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Medication adherence in pediatric transplantation and assessment methods: a systematic review

Authors Hoegy D , Bleyzac N, Robinson P, Bertrand Y, Dussart C, Janoly-Dumenil A

Received 3 January 2019

Accepted for publication 1 March 2019

Published 7 May 2019 Volume 2019:13 Pages 705—719

DOI https://doi.org/10.2147/PPA.S200209

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Johnny Chen



Delphine Hoegy,1,2 Nathalie Bleyzac,3,4 Philip Robinson,5 Yves Bertrand,3,6 Claude Dussart,1,7 Audrey Janoly-Dumenil1,2

1EA 4129 P2S Parcours Santé Systémique – Univ Claude Bernard Lyon 1, Univ Lyon 1, Lyon, France; 2Pharmacy, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 3Institut d’Hématologie et d’Oncologie Pédiatrique, Hospices Civils de Lyon, Lyon, France; 4EMR 3738, PK/PD Modeling in Oncology, université Lyon-Sud, Lyon, France; 5Direction de la Recherche Clinique et de l’Innovation, Hospices Civils de Lyon, Lyon, France; 6U1111-CNRS UMR 5308, University of Lyon I, ENS Lyon, Lyon, France; 7Central Pharmacy, Hospices Civils de Lyon, Lyon, France

Background: Medication adherence is a major concern in public health. It is fully established that immunosuppressive therapy (IT) and concomitant medications affect transplant outcomes in the pediatric population, showing interest in adherence to this therapy. The aim of the present review was to report on medication adherence in pediatric population post-transplantation. This will enable us to know the situation in this particular population.
Methods: A literature search was performed using the MEDLINE database. Studies that were published from January 1999 to January 2016 in English language and which investigated medication adherence in pediatric transplantation were included. The type of organ and the methods used to assess medication adherence were studied.
Results: A total of 281 records were identified, from which 34 studies were selected: 38% (n=13) on kidney transplantation, 32% (n=11) on liver transplantation, and 23% (n=10) on the transplantation of other organs. Medication adherence was found to be lower than 80% in two-thirds of the studies (64%), and varied from 22% to 97%. This wide range was explained in part by the important heterogeneity of assessment methods among studies. The methods used were objective, non-objective, or combined both types. Most studies did not fully describe the data collected: the time since transplantation, the period over which adherence was assessed, the population, the medications, and the threshold discriminating adherence and non-adherence.
Conclusion: The present study found poor medication adherence in the pediatric population post-transplantation. There was a wide range of medication adherence, explained largely by the heterogeneity of assessment methods. Future studies must consider the characteristics of each methodology, but also the threshold defining adherence should be chosen on the basis of clinical outcomes, and describe all data collected to gain precision. To improve adherence in this population, it is essential to identify factors influencing medication (IT and concomitant medications) adherence.

Keywords: medication adherence, patient compliance, child, transplantation

Introduction

Adherence is defined “as the extent to which a person’s behavior […] corresponds with agreed recommendations from a health care provider”. Medication adherence averages 50% among adults suffering from chronic diseases, and as poor medication adherence compromises the therapeutic approach it is a major concern in public health.1

In adults, immunosuppressive therapy (IT) adherence averages 48% after renal transplantation, which is the most frequent transplant procedure.2 In adults and pediatric populations, IT is recognized as essential after solid organ transplantation (SOT)3,4 and hematopoietic stem cell transplantation (HSCT).5 IT is part of treatment regimen post-transplantation that includes concomitant medications to prevent infection. After SOT in pediatric patients, the risk of biopsy-proven acute rejection is doubled, the risk of hospitalization is increased by 60%, and that of organ loss by 80% when patients considered non-adherent to IT.6 Medication adherence is therefore a major concern in pediatrics. In 2009, Dew et al49 published a meta-analysis that investigated medical regimen adherence after SOT in a pediatric population; the authors included studies that reported non-adherence to IT and/or clinical appointments. The authors concluded that there was a wide range of IT adherence rates due to the heterogeneity of methodological aspects and analysis of data in published studies. However, there is no recent systematic review that has investigated adherence to both IT and concomitant medications in a pediatric population after both SOT and HSCT. The aim of the present review was therefore to report on medication adherence in pediatric populations after both SOT and HSCT. This will provide an overview in this particular population, and a special focus will be made on the assessment methods used, which can be objective methods such as drug assays, and non-objective methods such as questionnaires.1,7

Methods

The MEDLINE database was searched for relevant studies published from January 1, 1999 to January 1, 2016 using the following search strategy: (“patient compliance” [Mesh] OR “medication adherence” [Mesh] OR medication compliance) AND (pediatr* OR child) AND (transplan*). The inclusion criteria were: studies in English language, reporting on pediatric transplant patients (age <21 years at the time of transplantation), measuring medication adherence, and describing the assessment method of medication adherence. Case reports, editorials, letters, and syllabi were excluded. Systematic and non-systematic reviews, as well as meta-analysis were excluded but checked for additional studies.11,49 The selection was independently reviewed by two of the authors (DH and AJD), and disagreements were resolved by consensus.

The analysis of selected studies consisted of description of organs, mean time since transplantation, population, medications; the methods used to assess medication adherence were also investigated.

Results

The first search strategy found 281 records; 221 were excluded because they did not talk about medication adherence in pediatric transplantation. A further 19 studies were excluded because a measure of medication adherence was not reported, and 7 because results obtained in pediatric subjects were not reported separately from other populations (Figure 1). Thus, 34 studies were included.

Figure 1 Review inclusion and exclusion flowchart followed PRISMA guidelines.

Thirteen studies concerned kidney transplantation (Table 1), and 11 liver transplantation (Table 2). Other studies reported IT adherence in heart transplantation (Table 3), HSCT (Table 4), or combined results of different organs in the same study (multi-organ studies) (Table 5).

Table 1 Medication adherence and assessment methods in kidney transplantation

Table 2 Medication adherence and assessment methods in liver transplantation

Table 3 Medication adherence and assessment methods in heart transplantation

Table 4 Medication adherence and assessment methods in hematopoietic stem cell transplantation

Table 5 Medication adherence and assessment methods in multi-organ studies

Among all types of organ, medication adherence ranged from 22%19to 97%.21 Medication adherence was found to be lower than 80% in 22 studies, between 80% and 90% in 5 studies,8,12,14,23,24 and 90% or greater in 7 studies.16,18,21,32,34,37,42 Among these 7 studies, 3 focused on kidneys,16,18,21 1 on liver,32 1 on heart,34 and 2 were multi-organ.37,42

Twenty studies reported the mean time of medication adherence measurement since transplantation, which ranged from 27 days35 to 9.4 years.31,33The majority of these studies (n=12) examined medication adherence 5 years or later after transplantation, and among these medication adherence ranged from 27%31 to 97% .37

The majority of studies (n=23) reported data for adolescents (≥10 years of age) only. Two studies reported data for children, in whom adherence was 30%41 and 91%.34 One study stratified according to the patient’s age, and concluded that medication adherence was poorer among adolescents (65%) than in children (81%).12

All included studies concerned IT. Twenty-two studies measured adherence to cyclosporine (CsA), 26 to tacrolimus (Tac), and 21 to both CsA and Tac. Three studies measured also concomitant medications: antibiotics, antivirals, antihypertensives for instance, without separated IT and concomitant medication adherence measures.35,41,42 One study compared IT to concomitant medications: IT adherence was poorer (60% vs 80%).41

Assessment methodologies

Period over which adherence was assessed

The majority of studies (n=24) reported the period over which adherence was assessed; this ranged from 7 days17,42 to 36 months.15,18The period was related to the method used: medication event monitoring systems (MEMS) generally examined adherence over a 1–6-month period,13,20,21,35,37medication possession ratio (MPR) over a 36-month period,15,18 and medication adherence measure (MAM) questionnaire over a 7-day period.17,42 Five studies13,20,21,35,37 examined medication adherence in a 3–6-month period: medication adherence ranged from 60%13 to 73%.35 Eight studies15,18,22,23,2931,38examined medication adherence over a 1–2.5-year period: medication adherence ranged from 27%38to 92%.18

Objective methods

Thirty-one studies assessed medication adherence using objective methods: drug assays (n=21), MEMS (n=6), MPR (n=2). A total of 21 studies used drug assays (Table 6) among which 2 did not mention the type of drug assay (level or SD).32,36 The 21 other studies considered either drug or metabolite levels in plasma, serum, or blood (n=10), and/or the SD that reports drug or metabolite levels over a period of time (n=11). SD studies (performed only for Tac) found medication adherence from 27%38 to 90%.41Studies using levels reported medication adherence that ranged from 27%31 to 84%.14 Six other studies used MEMS,13,20,21,35,37,40 which is a specific medication device recording date and timing of each use, and reported medication adherence ranged from 69%37 to 79%21 (Table 6).Two studies used MPR: medication adherence reported was 56%15 and 92%.18

Table 6 Methods used to assess medication adherence

Non-objective methods

Twenty studies assessed medication adherence by non-objective methods: questionnaires or interviews (n=16), the opinion of physicians and/or nurses (n=4), retrospective chart review (RCR; n=3). RCR evaluated the number of patient records documenting medication non-adherence: the medication adherence reported in the 3 studies was 50%,28 62%,27 and 91%.34 Among the 4 studies using the opinion of physicians and/or nurses,13,19,23,26 2 reported medication adherence by this method: 52%19 and 61%.26 The medication adherence, reported by the 16 studies using questionnaires and interviews ranged from 26%19 to 97%.21 Six studies used the MAM questionnaire,17,21,38,39,42,43 which is a specific and validated pediatric tool for adherence post-transplantation that evaluates the number of missed or late doses during the previous 7 days. The medication adherence from MAM questionnaire-studies ranged from 65%17 to 97%.21 Furthermore, a total of 7 studies reported caregiver or parent’s medication adherence. Among these, 3 studies compared patient and caregiver reports and found results that were close: 26% and 27%,19 70% and 70%,26 and 86% and 88%.39

Combined methods

Sixteen studies used several assessment methods and a total of 10 studies combined these to calculate medication adherence.13,14,16,19,23,24,32,38,41,43 With this methodology, medication adherence ranged from 22%19 to 94%,32 and 5 studies reported medication adherence greater than 80%.14,16,23,24,32 Four studies detailed precisely the combination of techniques.19,38,41,43

One combination technique defined non-adherence as below a threshold for at least one item used.19,41 Two studies used a combination of drug assays, nurse/physician’s opinion, and basal adherence assessment scale for immunosuppressive medication, a validated questionnaire on a 6-point scale. Medication adherence obtained with this combination technique was 22%19 and 30%.41 Another combination technique created balance scores of different methods, such as the multidimensional adherence classification system (MACS),38,43 which is a validated tool combining the MAM questionnaire and drug assay. Two studies used this technique: medication adherence was 27%38 and 65%.43

Discussion

To the best of our knowledge, this is the first time a systematic review has focused on medication adherence in a pediatric population after both SOT and HSCT. A total of 34 studies investigated medication adherence after transplantation over the last 16 years in pediatric populations, which is low considering the number of studies in other chronic diseases.44 Irrespective of the transplanted organ, medication adherence ranged widely among studies. It remained poor with two-thirds studies (64%) describing medication adherence lower than 80%, highlighting the importance of considering medication adherence in the pediatric population post-transplantation.

Data for HSCT, a relatively frequent procedure, is reported only in one study,35 whereas two studies reported data for heart-lung transplantation which is a rare procedure.34,36 This may be related to the short period required of IT after HSCT, as compared to the indefinite period required after SOT. Nevertheless, IT is essential for good prognosis after HSCT,5 and it is therefore of great interest to evaluate medication adherence after such transplantations.

All studies in this review investigated adherence to IT, underlining the importance of this concern in the post-transplantation period. Despite the need for an effective prevention of infections after transplantation, for instance, only 3 studies reported adherence to concomitant medications such as antibiotics.35,41,42 In adults, Russel et al have considered that adherence to a medication – measured by MEMS – allowed the extrapolation of results to the comedications.45 However in pediatrics, it is more appropriate to evaluate medication adherence for individual drugs41,46 as aspects such as medication flavor or form (syrup or pill) could cause different behaviors in children.7 It would be interesting that the 3 studies found in this review did compare IT adherence to concomitant medication adherence.

Most studies reported data for adolescents, which reflects a concern regarding medication adherence in this specific population after SOT and HSCT. Only one study compared data for children and adolescents, which is regrettable. This study revealed that medication adherence in children (81%) is higher than in adolescents (65%).12 The adolescence period of life is known to decrease medication adherence by several reasons;7 for instance, Dobbels et al enunciate the transition to adulthood health care system as an important factor of non-adherence during adolescence.10 This is confirmed by a study included in this present review which found that IT adherence after transition (32%) is lower than before (68%).32 In addition, adolescence is a time when difficulties in the parent–patient relationship are important.7 Regarding it, the unfrequent comparison of adolescent and caregiver reports on medication adherence (3 studies in this review using subjective methods) would be interested to consider more.

An important aspect to consider when interpreting data is the measurement method employed. At the time of writing no “gold standard” method exists,1,7 which explains the heterogeneity of those used in this review. Surprisingly, 16 studies used only 1 method whereas it is known that no single method is optimal.1,7 For example, drug assays will not detect patients who take their medications only before clinical visits. Conversely, MEMS is a longitudinal method taking into account “drug holidays” (when a patient discontinues medication of his/her own accord). Nevertheless, patients cannot be blinded to MEMS; it interferes with daily life and causes anxiety.45 In pediatric patients, all these methods have additional drawbacks. For instance, MEMS-based studies may be too difficult to be feasible in pediatric patients who are unable to take pills,20,21,35,40 and drug assay methods are invasive so this may be a limiting factor in pediatric patients.46 Yet, 23 of the 34 studies used this method, which could indicate that this is not a drawback too hard to surpass. In this review, only 10 studies (32%) used combined methods – 4 were published before 2005 and 6 after 2008 – suggesting that this is yet to become the preferred method. Among these studies, only a minority described precisely the combination method although this is essential to interpret data as the different combination techniques have different aims. One of the combination techniques has a high sensitivity: it underestimates medication adherence but misses less frequently non-adherent patients.19,41 Whereas the other combination technique used a well-balanced score (MACS),38,43 which allows categorization of patients according to their adherence.47

An additional difficulty for the interpretation of data in the present review is the definition of medication adherence which differed between each selected study, as synthetized in the Supplementary material (Table 7). It is interesting to note that many studies did not define a threshold discriminating medication adherence and non-adherence, and when they did so this was rarely based on clinical outcomes. Generally, 80% of taken medication is the arbitrary threshold discriminating medication adherence and non-adherence.1 To be relevant this threshold should be correlated to clinical outcomes, which was a posteriori investigated in 2 studies included herein; these found a close relationship between IT adherence and graft survival (p=0.017;18 p=0.0248) and also mortality (p=0.009).48 Also, Stuber et al30 constructed ROC curve to try answering about the appropriate SD cut-off for Tac.

Table 7 Assessment methods and definition of medication adherence or non-adherence by authors

Limitations

This review included studies from the MEDLINE database only. Given the topic of this review, studies are essentially published in PubMed and research on other database is unlikely to have added additional relevant articles. An additional point is that this review is not a meta-analysis. Dew Ma et al published a meta-analysis in 2009 focusing on medication adherence after pediatric SOT only.49 The authors recognized that there was a lack of studies in certain transplantation types (lung, intestine) and noted the heterogeneity in published articles concerning methodological aspects and the analysis of data. This still seems to be the case 10 years later.

Conclusion

This review revealed the poor medication adherence in the pediatric population post-transplantation, and underlined also the wide range of medication adherence reported in the literature. The heterogeneity of assessment methods explained at least in part this wide range found. Future studies must weigh the advantages and disadvantages of each methodology and describe all data collected to gain precision. It is also essential that the threshold discriminating adherence and non-adherence must be chosen on the basis of clinical outcomes. Beyond the observation of poor medication adherence, there is an obvious need to improve this situation. For that it is essential to identify factors of medication non-adherence to propose adapted interventions and so try to improve medication adherence in adolescents and children after SOT and HSCT.

Disclosure

The authors report no conflicts of interest in this work.

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