Introduction: Gastrointestinal (GI) bleeding remains a major morbid event during continuous flow left ventricular assist device (LVAD) support. Hypothesis: This study investigated whether a common ...

BACKGROUND:Maintenance steroid (MS) use in pediatric heart transplantation is variable. The purpose of this study was to evaluate the impact of MS use on graft outcomes. METHODS:All patients <18 years old in the Pediatric Heart Transplant Study database at the time of first heart transplant between 1993 and 2011 who survived ≥30 days post-transplant and were from centers with a protocolized approach to MS use were included (N = 2,178). Patients were grouped by MS use at 30 days post-transplant as MS+ or MS- (no MS use). Propensity score analysis was used to generate matched groups of MS+ and MS- patients based on pre-transplant and peri-transplant factors. Kaplan-Meier survival analysis was used to compare freedom from graft loss, graft loss secondary to rejection, rejection, rejection with severe hemodynamic compromise (RSHC), malignancy, and infection between groups. RESULTS:Of patients, 1,393 (64%) were MS+ and 785 (36%) were MS-. There were 315 MS- patients who had propensity matched MS+ controls. Kaplan-Meier estimates showed no difference in graft loss (p = 0.9) or graft loss secondary to rejection (p = 0.09). At 1 year post-transplant, there was no difference in freedom from rejection (p = 0.15) or malignancy (p = 0.07), but there was lower freedom from RSHC and infection in the MS- group (p = 0.05 and p = 0.02, respectively). CONCLUSIONS:MS use at 30 days post-transplant was not associated with enhanced graft survival after pediatric heart transplant. MS- patients had a higher incidence of RSHC and infection. These risks should be taken into consideration when determining MS use for pediatric recipients of heart transplants.

OBJECTIVE:Dating back to the first published report of the Fontan circulation in 1971, multiple studies have examined the long-term results of this standard procedure for palliation of single-ventricle heart disease in children. Although the technique has evolved over the last 4 decades to include a polytetrafluorethylene (PTFE) conduit for a large percentage of patients, the long-term outcome has not yet been established. The aim of the current study was to investigate the possibility of a late increasing risk for death after 15 years among patients with a modern Fontan operation and to evaluate late morbidity.METHODS:Between January 1, 1988, and December 31, 2011, 207 patients underwent the Fontan procedure using an internal or external PTFE conduit plus a bidirectional cavopulmonary connection. Survival and late adverse events were analyzed. Risk factors for early and late mortality were examined using hazard function methodology.RESULTS:At 1, 10, and 20 years, survival for the entire cohort was 95%, 88%, and 76%, respectively, with no deaths in the last 6 years of the study. Hazard modeling showed a 1.3% risk of death per year 24 years after the Fontan procedure, with no late increasing hazard phase. Freedom from reoperations was greater than 90% at 20 years and freedom from thrombotic complications was 98% at 20 years (with greater than 80% of patients on aspirin alone). Survival curves were superimposable for 16- to 20-mm conduits, and the freedom from any reoperation including transplantation was greater than 90% after 20 years. Multivariable risk factor analysis identified only earlier date of operation as a predictor of early and late mortality. By era of surgery, the 10-year predicated survival is 89% for patients undergoing surgery in 2000 and 94% for patients in 2010.CONCLUSIONS:Early and late survival after a Fontan operation with a PTFE conduit is excellent, with no late phase of increasing death risk after 20 years. Late functional status is good, the need for late reoperation is rare, and thrombotic complications are uncommon on a standard medical regimen including aspirin as the only anticoagulation medication.

Data from Cardiac Transplant Research Database ( CTRD ) were analyzed from 1999 to 2006 to examine the effects of different induction strategies at the time of cardiac transplantation. A total of 2090 primary heart transplants were categorized by induction with interleukin‐2 receptor blocker ( IL ‐2 RB ), antithymocyte globulin ( ATG ), or no induction ( NI ). Probabilities for rejection and infection were estimated with parametric time‐related models. Using these models, hazard was calculated for two theoretical patient profiles, one at lower risk for rejection and higher risk of infection (Profile 1) and higher risk for rejection and lower risk of infection (Profile 2). Of the 2090 transplants, 49.8% (1095) did not receive induction, 27.3% (599) received IL ‐2 RB , and 18.0% (396) received ATG . Profile 1 patients had lower hazard for rejection with IL ‐2 RB compared to ATG and NI (p < 0.01), but at the cost of increased risk of infection (5.0 vs. 1.8 vs. 1.6, respectively, at four wk, p < 0.01). Profile 2 patients experienced a fivefold decreased hazard for rejection when treated with IL ‐2 RB compared with ATG and NI (p < 0.01). In patients at high risk of infection, IL ‐2 RB reduced risk of rejection but at the expense of increased hazard for infection.

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3-16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1-8 µg/kg). There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T-segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.

BACKGROUND: The Cardiac Transplant Research Database (CTRD) collected data from 26 U.S. institutions from January 1, 1990 to December 31, 2008 providing the opportunity for construction of a comprehensive multivariable model of risk for death after transplantation. We analyzed risk factors for death over 19 years of experience to determine how risk profiles have changed over time and how they interact with age.METHODS: A multivariable parametric hazard model for death was created for 7,015 patients entered into the CTRD. Variables collected over 19 years of experience were examined as potential risk factors and tested for interaction with date of transplantation to determine if their relative risk (RR) changed over time.RESULTS: The hazard for death post-transplant occurred in 2 phases: an early phase of acute risk lasting <1 year, and a late phase of relatively low, gradually increasing risk (<0.1 event/year). In the early phase, predictive models showed that ventricular assist device (VAD) at the time of transplant did not increase the RR of death for recipient transplant at 30 years of age, but the RR of death was increased by 60% (p = 0.04) at 60 years of age. Of the late-phase variables found to be risk factors, the RR of age, date of transplant and pulmonary vascular resistance changed with respect to transplant year. The overall risk of death dropped importantly over the study period, but the RR of all other variables remained unchanged. RR was 2.6 (p < 0.0001) for 25-year-old African-American (AA) versus non-AA recipients and 1.6 for 60-year-old AA recipients (p = 0.02).CONCLUSION: Over 19 years, the baseline risk of death has decreased, but the specific risk factors and the magnitudes of their RR have remained unchanged. Therefore, despite advances in clinical management and improvement in overall survival, the risk profile for death after cardiac transplantation is similar to that in 1990. (C) 2014 International Society for Heart and Lung Transplantation. All rights reserved.

BACKGROUND: The purpose of these studies was to determine the incidence and survival of patients with specific malignancies with respect to age and transplant year and to compare the data with the normal non-transplant population.METHODS: Data from 6,211 primary cardiac transplants between July 31, 1993, and December 30, 2008, were collected by 35 institutions participating in the Cardiac Transplant Research Database. Data were compared with information collected by the Surveillance Epidemiology and End Results (SEER) Cancer Statistics Review 1975-2006.RESULTS: Multivariable analysis showed older age (relative risk [RR], 2.1; p < 0.0001) and earlier transplant year (RR, 1.8; p < 0.0001) were highly significant risk factors. Aggregate malignancy incidence in the modern era (2001 to 2008) did not differ significantly from the normal population, which appeared to be attributable to a lower rate of malignancies other than lung cancer, lymphoma, and melanoma (actual/expected ratio, 0.71). From 2001 to 2008, rates were significantly higher for lung cancer (actual/expected ratio, 1.86; p = 0.006) and lymphoma (actual/expected ratio, 4.3, p < 0.0001) than In the normal population. The highest risk for lymphoma was in younger adults who received transplants at ages 18 to 35 years (actual/expected ratio, 27). The highest risk for lung cancer was in patients who underwent transplantation at ages 55 to 65 years (actual/expected ratio, 28). Once diagnosed with malignancy, subsequent survival at 5 years was 21% for lung cancer and 32% for lymphoma.CONCLUSIONS: The risk of malignancy has markedly declined during a 15-year period such that the aggregate rate of malignancy approached that of the general population in the United States. However, the distribution of malignancies was not the same, with a greater prominence of lung cancer and lymphoproliferative disease. (C) 2014 International Society for Heart and Lung Transplantation. All rights reserved.

Ventricular assist device implantation is associated with gastrointestinal bleeding (GIB); however, outcomes in terms of initial and repeat GIB risk, severity, location of lesions, and endoscopic interventions need to be better defined. Consecutive patients from a database of adult patients with ventricular assist devices (VADs) implanted between January 1, 2000, and December 31, 2010, at a single center were reviewed and followed through May 31, 2011, in a retrospective manner. The GIB events were further classified by severity, lesion location, and lesion type. Hazard analysis models were calculated for the time to GIB events. Of 166 patients with a VAD, 38 patients experienced 84 GIB events. Seventeen patients experienced ≥2 GIB events. Maximal hazard for the first bleeding event was 2.23 events/patient-year at 21 days and declined to the constant hazard by 71 days postimplantation. The hazard for recurrent GIB was greatest immediately after the first GIB event. When considering all GIB events, most lesions (68%) were located in the proximal bowel. Angiodysplasia was the most common lesion type (17.5%) seen on endoscopy when all GIB events were considered, whereas ulcers were the most common type (13.8%) seen in initial GIB events. The actuarial risk of initial GIB events peaks in the first 3 months after VAD implantation followed by a stable lower risk of bleeding. The hazard for recurrent GIB events is substantially increased immediately after the initial GIB.

BACKGROUND: The accuracy of various risk models to predict early post-transplant mortality is limited by the type, quality, and era of the data collected. Most models incorporate a large number of recipient-derived and donor-derived variables; however, other factors related to specific institutional practices likely influence early mortality. The goal of this study was to determine if the addition of institutional practice variables would improve the predictive accuracy of a recipient/donor risk model in a modern cohort of heart transplant recipients.METHODS: Between 1999 and 2007, 3,591 primary heart transplants were performed at the 26 institutions participating in the Cardiac Transplant Research Database. Multivariable regression analysis in the hazard domain was used to identify recipient, donor, and institutional practice variables that were.. predictive of 1-year mortality. The derived model was used to predict institutional outcomes and compare them with observed outcomes first without and then with the inclusion of the institutional practice variables.RESULTS: Eleven individual plus 2 interaction recipient variables and 2 individual plus 2 interaction donor variables were predictive of increased mortality. The addition of institutional practice variables to the model identified 4 variables associated with decreased mortality: greater number of transplant cardiologists, a thoracic surgery fellowship, a surgery or cardiology attending taking donor call, and routine surveillance for antibody-mediated rejection. By using a p-value > 0.10 as a robust measure of similarity, the addition of institutional practice variables increased the number of institutions with similar predicted vs observed mortality from 18 of 26 institutions (69%) to 26 of 26 (100%), demonstrating improved predictive accuracy of the model.CONCLUSIONS: Multiple recipient and donor variables influence early survival but do not fully explain the difference in predicted and observed outcomes at the institutional level. Variations in staffing and clinical practice contribute to risk, and the addition of these variables to our risk model improved predictive accuracy. (C) 2013 International Society for Heart and Lung Transplantation. All rights reserved.

The Cardiac Transplant Research Database (CTRD) collected data from 26 US institutions starting in 1/1/1990, permitting analyses of risk factors over 19 years of improving outcomes in transplantation (tx). We examined risk factors to determine if their effects have changed over time.

Purpose: Over the last two decades, survival has improved after cardiac transplantation. The reasons for this improvement have not been fully explored. The purpose of this study was to examine the influence of age at the time of transplant on 5 year patient survival over two decades of experience. Methods and Materials: Outcomes data from 7,015 patients were collected from 1990-2008 from the Cardiac transplant Research Database (CTRD) were used in a multivariable analysis to generate a predictive model using recipient variables. Age at time of transplant was tested for interactions with date of transplant to determine if the relative risk for death changed over time. Results: Kaplan-Meier analysis for death of pts tx at ages 35, 35-59 and 60 show 5-year survivals of 67% (n 216), 78% (n 1289), and 76% (n 617), respectively from 2002-2008. Compared to 1990-1995 this is a decrease of 2% (p .5) for ages 35, and an increase of 6% for ages 35-59 (p .008); 9% for ages 60 (p .007). By multivariate analysis in the hazard domain both age (p .002) and date of tx (p .0001) were risk factors for death and these variables interact (p .0001). Predictive equations derived from this analysis show predicted 5-year survival for a pt tx at age 20 remains flat from 1990-2008, whereas pts tx at age 40 increase from 72% to 78%, and pts tx at age 60 increase from 74% to 85% (p .0001) for the model. Conclusions: Observed improvements in survival over two decades of cardiac transplantation at least in part can be explained by improvements in outcomes in older heart transplant recipients. The lack of improvement in the younger age group suggests that changes in clinical management that have resulted in improvements in survival in the older ages have not benefited the younger adult patients. Therefore, we submit that different clinical practices should be tailored based on age within the adult population.

Ventricular Assist Device (VAD) implantation is associated with an increased risk of gastrointestinal bleeding (GIB) events. Better characterization of the GIB events in patients with VADs is needed.

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4-7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001-2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.

Determining optimal timing for implant of ventricular assist device (VAD) in end-stage heart failure remains a challenge and may be aided by a risk assessment tool. For a cohort of 80 consecutive VAD implants at a single center, observed 1 year survival post-VAD was compared with the estimated survival had these patients not received a VAD, using the Seattle Heart Failure Model (SHFM). The SHFM was adjusted with a hazard ratio of 1.17 for inotrope use (Cochrane Meta-analysis of phosphodiesterase inhibitors) and a hazard ratio of 2.92 for balloon pump, ventilator, or renal replacement therapy (Comparative Outcome and Clinical Profiles in Transplantation [COCPIT] Model). Values immediately before surgery were used to calculate the SHFM score. Point estimates of 1 year survival were compared using Z scores. Mean age was 53 ± 14 (± standard deviation [SD]) years with mean left ventricular ejection fraction of 17 ± 6%. At the time of VAD implant, 92% were on inotropes, 53% had balloon pump, and 15% were intubated. For the entire cohort, 1 year survival without VAD predicted by the SHFM was 47% versus observed survival after VAD of 60% (p = 0.06). The model was most helpful in patients electively implanted with a left ventricular assist device (LVAD). In this group predicted 1 year survival on medical management was 49% versus an observed survival of 82% after LVAD placement (p < 0.05). The model was least helpful in patients undergoing placement of biventricular assist devices (BiVAD), where the model paradoxically predicted better survival with ongoing medical management. This indicated that the model was unable to forecast outcome in patients with higher severity of illness, for example, in cases warranting BiVAD placement. Observed 1 year survival was better with VAD versus that predicted with medical management. Tools such as the SHFM may aid in determining appropriate timing for VAD by providing an estimated survival with ongoing medical management. The model is best applied to more stable patients being considered for elective VAD implantation.

Purpose We determined the incidence and risk for PTLD among children as a function of age at time of transplant and EBV serology status. Methods and Materials Results Of 151 malignancy events, 147 (97%) were PTLD. Actuarial freedom from PTLD was lowest among patients From birth to 10 years of age, with the peak hazard for PTLD at one year post-transplantation occurring in patients 5.45 years old at transplant, (left panel). Among recipients of EBV+ donor hearts, EBV- recipients exhibited an increased risk of PTLD (p<0.0001, right panel). EBV- recipients of EBV- donor hearts showed no increased risk of PTLD over EBV+ recipients (p=0.65). A comparison of PTLD rates in three eras (1993-1996, 1997-2001, 2002-2007) showed no change in risk for PTLD in the first two eras (p=0.8), but there was a significant reduction in the most recent era (p=0.04). 14% of infants transplanted at birth were EBV+, rising to 64% of those transplanted at two months of age. Seropositivity declined to 32% by 18 months and increased thereafter. Conclusions We show that age is a strong risk factor for PTLD with greater long-term and short-term risk in early childhood than in infants and adolescents. EBV status of the recipient is important for those receiving EBV+hearts. We determined the incidence and risk for PTLD among children as a function of age at time of transplant and EBV serology status. Of 151 malignancy events, 147 (97%) were PTLD. Actuarial freedom from PTLD was lowest among patients From birth to 10 years of age, with the peak hazard for PTLD at one year post-transplantation occurring in patients 5.45 years old at transplant, (left panel). Among recipients of EBV+ donor hearts, EBV- recipients exhibited an increased risk of PTLD (p<0.0001, right panel). EBV- recipients of EBV- donor hearts showed no increased risk of PTLD over EBV+ recipients (p=0.65). A comparison of PTLD rates in three eras (1993-1996, 1997-2001, 2002-2007) showed no change in risk for PTLD in the first two eras (p=0.8), but there was a significant reduction in the most recent era (p=0.04). 14% of infants transplanted at birth were EBV+, rising to 64% of those transplanted at two months of age. Seropositivity declined to 32% by 18 months and increased thereafter. We show that age is a strong risk factor for PTLD with greater long-term and short-term risk in early childhood than in infants and adolescents. EBV status of the recipient is important for those receiving EBV+hearts.

Background. Total lymphoid irradiation (TLI) has been used in transplantation for over 20 years and is currently used in a number of major heart transplant centers as a secondary therapy for recalcitrant recurrent rejection or rejection with hemodynamic compromise. The purpose of this study is to evaluate the long-term risks and efficacy of TLI in the treatment of rejection.Methods. Between 1990 and 1996, 73 adult patients (from 211 adult transplant recipients) received TLI for recurrent rejection (71%), rejection with hemodynamic compromise (25%), and rejection with vasculitis (4%). The treatment consisted of 80 cGy twice per week for 5 weeks. Fifty-five patients received at least 80% of the full dose (>640 cGy). Follow-up ended December 31, 2007, comprising a total 18 year experience.Results. Patients treated with TLI exhibited a short-term decrease in hazard for rejection in the first 12 months posttransplantation (relative risk, 0.36) but exhibited increased cumulative rejection over the long term. There were no differences in the rates of infection, allograft coronary disease, or malignancy, but seven patients developed myelodysplasia or acute myelogenous leukemia, four of those being the rare but uniformly fatal acute megakaryocytic leukemia type 7.Conclusions. Patients treated with TLI seemed to experience a reduction in the early hazard for rejection, but long-term outcomes indicate that such patients continued to accumulate more rejection and rejection-death events, likely because these patients were overall at much higher risk for rejection than the other patient groups. We observed minimal long-term complications, except for the unique occurrence of myelodysplasia and acute megakaryocytic leukemia type 7.

BACKGROUND: This study was conducted to determine the effect of a disease-management model termed an "intensive surveillance protocol" (ISP) on survival in ventricular assist device (VAD) patients. This intervention consisted of a formalized, protocol-driven, multi-disciplinary team approach to VAD patient follow-up initiated August 1, 2006. The goal was to attain an internal program benchmark of 70% survival at 2 years. Historically, 2-year survival after VAD implant has been sub-optimal, and no patient management algorithms have been formally tested to determine their effect on 2-year survival.METHODS: The study comprised 76 patients, of whom 26 had a VAD as destination therapy (DT) and 50 as a bridge to transplant (BIT), from July 1, 2003, to June 30, 2008. Survival before and after initiation of ISP was compared. A parametric hazard multivariable analysis, with a time-varying covariable for implementation of ISP, was used to evaluate of other factors affecting survival.RESULTS: Survival at 16 months was 100% for DT patients who received a VAD after August 1, 2006 vs 64% for the earlier era (p = 0.06). For BIT, 16- month survival was 71% vs 43% (p = 0.03). Predicted 2-year survival before and after implementation of the ISP improved from 30% to 87% for DT (p = 0.02) and from 20% to 61% for BIT patients (p = 0.01). Predictors of midterm survival by multivariable analysis included ISP (p = 0.004), younger age (p = 0.03), non-emergent implant (p < 0.0001), and isolated left ventricular VAD (p < 0.0001). After adjustment for covariables, the ISP was associated with a 70% reduction in the hazard for death for the entire cohort (p = 0.004). The effect of ISP was also significant in the patients who received the HeartMate XVE (Thoratec, Pleasanton, CA), which spanned both eras of the study.CONCLUSIONS: Survival improved for DT and BIT VAD patients after implementation of the ISP, with a dramatic decrease in hazard for death. Although the transition from pulsatile to axial flow technology occurred during the study period and likely contributed to improved outcomes, the institution of the ISP provided an important and significant contribution to improved survival through a proactive approach to patient management, allowing earlier identification of potential adverse events. For optimal outcomes, VAD patients require intensive follow-up surveillance protocols that have previously become standard in the care of heart transplant patients. J Heart Lung Transplant 2011;30:879-87 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved.