A Systematic Review of Adherence to Immunosuppression among Pediatric Heart Transplant Patients

After pediatric heart transplant, commitment to lifelong immunosuppression is crucial to maintaining graft health. However, a review of the current literature surrounding adherence to immunosuppression in pediatric heart transplant patients is lacking. This systematic review aims to summarize the current landscape of adherence to immunosuppression in pediatric heart transplant patients. We conducted searches in PubMed MEDLINE, Embase, CENTRAL register of Controlled Trials (Wiley), and Scopus, from inception to March 2020. Studies were eligible if they outlined an aspect of adherence to immunosuppression and the measurement of adherence was performed with an objective or otherwise validated measure of adherence (e.g., drug levels, adherence questionnaires). The titles/abstracts of 880 articles were reviewed. After initial screening, 106 articles underwent full text review. As such, 14 articles were included in the final review. Baseline adherence estimates varied greatly, with most values between 40% and 70%. Nonadherence to immunosuppression is associated with worse outcomes (rejection, hospitalization, mortality), impaired quality of life, and mental health concerns in pediatric heart transplant patients. As nonadherence to immunosuppression is common and associated with worse outcomes, there is a need for further development and evaluation of interventions in this space.


Introduction
Pediatric heart transplantation is the standard of care for select patients with end-stage heart disease [1,2]. The primary indication for transplant differs by age, with congenital heart disease being most common in infants (57%) and cardiomyopathy being most common in older children (43% in children aged 1-10 years and 53% in children aged 11-17 years) [3].
After pediatric heart transplant (HTx), commitment to lifelong immunosuppression is necessary to maintain graft health. Most post-transplant immunosuppression regimens include a calcineurin inhibitor (CNI) and an antiproliferative agent [2,4]. Adequate adherence to these immunosuppressive medications is essential to preventing poor outcomes [5]. Estimates for rates of nonadherence within the pediatric population are wide ranging,

Study Characteristics
Study characteristics, including study design, are outlined in Table 1. Studies were published between 1998 and 2019. Eleven studies were conducted in the USA [6,[11][12][13][14][15][16][17][18][19][20] and three studies in Europe [21][22][23]. Study types included cross sectional (seven studies), cohort (six studies), and one randomized trial. The median number of pediatric heart transplant patients was 32, with a range of 12-138. Studies were looked at collectively to determine measures and rates of nonadherence. Studies were then divided into three themes: (1) CNI levels as a marker for nonadherence and correlation to poor outcomes (four studies), (2) impact of nonadherence on quality of life and mental health (seven studies), and (3) the effect of transition programs on adherence (three studies).

Measures and Rates of Nonadherence
Studies used a variety of subjective (e.g., self-report) and objective (e.g., drug levels) measures. The reported rates of adherence varied greatly. In five studies, the nonadherence rate ranged from 40 to 60% [6,13,17,21,23]. Grady et al. (2018) found that approximately 70% of participants had CNI levels within the target range [16], and Serrano-Ikkos et al. (1998) found 69.8% of patients had good adherence, based on CNI levels and selfreported data [22]. In two studies, approximately 20% of patients reported at least one late or missing dose of immunosuppression medication in the last week [13,18], and 28% of caregivers reported that their adolescent/young adult (AYA) took one or more doses of antirejection medications late in the past week [13]. Figure 2 is a graphical representation of reported nonadherence rates, as described above. caregivers reported that their adolescent/young adult (AYA) took one or more doses of antirejection medications late in the past week [13]. Figure 2 is a graphical representation of reported nonadherence rates, as described above. Table 2 outlines the different adherence measures used.

Name Overview
Medication Experience Scale for Immunosuppressants (MESI) [24] • Seven item self-report questionnaire, total scores between 4 and 33 • Higher scores reflect more negative attitudes towards immunosuppressant side effects The Medication Adherence Measure (MAM) [25] • A semi-structured clinical interview to assess medication adherence • Consists of three core modules and several treatment specific modules The Medication Level Variability Index (MLVI) for tacrolimus [26] • MLVI is calculated as the standard deviation of a set of at least three tacrolimus trough blood levels for each participant • A higher MLVI means less consistent medication adherence The Patient Assessment of Problems with the Heart Transplant Regimen [27] • Measures adherence to 15 components of the medical regimen (including immunosuppressants) • Higher scores indicate more adherence Multidimensional Adherence Classification System (MACS) [6] • A four-category classification system that uses a combination of self-reports and serum immunosuppressant assays • Developed in solid organ transplant patients

Medical Condition and Medication Knowledge
Questionnaire [11] • Assessment developed by study personnel to track medical knowledge, medication adherence, and self-reported confidence to transition from pediatric to adult health care Table 3 outlines the four studies that included immunosuppressant levels as a marker for nonadherence and poor outcomes. Immunosuppression variability is associated with hospitalization [6,14], rejection [6,14,19], and mortality [6,14]. More specifically, Kerr et al. (2020) looked at rejection risk following subtherapeutic CNI levels. The risk of rejection increased 6.9-fold in the 2 weeks following a subtherapeutic level, and increased 6.1-fold in the 3 months after presenting with a subtherapeutic level (as compared to time period after a therapeutic level) [17]. Further, 22% required treatment for rejection within 3 months of a subtherapeutic level [17]. When looking at self-reported nonadherence, mortality was significantly correlated with adolescent reports of missed doses [6]. In contrast, Ringewald et al. (2001) did not find an association between self-reported nonadherence and abnormal CSA level at admission for rejection. Notably, two-thirds of the patients with late rejection (11 out of 15) admitted to nonadherence [19]. Table 3. Studies exploring drug levels as a marker for nonadherence and rejection.
Medication Module of the Medication Adherence Measure (MAM) • Mortality was significantly correlated with adolescent reports of missed doses (r = 0.31, p < 0.05)

Multidimensional Adherence Classification System (MACS)
• Overall rate of nonadherence was 61% (across solid organ transplant groups) • Probability of experiencing a rejection episode in the past six months was significantly greater than the expected value for members of the Genuinely Non-adherent group than for members of the other three groups χ 2 (3, n = 82) = 14.5, p < 0.00 Table 3. Cont.

Author (Year) Adherence Measure Outcomes
Ringewald (2001) [19] Immunosuppressant drug levels (Tacrolimus and Cyclosporine) and variability (defined as the ratios of non-therapeutic CSA levels over total number of levels analyzed per patient) • Drug variability increased as the number of rejection episodes grew, and mean drug percent variability was higher in the group with rejection (p = 0.04). • Patients with no rejection had 10% variability for cyclosporine/tacrolimus, whereas drug variability was 20-25% in patients with >4 episodes of rejection.
Voluntary admission of irregular medication administration • Admitted nonadherence was not associated with an abnormal CSA concentration at admission for rejection. • Two thirds of the patients with late rejection (11 of 15) admitted to nonadherence.

•
The risk of rejection increased 6.9-fold in the 2 weeks following a subtherapeutic level, and 6.1-fold in the 3 months after presenting with a subtherapeutic level, as compared to time period after a therapeutic level.
Flippin (2000) [14] Cyclosporine levels and variability (defined as the ratios of non-therapeutic CSA levels over total number of levels analyzed per patient).
• 8 of 49 patients were defined as the high-variability group. • History of non-compliance with the chronic treatment plan was present in 5/8 patients as opposed to 0/41 patients in the low-variability group (p < 0.001).

•
The high-variability group had a significantly higher median number of hospitalized days (p = 0.036) and experienced significantly higher rates of recurrent rejection (p = 0.0003). • Patients with high variability had a significantly greater death rate more than 6 months after transplant (p = 0.01). CNI = calcineurin inhibitor, CSA = cyclosporin A. Table 4 outlines the seven studies that included the impact of nonadherence on quality of life and mental health. Some studies found that nonadherence was associated with patient mental health concerns on child and/or caregiver self-report tools [12,23], and poor quality of life scores further correlated with rejection episodes [12]. In two studies, specific psychiatric comorbidities, such as anxiety [18] and depression [21], were found to correlate with nonadherence. In contrast, two studies found that there were no associations between mental illness in the child and nonadherence [13,22], and that caregiver emotional distress did not seem to correlate with missed doses [13]. These findings may be explained by low rates of reported nonadherence, and an overall lower prevalence of adherence problems in the HTx group, as compared to other solid-organ transplant groups in the study [13].

•
High risk non-compliance group had significantly more disorders on the scales cardiac disorders (p = 0.020), exhaustion (p < 0.001), and epigastric pain (p = 0.002), and on the total score of the GBB (p = 0.002).
Health Questionnaire for Children and Young People  • No significant differences between the control group and patient group re: psychosomatic disorders Devine (2011) [12] The   Table 5 outlines the two studies discussing transition from pediatric to adult health care. Anton et al. (2019) utilized a two-year structured transition program consisting of seven two-hour sessions to improve patients' overall medical knowledge, medication adherence, readiness to transition, and parental perceptions of child's readiness to transition [11]. They found a statistically significant decrease in percentage of CNI levels out of range prior to beginning the transition program and after completing the transition program [11]. In addition to improving immunosuppression adherence, the program also enhanced overall patient medical and medication knowledge, which may prevent lapses in medical care [11]. Self-report (Assessment of Problems with the HT Regimen) Grady (2019) [15] Immunosuppression levels A standardized tailored transition program focused on increasing HT knowledge, self-care and self-advocacy skills and enhancing social support. It was designed to improve outcomes (i.e., adherence to immunosuppression and the medical regimen) for emerging adults who underwent HT as children and transferred to adult care • There were no significant between-group or within-group differences in percent of tacrolimus levels within target range over time (intervention 69-75%, usual care 72-58% (baseline to 6 months)).

•
Average overall self-reported adherence to the treatment regimen was similarly good in both groups, and no significant group/time interactions were detected. • The number of patients with adverse events through 3 and 6 months was low to moderate, with a trend toward more adverse events in the intervention group by 6 months.

•
The rates of keeping clinic and CNI blood-draw appointments were similar in both groups through 3 months and 6 months.

•
The number of episodes of treated acute rejection were low through 3 and 6 months but differed significantly between groups through 6 months (intervention = 5, usual care = 0, p = 0.021).
Self-report (Assessment of Problems with the HT Regimen) CNI = calcineurin inhibitor HT = heart transplant. Grady et al. (2019) studied a standardized transition program designed to improve outcomes (e.g., adherence to immunosuppression/medical regimen) for young adults who underwent heart transplant as children and transferred to adult care. The program focused on improving heart transplant knowledge, self-care and self-advocacy skills, and enhancing social support. The transition program included computer modules and multiple meetings/telephone calls with dedicated HTx staff. Patients were randomized into the intervention group or to usual care (e.g., standard transfer-of-care meeting). There were no significant between-group or within-group differences in percent of tacrolimus levels within target range from baseline to 6 months (intervention 69-75%, usual care 58-72%) [15]. Additionally, average overall self-reported adherence to the treatment regimen was similarly good in both groups, and no significant group/time interactions were detected. The intervention group actually ended up having significantly more episodes of acute rejection through the 6 months when compared to usual care, though the overall numbers were low (intervention = 5, usual care = 0). Table 6 outlines bias ratings for cohort studies, as scored by the Newcastle-Ottawa scale. Table 7 outlines bias ratings for cross-sectional studies, as scored by the modified Newcastle-Ottawa scale. Table 8 outlines the bias rating for the randomized trial, as scored by Version 2 of the Cochrane risk-of-bias tool for randomized trials. The six cohort studies scored between 7 and 9 out of 9 possible points, with points deducted for lack of controls/adjustments and self-reported outcomes. The seven cross-sectional studies scored between 6 and 8 out of 10 possible points, with points deducted for lack of description of non-respondents, lack of controls/adjustments, only self-reported outcomes, and incomplete presentation of measurement of association. The majority of points were deducted for lack of controls/adjustments for cofounders (20 points amongst 11 studies). The randomized trial scored a low overall risk, acknowledging the nonblinded participants and researchers.

Discussion
This systematic review outlined measures of adherence and baseline adherence estimates in pediatric heart transplant patients. Baseline adherence rates varied greatly, with most values between 40% and 70%, depending on measurement metrics. Adherence was measured most often with serum immunosuppression levels, though the way in which these levels were reported, interpreted, and assigned clinical significance differed between studies. Some studies also used a validated self-report measure. Variable immunosuppressant drug levels correlated with significant clinical outcomes, including rejection, hospitalizations, and death. Mental health comorbidities were associated with nonadherence in some studies. Finally, findings regarding the utility of transition programs in improving adherence in pediatric patients were mixed.
An agreed upon gold standard for measuring adherence would be beneficial for data analysis and identification of at-risk patients. By doing so, we would be better equipped to compare results between studies, especially in a patient population that is already limited in size. Of note, the lack of standardization for measuring adherence is not an issue unique to pediatric transplant recipients. In the adult literature, there are numerous tools to measure immunosuppression adherence [28]. The majority of these tools are self-report measures [28], which have their limitations (including Hawthorne-type effects and social desirability). While many pediatric studies utilized immunosuppressant drug levels to determine adherence, this was less common in the adult literature [28]. It is worth noting that recent efforts led to the development of the PROMIS Medication Adherence Scale (PMAS), which is a widely available, free self-report measure of adherence. Validation studies for PMAS are ongoing to evaluate its psychometric properties in different pediatric and adult patient populations [29].
Our findings are consistent with the literature, illustrating how intrapatient variability of a drug is associated with poor allograft outcomes (e.g., rejection, death) [30,31]. Cardiac allograft vasculopathy (CAV) is a cause of morbidity and mortality in pediatric heart transplant patients, and is a common indication for re-transplantation. Interestingly, the link between medication nonadherence and CAV has not been clearly elucidated. Per the International Society for Heart and Lung Transplantation (ISHLT) data, rejection within the first year is associated with CAV development [32]. However, in adults, tacrolimus intrapatient variability was not associated with cardiac allograft vasculopathy [33]. Pediatric patients with cardiac allograft vasculopathy have a 50% allograft survival rate at nearly three years [34]. A variety of factors can lead to CAV, including rejection [35].
The relationship between medication nonadherence, quality of life and mental health is likely multifactorial. Symptoms of anxiety and depression may make medication adherence more difficult and lead to intentional nonadherence. It is also possible that medication nonadherence may lead to emotional distress and physical symptoms, which may negatively impact quality of life and mental health. Adult heart transplant patients also struggle with mental health and socioeconomic comorbidities, as well as engaging with support networks [28]. When discussing medication adherence, time should be spent addressing a patient's mental health concerns to identify those that would benefit from psychiatric/psychological intervention.
Lastly, this review showcased the feasibility of two pediatric to adult heart transplant transition programs and their potential to improve immunosuppression adherence. These publications support the continued development of transition programs for these patients, with an opportunity for further research to improve adherence outcomes. In addition to transition programs, there may be a role for technology-based interventions to improve adherence in heart transplant patients. Digital interventions are already being used for children and adolescents with many chronic health conditions [36][37][38][39][40][41][42][43][44][45][46][47]. Gomis-Pastor et al. published one of the first studies using a mobile health intervention (mHeart) to improve immunosuppression adherence in adult heart transplant patients [48]. Use of the app was significantly associated with improved adherence to immunosuppression, increasing adherence rates from 61% to 87% [48]. A recently published systematic review on mobile health app interventions in transplant recipients showed that medication adherence improved in the majority of studies evaluating m-health as an intervention [49]. The continued development of technology-based interventions to improve medication adherence remains a promising area of research, one which may hopefully lead to improved health outcomes and quality of life.

Strengths and Limitations
The primary strength of this manuscript is its systematic approach to evaluating immunosuppression adherence in pediatric heart transplant patients. All articles were independently screened by at least two authors, and articles were evaluated for bias by two authors. The data were carefully studied and subsequently organized in an attempt to provide clinically relevant information.
One limitation of this paper is the heterogeneous nature of the data. The variety of ways in which immunosuppression levels were described, as well as the combination of different validated self-report measures and qualitative outcomes, precludes a metaanalysis. There is also a lack of controls and adjustments in the data analysis. The included studies have relatively small sample sizes, which is to be expected, given the nature of the pediatric heart transplant cohort. Patient follow-up varied amongst the included studies, limiting the interpretation of timing for outcomes associated with nonadherence. Lastly, only articles published in English were included in our review.
Given that immunosuppressive regimens have changed over the past few decades, comparing data from studies over a 20-year time span has its limitations. The majority of HTx patients are prescribed a three-drug maintenance immunosuppression regimen, including a CNI, antimetabolite, and corticosteroids. Cyclosporine is a CNI that was most popular in clinical practice in the 1980s [50], while tacrolimus was introduced in the early 1990s and has become the preferred CNI due to a more favorable side-effect profile [50]. Additionally, mycophenolate mofetil largely replaced azathioprine as the antimetabolite of choice after the clinical trial by Kobashingawa et al. (1998) showed reduced rates of rejection and improved survival with mycophenolate mofetil [51]. Sirolimus and everolimus are proliferation signal inhibitors that became available in the early 2000s [50]. These drugs may be used as part of a triple-drug regimen or for CNI avoidance, though particular use cases are beyond the scope of this manuscript. There may be a role for simplified medication regimens to improve adherence rates [52,53], which remains a meaningful topic for additional research and review.

Conclusions
Nonadherence to immunosuppression in pediatric heart transplant remains a challenge that has an impact on patient outcomes (rejection, hospitalization, mortality), quality of life, and mental health. A gold-standard adherence measure would assist with collective analysis and interpretation of the pediatric heart transplant literature. Transition programs are feasible interventions for young adult patients with the aim to improve adherence, but more research is needed to determine associated outcomes. Lastly, further studies are needed to identify additional strategies to improve adherence in pediatric heart transplant patients.  Embase ('heart transplantation'/exp OR 'heart transplant*':ti,ab OR (('organ transplantation'/exp OR transplant*:ti,ab) AND ('heart'/exp OR heart:ti,ab))) AND ('medication compliance'/exp OR 'adherence':ti,ab OR 'nonadherence':ti,ab OR 'non adherence':ti,ab OR 'compliance':ti,ab OR 'noncompliance':ti,ab OR 'non compliance':ti,ab) Remove review and meeting abstracts and animals in title. ] explode all trees #14 ("adherence" OR "nonadherence" OR "non adherence" OR "compliance" OR "noncompliance" OR "non compliance").ti,ab Scopus TITLE-ABS-KEY ("heart transplant*") AND TITLE-ABS-KEY (adherence OR nonadherence OR "non adherence" OR compliance OR noncompliance OR "non compliance") AND (LIMIT-TO (DOCTYPE, "ar"))