Medication Adherence Among Pediatric Post-Heart Transplant Patients in a Tertiary Care Hospital

Introduction

Heart transplantation in pediatric patients has made remarkable advances in Saudi Arabia. Of the 46 hearts transplanted in Saudi Arabia, 33 (72%) were for adult recipients, while 13 (28%) were for pediatric recipients, yielding good success rates and improved outcomes [1]. The recent introduction of the Berlin Heart EXCOR mechanical circulatory support system for pediatric patients awaiting heart transplantation underscores the King Abdulaziz Cardiac Center’s commitment to advancing this field [1]. This is particularly relevant given the high prevalence of pediatric heart disease in the region, with many patients requiring referral to cardiac centers for intervention [2]. Advances in surgical techniques, immunosuppressive therapies, and post-transplant care have contributed to enhanced survival and quality of life for children with end-stage heart failure. Despite the high rates of short-term survival following heart transplantation, patient non-adherence to the prescribed medication regimen has a significant impact on long-term survival [3]. As part of the post-transplant treatment protocol, immunosuppressive therapy is administered together with concurrent antimicrobial medications after solid-organ transplant, patients who were assessed as non-adherent to immunosuppressive therapy had an 80% greater chance of organ loss, a 60% increased risk of hospitalization, and a 2-fold risk of biopsy-proven acute rejection. [4] Therefore, one of the biggest concerns in transplant patients is medication adherence. Medication adherence is defined by the World Health Organization as “the degree to which the person’s behavior corresponds with the agreed recommendations from a health care provider” [5]. Dew et al (2009) published a meta-analysis of medication adherence in a pediatric population following a solid-organ transplant, finding that non-adherence rates varied across different aspects of the regimen, with non-adherence to clinic appointments and tests being the most prevalent. Psychosocial factors such as family functioning and the child’s psychological status were correlated with poorer adherence [6]. Hoegy et al (2019) conducted a systemic review of 34 studies that included 13 kidney transplantation patients, 11 liver transplantation patients, and 10 patients who received other organs, indicating poor medication adherence in the pediatric post-transplant population. Medication adherence was found to be lower than 80% in two-thirds of the studies (64%) and varied from 22% to 97%. The variation in the methods used for assessment contributed significantly to the wide range of medication adherence rates [7]. Another systemic review found that pediatric heart transplant patients frequently fail to adhere to immunosuppression, which is linked to worse outcomes like hospitalization, rejection, and death [8]. Nevertheless, Ringewald et al (2001) observed that non-adherence was linked to poor outcomes and late rejection following pediatric heart transplantation, which occurred frequently during adolescence [9]. Various techniques were used to evaluate non-adherence, including self-report and patient interviews. In addition to family or healthcare provider reports, medication drug levels, electronic medication monitoring, pill counts, and healthcare professional documentation during clinic visits are also useful techniques to assess adherence. Combining all these tools is considered optimal for assessing medication adherence levels in solid-organ transplantation patients [6–9]. The Immunosuppressive Therapy Adherence Scale (ITAS) is a 4-item questionnaire that includes Forgetfulness, Carelessness, Stopping, and Missing taking immunosuppressive medication. ITAS is a validated tool used to evaluate transplant recipients’ adherence to immunosuppressive therapy (IST). High adherence to IST was indicated by a maximum score of 12, whereas non-adherence was indicated by a score as low as 0 [10]. Given the growing incidence of non-adherence to immunosuppression and its negative correlation with outcomes, additional research in this area is necessary, particularly considering that non-adherence to immunosuppression in pediatric heart transplant patients is a significant issue, with estimates ranging from 40% to 70%, and this non-adherence is associated with worse outcomes, including rejection, hospitalization, and mortality [8,9]. The aim of this study was to assess the adherence to post-heart transplant immunosuppressive therapy in pediatric heart transplant patients at King Abdulaziz Cardiac Center.

Material and Methods

STUDY DESIGN:

This cross-sectional study was based on interviews combined with immunosuppressant level monitoring for all pediatric patients who underwent heart transplants at King Abdulaziz Medical City-Central Region over a period of 5 months from January to May 2024.

ETHICS APPROVAL:

Institutional review board (IRB) approval was obtained from King Abdullah International Medical Research Center (KAIMRC) in January 2024 (reference number RYD-23-419812-202767).

STUDY QUESTIONNAIRE:

The questionnaire consisted of 2 major sections. The first section included demographic and clinical data including patient age at study time, patient age at transplant year, gender, number of siblings, household status, parent job and educational level, family monthly income, person responsible for supporting the child, taking immunosuppressants, and the type, dose, and level. The immunosuppressant drug level based on our institutional hospital for tacrolimus post-transplant is 0–6 months: 10–12 ng/ml, 7–12 months 8–10 ng/ml, 1–2 years 6–8 ng/ml, and >3 years: 5–7 ng/ml. Patients are considered adherent if they are within the target therapeutic levels, and are considered non-adherent if the level is below the target therapeutic levels, setting a threshold of 80% to indicate adherence. The second section assessed medication adherence using the Immunosuppressive Therapy Adherence Scale, a validated 4-item questionnaire. ITAS questions focus on forgetfulness, carelessness, stopping and missing medication, and attitude toward taking immunosuppressant medications. The ITAS questions were answered with scores of 0, 1, 2, and 3 for frequencies of more than 50% of the time, 21–50% of the time, 1–20% of the time, and 0% (never), respectively. The highest IST adherence was indicated by a maximum score of 12, while the lowest adherence was indicated by a score of 0 [10]. We used an 80% or higher adherence rate cut-off (a score of at least 10 on the ITAS Score). Verbal consent was obtained from all patients. Confidentiality of data was maintained throughout the study period and thereafter.

STATISTICAL ANALYSIS:

Descriptive statistics such as mean (SD), median (IQR), and number (%) were applied to describe the characteristics of the data. Fisher’s exact test was used to check the association between 2 categorical variables. The Shapiro-Wilk test was used to check the normality of numeric variables and found that none of the variables were normally distributed. Hence, non-parametric tests such as the Mann-Whitney U test and Kruskal-Wallis test were used to compare the median values of numeric variables between 2 groups and more than 2 groups, respectively. The statistical significance was determined based on P value less than 0.05. All analyses were done using R software (version 4.3.3).

Results

We conducted interviews and monitored immunosuppressant levels for all pediatric patients who underwent heart transplants at King Abdulaziz Medical City-Central Region from January to May 2024. Therefore, the analysis in our cross-sectional study was based on data collected within this defined 5-month timeframe. A total of 20 parents received the survey, and 19 completed the questionnaire and were included in the final analysis. Among the pediatric post-heart transplant patients, 12 (60%) were males, and 8 (40%) were females, aged from 6 to 18 years, as shown in Table 1. Most patients (85%) were on tacrolimus, while 15% were on tacrolimus and sirolimus, as shown in Table 2. A high percentage of respondents (95%) reported “never: forgetting to take their immunosuppressive medication, while another substantial proportion (90%) reported “never” being careless in their medication intake. However, a small percentage reported occasional carelessness (5%). Around 5% of the participants reported missed doses or stopping the medication for the pediatric patient because of an illness not related to the transplant. Of the 19 participants, the majority scored 12, and 1 each scored 11, 10, and 9 (Figure 1), with a mean of adherence score 11.68 and SD of 0.82, as shown in Table 3. Associations of variables such as the number of siblings, household status, parental job, education level, and family income with the adherence score and therapeutic level result are shown in Tables 4 and 5.

Discussion

This is the first study of its kind that focused on assessing medication adherence among pediatric post-heart Transplant in Saudi Arabia. Diverse adherence rates among pediatric patients following heart transplantation have been documented. Some research found that most patients regularly follow their prescribed drug regimen, indicating high rates of adherence, which is similar to our findings. For example, Albert et al (2012) evaluated the compliance in infant and adolescent post-heart transplant patients, assessing how heart transplantation at different stages of life affects overall well-being and adherence to medical regimens. They concluded that compliance with medication regimens was high in all age groups, indicating good adherence to post-transplant medication [11]. The present study found lower adherence rates, with a minor fraction of patients exhibiting less-than-ideal adherence. This finding is consistent with a previous study conducted by Eaton et al (2018) that examined medication non-adherence in adolescents and young adults with solid-organ transplants. They included 47 patients, with 25% receiving kidney transplants, 47% receiving liver transplants, and 28% receiving heart transplants. They comprehensively evaluated adherence levels, and revealed that medication non-adherence was common (40%) among adolescents and young adults with solid-organ transplants [12–14].

In our study, we combined 2 assessment methods: the ITAS tool (subjective) and the therapeutic drug levels using electronic health records (objective) to assess patient adherence. Positive patterns with low non-adherence rates were found in the current study among pediatric patients after heart transplantation, which is in line with research using comparable assessment tools and reporting non-adherence rates of 14.3% and 28.3% [15,16]. Contrary to the current findings, some studies reported a higher non-adherence rate. For instance, descriptive correlational research using the ITAS with 230 patients undergoing kidney transplantation showed a non-adherence rate of 57.8% [17]. A small proportion of participants (5%) reported experiencing occasional carelessness, indicating the necessity of ongoing supervision and assistance to avoid adherence inconsistencies. When asked why they had stopped or missed their immunosuppressive medicine in the previous 3 months, most participants (85% and 90%, respectively) said it was never because they felt worse or for any other reason. Only a small percentage of participants (5%) reported they stopped or skipped taking their prescription for a variety of reasons. The responses to ITAS questions in our study and in the study by Taj et al (2021) showed a small proportion of participants (5%) reported being careless or stopped taking their immunosuppressive medication [18]. This emphasizes the importance of dealing with any issues or adverse effects that can result from the prescribed medication and to offer assistance and instruction to guarantee continuous adherence, even when the patient feels temporary discomfort.

Our study specifically examined risk factor parameters – number of siblings, household status, parental occupation, parental education level, and family income – in relation to medication adherence in post-heart transplantation patients. The statistical analyses conducted, including the Mann-Whitney U test and Kruskal-Wallis test, revealed no significant differences in adherence scores according to gender (P=0.183), age group (P=0.526), parental occupation (P=0.637), parents’ educational levels (P=0.7), or family income (P=0.845). This aligns with the findings of Dew et al (2009) and Shellmer et al (2011), indicating a complex interplay of factors influencing medication adherence in pediatric transplant recipients. While our results corroborate the existing literature in some aspects, the lack of significant differences in adherence scores based on the examined parameters suggests a need for further exploration and understanding of adherence patterns in this patient population. Moving forward, future research could delve deeper into the intricacies of these factors and their collective impact on post-transplantation medication adherence, aiming to develop tailored interventions that address the unique challenges faced by pediatric transplant patients in maintaining optimal adherence to their treatment regimens.

The strength of this study is that it is a pediatric study conducted in Saudi Arabia, and was based on the results of different patient support programs, and follow-up could be initiated to enhance and maintain the quality of services. The sample size was small because our heart transplant service was recently established and due to the limited eligibility for patients to undergo heart transplants at King Abdulaziz Medical City-Central Region. Studies with longer follow-up periods are needed.

Conclusions

Pediatric patients tend to have acceptable adherence to immunosuppressants early after heart transplant. Patient support programs might be recommended in the institution to follow patients for a longer time to assess the adherence and any additional related risk factors.