- Email: [email protected]
Survival and quality of life for children with end-stage heart failure who are not candidates for cardiac transplant
http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Survival and quality of life for children with end-stage heart failure who are not candidates for cardiac transplant Arash Alen Sabati, MD,a Jacqueline R. Szmuszkovicz, MD,a Cynthia Herrington, MD,b Mark Hermes, BS,a Hesham A. Mahmoud, CCRP,a Choo Phei Wee, BS,c Vaughn A. Starnes, MD,b and JonDavid Menteer, MDa From the aDivision of Cardiology; bDepartment of Cardiothoracic Surgery; and the cClinical Investigation Center at the Saban Research Institute; Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
KEYWORDS: Pediatric heart failure; pediatric heart transplant; congenital heart disease; congenital heart surgery; alloimmunization; panel reactive antibodies
BACKGROUND: Some pediatric patients referred for heart transplant (HTx) are sub-optimal candidates. Their outcomes without HTx are presumed to be dismal, but have not been well described. Knowledge about their outcomes is critical when weighing the risks between a high-risk transplant and “terminal” palliation. METHODS: We retrospectively reviewed all HTx referrals from January 2005 to July 2013. We excluded those who were listed for HTx, or who were denied HTx due to being “too well,” seeking only those who were in need of but not suitable for HTx. End-points included mortality and length of survival. RESULTS: Of 212 referrals, 39 (19%) (age 0 to 19 years, median 3.5 years) were denied HTx for reasons other than being too well. Twenty-eight (72%) had palliated congenital heart disease. Overall mortality during the follow-up period was 38% (n ¼ 15) with a median follow-up time of 195 days (8 to 2,832 days). Ten patients received subsequent cardiac surgery with 1 death (10%) and median follow-up of 2.6 years. Mortality risk was not influenced by age, weight, growth failure, congenital heart disease or single-ventricle physiology. Mechanical ventilation (hazard ratio 6.31, p ¼ 0.001) and inotrope dependence (hazard ratio 4.79, p ¼ 0.006) were associated with the highest risk of mortality. Quality of life was measured with the PedsQL cardiac module and completed by 11 of 16 eligible patients with an overall average score of 70.2 ⫾ 23.9. CONCLUSIONS: An advanced heart failure program can achieve satisfactory results for pediatric patients who are not suitable candidates for HTx. For some children, high-risk palliative surgery can result in better outcome than high-risk HTx. Mortality was related to the degree of heart failure at presentation rather than underlying heart disease. J Heart Lung Transplant 2015;34:906–911 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Arash Alen Sabati, MD, Division of Cardiology, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop #34, Los Angeles, CA 90027. Telephone: 323-631-2461. Fax: 323-361-1513. E-mail address: [email protected]
Advances in pediatric heart transplantation (HTx) have improved survival and quality of life for many children with end-stage heart failure.1 However, patients with alloimmunization, pulmonary vascular disease, evidence of medical non-compliance and other pre-transplant comorbid conditions continue to present challenges.2 Serious ethical
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.01.006
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dilemmas occur when deciding on the use of scarce donor organs in high-risk transplant recipients. For example, some children with previous corrective heart surgery who are diffusely alloimmunized against human leukocyte antigens (HLA) are unlikely or sometimes unable to receive a negative crossmatch at HTx.3,4 Although recent advancements may have improved outcomes for some patients with pre-sensitization, these patients still have an elevated likelihood of repeated, severe and/or medically refractory cardiac rejection, and at least double the mortality5 risk of patients who are not pre-sensitized, in the first year. Such patients also can expect both higher pre- and post-transplant mortality risk.5–8 When faced with near-certain death for patients referred with end-stage heart failure, some centers will acknowledge some increase in risk, but will nevertheless offer HTx. At our center, our strategy has been to offer alternative medical and surgical therapies for patients who we perceive to be at excessive risk of poor outcome from HTx. In this study we hope to begin examining a strategy that has been largely ignored in the medical literature—that of denying HTx as an option when “excessive” risk is present, and focusing on other surgical and medical options. We will not attempt to define the phenomenon of “excessive risk,” but rather attempt to describe the outcomes of alternative strategies of care in the modern era. Advancing medicine is often focused on pushing therapeutic boundaries for patients with high mortality risk. It is difficult to have a rational discussion of therapeutic options without knowing the mortality risk of the alternatives. Information about the outcome and quality of life of children not suited for HTx may help with decision-making regarding alternative medical and surgical therapies and their role in the treatment of children with end-stage heart failure. In this study, we sought to evaluate the outcomes of children presumed, at the time of referral, to have no hope of survival without HTx, but who were denied transplant candidacy.
Methods We performed a retrospective review of all identifiable referrals to our HTx program between January 2005 and July 2013, based on our database of transplant referrals. We reviewed the electronic medical records and excluded any patient referred for combined heart–lung transplantation, those who were accepted and listed for HTx, those considered “too well” for HTx, and those without adequate documentation of HTx evaluation/decision-making in the medical record. This search yielded a cohort of patients who were sick enough to need HTx, but were denied because they were considered to be at elevated risk of poor outcome. We collected demographic information, including primary and associated diagnoses and previous surgical interventions. We used HTx evaluation and in-patient physician notes to collect data regarding clinical status, including symptoms, New York Heart Association (NYHA) or Ross classification, inotrope dependence, intubation, mechanical support, and episodes of cardiac massage before referral. HLA antibody test results were obtained from all included patients from both the electronic medical record as well as the HLA laboratory database. Luminex single-antigen-bead
907 panel-reactive antibody (PRA) assays were used starting in July 2007; before that time, a cytotoxicity assay from the U.S. Centers for Disease Control and Prevention was used. The Organ Procurement and Transplantation Network cPRA calculator was used to express PRA percent.9 Reason for HTx denial was collected from transplant selection committee notes. The clinical course after HTx denial was also characterized, including mortality, date of last follow-up and NYHA class and clinical status at last follow-up. Patients were censored at the date of their last available clinic visit or physician contact. Quality of life was assessed for surviving patients and collected prospectively at routine visits or by telephone interview. We used the PedsQL Cardiac Module—a brief, but well-validated instrument in pediatric patients with cardiac diseases.10–12 This questionnaire is made up of 4 age-specific instruments, 1 for the parent to complete and, if appropriate, 1 for the child to complete as well. The questionnaire surveys the child’s physical, emotional, social and school function on a 0 to 4 scale. The surveys are scored providing an overall score, physical health summary and psychosocial health summary. These scores provide objective numbers and validated measures of quality of life. Intercooled STATA v13.1 (StataCorp, College Station, TX) was used for statistical analysis. Survival analysis was done using the Kaplan–Meier approach. A log-rank test was used to distinguish survival with categorical variables. Univariate analysis was performed using Cox proportional hazards modeling to assess the relationship between mortality and risk factors. Multivariate analysis was subsequently performed using the same approach to further assess the relationship between mortality and other possible factors. The results were summarized as hazard ratios, 95% confidence intervals and p-values. Statistical significance was set at 5% (2-sided) throughout the analyses.
Results Of 212 consecutive referrals for HTx evaluation, 2 patients did not survive the transplant evaluation; 7 additional patients were lost to follow-up and did not complete the transplant evaluation. Of the remaining 203 patients, 39 (19%) of those evaluated for HTx met inclusion criteria and represented the study population. Demographic data of this cohort and reason for transplant denial are outlined in Table 1. Twenty-eight patients (72%) in the study population had congenital heart disease (Table 2). Each of these patients had between 1 and 6 surgical procedures, with a mean of 2.6 operations. There were no patients on extracorporeal membrane oxygenation or a ventricular assist device who met the inclusion criteria. There were also no patients with cardiac arrest (in or out of hospital) in the 30 days before transplant referral. The overall follow-up was 8 days to 7.8 years, with a median follow-up of 195 days. There were 15 (38%) deaths, which occurred between 8 days and 5.2 years after transplant referral (mean 220 days, median 66 days). One third (n ¼ 5) of these mortalities occurred in the first 30 days after referral. One-year mortality was 33% (n ¼ 13), with 20 patients remaining at risk. Three-year mortality was 36% (n ¼ 14), with 18 patients remaining at risk. Mortality was increased (by log-rank test) for those who were mechanically ventilated (78% vs 27%, p ¼ 0.0002), inotrope-dependent (56% vs 26%, p ¼ 0.002) and for
908 Table 1
The Journal of Heart and Lung Transplantation, Vol 34, No 7, July 2015 Demographic Data at Time of Referral for HTx
Age Male gender Weight Congenital heart disease Single-ventricle physiology Inpatient at referral Intubated/mechanical ventilation on inotropic support NYHA/Ross Class II or III Class IV Reason for HTx denial Multi-organ or uncontrolled medical diseasea Antibody pre-sensitization (high PRA) Pulmonary vascular disease Medical non-compliance
6 weeks to 19 years (median 3.5 years) 22 (56%) 3.7–72.6 kg (median 13.4 kg) 28 (72%) 20 (51%) 21 (54%) 9 (23%) 16 (41%) 20 (51%) 19 (49%) 17 (44%) 13 (33%) 2 (5%) 7 (18%)
Data expressed as number (%) unless noted otherwise. HTx, heart transplantation; NYHA, New York Heart Association; PRA, panelreactive antibodies. a Venous or pulmonary artery anatomic abnormalities precluding Htx surgery (4), severe chromosomal abnormality thought to limit posttransplant prognosis (6), severe neurological injury (2), hepatic and renal dysfunction (1), Pompe disease (1), renal failure and multi-organ ischemia (2) and diffuse fungemia (1).
inpatient (vs outpatient) HTx evaluations (48% vs 28%, p ¼ 0.03). Those with NYHA/Ross Class IV symptoms had higher mortality than those who were either Class II or III (53% vs 25%, p ¼ 0.0065). A high level of covariance for these factors was confirmed. Males also had higher mortality (57% vs 22%, p ¼ 0.02). Mortality was not influenced by age, weight, growth failure, presence of developmental delay, congenital heart disease, number of previous cardiac surgical procedures or single-ventricle physiology. Of the 21 inpatient HTx referrals, 16 were on inotropes at the time of referral. The 5 who were not on inotropes at the
Table 2 Types of Congenital Heart Disease in the Study Population n (%) Single-ventricle physiology Hypoplastic left heart syndrome Unbalanced atrioventricular canal Double-outlet right ventricle variants Tricuspid atresia Ebstein’s anomaly of the tricuspid valve Pulmonary atresia with intact ventricular septum Two-ventricle physiology Aortic stenosis Truncus arteriosus Corrected transposition of the great arteries Tetralogy of Fallot
20 12 3 2 1 1 1
(51%) (31%) (8%) (5%) (3%) (3%) (3%)
9 3 2 2 1
(23%) (8%) (5%) (5%) (3%)
time of HTx consideration were subsequently discharged successfully on oral heart failure medication regimens. Of the 16 patients on inotropes, 3 had subsequent cardiac surgery and were weaned from inotropic support, and 2 were able to be weaned off inotropes without subsequent cardiac surgery. Of the remaining 9 patients, 7 were also intubated, and these patients died. The median survival time from HTx referral for all inpatients was 66 days (range 3 days to 3.9 years). Pre-sensitized patients had mean cPRA of 91.8 ⫾ 14%. All these patients had congenital heart disease, and 9 of 13 had single-ventricle physiology. Twelve of the 13 had Z2 previous cardiac surgical procedures, and 1 with only a single cardiac surgery. Eight of the 13 presented with decompensated heart failure symptoms or NYHA/Ross Class IV symptoms: 6 were on inotropic support at the time of HTx evaluation and 2 were intubated. There were 7 deaths among the pre-sensitized patients (54%) occurring 8 to 148 days (mean 68 days) after referral. All these deaths occurred among the patients presenting with decompensated heart failure. Follow-up for the surviving patients was 195 days to 3.9 years (mean 2 years), with all patients being NYHA/Ross Class II or III at last follow-up. High PRA patients were not more likely to die than other high-risk patients (54% vs 31%, p ¼ 0.18). This was also not
Table 3
Univariate Analysis
Risk factor Age (years) Z11 3.5–11 1–3.49 o1 Weight (kg) Z34 14–33.99 7.6-13.99 o7.6 Male gender Growth failure Congenital heart disease Single-ventricle physiology High PRA (vs other patients) Mechanically ventilated Inotropic support NYHA/Ross Class IV Inpatient at referral Subsequent cardiac surgery
Hazard ratio 95% CI
p-value
1 0.67 3 1.87
— (0.09–4.77) (0.61–14.75) (0.34–10.29)
— 0.69 0.177 0.473
1 1.64 2.42 2.8 4.05 1.65 0.8
— (0.27–9.99) (0.45–12.92) (0.54–14.62) (1.14–14.48) (0.59–4.65) (0.27–2.33)
— 0.589 0.3 0.223 0.031 0.341 0.677
1.62
(0.58–4.56)
0.361
2.01
(0.7–5.77)
0.193
6.31
(2.13–18.68)
0.001
4.79 4.45 3.38 0.13
(1.57–14.58) (1.38–14.39) (1.05–10.85) (0.02–1.03)
0.006 0.013 0.041 0.053
Univariate analysis was performed with Cox proportional hazard modeling. For age and weight, the patients were divided into quartiles, with the groups Z11 years and Z34 kg used as reference. Patients with high PRA as the reason for heart transplant denial were compared with all other reasons for heart transplant denial. NYHA Class IV patients were compared with those who were Class II and III. CI, confidence interval; PRA, panel-reactive antibodies.
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significant in the univariate analysis (Table 3), and thus not included in the multivariate analysis. Ten patients had subsequent palliative cardiac surgery after HTx referral. The reasons they were not HTx candidates were as follows: 2 were pre-sensitized; 7 had medical disease; and 1 was medically non-compliant. Surgical procedures included: Glenn followed by fenestrated Fontan (n ¼ 1); fenestrated Fontan (n ¼ 3); atrioventricular valve replacement with left atrial reduction (n ¼ 1); conversion to 2-ventricle circulation (n ¼ 1); Ross procedure (n ¼ 1); coronary artery repair (n ¼ 1); pulmonary arterioplasty with unifocalization (n ¼ 1); and palliative 8-mm Blalock–Taussig shunt (n ¼ 1). There was 1 death in this group, which was significantly less when compared with patients who did not have surgical procedures (10% vs 48%, p ¼ 0.02). Follow-up for the remaining 9 patients was 15 days to 7 years (mean 2.8 years). One of these patients was NYHA Class IV at last follow-up, and the remaining 8 patients were all NYHA/Ross Class I or II. Both uni- and multivariate analyses were done using Cox proportional hazard modeling. Univariate analysis (Table 3) yielded male gender, mechanical ventilation, inotropic support, NYHA Class IV and inpatient at referral as significant risk factors. Age, weight, growth failure, congenital heart disease and single-ventricle physiology were not significant. Those patients with subsequent cardiac surgery approached significance (p ¼ 0.053). Many of the significant risk factors from both the log rank test and the univariate analysis were markers of severity of heart failure. These variables were so closely associated that we were unable to separate NYHA class, mechanical ventilation, inotropic support and inpatient status from each other to evaluate their independent contribution. As we were limited by our sample size and the interrelation of the data, these variables were analyzed together in the multivariate analysis as “markers of severe heart failure,” along with gender (Table 4). We examined those patients with any markers of severe heart failure and those without (Figure 1) using the Kaplan–Meier method. Patients with any markers of severe heart failure had lower survival compared with those not having markers (p ¼ 0.021). In addition to survival analysis we examined severity of disease at follow-up as well as quality of life in surviving patients. NYHA class was available for 21 of 23 (91%) surviving patients (Figure 2). In general, NYHA class improved in surviving patients. Of these surviving patients, 16 qualified for the quality-of-life survey and 11 (69%) were recruited. The remaining patients either followed up with outside cardiologists or are seen so infrequently now that they did not have a clinic visit during the study period. The results of the PedsQL was an overall score of 70.2 ⫾ 23.9, a physical Table 4
Figure 1 Kaplan–Meier survival curve based on presence of any of the “markers of severe heart failure” at the time of HTx evaluation: NYHA Class IV symptoms; inotrope dependence; need for mechanical ventilation; and/or inpatient HTx evaluation. The difference in survival when any risk factors are present versus no risk factors was significant (p ¼ 0.021).
health summary score of 69.6 ⫾ 22.3 and a psychosocial health summary score of 70.5 ⫾ 24.6. Although there was no control population for direct comparison, these results compare favorably to previously reported results from PedsQL cardiac in both patients with heart failure and HTx as well as patients with congenital heart disease.
Discussion Children with heart failure are living longer for multiple reasons, including medical and surgical care. In the past 2 decades, there has been considerable effort placed into overcoming immune barriers to HTx for high-risk patients, and this has sometimes been met with terrible results. This study offers a perspective that high-risk transplant may not be the best, or only, option for some end-stage heart failure patients—even if they have “exhausted” their other surgical and medical options. We are not trying to suggest that highrisk HTxs are completely unnecessary, or that the pursuit of overcoming the immune barriers of pre-sensitization is an ignoble cause. HTx can be a life-saving intervention for many children with end-stage heart failure.
Multivariate Analysis Hazard ratio 95% CI
Male gender 3.81 Any “markers of severe 3.78 heart failure”
p-value
(1.06–13.66) 0.04 (1.04–13.72) 0.04
Figure 2 NYHA class of surviving patients at HTx referral and at last follow-up. NYHA class at follow-up was available for 21 of 23 surviving patients.
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We acknowledge that the definition of an “excessiverisk” transplant candidate is a moving target—defined barriers to HTx are constantly evolving, usually decreasing, as we identify and overcome the obstacles of specific subpopulations of patients. However, a long wait for an HTx, filled with multiple infusions, long hospital stays and repeated immune desensitization therapies, may in some cases be the road to a predictably short post-transplant life, and may also rob patients of an acceptable quality of life. Although denial of HTx listing is a difficult end-point for many families, it is important to emphasize the possibility that a child may survive longer and perhaps have a better quality of life without HTx when the transplant selection team considers the procedure to be too risky. This study uniquely characterizes the outcomes of a group of children with death-prone heart failure who have been denied access to transplant listing. Many patients, by the time the HTx team is consulted, have been denied further surgical palliation because of surgical risk. However, some of these surgical interventions may be reconsidered after the child is denied HTx. There is currently little published information about this group of ultra–high-risk heart failure patients, who have been through an HTx evaluation but who are considered unsuitable for HTx. Because of the heterogeneity of the patient population and relative paucity of literature regarding the group as a whole, there is no appropriate control population for comparison with these children. Although the outcomes attained for these patients are largely descriptive, they offer the chance to reframe the prognosis of heart failure not amenable to successful HTx. Our data suggest that pediatric patients referred for HTx evaluation in compensated heart failure, and then treated aggressively after being denied access to transplant listing, have 75% survival at 4 years. Although this statistic is worse than modern HTx outcomes for normal-risk patients, it may be a reasonable outcome when weighed against the combination of increased wait-list and post-transplant mortality of an HTx performed with a positive crossmatch or other risky circumstances. Furthermore, the 3-year mortality is almost equal to the 1-year mortality, suggesting that most of the attrition is early (to decompensated heart failure) and that those who survive the first year may have a reasonable chance of mid-term survival. Patients referred for HTx as inpatients with decompensated heart failure had a far greater likelihood of dying during hospitalization. Because of the sample size and the interrelation of the individual “markers of severe heart failure,” we were unable to separate them and perform multivariate testing on individual variables, but instead included patients in the multivariate analysis if they had any of these risk factors present. Importantly, underlying cardiac disease, age, weight and single-ventricle physiology were not predictors of mortality. Antibody pre-sensitized patients, all of whom had underlying cardiac disease, were not at increased risk of mortality compared with the rest of the study population. This is a group with 2 significant risk factors of reduced survival after HTx. Males were at higher risk of death compared with females in both uni- and bivariate analyses. Although a
female gender advantage has been found in some other disease processes,13 the significance of this finding in a population of pediatric heart failure patients is not clear. It is challenging to balance acute surgical risks with longer term quality and quantity of life. For example, it is difficult to decide whether a 30% to 50% mortality risk is acceptable for a procedure that has the potential to dramatically improve a patient’s life, especially when comparing it with the possibility of simply waiting for a heart transplant, where the risks are taken on passively and continuously. For our population, when surgical options were available to correct hemodynamic derangements, regardless of the perceived high surgical risk, these patients did markedly better when compared with published outcomes from “high-risk” HTxs. Before their HTx evaluation and denial, these children were all considered unacceptable surgical candidates, but in the hands of an experienced surgeon these patients achieved acceptable overall outcomes, with a quality of life comparable to that of other children with congenital heart disease as well as successful HTx recipients.11,12 Although we cannot propose formal criteria for surgical intervention, close collaboration between the transplant and cardiac surgery teams can lead to appropriate patient selection. The quality-of-life data we reported from PedsQL surveys suggest that not only are these children surviving, but they also have a reasonable quality of life. Compared with the PedsQL scores reported by Mellion et al,12 our patient population had similar scores to a general population of children with single-ventricle physiology (average total score 64.6 to 72.5). Healthy children from Mellion’s cohort reported average total scores ranging from 84.9 to 86.9. Another large quality-of-life study by Varni et al reported children with chronic asthma having average total scores of 68.8 to 74.9.14 In 2013, Menteer et al reported that children with chronic heart failure secondary to dilated cardiomyopathy had PedsQL scores averaging 67, also comparable to our patients.11 Although a direct comparison to these groups or a control group is not possible, the proximity of the quality-of-life scores to the scores of their peers with similar underlying cardiac conditions or to other children with chronic diseases10,12,14 suggests that their quality of life is reasonable.
Limitations The present study is limited by its predominantly retrospective nature and the population size. Our center is a major referral center, so some patients returned to their home institution, and follow-up time in some cases was limited. We contacted families and cardiologists outside our institution to overcome as much of this limitation as possible. Because of the small sample and variable followup times, the long-term survival estimates, even with appropriate censuring, may be limited. There is not an appropriate control population for a direct comparison of survival. Although we have made inferences based on the
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available literature, much of the data in this high-risk group of patients remain descriptive. Our outcome measures may also become obsolete due to the increased use of ventricular assist devices (VADs). Our institutional practice over this era was to not deploy a VAD except as a bridge to transplant, so there were no VADs used in our patient population. VAD use as destination therapy has the potential to dramatically change the landscape of end-stage heart failure for children, even many of those with congenital heart disease. In addition, the use of VADs to bridge patients to transplant candidacy (e.g., for those with potential for pulmonary vascular remodeling or undergoing immune desensitization) has already changed the landscape of transplant candidacy. Criteria for transplant candidacy vary by institution. Our center had reasonably uniform management principles with regard to pre-transplant risk assessment during the time of this study, and it is this set of principals that made our study possible. However, this potentially limits the reproducibility of our findings. Finally, our quality-of-life analysis is biased by patient selection, because we only collected data on the surviving patients. In conclusion, an advanced heart failure program can achieve satisfactory survival and quality of life for pediatric patients who are not suitable candidates for HTx, especially those outpatients presenting with compensated heart failure. Selected children may benefit, beyond expectations, from carefully chosen, high-risk palliative surgery, or may survive longer than expected with aggressive medical therapy, without the long hospitalizations and multiple medical complexities of high-risk HTx. The patients who are least likely to survive after denial of HTx listing are those who are inpatients at referral, NYHA Class IV, mechanically ventilated or inotropedependent. This information may help some physicians and families reframe a determination of non-candidacy for HTx as the beginning of reassessment for these patients, with potential for longer and better life as a non-transplant candidate compared with living as a high-risk HTx candidate with a very poor pre- and post-transplant prognosis.
Disclosure statement The authors have no conflicts of interest to disclose. We thank the MAPI Research Trust, Lyon, France, for their permission to use the
911 PedsQL. This study was supported by a grant from the Paige Foundation, Hermosa Beach, California.
References 1. Webber SA, McCurry K, Zeevi A. Heart and lung transplantation in children. Lancet 2006;368:53-69. 2. Tjang YS, Stenlund H, Tenderich G, et al. Pediatric heart transplantation: current clinical review. J Card Surg 2008;23:87-91. 3. Betkowski AS, Graff R, Chen JJ, et al. Panel-reactive antibody screening practices prior to heart transplantation. J Heart Lung Transplant 2002;21:644-50. 4. Zangwill SD, Ellis TM, Zlotocha J, et al. The virtual crossmatch—a screening tool for sensitized pediatric heart transplant recipients. Pediatr Transplant 2006;10:38-41. 5. Mahle WT, Tresler MA, Edens RE, et al. Allosensitization and outcomes in pediatric heart transplantation. J Heart Lung Transplant 2011;30:1221-7. 6. Jacobs JP, Quintessenza JA, Boucek RJ, et al. Pediatric cardiac transplantation in children with high panel reactive antibody. Ann Thorac Surg 2004;78:1703-9. 7. Pollock-BarZiv SM, den Hollander N, Ngan BY, et al. Pediatric heart transplantation in human leukocyte antigen sensitized patients: evolving management and assessment of intermediate-term outcomes in a high-risk population. Circulation 2007;116(suppl): I172-8. 8. Loh E, Bergin JD, Couper GS, et al. Role of panel-reactive antibody cross-reactivity in predicting survival after orthotopic heart transplantation. J Heart Lung Transplant 1994;13:194-201. 9. U.S. Department of Health and Human Services. Organ Procurement and Transplantation Network. 2014. http://optn.transplant.hrsa.gov/ resources/allocationcalculators.asp?index=78/. Accessed October 1, 2013. 10. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001;39: 800-12. 11. Menteer J, Beas VN, Chang JC, et al. Mood and health-related quality of life among pediatric patients with heart failure. Pediatr Cardiol 2013;34:431-7. 12. Mellion K, Uzark K, Cassedy A, et al. Health-related quality of life outcomes in children and adolescents with congenital heart disease. J Pediatr 2014;164:781-8. 13. Manktelow BN, Seaton SE, Field DJ, et al. Population-based estimates of in-unit survival for very preterm infants. Pediatrics 2013;131: e425-32. 14. Varni JW, Limbers CA, Burwinkle TM. Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/ severities utilizing the PedsQL 4.0 Generic Core Scales. Health Qual Life Outcomes. 2007;5:43.
ORIGINAL CLINICAL SCIENCE
Survival and quality of life for children with end-stage heart failure who are not candidates for cardiac transplant Arash Alen Sabati, MD,a Jacqueline R. Szmuszkovicz, MD,a Cynthia Herrington, MD,b Mark Hermes, BS,a Hesham A. Mahmoud, CCRP,a Choo Phei Wee, BS,c Vaughn A. Starnes, MD,b and JonDavid Menteer, MDa From the aDivision of Cardiology; bDepartment of Cardiothoracic Surgery; and the cClinical Investigation Center at the Saban Research Institute; Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
KEYWORDS: Pediatric heart failure; pediatric heart transplant; congenital heart disease; congenital heart surgery; alloimmunization; panel reactive antibodies
BACKGROUND: Some pediatric patients referred for heart transplant (HTx) are sub-optimal candidates. Their outcomes without HTx are presumed to be dismal, but have not been well described. Knowledge about their outcomes is critical when weighing the risks between a high-risk transplant and “terminal” palliation. METHODS: We retrospectively reviewed all HTx referrals from January 2005 to July 2013. We excluded those who were listed for HTx, or who were denied HTx due to being “too well,” seeking only those who were in need of but not suitable for HTx. End-points included mortality and length of survival. RESULTS: Of 212 referrals, 39 (19%) (age 0 to 19 years, median 3.5 years) were denied HTx for reasons other than being too well. Twenty-eight (72%) had palliated congenital heart disease. Overall mortality during the follow-up period was 38% (n ¼ 15) with a median follow-up time of 195 days (8 to 2,832 days). Ten patients received subsequent cardiac surgery with 1 death (10%) and median follow-up of 2.6 years. Mortality risk was not influenced by age, weight, growth failure, congenital heart disease or single-ventricle physiology. Mechanical ventilation (hazard ratio 6.31, p ¼ 0.001) and inotrope dependence (hazard ratio 4.79, p ¼ 0.006) were associated with the highest risk of mortality. Quality of life was measured with the PedsQL cardiac module and completed by 11 of 16 eligible patients with an overall average score of 70.2 ⫾ 23.9. CONCLUSIONS: An advanced heart failure program can achieve satisfactory results for pediatric patients who are not suitable candidates for HTx. For some children, high-risk palliative surgery can result in better outcome than high-risk HTx. Mortality was related to the degree of heart failure at presentation rather than underlying heart disease. J Heart Lung Transplant 2015;34:906–911 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Arash Alen Sabati, MD, Division of Cardiology, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop #34, Los Angeles, CA 90027. Telephone: 323-631-2461. Fax: 323-361-1513. E-mail address: [email protected]
Advances in pediatric heart transplantation (HTx) have improved survival and quality of life for many children with end-stage heart failure.1 However, patients with alloimmunization, pulmonary vascular disease, evidence of medical non-compliance and other pre-transplant comorbid conditions continue to present challenges.2 Serious ethical
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.01.006
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dilemmas occur when deciding on the use of scarce donor organs in high-risk transplant recipients. For example, some children with previous corrective heart surgery who are diffusely alloimmunized against human leukocyte antigens (HLA) are unlikely or sometimes unable to receive a negative crossmatch at HTx.3,4 Although recent advancements may have improved outcomes for some patients with pre-sensitization, these patients still have an elevated likelihood of repeated, severe and/or medically refractory cardiac rejection, and at least double the mortality5 risk of patients who are not pre-sensitized, in the first year. Such patients also can expect both higher pre- and post-transplant mortality risk.5–8 When faced with near-certain death for patients referred with end-stage heart failure, some centers will acknowledge some increase in risk, but will nevertheless offer HTx. At our center, our strategy has been to offer alternative medical and surgical therapies for patients who we perceive to be at excessive risk of poor outcome from HTx. In this study we hope to begin examining a strategy that has been largely ignored in the medical literature—that of denying HTx as an option when “excessive” risk is present, and focusing on other surgical and medical options. We will not attempt to define the phenomenon of “excessive risk,” but rather attempt to describe the outcomes of alternative strategies of care in the modern era. Advancing medicine is often focused on pushing therapeutic boundaries for patients with high mortality risk. It is difficult to have a rational discussion of therapeutic options without knowing the mortality risk of the alternatives. Information about the outcome and quality of life of children not suited for HTx may help with decision-making regarding alternative medical and surgical therapies and their role in the treatment of children with end-stage heart failure. In this study, we sought to evaluate the outcomes of children presumed, at the time of referral, to have no hope of survival without HTx, but who were denied transplant candidacy.
Methods We performed a retrospective review of all identifiable referrals to our HTx program between January 2005 and July 2013, based on our database of transplant referrals. We reviewed the electronic medical records and excluded any patient referred for combined heart–lung transplantation, those who were accepted and listed for HTx, those considered “too well” for HTx, and those without adequate documentation of HTx evaluation/decision-making in the medical record. This search yielded a cohort of patients who were sick enough to need HTx, but were denied because they were considered to be at elevated risk of poor outcome. We collected demographic information, including primary and associated diagnoses and previous surgical interventions. We used HTx evaluation and in-patient physician notes to collect data regarding clinical status, including symptoms, New York Heart Association (NYHA) or Ross classification, inotrope dependence, intubation, mechanical support, and episodes of cardiac massage before referral. HLA antibody test results were obtained from all included patients from both the electronic medical record as well as the HLA laboratory database. Luminex single-antigen-bead
907 panel-reactive antibody (PRA) assays were used starting in July 2007; before that time, a cytotoxicity assay from the U.S. Centers for Disease Control and Prevention was used. The Organ Procurement and Transplantation Network cPRA calculator was used to express PRA percent.9 Reason for HTx denial was collected from transplant selection committee notes. The clinical course after HTx denial was also characterized, including mortality, date of last follow-up and NYHA class and clinical status at last follow-up. Patients were censored at the date of their last available clinic visit or physician contact. Quality of life was assessed for surviving patients and collected prospectively at routine visits or by telephone interview. We used the PedsQL Cardiac Module—a brief, but well-validated instrument in pediatric patients with cardiac diseases.10–12 This questionnaire is made up of 4 age-specific instruments, 1 for the parent to complete and, if appropriate, 1 for the child to complete as well. The questionnaire surveys the child’s physical, emotional, social and school function on a 0 to 4 scale. The surveys are scored providing an overall score, physical health summary and psychosocial health summary. These scores provide objective numbers and validated measures of quality of life. Intercooled STATA v13.1 (StataCorp, College Station, TX) was used for statistical analysis. Survival analysis was done using the Kaplan–Meier approach. A log-rank test was used to distinguish survival with categorical variables. Univariate analysis was performed using Cox proportional hazards modeling to assess the relationship between mortality and risk factors. Multivariate analysis was subsequently performed using the same approach to further assess the relationship between mortality and other possible factors. The results were summarized as hazard ratios, 95% confidence intervals and p-values. Statistical significance was set at 5% (2-sided) throughout the analyses.
Results Of 212 consecutive referrals for HTx evaluation, 2 patients did not survive the transplant evaluation; 7 additional patients were lost to follow-up and did not complete the transplant evaluation. Of the remaining 203 patients, 39 (19%) of those evaluated for HTx met inclusion criteria and represented the study population. Demographic data of this cohort and reason for transplant denial are outlined in Table 1. Twenty-eight patients (72%) in the study population had congenital heart disease (Table 2). Each of these patients had between 1 and 6 surgical procedures, with a mean of 2.6 operations. There were no patients on extracorporeal membrane oxygenation or a ventricular assist device who met the inclusion criteria. There were also no patients with cardiac arrest (in or out of hospital) in the 30 days before transplant referral. The overall follow-up was 8 days to 7.8 years, with a median follow-up of 195 days. There were 15 (38%) deaths, which occurred between 8 days and 5.2 years after transplant referral (mean 220 days, median 66 days). One third (n ¼ 5) of these mortalities occurred in the first 30 days after referral. One-year mortality was 33% (n ¼ 13), with 20 patients remaining at risk. Three-year mortality was 36% (n ¼ 14), with 18 patients remaining at risk. Mortality was increased (by log-rank test) for those who were mechanically ventilated (78% vs 27%, p ¼ 0.0002), inotrope-dependent (56% vs 26%, p ¼ 0.002) and for
908 Table 1
The Journal of Heart and Lung Transplantation, Vol 34, No 7, July 2015 Demographic Data at Time of Referral for HTx
Age Male gender Weight Congenital heart disease Single-ventricle physiology Inpatient at referral Intubated/mechanical ventilation on inotropic support NYHA/Ross Class II or III Class IV Reason for HTx denial Multi-organ or uncontrolled medical diseasea Antibody pre-sensitization (high PRA) Pulmonary vascular disease Medical non-compliance
6 weeks to 19 years (median 3.5 years) 22 (56%) 3.7–72.6 kg (median 13.4 kg) 28 (72%) 20 (51%) 21 (54%) 9 (23%) 16 (41%) 20 (51%) 19 (49%) 17 (44%) 13 (33%) 2 (5%) 7 (18%)
Data expressed as number (%) unless noted otherwise. HTx, heart transplantation; NYHA, New York Heart Association; PRA, panelreactive antibodies. a Venous or pulmonary artery anatomic abnormalities precluding Htx surgery (4), severe chromosomal abnormality thought to limit posttransplant prognosis (6), severe neurological injury (2), hepatic and renal dysfunction (1), Pompe disease (1), renal failure and multi-organ ischemia (2) and diffuse fungemia (1).
inpatient (vs outpatient) HTx evaluations (48% vs 28%, p ¼ 0.03). Those with NYHA/Ross Class IV symptoms had higher mortality than those who were either Class II or III (53% vs 25%, p ¼ 0.0065). A high level of covariance for these factors was confirmed. Males also had higher mortality (57% vs 22%, p ¼ 0.02). Mortality was not influenced by age, weight, growth failure, presence of developmental delay, congenital heart disease, number of previous cardiac surgical procedures or single-ventricle physiology. Of the 21 inpatient HTx referrals, 16 were on inotropes at the time of referral. The 5 who were not on inotropes at the
Table 2 Types of Congenital Heart Disease in the Study Population n (%) Single-ventricle physiology Hypoplastic left heart syndrome Unbalanced atrioventricular canal Double-outlet right ventricle variants Tricuspid atresia Ebstein’s anomaly of the tricuspid valve Pulmonary atresia with intact ventricular septum Two-ventricle physiology Aortic stenosis Truncus arteriosus Corrected transposition of the great arteries Tetralogy of Fallot
20 12 3 2 1 1 1
(51%) (31%) (8%) (5%) (3%) (3%) (3%)
9 3 2 2 1
(23%) (8%) (5%) (5%) (3%)
time of HTx consideration were subsequently discharged successfully on oral heart failure medication regimens. Of the 16 patients on inotropes, 3 had subsequent cardiac surgery and were weaned from inotropic support, and 2 were able to be weaned off inotropes without subsequent cardiac surgery. Of the remaining 9 patients, 7 were also intubated, and these patients died. The median survival time from HTx referral for all inpatients was 66 days (range 3 days to 3.9 years). Pre-sensitized patients had mean cPRA of 91.8 ⫾ 14%. All these patients had congenital heart disease, and 9 of 13 had single-ventricle physiology. Twelve of the 13 had Z2 previous cardiac surgical procedures, and 1 with only a single cardiac surgery. Eight of the 13 presented with decompensated heart failure symptoms or NYHA/Ross Class IV symptoms: 6 were on inotropic support at the time of HTx evaluation and 2 were intubated. There were 7 deaths among the pre-sensitized patients (54%) occurring 8 to 148 days (mean 68 days) after referral. All these deaths occurred among the patients presenting with decompensated heart failure. Follow-up for the surviving patients was 195 days to 3.9 years (mean 2 years), with all patients being NYHA/Ross Class II or III at last follow-up. High PRA patients were not more likely to die than other high-risk patients (54% vs 31%, p ¼ 0.18). This was also not
Table 3
Univariate Analysis
Risk factor Age (years) Z11 3.5–11 1–3.49 o1 Weight (kg) Z34 14–33.99 7.6-13.99 o7.6 Male gender Growth failure Congenital heart disease Single-ventricle physiology High PRA (vs other patients) Mechanically ventilated Inotropic support NYHA/Ross Class IV Inpatient at referral Subsequent cardiac surgery
Hazard ratio 95% CI
p-value
1 0.67 3 1.87
— (0.09–4.77) (0.61–14.75) (0.34–10.29)
— 0.69 0.177 0.473
1 1.64 2.42 2.8 4.05 1.65 0.8
— (0.27–9.99) (0.45–12.92) (0.54–14.62) (1.14–14.48) (0.59–4.65) (0.27–2.33)
— 0.589 0.3 0.223 0.031 0.341 0.677
1.62
(0.58–4.56)
0.361
2.01
(0.7–5.77)
0.193
6.31
(2.13–18.68)
0.001
4.79 4.45 3.38 0.13
(1.57–14.58) (1.38–14.39) (1.05–10.85) (0.02–1.03)
0.006 0.013 0.041 0.053
Univariate analysis was performed with Cox proportional hazard modeling. For age and weight, the patients were divided into quartiles, with the groups Z11 years and Z34 kg used as reference. Patients with high PRA as the reason for heart transplant denial were compared with all other reasons for heart transplant denial. NYHA Class IV patients were compared with those who were Class II and III. CI, confidence interval; PRA, panel-reactive antibodies.
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significant in the univariate analysis (Table 3), and thus not included in the multivariate analysis. Ten patients had subsequent palliative cardiac surgery after HTx referral. The reasons they were not HTx candidates were as follows: 2 were pre-sensitized; 7 had medical disease; and 1 was medically non-compliant. Surgical procedures included: Glenn followed by fenestrated Fontan (n ¼ 1); fenestrated Fontan (n ¼ 3); atrioventricular valve replacement with left atrial reduction (n ¼ 1); conversion to 2-ventricle circulation (n ¼ 1); Ross procedure (n ¼ 1); coronary artery repair (n ¼ 1); pulmonary arterioplasty with unifocalization (n ¼ 1); and palliative 8-mm Blalock–Taussig shunt (n ¼ 1). There was 1 death in this group, which was significantly less when compared with patients who did not have surgical procedures (10% vs 48%, p ¼ 0.02). Follow-up for the remaining 9 patients was 15 days to 7 years (mean 2.8 years). One of these patients was NYHA Class IV at last follow-up, and the remaining 8 patients were all NYHA/Ross Class I or II. Both uni- and multivariate analyses were done using Cox proportional hazard modeling. Univariate analysis (Table 3) yielded male gender, mechanical ventilation, inotropic support, NYHA Class IV and inpatient at referral as significant risk factors. Age, weight, growth failure, congenital heart disease and single-ventricle physiology were not significant. Those patients with subsequent cardiac surgery approached significance (p ¼ 0.053). Many of the significant risk factors from both the log rank test and the univariate analysis were markers of severity of heart failure. These variables were so closely associated that we were unable to separate NYHA class, mechanical ventilation, inotropic support and inpatient status from each other to evaluate their independent contribution. As we were limited by our sample size and the interrelation of the data, these variables were analyzed together in the multivariate analysis as “markers of severe heart failure,” along with gender (Table 4). We examined those patients with any markers of severe heart failure and those without (Figure 1) using the Kaplan–Meier method. Patients with any markers of severe heart failure had lower survival compared with those not having markers (p ¼ 0.021). In addition to survival analysis we examined severity of disease at follow-up as well as quality of life in surviving patients. NYHA class was available for 21 of 23 (91%) surviving patients (Figure 2). In general, NYHA class improved in surviving patients. Of these surviving patients, 16 qualified for the quality-of-life survey and 11 (69%) were recruited. The remaining patients either followed up with outside cardiologists or are seen so infrequently now that they did not have a clinic visit during the study period. The results of the PedsQL was an overall score of 70.2 ⫾ 23.9, a physical Table 4
Figure 1 Kaplan–Meier survival curve based on presence of any of the “markers of severe heart failure” at the time of HTx evaluation: NYHA Class IV symptoms; inotrope dependence; need for mechanical ventilation; and/or inpatient HTx evaluation. The difference in survival when any risk factors are present versus no risk factors was significant (p ¼ 0.021).
health summary score of 69.6 ⫾ 22.3 and a psychosocial health summary score of 70.5 ⫾ 24.6. Although there was no control population for direct comparison, these results compare favorably to previously reported results from PedsQL cardiac in both patients with heart failure and HTx as well as patients with congenital heart disease.
Discussion Children with heart failure are living longer for multiple reasons, including medical and surgical care. In the past 2 decades, there has been considerable effort placed into overcoming immune barriers to HTx for high-risk patients, and this has sometimes been met with terrible results. This study offers a perspective that high-risk transplant may not be the best, or only, option for some end-stage heart failure patients—even if they have “exhausted” their other surgical and medical options. We are not trying to suggest that highrisk HTxs are completely unnecessary, or that the pursuit of overcoming the immune barriers of pre-sensitization is an ignoble cause. HTx can be a life-saving intervention for many children with end-stage heart failure.
Multivariate Analysis Hazard ratio 95% CI
Male gender 3.81 Any “markers of severe 3.78 heart failure”
p-value
(1.06–13.66) 0.04 (1.04–13.72) 0.04
Figure 2 NYHA class of surviving patients at HTx referral and at last follow-up. NYHA class at follow-up was available for 21 of 23 surviving patients.
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We acknowledge that the definition of an “excessiverisk” transplant candidate is a moving target—defined barriers to HTx are constantly evolving, usually decreasing, as we identify and overcome the obstacles of specific subpopulations of patients. However, a long wait for an HTx, filled with multiple infusions, long hospital stays and repeated immune desensitization therapies, may in some cases be the road to a predictably short post-transplant life, and may also rob patients of an acceptable quality of life. Although denial of HTx listing is a difficult end-point for many families, it is important to emphasize the possibility that a child may survive longer and perhaps have a better quality of life without HTx when the transplant selection team considers the procedure to be too risky. This study uniquely characterizes the outcomes of a group of children with death-prone heart failure who have been denied access to transplant listing. Many patients, by the time the HTx team is consulted, have been denied further surgical palliation because of surgical risk. However, some of these surgical interventions may be reconsidered after the child is denied HTx. There is currently little published information about this group of ultra–high-risk heart failure patients, who have been through an HTx evaluation but who are considered unsuitable for HTx. Because of the heterogeneity of the patient population and relative paucity of literature regarding the group as a whole, there is no appropriate control population for comparison with these children. Although the outcomes attained for these patients are largely descriptive, they offer the chance to reframe the prognosis of heart failure not amenable to successful HTx. Our data suggest that pediatric patients referred for HTx evaluation in compensated heart failure, and then treated aggressively after being denied access to transplant listing, have 75% survival at 4 years. Although this statistic is worse than modern HTx outcomes for normal-risk patients, it may be a reasonable outcome when weighed against the combination of increased wait-list and post-transplant mortality of an HTx performed with a positive crossmatch or other risky circumstances. Furthermore, the 3-year mortality is almost equal to the 1-year mortality, suggesting that most of the attrition is early (to decompensated heart failure) and that those who survive the first year may have a reasonable chance of mid-term survival. Patients referred for HTx as inpatients with decompensated heart failure had a far greater likelihood of dying during hospitalization. Because of the sample size and the interrelation of the individual “markers of severe heart failure,” we were unable to separate them and perform multivariate testing on individual variables, but instead included patients in the multivariate analysis if they had any of these risk factors present. Importantly, underlying cardiac disease, age, weight and single-ventricle physiology were not predictors of mortality. Antibody pre-sensitized patients, all of whom had underlying cardiac disease, were not at increased risk of mortality compared with the rest of the study population. This is a group with 2 significant risk factors of reduced survival after HTx. Males were at higher risk of death compared with females in both uni- and bivariate analyses. Although a
female gender advantage has been found in some other disease processes,13 the significance of this finding in a population of pediatric heart failure patients is not clear. It is challenging to balance acute surgical risks with longer term quality and quantity of life. For example, it is difficult to decide whether a 30% to 50% mortality risk is acceptable for a procedure that has the potential to dramatically improve a patient’s life, especially when comparing it with the possibility of simply waiting for a heart transplant, where the risks are taken on passively and continuously. For our population, when surgical options were available to correct hemodynamic derangements, regardless of the perceived high surgical risk, these patients did markedly better when compared with published outcomes from “high-risk” HTxs. Before their HTx evaluation and denial, these children were all considered unacceptable surgical candidates, but in the hands of an experienced surgeon these patients achieved acceptable overall outcomes, with a quality of life comparable to that of other children with congenital heart disease as well as successful HTx recipients.11,12 Although we cannot propose formal criteria for surgical intervention, close collaboration between the transplant and cardiac surgery teams can lead to appropriate patient selection. The quality-of-life data we reported from PedsQL surveys suggest that not only are these children surviving, but they also have a reasonable quality of life. Compared with the PedsQL scores reported by Mellion et al,12 our patient population had similar scores to a general population of children with single-ventricle physiology (average total score 64.6 to 72.5). Healthy children from Mellion’s cohort reported average total scores ranging from 84.9 to 86.9. Another large quality-of-life study by Varni et al reported children with chronic asthma having average total scores of 68.8 to 74.9.14 In 2013, Menteer et al reported that children with chronic heart failure secondary to dilated cardiomyopathy had PedsQL scores averaging 67, also comparable to our patients.11 Although a direct comparison to these groups or a control group is not possible, the proximity of the quality-of-life scores to the scores of their peers with similar underlying cardiac conditions or to other children with chronic diseases10,12,14 suggests that their quality of life is reasonable.
Limitations The present study is limited by its predominantly retrospective nature and the population size. Our center is a major referral center, so some patients returned to their home institution, and follow-up time in some cases was limited. We contacted families and cardiologists outside our institution to overcome as much of this limitation as possible. Because of the small sample and variable followup times, the long-term survival estimates, even with appropriate censuring, may be limited. There is not an appropriate control population for a direct comparison of survival. Although we have made inferences based on the
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available literature, much of the data in this high-risk group of patients remain descriptive. Our outcome measures may also become obsolete due to the increased use of ventricular assist devices (VADs). Our institutional practice over this era was to not deploy a VAD except as a bridge to transplant, so there were no VADs used in our patient population. VAD use as destination therapy has the potential to dramatically change the landscape of end-stage heart failure for children, even many of those with congenital heart disease. In addition, the use of VADs to bridge patients to transplant candidacy (e.g., for those with potential for pulmonary vascular remodeling or undergoing immune desensitization) has already changed the landscape of transplant candidacy. Criteria for transplant candidacy vary by institution. Our center had reasonably uniform management principles with regard to pre-transplant risk assessment during the time of this study, and it is this set of principals that made our study possible. However, this potentially limits the reproducibility of our findings. Finally, our quality-of-life analysis is biased by patient selection, because we only collected data on the surviving patients. In conclusion, an advanced heart failure program can achieve satisfactory survival and quality of life for pediatric patients who are not suitable candidates for HTx, especially those outpatients presenting with compensated heart failure. Selected children may benefit, beyond expectations, from carefully chosen, high-risk palliative surgery, or may survive longer than expected with aggressive medical therapy, without the long hospitalizations and multiple medical complexities of high-risk HTx. The patients who are least likely to survive after denial of HTx listing are those who are inpatients at referral, NYHA Class IV, mechanically ventilated or inotropedependent. This information may help some physicians and families reframe a determination of non-candidacy for HTx as the beginning of reassessment for these patients, with potential for longer and better life as a non-transplant candidate compared with living as a high-risk HTx candidate with a very poor pre- and post-transplant prognosis.
Disclosure statement The authors have no conflicts of interest to disclose. We thank the MAPI Research Trust, Lyon, France, for their permission to use the
911 PedsQL. This study was supported by a grant from the Paige Foundation, Hermosa Beach, California.
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