1.2 
Everolimus  3.0  1.6  1.7  .11  1.2 
Steroids  97.8  97.5  98.0  .78  98.0 
Induction        < .01   
Not used  12.0  14.1  15.4    15.9 
ALG/ATG  5.2  2.4  3.2    5.0 
Daclizumab  14.8  0.4  0.2    0.7 
Basiliximab  67.1  83.0  80.8    76.1 
Other  0.9  0.1  0.4    2.3 

ALG, antilymphocyte globulin; ATG, antithymocyte globulin, MMF, mycophenolate mofetil; MPS, mycophenolate sodium.

Survival

Recipient survival in the 2008 to 2017 and 1984 to 2007 periods is compared in Figure 5. Compared with the earlier period, the 2008 to 2017 period showed a statistically significant improvement in survival, attributable to increased survival rates both at 1 year and over the longer term. The 1-year survival rate showed a mean improvement of 2.5%. Beyond the first year, the yearly death rate decreased from 2.2% to 1.6%. This trend toward improved survival continued within the 2008 to 2017 study period, approaching significance (P <.056) for the comparison between the 2014 to 2016 and 2008 to 2011 3-year transplant periods (Figure 6).

Figure 5.

Comparison of survival curves for the 2008-2017 and 1984-2007 periods.

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Figure 6.

Comparison of survival curves for 2008-2016 by 3-year period.

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The dominant variables influencing survival during the study period were recipient age and the type of pretransplant circulatory support (Table 6). Compared with pediatric recipients (< 16 years old), recipients older than 60 years at the time of transplant had a 70% higher mortality risk (P <.001), whereas the increased risk in recipients between the ages of 16 and 60 years was > 30% (P <.07). Previous ECMO increased the mortality risk by more than 40% (P <.008) compared with patients with no circulatory support device. However, results for recipients with a balloon pump or ventricular assist device were indistinguishable from those of patients with no support device (Table 6). During the 2008 to 2017 study period, there was no evidence that survival was influenced by donor age or urgent vs elective transplant.

Table 6.

Univariate Survival Analysis by Baseline Characteristics of the Recipient, Donor, and Procedure (2008-2017)

  HR (95%CI)  P  Survival, y, median (95%CI) 
Recipient age
<16 y    — 
16-60 y  1.3 (1.0-1.8)  .07  — 
> 60 y  1.7 (1.3-2.4)  .001  9.2 (8.6-9.8) 
Type of transplant
Single transplant    — 
Combined transplant  1.5 (1.0 -2.3)  .06  — 
Retrasplant  1.4 (0.9-2.2)  .15  — 
Donor age
≤ 45 y    10.0 (9.3-10.6) 
> 45 y  1.0 (0.9-1.1)  .97  10.0 (9.2-10.8) 
Urgency code
Elective    — 
Urgent  1.1 (1.0-1.3)  .11  10.0 (9.4-10.7) 
Type of support
No support    — 
Balloon pump  1.0 (0.8-1.3)  .65  — 
ECMO  1.4 (1.1-1.8)  .008  — 
Ventricular assist device  1.1 (0.9-1.3)  .49  — 

95%CI, 95% confidence interval; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio.

Causes of Death

During the study period, the principal cause of death in the first posttransplant year was primary graft failure (32.6%), especially in the first month (43.5%), followed by infection (22.9%). Between the first and fifth posttransplant years, the most frequent causes of death were graft vascular disease/cardiac arrest (27.8%) and cancer (21.1%) (Figure 7). Overall, acute rejection caused 8% of posttransplant deaths, with the rate almost 3-fold higher (17.8%) between the first and fifth posttransplant years than in the first year (6.1%).

Figure 7.

Main causes of death by time since transplant in the 2008-2017 period. CA, cardiac arrest; GVD, graft vascular disease.

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Almost all patients included in the present analysis survived the first year after transplant. Among those who did not, infection increased significantly as the cause of death between the 2008 to 2010 and 2011 to 2013 transplant periods, thereafter remaining stable (Figure 8). In contrast, primary graft failure showed a progressive and statistically significant decline as the cause of death in the first posttransplant year. Mortality due to transplant rejection has remained stable over the last decade (Figure 8).

Figure 8.

Main causes of death occurring in the first year after transplant (2008-2016) by 3-year period. P values indicate the significance of the trend between 3-year periods, excluding 2017. Only 17 patients receiving a heart transplant in 2017 had completed ≥ 1-year follow-up at the time of database closure.

(0.11MB).
DISCUSSION

Heart transplant activity in Spain has remained steady in recent years, at approximately 250 to 300 transplants a year. Given current donor characteristics and the exclusive sourcing of hearts from brain-dead donors, these figures are likely very close to the upper limit for heart transplant in Spain. Relaxation of the criteria for donor hearts, especially to allow donation after circulatory death, could increase organ supply, as demonstrated in small-scale studies in other countries.3 Organ supply could also be increased by routine use of coronary angiography in older donors or those with cardiovascular risk factors, who currently constitute the majority of heart donors in Spain.4

The data from 2017 confirm and in some instances reinforce the trends observed over the past decade. In addition to the increasing use of older donors who until recently would have been considered “borderline”, perhaps the most remarkable finding is the change in the type of circulatory support at the time of urgent intervention. The previous RETC report already revealed the worse short-term survival among recipients supported by ECMO than among those with ventricular assist devices.2 These findings were recently confirmed by a more comprehensive analysis of the RETC data5 and form the basis for the recent adjustment of the urgency code criteria, introduced by the Organización Nacional de Trasplantes (Spanish National Transplant Organization) in June 2017. Clinical stabilization with ventricular assist devices maintains the recipient in a better medical and hemodynamic condition during the transplant procedure, thus reducing the need for mechanical ventilation.6,7 Using this approach, it is possible to achieve survival levels similar to those obtained after elective transplant.

The current data maintain the trend toward improved outcomes seen in previous reports. This trend did not reach statistical significance, probably due to the small sample size; nonetheless, the trend is apparent even over the past 10 years. The most notable development has been the reduction in early posttransplant mortality. This has been achieved largely through the progressive decline in deaths due to primary graft failure, as well as the stabilization of mortality due to infection and acute rejection. The declining rate of primary graft failure can be explained by improved prevention due to the decline in mean ischemia time, in combination with improved therapy through the broad implementation of circulatory support programs, which are especially effective for the treatment of this serious complication.8

CONCLUSIONS

Heart transplant activity in Spain has stabilized at approximately 250 to 300 procedures per year. In 2017, there was an increase in the prettransplant use of ventricular assist devices and a continuation of the trend to use organs from older donors. Recipient survival continued to show a trend toward progressive improvement.

CONFLICTS OF INTEREST

F. González-Vílchez has participated in Novartis educational presentations and has received compensation for travel costs from Pfizer and Bayer. M.G. Crespo-Leiro is the recipient of a CIBERCV grant, has participated in educational presentations for Novartis, Astellas, MSD, and Abbott, and has received compensation for travel costs from Novartis and Astellas. J. González-Costelo acts as a consultant for Alnylam, Abbot, Pfizer, and Novartis, has delivered lectures for Novartis, and has received compensation for travel costs from Astellas and Servier.

APPENDIX
COLLABORATORS IN THE SPANISH HEART TRANSPLANT REGISTRY, 1984-2017

Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid  Javier Segovia-Cubero, Manuel Gómez-Bueno, Francisco Hernández-Pérez 
Hospital Universitario y Politécnico La Fe, Valencia  Soledad Martínez-Penades, Mónica Cebrián-Pinar, Raquel López-Vilella, Ignacio Sánchez-Lázaro, Luis Martínez-Dolz 
Complejo Hospitalario Universitario de A Coruña, A Coruña  María J Paniagua-Martín, Eduardo Barge-Caballero, Gonzalo Barge-Caballero, David Couto-Mallón 
Hospital Universitario Reina Sofía, Córdoba  Amador López-Granados, Carmen Segura-Saintgerons, Dolores Mesa, Martín Ruiz, Elías Romo, Francisco Carrasco, José López-Aguilera 
Hospital Universitario Marqués de Valdecilla, Santander  Manuel Cobo, Miguel Llano-Cardenal, José A. Vázquez de Prada, Francisco Nistal-Herrera 
Hospital Gregorio Marañón (adults), Madrid  María Jesús Valero, Juan Fernández-Yáñez, Paula Navas, Carlos Ortiz, Adolfo Villa, Eduardo Zataraín, Manuel Martínez-Sellés 
Hospital Universitario 12 de Octubre, Madrid  María Dolores García-Cosío, Laura Morán-Fernández, Zorba Blázquez 
Hospital de la Santa Creu i Sant Pau, Barcelona  Eulàlia Roig-Minguell, Vicens Brossa-Loidi, Sonia Mirabet-Pérez, Laura López-López 
Hospital Universitario Virgen del Rocío, Sevilla  Ernesto Lage-Gallé, Diego Rangel-Sousa 
Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona  Nicolás Manito-Lorite, Carles Díez-López, Josep Roca-Elías 
Clínica Universitaria de Navarra, Pamplona  Gregorio Rábago-Aracil 
Hospital Clínic Universitari, Barcelona  María Ángeles Castel, Marta Farrero, Ana García-Álvarez 
Hospital Universitario Central de Asturias, Oviedo  José Luis Lambert-Rodríguez, Beatriz Díaz-Molina, María José Bernardo-Rodríguez 
Hospital Universitario Gregorio Marañón (pediatric), Madrid  Manuela Camino-López, Juan Miguel Gil-Jaurena, Nuria Gil-Villanueva 
Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia  Iris Garrido-Bravo 
Hospital Universitario Miguel Servet, Zaragoza  Teresa Blasco-Peiró, Ana Pórtoles-Ocampo, Marisa Sanz-Julve 
Clínico Universitario, Valladolid  Luis de la Fuente-Galán, Javier Tobar-Ruiz, Ana María Correa-Fernández 
Hospital Universitario La Paz, Madrid  Luis García-Guereta Silva, Álvaro González-Rocafort, Carlos Labradero-de Lera, Luz Polo- López 
Hospital Universitario Vall d’Hebron, Barcelona  Dimpna C. Albert-Brotons, Ferrán Gran-Ipiña, Raúl Abella-Antón 

.

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Collaborators are listed in the Appendix.

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