Impacto de la variabilidad intrapaciente en la concentración sanguínea de anticalcineurínicos en los resultados del trasplante cardiaco

[Abstract] Introduction and objectives. Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. Methods. We retrospectively studied patients aged ≥ 18 years, with a first heart transplant performed between 2000 and 2014 and surviving ≥ 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. Results. The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation > 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P = .056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P = .065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P = .011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. Conclusions. IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.[Resumen] Introducción y objetivos. El objetivo es estudiar el impacto clínico de la variabilidad intrapaciente (VIP) de la concentración sanguínea de los anticalcineurínicos en el trasplante cardiaco, pues la información actual es escasa. Métodos. Se analizó retrospectivamente a pacientes de edad ≥ 18 años con un trasplante cardiaco realizado entre 2000 y 2014 y con supervivencia ≥ 1 año. La VIP se valoró mediante el coeficiente de variación de concentraciones entre los meses 4 a 12 postrasplante. El compuesto de rechazo, mortalidad o pérdida del injerto y la mortalidad o pérdida del injerto 1-5 años tras el trasplante se analizaron mediante regresión de Cox. Resultados. Se estudió a 1.581 receptores (edad, 56 años; mujeres, 21%), tratados con ciclosporina (790 pacientes) o tacrolimus (791 pacientes). En el análisis multivariable, un coeficiente de variación > 27,8% tendió a asociarse con el compuesto de rechazo/mortalidad (HR = 1,298; IC95%, 0,993-1,695; p = 0,056) y con la mortalidad (HR = 1,387; IC95%, 0,979-1,963; p = 0,065) a los 5 años. La asociación con el rechazo fue significativa al analizar a la población sin rechazos durante el primer año del trasplante (HR = 1,609; IC95%, 1,129-2,295; p = 0,011). El tacrolimus tuvo menos VIP que la ciclosporina, junto con unos mejores resultados por la menor influencia de la VIP. Conclusiones. La VIP de los anticalcineurínicos, especialmente con la inmunosupresión basada en el tacrolimus, se asocia solo marginalmente con los resultados a medio plazo del trasplante cardiaco, aunque puede tener influencia en los pacientes más estables durante el primer año tras el trasplante

Cold ischemia >4 hours increases heart transplantation mortality. An analysis of the Spanish heart transplantation registry

[Abstract] Background. Cold ischemia time (CIT) has been associated to heart transplantation (HT) prognosis. However, there is still uncertainty regarding the CIT cutoff value that might have relevant clinical implications. Methods. We analyzed all adults that received a first HT during the period 2008–2018. CIT was defined as the time between the cross-clamp of the donor aorta and the reperfusion of the heart. Primary outcome was 1-month mortality. Results. We included 2629 patients, mean age was 53.3 ± 12.1 years and 655 (24.9%) were female. Mean CIT was 202 ± 67 min (minimum 20 min, maximum 600 min). One-month mortality per CIT quartile was 9, 12, 13, and 19%. One-year mortality per CIT quartile was 16, 19, 21, and 28%. CIT was an independent predictor of 1-month mortality, but only in the last quartile of CIT >246 min (odds ratio 2.1, 95% confidence interval 1.49–3.08, p < .001). We found no relevant differences in CIT during the study period. However, the impact of CIT in 1-month and 1-year mortality decreased with time (p value for the distribution of ischemic time by year 0.01), particularly during the last 5 years. Conclusions. Although the impact of CIT in HT prognosis seems to be decreasing in the last years, CIT in the last quartile (>246 min) is associated with 1-month and 1-year mortality. Our findings suggest the need to limit HT with CIT > 246 min or to use different myocardial preservation systems if the expected CIT is >4 h

Impacto de la edad del donante-receptor en la supervivencia al trasplante cardiaco. Subanálisis del Registro Español de Trasplante Cardiaco

[Abstract] Introduction and objectives. The age of heart transplant recipients and donors is progressively increasing. It is likely that not all donor-recipient age combinations have the same impact on mortality. The objective of this work was to compare survival in transplant recipients according to donor-recipient age combinations. Methods. We performed a retrospective analysis of transplants performed between 1 January 1993 and 31 December 2017 in the Spanish Heart Transplant Registry. Pediatric transplants, retransplants and combined transplants were excluded (6505 transplants included). Four groups were considered: a) donor < 50 years for recipient < 65 years; b) donor < 50 years for recipient ≥ 65 years; c) donor ≥ 50 years for recipient ≥ 65 years, and d) donor ≥ 50 years for recipient < 65 years. Results. The most frequent group was young donor for young recipient (73%). There were differences in the median survival between the groups (P < .001): a) younger-younger: 12.1 years, 95%CI, 11.5-12.6; b) younger-older: 9.1 years, 95%CI, 8.0-10.5; c) older-older: 7.5 years, 95%CI, 2.8-11.0; d) older-younger: 10.5 years, 95%CI, 9.6-12.1. On multivariate analysis, independent predictors of mortality were the age of the donor and the recipient (0.008 and 0.001, respectively). The worst combinations were older-older vs younger-younger (HR, 1.57; 95%CI, 1.22-2.01; P < .001) and younger-older vs younger-younger (HR, 1.33; 95%CI, 1.12-1.58; P = .001). Conclusions. Age (of the donor and recipient) is a relevant prognostic factor in heart transplant. The donor-recipient age combination has prognostic implications that should be identified when accepting an organ for transplant.[Resumen] Introducción y objetivos. La edad de receptores y donantes cardiacos se está incrementando progresivamente. Es probable que no todas las combinaciones tengan el mismo impacto en la mortalidad. El objetivo de este trabajo es comparar la supervivencia de los pacientes trasplantados según la combinación de edades de donante y receptor. Métodos. Análisis retrospectivo del Registro Español de Trasplante Cardiaco de los trasplantes realizados entre el 1 de enero de 1993 y el 31 de diciembre de 2017. Se excluyeron los pediátricos, los retrasplantes y los trasplantes combinados (se incluyeron 6.505 trasplantes). Se consideraron 4 grupos: a) donante menor de 50 años para receptor menor de 65 años; b) donante menor de 50 años para receptor de edad ≥ 65 años; c) donante de edad ≥ 50 años para receptor de 65 o más, y d) donante de edad ≥ 50 años para receptor menor de 65. Resultados. El grupo más frecuente fue el de donante joven para receptor joven (73%). Hubo diferencias en la mediana de supervivencia entre los grupos (p < 0,001): a) joven-joven: 12,1 años (IC95%, 11,5-12,6); b) joven-mayor: 9,1 años (IC95%, 8,0-10,5); c) mayor-mayor: 7,5 años (IC95%, 2,8-11,0), y d) mayor-joven: 10,5 años (IC95%, 9,6-12,1). En el análisis multivariante, las edades del donante y del receptor resultaron predictoras independientes de la mortalidad (0,008 y 0,001 respectivamente). Las peores combinaciones fueron mayor-mayor frente a joven-joven (HR = 1,57; IC95%, 1,22-2,01; p < 0,001) y joven-mayor frente a joven-joven (HR = 1,33; IC95%, 1,12-1,58; p = 0,001). Conclusiones. La edad (del donante y del receptor) es un factor pronóstico relevante en el trasplante cardiaco. La combinación de edades de donante y receptor posee implicaciones pronósticas que se debe conocer a la hora de aceptar un órgano para trasplante

Complicaciones infecciosas relacionadas con la asistencia circulatoria mecánica de corta duración en candidatos a trasplante cardiaco urgente

[Abstract] Introduction and objectives. Short-term mechanical circulatory support is frequently used as a bridge to heart transplant in Spain. The epidemiology and prognostic impact of infectious complications in these patients are unknown. Methods. Systematic description of the epidemiology of infectious complications and analysis of their prognostic impact in a multicenter, retrospective registry of patients treated with short-term mechanical devices as a bridge to urgent heart transplant from 2010 to 2015 in 16 Spanish hospitals. Results. We studied 249 patients, of which 87 (34.9%) had a total of 102 infections. The most frequent site was the respiratory tract (n = 47; 46.1%). Microbiological confirmation was obtained in 78 (76.5%) episodes, with a total of 100 causative agents, showing a predominance of gram-negative bacteria (n = 58, 58%). Compared with patients without infection, those with infectious complications showed higher mortality during the support period (25.3% vs 12.3%, P = .009) and a lower probability of receiving a transplant (73.6% vs 85.2%, P = .025). In-hospital posttransplant mortality was similar in the 2 groups (with infection: 28.3%; without infection: 23.4%; P = .471). Conclusions. Patients supported with temporary devices as a bridge to heart transplant are exposed to a high risk of infectious complications, which are associated with higher mortality during the organ waiting period.[Resumen] Introducción y objetivos. El uso de dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante es frecuente en España. Se desconocen la epidemiología y la repercusión de las complicaciones infecciosas en estos pacientes. Métodos. Descripción sistemática de la epidemiología y análisis de la repercusión pronóstica de las complicaciones infecciosas en un registro multicéntrico retrospectivo de pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante cardiaco urgente entre 2010 y 2015 en 16 hospitales españoles. Resultados. Se estudió a 249 pacientes; 87 (34,9%) de ellos tuvieron un total de 102 infecciones. La vía respiratoria fue la localización más frecuente (n = 47; 46,1%). En 78 casos (76,5%) se obtuvo confirmación microbiológica; se aislaron en total 100 gérmenes causales, con predominio de bacterias gramnegativas (n = 58, 58%). Los pacientes con complicaciones infecciosas presentaron mayor mortalidad durante el periodo de asistencia circulatoria mecánica (el 25,3 frente al 12,3%; p = 0,009) y menor probabilidad de recibir un trasplante (el 73,6 frente al 85,2%; p = 0,025) que los pacientes sin infección. La mortalidad posoperatoria tras el trasplante fue similar en ambos grupos (con infección, el 28,3%; sin infección, el 23,4%; p = 0,471). Conclusiones. Los pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente al trasplante cardiaco están expuestos a un alto riesgo de complicaciones infecciosas, las cuales se asocian con una mayor mortalidad en espera del órgano

Incidence and Prognosis of Colorectal Cancer After Heart Transplantation: Data From the Spanish Post-Heart Transplant Tumor Registry

In this observational and multicenter study, that included all patients who underwent a heart transplantation (HT) in Spain from 1984 to 2018, we analyzed the incidence, management, and prognosis of colorectal cancer (CRC) after HT. Of 6,244 patients with a HT and a median follow-up of 8.8 years since the procedure, 116 CRC cases (11.5% of noncutaneous solid cancers other than lymphoma registered) were diagnosed, mainly adenocarcinomas, after a mean of 9.3 years post-HT. The incidence of CRC increased with age at HT from 56.6 per 100,000 person-years among under 45 year olds to 436.4 per 100,000 person-years among over 64 year olds. The incidence rates for age-at-diagnosis groups were significantly greater than those estimated for the general Spanish population. Curative surgery, performed for 62 of 74 operable tumors, increased the probability of patient survival since a diagnosis of CRC, from 31.6% to 75.7% at 2 years, and from 15.8% to 48.6% at 5 years, compared to patients with inoperable tumors. Our results suggest that the incidence of CRC among HT patients is greater than in the general population, increasing with age at HT

Pulmonary vascular remodeling and prognosis in patients evaluated for heart transplantation: insights from the OCTOPUS-CHF study

[Abstract] Objective: In patients with advanced heart failure, the intravascular optical coherence tomography (OCT) of subsegmental pulmonary artery measurements is correlated with right heart catheterization parameters. Our aim was to study the prognostic value of pulmonary OCT, right heart catheterization data, and the echocardiographic estimation of pulmonary pressure in patients studied for elective heart transplants. Methods: This research is an observational, prospective, multicenter study involving 90 adults with a one-year follow-up. Results: A total of 10 patients (11.1%) died due to worsening heart failure before heart transplantation, 50 underwent a heart transplant (55.6%), and 9 died in the first year after the transplant. The patients with and without events (mortality or heart failure-induced hospitalization) had similar data regarding echocardiography, right heart catheterization, and pulmonary OCT (with a median estimated pulmonary artery systolic pressure of 42.0 mmHg, interquartile range (IQR) of 30.3-50.0 vs. 47.0 mmHg, IQR 34.6-59.5 and p = 0.79, median pulmonary vascular resistance of 2.2 Wood units, IQR 1.3-3.7 vs. 2.0 Wood units, IQR 1.4-3.2 and p = 0.99, and a median pulmonary artery wall thickness of 0.2 ± 0.5 mm vs. 0.2 ± 0.6 mm and p = 0.87). Conclusion: Pulmonary vascular remodeling (evaluated with echocardiography, right heart catheterization, and pulmonary OCT) was not associated with prognosis in a selected sample of adults evaluated for elective heart transplants. Pulmonary OCT is safe and feasible for the evaluation of these patients.Instituto de Salud Carlos III; PI18/00254European Regional Development Fund; CB16/11/0050

Valor pronóstico de la concentración sérica de lactato de los receptores de trasplante cardiaco urgente: subanálisis del estudio multicéntrico español ASIS-TC

[Abstract] Introduction and objectives. To study the prognostic value of serum lactate in patients under temporary preoperative mechanical circulatory support who underwent urgent heart transplant. Methods. We conducted a subanalysis of a Spanish multicenter registry recording data on patients under temporary mechanical circulatory support listed for highly urgent heart transplant from 2010 to 2015. Participants selected for the present study were those who received a transplant and who had known preoperative serum lactate levels. The main study outcome was 1-year survival after transplant. Results. A total of 177 heart transplant recipients were studied; preoperatively, 90 were supported on venoarterial extracorporeal membrane oxygenation, 51 on temporary left ventricular assist devices, and 36 on temporary biventricular assist devices. Preoperative hyperlactatemia (≥ 2 mmol/L) was present in 44 (25%) patients. On multivariable analysis, pretransplant serum lactate was identified as an independent predictor of 1-year posttransplant survival (adjusted HR per 0.1 mmol/L, 1.02; 95%CI, 1.01-1.03; P = .007). One-year posttransplant survival was 53.1% (95%CI, 45.3-60.9) in patients with preoperative hyperlactatemia and 75.6% (95%CI, 71.8-79.4) in those without preoperative hyperlactatemia (adjusted HR, 1.94; 95%CI, 1.04-3.63; P = .039). Preoperative hyperlactatemia correlated with adverse outcomes in patients supported with extracorporeal membrane oxygenation, but not in patients supported on ventricular assist devices. Conclusions. Preoperative serum lactate is a strong independent predictor of worse outcomes in patients undergoing urgent heart transplant on short-term mechanical circulatory support.[Resumen] Introducción y objetivos. Analizar el impacto del lactato sérico en receptores de trasplante cardiaco urgente en asistencia circulatoria mecánica de corta duración preoperatoria. Métodos. Se realizó un subanálisis de un registro multicéntrico español basado en pacientes incluidos en «urgencia grado 0» para trasplante cardiaco con asistencia circulatoria mecánica preoperatoria de corta duración entre 2010 y 2015. Se seleccionó a los receptores de trasplante con cifras preoperatorias de lactato conocidas. El desenlace principal fue la supervivencia 1 año tras el trasplante. Resultados. Se estudió a 177 receptores de trasplante cardiaco urgente, de los que 90 necesitaron asistencia preoperatoria con oxigenador extracorpóreo de membrana venoarterial, 51 con asistencia ventricular izquierda y 36 con asistencia biventricular. De ellos, 44 (25%) presentaban hiperlactatemia antes del trasplante (≥ 2 mmol/l). En el análisis multivariable, la cifra de lactato sérico resultó predictora independiente de mortalidad tras el trasplante (cada 0,1 mmol/l, HR ajustada = 1,02; IC95%, 1,01-1,03; p = 0,007). La supervivencia estimada al año del trasplante cardiaco fue del 53,1% (IC95%, 45,3-60,9) en los pacientes con hiperlactactemia preoperatoria y el 75,6% (IC95%, 71,8-79,4) en los pacientes sin hiperlactatemia (HR ajustada = 1,94; IC95%, 1,04-3,63; p = 0,039). El impacto pronóstico de la hiperlactatemia fue significativo en los pacientes asistidos con oxigenador extracorpóreo de membrana venoarterial, pero no en aquellos con dispositivos de asistencia ventricular. Conclusiones. Los valores preoperatorios de ácido láctico son un potente factor pronóstico independiente en receptores de trasplante cardiaco urgente

Pulmonary Vascular Remodeling and Prognosis in Patients Evaluated for Heart Transplantation: Insights from the OCTOPUS-CHF Study

Objective: In patients with advanced heart failure, the intravascular optical coherence tomography (OCT) of subsegmental pulmonary artery measurements is correlated with right heart catheterization parameters. Our aim was to study the prognostic value of pulmonary OCT, right heart catheterization data, and the echocardiographic estimation of pulmonary pressure in patients studied for elective heart transplants. Methods: This research is an observational, prospective, multicenter study involving 90 adults with a one-year follow-up. Results: A total of 10 patients (11.1%) died due to worsening heart failure before heart transplantation, 50 underwent a heart transplant (55.6%), and 9 died in the first year after the transplant. The patients with and without events (mortality or heart failure-induced hospitalization) had similar data regarding echocardiography, right heart catheterization, and pulmonary OCT (with a median estimated pulmonary artery systolic pressure of 42.0 mmHg, interquartile range (IQR) of 30.3-50.0 vs. 47.0 mmHg, IQR 34.6-59.5 and p = 0.79, median pulmonary vascular resistance of 2.2 Wood units, IQR 1.3-3.7 vs. 2.0 Wood units, IQR 1.4-3.2 and p = 0.99, and a median pulmonary artery wall thickness of 0.2 +/- 0.5 mm vs. 0.2 +/- 0.6 mm and p = 0.87). Conclusion: Pulmonary vascular remodeling (evaluated with echocardiography, right heart catheterization, and pulmonary OCT) was not associated with prognosis in a selected sample of adults evaluated for elective heart transplants. Pulmonary OCT is safe and feasible for the evaluation of these patients

Venoarterial Extracorporeal Membrane Oxygenation with or without Simultaneous Intra-Aortic Balloon Pump Support as a Direct Bridge to Heart Transplantation: Results from a Nationwide Spanish Registry

[Abstract] OBJECTIVES To investigate the potential clinical benefit of an intra-aortic balloon pump (IABP) in patients supported with venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a bridge to heart transplantation (HT). METHODS We studied 169 patients who were listed for urgent HT under VA-ECMO support at 16 Spanish institutions from 2010 to 2015. The clinical outcomes of patients under simultaneous IABP support (n = 73) were compared to a control group of patients without IABP support (n = 96). RESULTS There were no statistically significant differences between the IABP and control groups with regard to the cumulative rates of transplantation (71.2% vs 81.2%, P = 0.17), death during VA-ECMO support (20.6% vs 14.6%, P = 0.31), transition to a different mechanical circulatory support device (5.5% vs 5.2%, P = 0.94) or weaning from VA-ECMO support due to recovery (2.7% vs 0%, P = 0.10). There was a higher incidence of bleeding events in the IABP group (45.2% vs 25%, P = 0.006; adjusted odds ratio 2.18, 95% confidence interval 1.02–4.67). In-hospital postoperative mortality after HT was 34.6% in the IABP group and 32.5% in the control group (P = 0.80). One-year survival after listing for urgent HT was 53.3% in the IABP group and 52.2% in the control group (log rank P = 0.75). Multivariate adjustment for potential confounders did not change this result (adjusted hazard ratio 0.94, 95% confidence interval 0.56–1.58). CONCLUSIONS In our study, simultaneous IABP therapy in transplant candidates under VA-ECMO support did not significantly reduce morbidity or mortality

Malignancy following heart transplantation: differences in incidence and prognosis between sexes – a multicenter cohort study

[Abstract] Male patients are at increased risk for developing malignancy postheart transplantation (HT); however, real incidence and prognosis in both genders remain unknown. The aim of this study was to assess differences in incidence and mortality related to malignancy between genders in a large cohort of HT patients. Incidence and mortality rates were calculated for all tumors, skin cancers (SCs), lymphoma, and nonskin solid cancers (NSSCs) as well as survival since first diagnosis of neoplasia. 5865 patients (81.6% male) were included. Total incidence rates for all tumors, SCs, and NSSCs were lower in females [all tumors: 25.7 vs. 44.8 per 1000 person‐years; rate ratio (RR) 0.68, (0.60–0.78), P < 0.001]. Mortality rates were also lower in females for all tumors [94.0 (77.3–114.3) vs. 129.6 (120.9–138.9) per 1000 person‐years; RR 0.76, (0.62–0.94), P = 0.01] and for NSSCs [125.0 (95.2–164.0) vs 234.7 (214.0–257.5) per 1000 person‐years; RR 0.60 (0.44–0.80), P = 0.001], albeit not for SCs or lymphoma. Female sex was associated with a better survival after diagnosis of malignancy [log‐rank p test = 0.0037; HR 0.74 (0.60–0.91), P = 0.004]. In conclusion, incidence of malignancies post‐HT is higher in males than in females, especially for SCs and NSSCs. Prognosis after cancer diagnosis is also worse in males