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Transplantation and Adherence: Evaluating Tacrolimus Usage in Pediatric Patients With Cancer

Micah A. Skeens
Mary S. Dietrich
Nancy Ryan-Wenger
Mary Jo Gilmer
Shelagh A. Mulvaney
Terrah Foster Akard
CJON 2020, 24(5), E57-E64 DOI: 10.1188/20.CJON.E57-E64

Background: Researchers have estimated that about 50% of pediatric patients with chronic illness adhere to tacrolimus therapy, a medication responsible for preventing critical side effects in patients undergoing hematopoietic stem cell transplantation (HSCT).

Objectives: The purpose of this study was to describe patient adherence to tacrolimus by reviewing documentation from the electronic health record and therapeutic drug levels.

Methods: This retrospective descriptive study examined 357 clinic visits by 57 patients undergoing HSCT. Direct (tacrolimus levels) and indirect (subjective reporting) measures were evaluated.

Findings: The authors found that, in 51% of visits, adherence was not documented. The overall nontherapeutic drug level rate was 60%. Because of the small sample size, nonadherence did not statistically correlate with nontherapeutic levels. The findings highlight the need for adherence awareness, assessment, and documentation in clinical practice.

Hematopoietic stem cell transplantation (HSCT) is an aggressive medical treatment associated with high morbidity and mortality rates. These rates are influenced by underlying disease, as well as complications that may occur during or immediately following the transplantation. The main risks of allogeneic HSCT are increased susceptibility to infection and transplant-related complications, such as graft-versus-host disease (GVHD). The process can be physically and emotionally difficult for children and their parent caregivers. HSCT recipients need to adhere to multifaceted outpatient regimens that require strict personal hygiene, environmental restrictions, and complex medication regimens (Morrison et al., 2017).

Adherence to immunosuppressant medications during the acute phase after transplantation is critical to prevent GVHD and avoid graft failure. GVHD is a major potential complication and occurs in about 35%–50% of all allogeneic transplantations (Murray et al., 2018; Zeiser & Blazar, 2017). GVHD is the effect of immunologic activation of donor lymphocytes attacking major and minor human leukocyte antigen mismatches from the recipient (Ferrara et al., 2009). Acute GVHD occurs in the first 100 days following transplantation. Survival rates range from 30% to 50%; however, morbidity and mortality can be decreased through prophylactic immunosuppressants. Immunosuppressant medications are a class of drug used to suppress the body’s immune system to prevent rejection in solid organ and HSCTs. The most frequently prescribed immunosuppressive agents are cyclosporine and tacrolimus. Despite cost and unpleasant side effects, adherence is crucial to improved outcomes and increased quality of life. More complex medication regimens are associated with nonadherence; therefore, pediatric recipients of HSCT who must follow difficult post-transplantation regimens are at high risk for poor adherence (Coleman et al., 2012). Lack of adherence to any of these regimens can be life threatening.

Rates of Adherence

Rates of adherence to recommended treatment have been reported at about 50% overall in pediatric patients. These rates are typically lower for patients with chronic disease when compared to acute illnesses adherence rates. Few studies have reported on treatment adherence rates in HSCT specifically for pediatric patients; therefore, the current foundation for clinical practice is based on limited and somewhat dated literature. Across adult and pediatric studies, HSCT treatment adherence rates range from 33% to 95% (Chieng et al., 2013; Hoodin, 1993; McGrady et al., 2014; Phipps & DeCuir-Whalley, 1990). Studies of pediatric patients undergoing HSCT treatment report adherence rates ranging from 57% to 97% during the acute phase (first 100 days post-transplantation) (McGrady et al., 2014; Pai et al., 2018; Phipps & DeCuir-Whalley, 1990). Based on documentation, the most important determinants of nonadherence to treatment regimens are complexity and treatment regimen duration (Belaiche et al., 2017; Dew et al., 2018; Killian et al., 2018; Quine et al., 2012; Varni & Wallander, 1984). Pediatric patients undergoing difficult HSCT treatment that requires lifelong medication are at high risk for medication nonadherence. Significant implications of treatment nonadherence include unnecessary testing, additional treatment, readmissions, medical complications, and patient death.

Few studies have described treatment adherence in stem cell transplantation. A systematic review by Morrison et al. (2017) found only five studies addressing adherence. Of the five, only two were pediatric (McGrady et al., 2014; Phipps & DeCuir-Whalley, 1990), and one combined an adult and pediatric trial (Martin et al., 2012). Pai et al. (2018) prospectively examined treatment adherence in 50 pediatric patients undergoing HSCT during the acute phase post-transplantation. None of these studies specifically examined adherence to immunosuppressant therapy for pediatric patients undergoing HSCT. Therefore, the purpose of this study was to retrospectively explore adherence to tacrolimus during the acute phase in outpatient pediatric patients undergoing stem cell transplantation.

Methods

Participants and Setting

This retrospective descriptive study included a sample of patients (N = 57) who received allogeneic HSCT from 2009 to 2016. Inclusion criteria included (a) patients from birth to 21 years of age (b) patients on tacrolimus-based immunosuppressant therapy, and (c) patients who were at three or more weeks of evaluation as outpatients. Exclusion criteria included initial discharge after day 100, disease progression, and early taper or change to other immunosuppressive medications. Interpretation of a single medication level can be unclear related to several factors, including drug–drug interaction, diet, and timing of medication; therefore, only patients with three or more weeks of documented outpatient evaluation were included.

The study setting was Nationwide Children’s Hospital in Columbus, Ohio, a large tertiary hospital that performs about 40 transplantations annually. Of those, approximately 15 are allogeneic HSCTs requiring immunosuppressant therapy. Unless otherwise indicated by a clinical trial, tacrolimus was the standard immunosuppressive agent.

Procedures

After hospital and university institutional review board approvals, the principal investigator (PI) collected data via the electronic health record (EHR). Reviews began with the first post-transplantation outpatient clinic visit. Data collection continued until the start of tacrolimus tapering, which begins about three to nine months post-transplantation. The PI recorded data on all patients on the medical record data form, which was created by the authors of this study. To ensure data reliability, a practitioner with 15 years of experience in HSCT acted as a secondary reviewer, extracting data on approximately 20% of participants. Agreement between the two reviewers was 98%. Patients had different post-transplantation discharge days; therefore, the number of visits evaluable for tacrolimus adherence differed per patient.

Measures

The medical record data form included factors that could potentially contribute to adherence. Data collected included gender, age in years at transplantation, diagnosis, total number of medications (weekly), preparative regimen, and transplantation characteristics. Adherence was measured using indirect (self-report, documentation by provider) and direct (drug levels) measures.

Indirect Measure: The PI recorded patient nonadherence based on any subjective notes in the EHR from a physician or nurse indicating that the patient was nonadherent to tacrolimus. The authors planned to collect the number of missed doses; however, providers did not document this information.

Direct Measure: Tacrolimus was measured using the random whole blood concentration of 5–15 ng/ml (measured by LC-tandem mass spectrometric assay) or 8–20 ng/ml (measured by chemiluminescent immunoassay technique) (Jacobson et al., 1998; Yanagisawa et al., 2010; Yanik et al., 2000). The PI recorded weekly levels of tacrolimus documented in the EHR. Patients were nontherapeutic if tacrolimus levels were outside the therapeutic range of 5–15 ng/ml.

Analysis

IBM SPSS Statistics, version 24.0, was used for statistical analysis. Descriptive statistics were used to describe demographics, transplantation characteristics, indirect and direct adherence, and variables associated with nonadherence to tacrolimus therapy. Chi-square tests of independence were used to test for differences between the characteristics of the groups of participants who maintained therapeutic levels and those who did not. An alpha of p < 0.05 was used for determining statistical significance.

Results

Participants

Ninety-seven patients received tacrolimus and were initially eligible for this study. Twenty patients were excluded because of discharge after day 100, death related to transplantation complications, disease progression, and early taper or change to other immunosuppressive medications. Ten patients were excluded because they had fewer than three outpatient tacrolimus levels. The final study sample was 57 patients.

Table 1 summarizes the demographic characteristics of the 57 patients. The mean age was 8.51 years (range = 1 month to 21 years) and the majority were White (n = 44) with a malignant diagnosis (n = 35). The majority of patients (n = 38) underwent a matched unrelated donor transplantation with bone marrow (n = 41) as the stem cell source. The most common preparative regimen was anti-thymocyte globulin (n = 24).

Adherence to Tacrolimus Therapy

An evaluation of the EHR documented 357 clinic visits for the 57 patients (range = 4–23 clinic visits per patient). Providers did not document subjective (indirect) adherence in 51% of the visits. In 175 visit notes referencing adherence, providers cited six episodes of nonadherence in three patients. Because of the small number of documented nonadherence, subjective nonadherence did not statistically correlate with nontherapeutic levels; however, 50% (n = 3) of the documented nonadherent visits also had nontherapeutic levels. In contrast, serum assay levels were nontherapeutic in only 17% (n = 4) of patients with documented subjective adherence.

Table 2 illustrates the summaries of the weekly tacrolimus levels for all patients. More than half of the patients (n = 34) demonstrated nontherapeutic levels (less than 5 or greater than 15 ng/ml) for at least one of their weekly visits. Within the first three weeks postdischarge (time frame during which most of the same had weekly data), median values ranged from 8.7 to 9.4 ng/ml, and the percent of patients with nontherapeutic levels ranged from 16% (n = 5) to 24% (n = 7). The tacrolimus levels for 53% of patients (n = 30) were nontherapeutic 20% or more of the time. Approximately 34% of the patients were nontherapeutic 40% or more of the time.

Tacrolimus Adherence and Associated Variables

Table 3 provides summaries and comparisons of the characteristics of the nontherapeutic and therapeutic groups of patients. As shown, those who had at least one nontherapeutic level were in the postdischarge period for a longer number of weeks than those with all therapeutic levels (mean = 7.6 weeks, SD = 2.8 versus mean = 6 weeks, SD = 2; p = 0.002). The majority of patients in the therapeutic and nontherapeutic groups were male and with malignant diagnosis (difference between groups, p < 0.05). Although not statistically significant, the nontherapeutic group included 2.5 times more females. Children aged 1–5 years were most commonly outside the therapeutic range (n = 12); however, school-aged children (i.e., those aged 6–10 years) (n = 7) and adolescents (i.e., those aged 11–20 years) (n = 8) were of the majority in the therapeutic group.

Tacrolimus Adherence and Outcomes

Effect of nonadherence could not be correlated with clinical outcomes because of the small number of documented nonadherent episodes. The overall postdischarge GVHD rate for participants was 39%. There was no statistically significant difference between the therapeutic and nontherapeutic groups for GVHD. The nontherapeutic group had a GVHD rate of 41% compared to 35% for the therapeutic group (p = 0.627). The readmission rate was approximately 30% for each group (p = 0.934).

Discussion

To the best of the authors’ knowledge, these are the first known results attempting to examine adherence to tacrolimus in the acute post-transplantation phase in pediatric patients undergoing allogeneic HSCT. Previously reported literature on solid-organ transplantations suggests tacrolimus levels outside of the therapeutic range correlate with adherence (de Oliveira et al., 2017; Eaton et al., 2018; Fredericks & Dore-Stites, 2010; Rich et al., 2018; Shemesh & Fine, 2010); therefore, the authors’ results suggest an overall adherence rate of approximately 60% using the direct serum assay method. Across studies of adherence to general medications in the post-transplantation population, adherence rates are reported to be from 33% to 95% using various measures (Morrison et al., 2017). The effect of nonadherence of prescribed treatment to clinical outcomes is not reported. However, poor adherence rates, as reported in this study, can influence clinical outcomes, specifically increased GVHD, hospitalizations, recurrence, and death.

Studies of pediatric patients undergoing solid organ transplantation indicate that nonmodifiable factors, such as gender, age, and time since transplantation, influence overall adherence (Boucquemont et al., 2019; Dew et al., 2009; Killian, 2017; Shellmer et al., 2011). Although not statistically significant in the current study, more than two times the number of females were noted in the nontherapeutic group. Gender was obtained via the EHR, and gender differences vary among age and underlying diagnosis. Some studies report associations between males and higher nonadherence rates (Boucquemont et al., 2019; Dew et al., 2009; Dobbels et al., 2010). However, another study reported no differences in adherence based on gender (Killian, 2017). Reasons for the increased rate of females with nontherapeutic levels in this study are unclear. Also of interest in the current study, children aged 1–5 years were most frequently in the nontherapeutic group. These results are similar to the inpatient retrospective study that reported lower adherence based on subjective report in children aged 2–12 years (Phipps & DeCuir-Whalley, 1990). However, other studies have suggested that nonadherence is highest in the adolescent age group (Connelly et al., 2015; Hoegy et al., 2019; Killian et al., 2018; Mehta et al., 2017; Vandermorris et al., 2020). The younger age group is understudied in adherence literature. Further studies evaluating family factors, as well as facilitators and barriers to adherence in the pediatric HSCT population, are needed.

The current study found no correlation between GVHD rates and readmissions between groups. The authors did not specifically evaluate infections; however, Pai et al. (2018) examined 50 outpatients and found a statistically significant correlation between adherence rates to higher infection rates (p < 0.005); an average adherence rate of 63% during the acute phase post-transplantation was reported. Pai et al. (2018) also did not focus on immunosuppressant medications.

Three studies of the pediatric HSCT population and treatment adherence did not examine concurrent immunosuppressant medications (McGrady et al., 2014; Pai et al., 2018; Phipps & DeCuir-Whalley, 1990). There was considerable variability in adherence measurement methods among the studies. One study of 54 patients retrospectively examined adherence in the inpatient setting (Phipps & DeCuir-Whalley, 1990). Nursing documentation and nursing diagnosis were used to assess adherence. The overall adherence rate was reported at 50%; however, the study did not specifically examine immunosuppressive medications.

A study by McGrady et al. (2014) examined adherence to outpatient medications in the adolescent population (defined as those aged 12–18 years) post-transplantation. The study found that patients took an average of 73% of their medications. At least one dose was missed approximately three days per week. In addition, adherence worsened over time. Despite a small sample size (N = 6), the results of the study suggest that adherence in the pediatric HSCT population is poor.

Limitations

The authors acknowledge several limitations to the study. The study was a small retrospective descriptive study conducted at one site. The authors planned to collect the number of missed doses; however, providers did not document this information. The acute phase of transplantation had a variable length of time and, therefore, a different number of opportunities for adherence related to longer inpatient stays, readmissions, and early weaning of immunosuppressants. Some of the findings are contrary to the findings in other studies about patient adherence to medications associated with chronic illness. This could be related to the small sample size or perhaps it is unique to this specific population and needs further study.

There is also concern for the reliability of adherence self-report. Using one method of adherence can lead to threats of bias; therefore, the direct measure of tacrolimus assays was also included in this study. The authors acknowledge that many factors effect therapeutic levels of immunosuppression. Changes in blood levels can happen as a result of other factors, including absorption problems, diet, and drug-drug interactions (Shemesh et al., 2017; Shemesh & Fine, 2010).

Implications for Practice

Patients and families often hide nonadherence to medications (Brown et al., 2016). Similarly, it is well known that adherence is under reported, as noted in the current study in which 51% of clinic visit records did not document adherence or nonadherence. Providers and parents also overestimate medication adherence (Brown et al., 2016; Cain et al., 2020; Morrison et al., 2017). Similar to Hoodin (1993), who reported an indirect adherence rate of approximately 95%, the current study reported 96% adherence in those patients where adherence was reported subjectively and documented.

Nurses are key to a multidimensional approach to ensure medication adherence. As a strategy to evaluate adherence, subjective (e.g., self-report, caregiver report, clinician assessment) and objective (e.g., serum assays, pill count, electronic monitoring, direct observation) methods have the most sensitivity and specificity (Brown et al., 2016; Dew et al., 2009; Fredericks & Dore-Stites, 2010; Plevinsky et al., 2019; Quittner et al., 2008). A combination of routine self-report, serum assays where available, and pill counts could provide a more thorough assessment with little disruption to current practice.

Although this study’s sample was small, participants reported episodes of nonadherence, and 50% had nontherapeutic levels. Compared to the group that reported adherence, only 17% had nontherapeutic levels. Hoodin et al. (1993) has suggested fabricated self-report rates based on finding adherence rates of 50% when indirect measures of adherence were correlated with pill counts. This study’s findings support recommendations for more direct measures of adherence monitoring.

In addition, the current study’s findings support nurses following a more consistent and direct measure of medication adherence to establish accuracy about adherence and to prevent adverse events from nonadherence to prescribed medications. A provider’s relationship with the patient has been shown to influence adherence (Brown et al., 2016) and is essential to quality outcomes. The nurse’s relationship with the patient and family is crucial to accurate assessment and implementation of interventions to improve overall adherence.

Implications for Research

Adherence research is multifaceted and includes assessment/measurement, education, and communication by healthcare providers, nurses, and the healthcare system as a whole. Research regarding pediatric patients undergoing HSCT is needed in all of these domains. Nurses play a key role in each of these areas and can contribute significantly to improving outcomes. The amount of nonadherence that is clinically meaningful in HSCT is unknown. Future research is needed in clinical outcomes associated with adherence assessment, as well as a better understanding of barriers and facilitators to improve outcomes in this vulnerable population. Research using knowledge from other pediatric chronic illnesses to design intervention trials to improve overall adherence is also essential. Nurses should be included in the development and conduct of such studies.

Conclusion

There is a significant need for additional multisite adherence research in the pediatric stem cell transplantation population. Additional studies are needed to determine facilitators and barriers, best measurement methods, correlations to outcomes, as well as interventions to improve adherence. Collaboration across institutions and disciplines is needed to identify areas at risk and potential interventions to improve adherence. Educational interventions with nurses and providers should emphasize the importance of open communication related to adherence. The potential severe consequences of poor adherence, such as GVHD, infection, and mortality require the transplantation community to move adherence research to the forefront. Good adherence is fundamental to safe and cost-efficient transplantation with optimal long-term outcomes.

About the Author(s)

Micah A. Skeens, PhD, RN, CPNP, is a nurse scientist and nurse practitioner at Nationwide Children’s Hospital in Columbus, OH; Mary S. Dietrich, PhD, MS, is a professor of statistics and measurement in the School of Medicine and the School of Nursing at Vanderbilt University in Nashville, TN; Nancy Ryan-Wenger, PhD, RN, PNP, FAAN, is a professor emeritus in the School of Nursing at The Ohio State University in Columbus; Mary Jo Gilmer, PhD, MBA, FAAN, is a professor of nursing and medicine (pediatrics) in the School of Nursing at Vanderbilt University; Shelagh A. Mulvaney, PhD, is an associate professor in the School of Nursing and in the Department of Pediatrics and the Department of Biomedical Informatics, both at Vanderbilt University Medical Center; and Terrah Foster Akard, PhD, RN, FAAN, is an associate professor in the School of Nursing at Vanderbilt University. The authors take full responsibility for this content. Skeens was supported by a Doctoral Degree Scholarship in Cancer Nursing, DSCN-14-075-01-SCN, from the American Cancer Society. The article has been reviewed by independent peer reviewers to ensure that it is objective and free from bias. Skeens can be reached at micah.skeens@nationwidechildrens.org, with copy to CJONEditor@ons.org. (Submitted December 2019. Accepted April 3, 2020.)

 

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