Ventricular assist devices (VADs) have proven to be reliable for providing hemodynamic support for medically resistant heart failure patients awaiting cardiac transplantation in both adult and pediatric populations.1,2 VADs have been shown to improve some of the modifiable pretransplant risk factors for poor outcomes like cardiac and renal function.3–6 However, the outcomes for cardiac transplantation (including the ones that are bridged to transplant (BTT) with a VAD) also depends on some nonmodifiable factors (gender, race, diagnosis, etc.).7–9 Age is one of the important nonmodifiable determinants of posttransplant outcomes, and among conventional age groupings, adolescents (age 12–17 years) in particular, have poor outcomes for heart transplantation (HTx).10 In fact, across all solid organ transplantations, the adolescent age group has been shown to have the worst transplant outcomes compared with younger patients.11 On the other hand, all recipients greater than or equal to 18 years old are grouped into a broad “adult category”, the posttransplant outcomes of which is thought better than adolescents except for the oldest of recipients greater than 65 years old.
The reasons for poor transplant outcomes in adolescents seem to be multiple. Studies show that adolescent physiology has effects on the pharmacokinetics of drug metabolism and the degree of sensitization to human leukocyte antigens.12–14 Also, critically ill adolescents are more likely to have psychosocial problems and medication noncompliance.15,16 The latter is felt to be a strong driver of the adolescent effect because survival greater than 1 year is where adolescent outcomes diverge. Moreover, in case of cardiac transplant, history of multiple surgical procedures (congenital heart disease [CHD]) may play a role in poor outcomes.17
There is a growing concern that the worse outcomes observed in adolescents extend beyond the adolescent years into the young adulthood. Of note, recently, it has been shown that the poor outcomes for HTx start in older adolescents (15 years) instead from the standard start age of adolescent years (12 years), and continue into young adulthood (30 years).18 Therefore, the study sought to examine whether the poor outcomes for HTx related to adolescent age are also observed in recipients who are BTT with a VAD and whether and how far this effect extends beyond the standard definition of adolescent age (12–18 years).
Materials and Methods
United States Organ Sharing (UNOS) database was used to identify all HTxs BTT with a VAD in 8–39 years old recipients from January 2005 to June 2016. To determine whether a difference exists in the posttransplant survival for different ages, 5 years survivals were plotted for each year of age. Also, posttransplant survival was compared (log-rank test) to determine the statistically significant change in survival between each year of age. Based on the survival comparison for each year of age, two inflection points for significant change in survival were identified. Based on these inflection points for change in survival, patients were divided into three age groups. Pretransplant characteristics and posttransplant outcomes were compared between the three groups.
Summary statistics were presented as median (interquartile range) for continuous variables and count (%) for categorical variables. Continuous variables were compared using Student’s-t test (normally distributed data) and Mann–Whitney U test (skewed data), whereas categorical variables were compared using Chi-square test. Life tables were used to calculate the 5 years posttransplant survival while Kaplan-Meier survival comparison was used to determine the overall survival and log-rank test was used to determine the equality of curves. Patient characteristics at transplant associated with overall mortality (exploratory p < 0.2) in univariate analysis were incorporated into a multivariate Cox-proportional hazard model to find out independent predictors (p < 0.05) of overall mortality. Data were analyzed on IBM SPSS version 24 (IBM Corp. Released 2015. IBM SPSS Statistics for Mac OS, Version 24.0. Armonk, NY: IBM Corp.).
Of 5,655 HTxs in patients 8–49 years of age, 1,848 (33%) transplants were bridged with a VAD. A decline in posttransplant survival was noted after 14 years of age, which improved at around 30 years of age (Figure 1). Group 1 (8–14 years) had 237 (13%) recipients, group 2 (15–29 years) had 787 (43%) recipients, and group 3 (30–39 years) had 824 (44%) recipients. Group 2 was subdivided into “older adolescents” (ages 15–17 years, n = 168) and “young adults” (ages 18–29 years, n = 619).
Patient Characteristics at Transplant
Summary of comparison of all analyzed baseline characteristics VAD types are presented in Tables 1 and 2, respectively.
Group 2 (ages 15–29 years) versus group 1 (ages 8–14 years).
Group 2 had less females (29% vs. 43%; p < 0.001) and patients with a transplant diagnosis of CHD (5.5% vs. 14%; p < 0.001). Group 2 also had less number of patients with high (> 3 wood units) pulmonary vascular resistance (18% vs. 42%; p < 0.001), poor renal function (5.2% vs. 13%; p < 0.001), intravenous (IV) inotropic support (21% vs. 33%; p < 0.001), and ventilator support (4.7% vs. 19%; p < 0.001), but had more patients on chronic steroid support (10% vs. 4.6%; p = 0.007). Additionally, group 2 was more likely to have a donor to recipient weight ratio (DRWR) of less than 0.8 (11% vs. 2.5%; p < 0.001). Among VAD types, group 2 patients were more likely to be on continuous flow (73% vs. 41%; p < 0.001) and intracorporeal devices (78% vs. 42%; p < 0.001). Also, group 2 patients were more likely to be on a left VAD (LVAD: 76% vs. 68%; p = 0.010) and total artificial heart (TAH: 4.3% vs. 1.3%; p = 0.028) and were less likely on a biventricular device (BiVAD: 19% vs. 29%; p < 0.001).
Group 2 (ages 15–29 years) versus group 3 (ages 30–39 years).
Group 2 had more patients with a transplant diagnosis of CHD (5.5% vs. 1.2%; p < 0.001). Group 2 also had more number of patients with higher total bilirubin (28% vs. 23%; p = 0.017), IV inotropic support (21% vs. 14%; p < 0.001), ventilator support (4.7% vs. 2.8%; p = 0.043), and chronic steroid support (10% vs. 7%; p = 0.016), but had less number of patients with high (> 3 wood units) pulmonary vascular resistance (18% vs. 23%; p = 0.038). Among VAD types, group 2 patients were less likely to be on continuous flow (73% vs. 82%; p < 0.001) and intracorporeal devices (78% vs. 86%; p < 0.001). Also, group 2 patients were less likely to be on LVAD (76% vs. 82%; p = 0.002) and more likely to be on BiVAD (19% vs. 12%; p = 0.001).
Group 2 (15–29 years) had higher incidence for acute rejection episodes (24% vs. 175; p = 0.032) and being treated for rejection within 1 year posttransplant (24% vs. 18%; p = 0.045) compared with group 1 (ages 8–14 years). Compared with group 3 (ages 30–39 years), group 2 had lower incidence of posttransplant dialysis (7.6 vs. 12%; p = 0.002) and stroke (2% vs. 4.1%; p = 0.015). Comparison of posttransplant events is summarized in Table 3.
Group 2 (15–29 years) was found to have worse post-HTx survival compared with group 1 (p < 0.001) and group 3 (p = 0.005) (Figure 2). Multivariate analysis for predictors of mortality showed that being in ages 15–29 years is an independent risk factor for posttransplant mortality compared with ages 8–14 (hazard ratio: 3.676; p < 0.001) and ages 30–39 years (hazard ratio: 1.424; p < 0.001) (Table 4). On subdividing group 2 into “older adolescents” (15–17 years) and “young adults” (18–29 years), post-HTx survival was similar between the two subgroups (p = 0.353) (Figure 3). A summary of causes of posttransplant mortality among the age groups is presented in Table 5.
Grouping of patients in medicine should be done keeping in mind the physiologic similarities and common risk factors for a particular age range. The inflection points for changes in survival have made this evident that following the standard or conventional cutoffs for age ranges inappropriately groups vulnerable populations of young adults (18–29 years) with older age patients in a broader “adult group.” The 22 years old is more akin to the 18 years old than the 40 years old physically, psychologically, and socially. They are likely to receive general adult treatment protocols which can put them at risk of poor posttransplant outcomes as they are not designed keeping their specific physiologic and social differences (pharmacokinetics, Human Leukocyte Antigen response, etc.) in mind. In younger patients, the body is growing and goes through rapid physiologic changes as well as responds to stressors differently. Literature has described the difference in physiology for adolescents leading to poor transplant outcomes, and the maturation of their physiology is gradual and is not complete at 18 years old.14 Most likely, the young adults who are often grouped with all adults have the similar physiology to older adolescents, which more than the course of young adulthood gradually transforms into adult physiology.
Critically ill patients like HTx patients bridged with a VAD require long-term medical care and follow-up and have to live a “vulnerable” life compared with the general healthy population because of a constant lifelong risk for deterioration of their medical condition. For these patients, psychosocial factors in addition to physiologic factors also play a key role in determining the long-term outcome.15 Medication compliance including transparent and engaging communication is an integral to positive outcomes after a HTx and adolescents are not great communicators at times and evidence clearly demonstrates issues with medication noncompliance.16 The decrease in survival around 15 years of age and then increase in survival around 30 years of age in the current study can perhaps also be explained due to the psychosocial factors affecting medication compliance, communication, and general self-care. Until around 15 years of age, parents/guardians are usually responsible to taking care of child’s health and medication compliance. Around 15 years is the age at which children start feeling more independent and are at risk for carelessness about themselves. This behavioral change continues into the young adulthood until they become psychologically mature, and by the age of around 30 years, there is a general shift toward a responsible approach to life and a move away from the care-free lifestyle. This “age 30 transition” (28–33 years) is a period when a person is likely to take important decisions regarding life partner, parenthood, family, work, and lifestyle.19 These behavioral changes can have impact on personal health and medication compliance, which in turn can impact posttransplant survival.
The study analyzed and compared pretransplant baseline characteristics in each age group to note differences and see what their impact was on the poor outcomes observed for patients age 15–29 years. Despite the age group of 8–14 years old only differing from our at-risk (15–29 years) cohort in a significantly higher frequency of several well-documented risk factors (more females, patients with a diagnosis of CHD, poor renal function, IV inotropic, and ventilator support), their survival was better than the 15–29 years old cohort. This clearly demonstrates that being in age group of 15–29 years is a strong risk factor for poor transplant outcomes, as was clearly demonstrated in the multivariable analysis.
The at-risk group (15–29 years) was further divided into older adolescents and young adults to check whether there is a difference in survival. The similar survival between the subgroups makes it evident that no difference exists in the survival of young adults compared with older adolescents. Therefore, it may be more suitable for young adult patients to receive evaluation and treatment protocols for pre and posttransplant care similar to adolescent protocols and not adult protocols. Also, when new protocols for cardiac transplantation and VADs are designed for a certain age group, the physiologic and psychological aspects of that age group should be kept in mind and not the predetermined accepted traditional age groupings.
Our study had certain limitations. As it is a retrospective study from a national database, there is always a possibility of inaccurate data collection. Another important limitation was that medication compliance could not be calculated as UNOS database has discontinued recording medication noncompliance events after 2006. Unfortunately, we do not have sufficient posttransplant information in the UNOS dataset which can give possible explanation of the worse outcomes in 15–29 years age patients.
In conclusion, older adolescents and young adults, both, have similarly poor post-HTx survival when BTT with a VAD compared with younger children and middle-aged patients. Grouping patient outcomes by the standard definitions mislabels younger adolescents (12–14 years old) as a vulnerable cohort and misses a vulnerable young adult (18–29 years old) recipient population in need of additional scrutiny and care. The similarities in older adolescents and young adults should be carefully considered when formulating treatment protocols for older adolescents and young adults.
1. Lima B, Mack M, Gonzalez-Stawinski GVVentricular assist devices: The future is now. Trends Cardiovasc Med 2015.25: 360369,
2. O’Connor MJ, Rossano JWVentricular assist devices in children. Curr Opin Cardiol 2014.29: 113121,
3. Bhimaraj A, Uribe C, Suarez EEPhysiological impact of continuous flow on end-organ function: Clinical implications in the current era of left ventricular assist devices. Methodist Debakey Cardiovasc J 2015.11: 1217,
4. Maybaum S, Mancini D, Xydas S, et al.LVAD Working Group: Cardiac improvement during mechanical circulatory support: A prospective multicenter study of the LVAD Working Group. Circulation 2007.115: 24972505,
5. May LJ, Montez-Rath ME, Yeh J, et al.Impact of ventricular assist device placement on longitudinal renal function in children with end-stage heart failure. J Heart Lung Transplant 2016.35: 449456,
6. Zafar F, Morales DL, Lorts A, et al.Pre-transplantation mechanical circulatory support duration effects candidacy and graft longevity. J Heart Lung Transplan 2016.35: S71,
7. Rossano JW, Dipchand AI, Edwards LB, et al.International Society for Heart and Lung Transplantation: The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant 2016.35: 11851195,
8. Allen JG, Weiss ES, Arnaoutakis GJ, et al.The impact of race on survival after heart transplantation: An analysis of more than 20,000 patients. Ann Thorac Surg 2010.89: 19561963; discussion 1963–1964,
9. Singh TP, Naftel DC, Addonizio L, et al.Association of race and socioeconomic position with outcomes in pediatric heart transplant recipients. Am J Transplant 2010.10: 21162123,
10. Dipchand AI, Kirk R, Edwards LB, et al.International Society for Heart and Lung Transplantation: The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Heart Transplantation Report–2013; focus theme: Age. J Heart Lung Transplant 2013.32: 979988,
11. Dharnidharka VR, Lamb KE, Zheng J, Schechtman KB, Meier-Kriesche HUAcross all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis. Pediatr Transplant 2015.19: 471476,
12. Rossano JW, Morales DL, Zafar F, et al.Impact of antibodies against human leukocyte antigens on long-term outcome in pediatric heart transplant patients: An analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg 2010.140: 694699, 699.e1,
13. Everitt MD, Hammond ME, Snow GL, et al.Biopsy-diagnosed antibody-mediated rejection based on the proposed International Society for Heart and Lung Transplantation working formulation is associated with adverse cardiovascular outcomes after pediatric heart transplant. J Heart Lung Transplant 2012.31: 686693,
14. Hsu DTBiological and psychological differences in the child and adolescent transplant recipient. Pediatr Transplant 2005.9: 416421,
15. Lewis M, Vitulano LABiopsychosocial issues and risk factors in the family when the child has a chronic illness. Child Adolesc Psychiatr Clin N Am 2003.12: 389399, v,
16. Oliva M, Singh TP, Gauvreau K, Vanderpluym CJ, Bastardi HJ, Almond CSImpact of medication non-adherence on survival after pediatric heart transplantation in the U.S.A. J Heart Lung Transplant 2013.32: 881888,
17. Savla J, Lin KY, Lefkowitz DS, et al.Adolescent age and heart transplantation outcomes in myocarditis or congenital heart disease. J Heart Lung Transplant 2014.33: 943949,
18. Baker RS, Rizwan R, Bryant R 3rd, et al.Poor Outcomes after heart transplant: Being a teenager does not stop at age 18. J Heart Lung Transplant 2017.36: S105S106,
19. Levinson DJA concept of adult development. American Psychologist. 1986.41: 313,