Expert Review of Pharmacoeconomics & Outcomes Research
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Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults Rana Ahmed & Parisa Aslani To cite this article: Rana Ahmed & Parisa Aslani (2013) Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults, Expert Review of Pharmacoeconomics & Outcomes Research, 13:6, 791-815 To link to this article: http://dx.doi.org/10.1586/14737167.2013.841544
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Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults Expert Rev. Pharmacoecon. Outcomes Res. 13(6), 791–815 (2013)
Rana Ahmed and Parisa Aslani* Room N502, Pharmacy Building (A15), The University of Sydney, NSW, 2006 Australia *Author for correspondence: Tel.: +61 290 366 541 Fax: +61 293 514 391 [email protected]
Suboptimal adherence to treatment regimens is a major obstacle to treatment efficacy and positive outcomes for patients. While poor adherence is common across a variety of chronic conditions, an area which presents unique challenges to clinicians and researchers is non-adherence among pediatric populations. These challenges are well illustrated by the management of attention-deficit/hyperactivity disorder (ADHD), a pervasive pediatric psychiatric condition. The average rates of non-adherence in children and adults ranged between 15 and 87%. Factors predicting increased adherence/persistence included the use of long-acting formulations, younger age, Caucasian background, family structure and the presence and treatment of comorbidities. Decreased adherence/persistence were predicted by multiple daily dosing, family history of ADHD, experiences of adverse effects, stigma and treatment inefficacy. The broad range of non-adherence rates identified reflects the complexities of adherence research in ADHD, and highlights the need for better standardization of adherence/persistence definitions and measurement approaches. KEYWORDS: attention-deficit/hyperactivity disorder • medication adherence • medication compliance • medication persistence • psychostimulant • review
The multi-faceted dimensions of chronic health conditions are reflected in the complexity of their management practices, which stipulate the utilization of multiple treatment modalities and interventions, often over a prolonged period of time and across multiple settings. While this approach allows for more holistic management, it nevertheless presents several challenges to those affected [1]. Perhaps the most apparent of these challenges is adherence, with figures from developed countries highlighting that only 50% of patients with chronic disease are adherent to their treatments [2]. As medication adherence has a central role in predicting morbidity and mortality associated with chronic illness [3], deviations from prescribed regimens can be expected to lead to a range of undesirable outcomes [4–6]. In the short term, non-adherence can affect treatment efficacy and tolerability while in the long term it can lead
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to poor therapeutic outcomes and increased economic disease burden [7,8]. Comparatively, adherence to treatment regimens has been associated with positive health outcomes, patient safety and improvements in quality of life [9–13] even when the treatment used is a placebo [14,15]. By extension, improving adherence can reduce medical expenditure and overall disease burden [4]. Non-adherence is considered to be a serious public health issue [13], presenting challenges not only to affected individuals, but to clinicians and policy makers alike. The gravity of this issue is heightened by the recognition that the prevalence of medication non-adherence is approaching ‘crisis proportions’ [16]. This, coupled with the steady rise in the incidence of chronic conditions [17] has catalyzed significant interest in investigating the underlying issues associated with non-adherence and developing ways to remedy this.
2013 Informa UK Ltd
ISSN 1473-7167
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While extensive research has been conducted exploring these issues in a variety of conditions and populations, an area which poses unique challenges is medication adherence in pediatric populations [18,19]. Depending on the chronic condition in question, medication adherence rates among pediatric populations can be as low as 11% [20]. What is of great interest in the pediatric setting is that the traditional patient–clinician dynamic is complicated as the parent becomes an intermediary between their child and the clinician [21]. Children may have limited involvement in the treatment decisions made during consultations and can often be unaware of the purpose of prescribed treatments [18]. In turn, medication adherence does not necessarily depend on the patient (child) alone, but also on the parent or caregiver who will often assume sole responsibility for administering the medication [18,22]. This parental involvement has the potential to introduce a number of factors which could influence adherence to treatment regimens. With regard to chronic illnesses in particular, parents often discontinue medications upon perceived resolution of symptoms, lack of effectiveness or observation of adverse effects [18]. These issues are particularly apparent in pediatric psychiatric disorders [19] which often require pharmacological intervention well into adolescence and even adulthood [23–26]. Public resistance to biomedical conceptualizations for such disorders [27], and negative attitudes toward their treatment using medications may encourage premature termination of treatment. These issues are exemplified in attention-deficit/hyperactivity disorder (ADHD) which is a common chronic psychiatric disorder of childhood characterized by persistent and impairing symptoms of inattention, hyperactivity and impulsivity. The disorder is believed to affect between 5.9 and 7.1% of children and adolescents [28], with prevalence peaking during middle childhood and declining over time. The prevalence of ADHD among adults has been estimated to be approximately 2.5% [29]. The experience of ADHD symptoms during adolescence and adulthood has been associated with impaired academic, occupational and social performance in addition to strained family relationships [30,31]. Current ADHD treatment guidelines recommend a multifaceted approach to treatment [32,33] incorporating the use of medications in conjunction with psychological and behavioral interventions where appropriate [34,35]. Stimulant medications such as methylphenidate (MPH) are considered first-line therapy for ADHD [36,37] as they have been shown to significantly improve symptoms [38–41] and are efficacious in approximately 80% of users [38]. Due to the chronicity and nature of the impairing symptoms associated with ADHD, the use of such medications is often required over extended periods of time. Hence, adherence to these long-term medication regimens is important in the treatment of ADHD [1,42,43]. Despite strong empirical evidence supporting their safety and efficacy [44,45], adherence rates to stimulant medications for ADHD are poor [46] and persistence rates of 15% 1 year after treatment initiation have been reported [47]. These suboptimal figures are believed to be a major barrier to positive treatment 792
outcomes [1]. Poor medication adherence in ADHD not only leads to symptomatic relapse [48], but it can also affect clinicians’ ability to determine treatment efficacy and to assess the need for dose or medication changes [49,50]. The severity of this predicament is emphasized by the understanding that ADHD is as prevalent as asthma in school-aged populations [51] and accounts for greater annual healthcare expenditure [52]. Hence, although this area hasn’t traditionally been the focus of much interest, over the past 5 years there has been a surge in research examining the extent and causes of non-adherence to ADHD medications. By reviewing the findings of recent research, this article aimed to explore the prevalence of non-adherence to ADHD medications and to provide insight into why users of ADHD medications cease treatment despite the persistence of symptoms and impairments. Users were defined as children, adolescents and adults with ADHD. The article begins with background information about the adherence measures used in the retrieved studies and is followed by the summarized findings of the literature search. Adherence & persistence Definitions
Adherence is a multi-faceted construct which at the core level is founded upon a patient’s understanding of the severity of their illness, their belief in the efficacy of a chosen intervention and in their ability to control their symptoms using this intervention [53]. While differences exist in how adherence is defined between studies, the term is generally understood to reflect the extent to which a patient’s actions correspond with the agreed recommendations of healthcare providers (HCPs) [54]. Medication adherence more specifically, is defined as the act of conforming to HCPs’ recommendations about the timing, dosage and administration frequency of the medication [53]. Comparatively, medication persistence is a measure of treatment continuity, defined as the length of time from the initiation of therapy to its discontinuation [53]. Therefore, although these two terms are often used interchangeably in the literature it is important to recognize that they are unique and are at times two mutually exclusive constructs. Saying patients are adherent to their medication regimens does not necessarily imply that they are persistent, and the opposite is also true. To clarify, patients who purposefully skip some of their prescribed daily doses of medication would not be considered to be adherent, however they may be persistent provided that they continue treatment for the agreed period of time specified by their HCPs. In this way, it is often simpler to view adherence as whether or not patients takes their medication as prescribed for the duration of time that they are persistent with treatment [55]. Measurement
Owing to these definitional differences, adherence and persistence are measured differently, as will be demonstrated in the included studies, although both can be determined by prospective and retrospective approaches. In prospective examinations, Expert Rev. Pharmacoecon. Outcomes Res. 13(6), (2013)
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Medication adherence & persistence in ADHD
adherence is measured over a specified period of time and reported as a percentage of the doses taken by the patient against the doses prescribed. In these studies, adherence can be determined using direct or indirect methods of measurement, each with their individual advantages and disadvantages. Direct methods of investigation include observation of therapy and measurement of drug or metabolite concentrations in samples of a patient’s saliva, urine or blood. While these approaches provide the most objective assessments of adherence, direct observation can be impractical and burdensome for clinicians in practice while the analysis of biological samples can be a costly and invasive process for patients. Comparatively, indirect measures of adherence are generally easier to implement but may be more prone to error and distortion. These include patient or parent self-reports/questionnaires, pill counts and the use of electronic medication monitors [8]. The use of patient questionnaires is a relatively simple approach to measuring adherence however there is much controversy surrounding the accuracy and reliability of patients’ reports, which often lead to an overestimation of adherence levels [56]. Pill counting which involves determining the number of pills remaining in patients’ medication bottles or blister packs, may be perceived to provide a more accurate measure of adherence. However, this too is subject to distortion as patients may switch pills between medication bottles or even discard a certain amount of pills prior to clinic visits in an attempt to appear adherent [57–59]. Further, these approaches do not provide insight into the specific timing of dosages whereas the use of electronic monitoring devices such as the medication event management system (MEMS) allows such information to be obtained. These devices are increasingly becoming known as the gold standard for medication adherence measurement [60]. They generally consist of a computer chip inserted into the cap of the medication bottle which is capable of recording the dates and times that the container was opened. This information can then be downloaded from the chip directly into a computer program for analysis. While this information is useful in providing insight into the timing and frequency of medication use, it does not document whether a patient actually took the correct dose of the medication or whether it was taken at all. It is also important to note that MEMS data may be inaccurate in instances where patients remove their total daily dose (or additional doses) from the pill bottle, rather than opening the bottle on every occasion that a dose is required. Nevertheless these devices are still considered to provide the most accurate measures of adherence, although they are not routinely used in clinical practice due to their cost. Adherence can also be determined through retrospective examinations which generally involve the study of pharmacy claims databases for information about how frequently patients refill their prescriptions. The time between the initial dispensing of the medication and when the prescription would run out without further refills is used as a proxy for adherence. The most commonly reported outcome measure in these studies is the medication or drug possession ratio (MPR/DPR) which is www.expert-reviews.com
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a reflection of the dispensed doses in relation to the dispensing period being examined [61]. The MPR is generally calculated as the total days’ medication supply issued to a patient divided by the number of days the patient should have been taking the medication, which in most cases is equivalent to the number of days between prescription refills. MPR values ‡0.8 are taken to reflect adequate treatment adherence. These studies do not provide the detailed insight into patients’ medication-taking behaviors provided by MEMS for example, however their strength lies in their inclusion of prescription information of thousands of patients from community settings, allowing for strong insight into real-world medication utilization. Persistence can also be measured in both prospective and retrospective studies, although unlike adherence, it is reported as a continuous variable in terms of the number of days of continuous therapy from the point of initiation until the end of the observation period. A number of studies also report persistence as a dichotomy where patients are classified as persistent or non-persistent at the conclusion of the study period [62]. In retrospective studies, a permissible gap between consecutive refills of a prescription is pre-specified based on the specific properties and dosing regimen of the medication being examined. As long as patient records indicate that prescription refills were obtained within this ‘gap’, that patient is considered to be persistent. There are, therefore, numerous approaches to conducting studies of adherence and varying definitions of the term itself. It is for this reason that a meta-analysis of the studies identified in this review was not possible. Instead, the studies have been categorized according to whether they have adopted prospective or retrospective examinations of adherence and persistence. A summary of their findings is presented in light of the definitions they have used and in comparison with those of other studies where possible. Methods Literature search & search strategy
The electronic databases Medline, PsycINFO and Embase were searched for articles between January 2008 and April 2013. Combinations of the following search terms and key words were used to identify appropriate studies: medication adherence, medication compliance, medication persistence, patient compliance, patient adherence, medication nonadherence, medication noncompliance, patient noncompliance, treatment refusal, patient acceptance of healthcare, attention deficit disorder with hyperactivity, ADHD, treatment, stimulant, medication, drug therapy. Search terms within similar categories were combined with OR and then combined with the results of other categories using AND. The reference lists of review articles and relevant studies were also examined for further potentially appropriate studies. Studies were limited to those published in peer-reviewed journals and in the English language. The titles and abstracts of the articles obtained through these systematic literature searches were screened for eligibility. Only those articles which appeared relevant were examined in detail for inclusion. 793
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Inclusion & exclusion criteria
Eligible studies met the following criteria: study sample included children, adolescents or adults with an official diagnosis of ADHD and who were being treated using medication; ADHD medication(s) under examination clearly identified; empirical data on rates of adherence/persistence to ADHD medications obtained through direct or indirect measures presented and adherence/persistence clearly defined. The presence of any of the following was used to ascertain the inclusion of participants with an official ADHD diagnosis in the reviewed articles: structured diagnostic assessments based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or its Text Revision (DSM-IV-TR); record of ADHD diagnosis according to DSM-IV or DSM-IV-TR criteria in patient medical records and record of diagnostic codes for ADHD in retrospective databases. The following types of studies were excluded: those that used patient records of ADHD medication use as a proxy for a diagnosis of ADHD; those that examined adherence to alternative ADHD treatments, for example, behavioral therapy; those that reported only on patient treatment preferences without reference to treatment adherence and those that did not report specific adherence measures. Data extraction
The following information was extracted from each retrieved study: country where the study was conducted; number and age of participants; study design; study duration; medications examined; adherence/persistence definition, measures and outcomes. Studies were categorized according to whether they adopted prospective or retrospective approaches to measuring adherence/persistence to ADHD medications. Results Study selection
The search strategy yielded a total of 940 citations (FIGURE 1). After title and abstract screening, 860 of these were excluded and the full text of the remaining 80 articles was obtained. Of these, 19 articles met the inclusion criteria and were included in the final review. The excluded articles either presented the findings of non-primary research (reviews and editorial articles) Medline (203 citations)
940 citations
860 excluded on the basis of title and abstract review
80 citations
61 excluded after full-text analysis: – No inclusion of adherence measures (n = 9) – Examined treatment preferences only (n = 13) – Non-primary research (review, editorial) (n = 21) – Factors influencing treatment initiation only (n = 3) – Related to non-pharmacological ADHD treatments (n = 8) – Patient medication use as proxy for ADHD diagnosis (n = 7)
19 citations
Included in review (16,546 adults; 161,828 children/adolescents)
PsycINFO (109 citations) Embase (628 citations) Ref. list (9 citations)
(n = 21), did not include specific adherence measures (n = 9), examined ADHD treatment preferences without reference to adherence (n = 13), explored adherence to non-pharmacological ADHD treatments (n = 8), utilized participants’ ADHD medication use as a proxy for ADHD diagnosis (n = 7) or looked at factors influencing initiation of treatment only (n = 3). Of the 19 retrieved articles, 2 [63,64] reported on alternate findings from the same investigation. However, for ease of reference henceforth, the total number of studies will be referred to as 19. The 19 studies report on findings related to a total of 16, 546 adults and 161, 828 children and adolescents treated with medications for the management of their ADHD. Most of the studies were conducted in the USA (n = 9), followed by England (n = 2), Taiwan (n = 3), Canada (n = 1), Germany (n = 1), Italy (n = 1), Korea (n = 1) and Spain (n = 1). Just under half of these studies involved prospective assessments of adherence [63–71] and of these, six included child and adolescent participants [63–68] while the remaining three studies examined only adult populations (TABLE 1) [69–71]. In these studies, medication adherence was assessed through the use of indirect measures including pill counts [67–69,71], parent/patient reports [63–65,68,69], clinician interviews/assessments [63,66,68,70] and electronic monitoring devices such as MEMS [68,69]. The remaining 10 studies adopted a retrospective approach to explore treatment adherence and persistence [72–81] generally by analyzing claims data from large health databases (TABLE 2). Only one included direct measures of adherence, whereby participant saliva samples were obtained and assayed to measure levels of the medication used [72]. Six of these retrospective studies included children and adolescents [72–77] while adult participants were additionally included in the remaining four studies [78–81]. It is important to note that although some of these studies have conducted their investigations using similar methods, they do not necessarily use the same criteria for defining adequate adherence or persistence levels. Therefore, to avoid ambiguity or inaccuracies, a summary of the investigative approaches, outcome-of-interest measures and definitions used in these studies is provided in TABLES 1 & 2 and should be referred to when examining the key findings presented below.
Figure 1. Results of search strategy and process for the identification of studies included for review. Please note that the 19 included citations report on the findings of 18 investigations. Ref. list = Citations sourced from the reference lists of relevant articles.
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Prevalence of non-adherence & treatment cessation in ADHD Prospective assessments of adherence & persistence Studies of children & adolescents
Of the six prospective studies (TABLE 1) exploring medication adherence and persistence in children and adolescents with ADHD [63– 68], three explored adherence to both immediate-release (IR) and osmotic release oral system (OROS)-MPH [63–65]; one focused on adherence to a non-OROS extended-release (XR)-MPH preparation called Equasym XL1 (EXL) [66]; one examined adherence to IR-MPH only [67] and one measured adherence to OROS-MPH only [68]. The findings of a large open-label observational study conducted in Taiwan are presented by Gau et al. [63] and Chou et al. [64]. Daily parent/patient reports of missed doses and clinician interviews were used to measure adherence rates to IR and OROS-MPH. Gau et al. focused on determinants of adherence to IR-MPH [63]. From an initial sample of 607 children initiated on IR-MPH, 240 (39.5%) were observed to have poor adherence (i.e., overall IR-MPH adherence rate, 60.5%) and of these, 137 were switched to OROS-MPH, with only 124 completing the assessment period [63]. After initiating the switch, more than 80% of these children demonstrated improved adherence and reduced symptom severity. Chou et al. provided insight into the determinants of adherence to OROS-MPH among the 137 children switched to OROS-MPH [64]. Of those with available data (124), only 38 (27.7%) were observed to have poor adherence (i.e., overall adherence rate to OROS-MPH, 72.3%). It is important to note that the authors of both studies have not included details about how or why the 137 children were selected to be switched to OROS-MPH, other than the fact that they were considered to have poor adherence to IR-MPH. However, when considering that the remaining 103 children who also had poor adherence remained on IR-MPH, it becomes apparent that there may be potential selection biases which may influence the results presented. Similar findings were seen in another observational study conducted by Tzang et al., where parent reports were also used to measure and compare adherence rates with IR and OROSMPH [65]. The study was conducted over a comparatively longer 48-week period and involved a total of 757 children diagnosed with ADHD who were allocated to either IR-MPH (n = 265), OROS-MPH (n = 293), IR and OROS-MPH (n = 129) or no treatment (n = 70) depending on their clinical needs. A total of 67.2% of the children on OROS-MPH were deemed to have good adherence compared with only 36.2% of children who exhibited good adherence to IR-MPH (p < 0.0001). Rothenberger et al. used clinician rating scales to determine adherence rates to the XR-MPH preparation [66], EXL in a post-marketing, open-label observational study. The study involved 822 children newly initiated on EXL and monitored over a 6- to 12-week period to determine treatment satisfaction and adherence. The treating physician graded adherence to treatment using a scale ranging from 1 (very good adherence), www.expert-reviews.com
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to 6 (inadequate adherence). Mean adherence scores improved from 2.1 ± 1.2 to 1.5 ± 1.0, and of the 773 children with adherence ratings available on the final clinic visit, 67.9 and 22.6% had very good (1) or good (2) adherence, respectively. Adherence was continually superior with EXL in comparison with adherence to prior treatments and especially among children previously treated using multiple doses of IR-MPH, with 57.7% of them exhibiting better adherence to EXL. Atzori et al. used pill counts to assess adherence to treatment among 134 children treated with IR-MPH [67]. Pill counts were conducted by the clinician at the conclusion of each month for 36 months. At the end of the 36-month study period, 46% (n = 62) of children remained on treatment, 24% (n = 32) ceased treatment due to functional remission and 30% (n = 40) due to other reasons. Of these 40 children, 50% suspended treatment for poor adherence, that is, approximately 15% of the total sample exhibited poor adherence that led to treatment discontinuation during the study period. The authors, however, did not specify whether those who remained on treatment met criteria for good adherence. Importantly, treatment discontinuation in this study was also as a result of symptomatic remission. Yang et al. used pill counts in conjunction with parental reports, clinician rating scales and the MEMS to measure adherence to OROS-MPH in a sample of 39 children over an 8-week period [68]. Adherence rates as determined by pill counts, parent report, MEMS and the clinician rating scale were 87.2, 82.1, 53.8 and 68.3%, respectively. Therefore, using MEMS as the reference standard, 46.2% of the children did not meet criteria for adherence within the 8-week study period. In comparison with MEMS, the other measures overestimated patient adherence. Studies of adults
A total of three studies examined medication adherence in adults diagnosed with ADHD [69–71] using a prospective approach. Two of these studies explored adherence to both IRand OROS-MPH [70,71] while the remaining study focused on adherence to IR- and XR-mixed amphetamine salts (MAS) [69]. Adler et al. conducted a randomized crossover study in which patient reports, pill counts and MEMS were used to determine adherence rates to IR- and XR-MAS [69]. The study involved 49 adults who received treatment with either IR-MAS (requiring three daily doses) or XR-MAS (requiring one morning dose daily) for 3 weeks. At the conclusion of the 3-week period and following a 7-day washout period, participants were switched onto the alternate MAS preparation for another 3 weeks. Daily self-reports of adherence were collected during weekly follow-up clinic visits where clinicians also conducted pill counts. The information obtained through MEMS was used to determine the following: dosage adherence which required that ‡75% of prescribed doses to be taken; time adherence which required that ‡80% of prescribed doses to be taken at the correct time and regimen adherence which required that the complete daily dosing regimen to be taken on ‡90% of days. 795
796
Country
Taiwan
Taiwan
Chou et al. (2009)
Tzang et al. (2012)
757
137
607
n
Mean, 10.1 (2.7); range, 6–18
Mean, 10.7 (2.5)
Mean, 10.4 (2.6)
Sample age years (SD)
Parent/patient reports: Verbal feedback about frequency of missed doses
Parent reports: Feedback about adherence during final clinic visit
OROS-MPH
IR and OROS-MPH
Open-label prospective observational study
Prospective observational study
Adherence measures
Parent/patient reports: Yes/no responses to questions (unspecified) Clinician interviews: Standard interview (unspecified content)
Medication(s) examined
IR and OROS-MPH
Open-label prospective observational study
Design
[63]
[64]
[65]
Of the 124 children who completed the assessment period after being switched onto OROS-MPH, 27.7% had poor adherence based on parental/patient global adherence reports, i.e., overall adherence rate = 72.3% Parent adherence reports were provided for 621 children at the final clinic visit (week 48). 67.2% of children using OROS-MPH were considered to have ‘good adherence’ compared with 36.2% of children using IR-MPH.
Poor adherence: ‡1 doses missed on ‡2 school days per week for 3 weeks OR parents/patients report poorer adherence to OROS-MPH than IR-MPH Adherence via parent reports not clearly defined
Ref.
Among the initial study sample of 607 children treated with IR-MPH, 240 (39.5%) had poor adherence, i.e., overall adherence rate = 60.5%. Of the 137 children switched onto OROS-MPH, ‡80% had their adherence evaluated as ‘a little’ or ‘much’ better compared with previous use of IRMPH.
Results
Poor adherence: ‡1 doses missed on ‡2 school days per week for 4 school weeks
Adherence definitions
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Taiwan
Gau et al. (2008)
Child and adolescent studies
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults.
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n
Italy
Atzori et al. (2009)
134
822
Mean, 9 (2); range, 4–16
Mean, 10.1 (2.5); range, 6–17
Sample age years (SD)
EXL
IR-MPH
Medical chart review
Medication(s) examined
Open-label prospective observational study
Design
Pill counts: Number of unused pills counted by treating physician at the end of each month
Clinician rating scale: Grade provided by treating physician to reflect patient adherence
Adherence measures
The mean adherence score (SD) improved from 2.1 (1.2) to 1.5 (1.0) while subjects were using EXL and adherence was consistently superior to prior treatment. 57.7% of patients previously on multi-dose IR-MPH had better adherence on EXL. At 36 months, 46% of the initial population remained on IR-MPH, 24% stopped for functional remission and 30% stopped for other reasons. Of these, 50% did not satisfy the criteria for ‘good’ adherence, i.e., approximately 15% of the total sample did not adhere to treatment.
‘Good’ adherence: ‡80% of prescribed pills taken monthly for ‡8 months
Results
Adherence grades: Scale ranged from 1 (very good adherence) to 6 (inadequate adherence)
Adherence definitions
[67]
[66]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Germany
Rothenberger et al. (2011)
Child and adolescent studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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797
798
Country
n
Korea
39
Mean, 10.4 (2.2)
Sample age years (SD)
Prospective observational study
Design
OROS-MPH
Medication(s) examined
Parent reports: Global adherence estimated by parents using a value between 0 and 100% Pill counts: Unused pills counted by research assistant at follow-up clinic visits. Actual pill count calculated as a percentage of prescribed pills. MEMS: Number of doses taken on schedule (container opened within 3-h time frame) as a percentage of prescribed doses Clinician rating scale: Grade provided by treating physician to reflect patient adherence
Adherence measures
Good adherence: Values ‡80% as determined by parent reports, pill counts and MEMS Values >5 as determined by clinician rating scale where 1 reflects complete treatment refusal and 7 reflects active responsibility for treatment
Adherence definitions
When reported as continuous variables, mean adherence values (SD) for OROS-MPH were as follows; parentreport: 90.1% (16.25); pill count: 94.1% (8.62); MEMS: 77.58% (19.13) and clinician rating: 4.58 (0.99). When dichotomized at the ‡80% and >5 (clinician rating) thresholds, the percentage of adherent patients according to each measure were as follows; 82.1% (parent reports); 87.2% (pill count); 53.8% (MEMS) and 68.3% (clinician rating)
Results
[68]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Yang et al. (2012)
Child and adolescent studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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USA
Country
49
n
Mean, 35.7 (10.3)
Sample age years (SD)
Randomized crossover study
Design
IR- and XR-MAS
Medication(s) examined
Patient reports: Patients record whether medication was taken within 30 min of waking (morning dose) and at 5-h intervals (±30 min) (subsequent doses) Pill counts: Conducted by clinician weekly to determine percentage of pills taken MEMS: Number of doses taken at the prescribed dose and within the prescribed time
Adherence measures
Adherence: Taking all doses (±20%) as prescribed by measurement criteria for patient reports and pill counts For MEMS measures, dosage adherence was defined as ‡75% of prescribed doses taken and time adherence defined as ‡80% of doses taken at the correct time
Adherence definitions
According to patient reports and pill counts, 92.6 and 90.4% of patients were adherent to IR-MPH, respectively. When treated using XR-MAS, 98.8 and 96.9% of patients were adherent to treatment based on patient reports and pill counts, respectively. No significant differences were observed between these two adherence measures According to MEMS measures, 42.7% satisfied the criteria for dosage adherence and only 4.5% for time adherence while being treated with IR-MAS. Comparatively, 66.2% met criteria for dosage adherence and 43.7% for time adherence when treated with XR-MAS. These differences were statistically significant
Results
[69]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Adler et al. (2011)
Adult studies
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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799
800
Country
USA
Spencer et al. (2011)
53
70
n
Mean, 37.4 (9.7)
Mean, 30 (9.6)
Sample age years (SD)
Single-blind, randomized, parallel study
Naturalistic chart review
Design
Clinician interview: Brief adherence assessment questionnaire used during follow-up clinic visits at 3 and 6 months after treatment initiation
Pill counts: Conducted on a weekly basis by physicians to determine percentage of pills taken
IR and OROS-MPH
Adherence measures
IR and OROS-MPH
Medication(s) examined
[70]
[71]
Adherence was better among users of OROSMPH with 46% measured to have complete adherence compared with 17% of those treated with IR-MPH. Statistically significant differences in the number of missed doses between the two treatment groups was observed, with approximately twice missed pills being reported among IR-MPH users Adherence: Patients dichotomized as having either complete adherence or missed doses
Ref.
Non-adherence rates among those treated using IR-MPH were as follows: 37.1% (mildly); 11.4% (moderately) and 4.7% (highly). Comparatively, only 2.9% of patients treated using OROS-MPH were mildly non-adherent and none met the criteria for moderate or high nonadherence.
Results
Non-adherence: Patient not taking medication (over 3-month period) for: ‡5 days: mildly non-adherent ‡10 days: moderately nonadherent ‡20 days: highly non-adherent
Adherence definitions
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Spain
RamosQuiroga et al. (2008)
Adult studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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Country
www.expert-reviews.com
USA
Winterstein et al. (2008)
40,052
254
n
Range: 5–20
Mean, 7.8 (0.8); range, 7–9.9
Sample age (SD) years
Crosssectional analysis of Medicaid beneficiaries cohort
Retrospective comparison of MTA study data on adherence
Design
[72]
[73]
Allowing for a 3-month gap between prescription refills, the percentage of patients who were persistent were as follows: 49.9% after 1 year; 32.8% after 2 years; 17.2% after 5 years and 15.4% after 9 years. Comparatively, allowing for a 1-month gap only 47.4% persisted after 6 months and 26.9% after 1 year. No differences in persistence between the different medications were presented Persistence: Continuous refills of index treatment without a 1- or 3-month gap between drug claims Claims analysis: Persistence based on gap between prescription refills
Stimulant medications and ATX
Ref.
According to parent reports, only 3.1% of the children did not meet criteria for verbal adherence to IR-MPH. Comparatively, physiological adherence results indicated that 24.8% of the children were non-adherent, indicating that parent reports may overestimate adherence levels
Results
Verbal adherence: At ‡80% of monthly visits, parents report child has taken the medication on the day and has good overall adherence Physiological adherence: MPH detectable in ‡50% of child saliva samples
Adherence/ persistence definitions
Parent reports: Verbal feedback given about global adherence and whether child took medication on day of clinic visit Saliva assays: Four assays conducted over treatment period to detect MPH levels
Adherence/ persistence measures
IR-MPH
Medication(s) examined
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Pappadopulos et al. (2009)
Child and adolescent studies
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults.
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801
802
Country
n
UK
Wong et al. (2009)
983
9559
Range: 15– 21
Range: 6–12
Sample age (SD) years
Cohort study using data from GPRD database
Pharmacy and medical claims analysis
Design
Claims analysis: Persistence based on length of stimulant treatment episodes
Claims analysis: Persistence based on gap between prescription refills
MPH, DEX, ATX
Adherence/ persistence measures
IR and OROS-MPH, IR- and XR-MAS
Medication(s) examined
[74]
[75]
The percentages of patients who persisted with treatment were as follows: 83% after 1 year; 54% after 2 years; 36% after 3 years; 24% after 4 years; 22% after 5 years and 17% after 6 years. No differences in persistence between the different medications were presented Persistence: Continuous refills of the same medication without a ‡6 month gap between successive refills
Ref.
The mean stimulant treatment episodes for each medication were as follows: 145.4 ± 37.5 days (IR-MPH); 160.8 ± 32.3 days (OROSMPH); 150.8 ± 36.2 days (IR-MAS) and 158.0 ± 36.2 days (XR-MAS).
Results
Persistence: Continuous refills of the same stimulant without a ‡30-day gap between successive refills Stimulant treatment episode: Date of first stimulant script to date of last supply OR 180 days after first stimulant prescription (whichever came first)
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Olfson et al. (2009)
Child and adolescent studies (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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Country
n
www.expert-reviews.com
USA
Palli et al. (2012)
46,135
610
Mean, 9.2; range: 6–19
Range, 6–28
Sample age (SD) years
Longitudinal claims analysis of Medicaid extract
Descriptive populationbased cohort study using THIN data
Design
Claims analysis: Persistence based on gap between prescription refills
Claims analysis: Persistence based on gap between prescription refills
SA-S, IA-S, LA-S
Adherence/ persistence measures
MPH, DEX, ATX
Medication(s) examined
[76]
[77]
The mean persistence values for each stimulant type were as follows: 79.97 days (SA-S); 76.59 days (IA-S) and 104.96 days (LA-S). Overall, children who received index LA-S medications had 29% longer persistence than those on SA/IA-S Persistence: Sum of days the patient remained on stimulant therapy from the first prescription date without a ‡30-day gap between successive refills of the same stimulant
Ref.
Of the 213 children who initiated treatment between 6 and 12 years of age, 61.5% did not persist beyond 18 years. The median treatment duration for this group was 5.9 years. Comparatively, 57.2% of the 397 who began treatment between 13 and 17 years of age did not persist beyond 18 years. The median treatment duration was 1.6 years. No differences in persistence between the different medications were presented
Results
Persistence: Continuous refills of the same medication without a >6-month gap between successive refills Treatment duration: Date of first script to the calculated end date of the last script in the database where criteria for persistence were satisfied
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
UK
McCarthy et al. (2012)
Child and adolescent studies (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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803
804
Country
Canada
Lachaine et al. (2012)
15,838
60,010
n
Mean, 14 (8); range, 2.5–90
Mean, 20.7; range, 6 to >65
Sample age (SD) years
Claims analysis: Adherence calculated by determining ratio of number of days’ therapy supplied to the total number of days persistent Persistence based on gap between prescription refills and the end of the follow-up period
Claims analysis: Adherence calculated as the ratio of the number of days’ therapy received to the number of days treatment expected to last (365 days) Persistence based on gap between prescription refills
SA-S, LA-S, LA-NS
Crosssectional retrospective prescription claims analysis
Adherence/ persistence measures
SA-S, IA-S, LA-S, ATX
Medication(s) examined
Claims analysis of a managed care population
Design
[78]
[79]
The adherence rates for the different medication categories were as follows: 39.4% (SAS); 63% (LA-S) and 60.2% (LA-NS). Persistence rates at 12 months were as follows: 59.6% (SAS); 81.1% (LA-S) and 61.7% (LA-NS) Adherence: Values >80% indicate adherence Persistence: Continuation of treatment without a ‡90 day gap between end date of last prescription duration and new prescription claim
Ref.
Persistence and adherence were significantly greater for patients: using SA/IA/LA-S compared with ATX; using amphetamine rather than methylphenidate stimulant preparations; and those using LA medications compared with SA/IA medications irrespective of the specific agent
Results
Adherence: Not dichotomized, reported as continuous variable ranging from 0 to 1 (complete adherence) Persistence: Number of days that the patient remained on initial therapy without a ‡30-day gap between end of last prescription claim and the end of the follow-up period (366-day duration)
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Christensen et al. (2010)
Studies including adults
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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www.expert-reviews.com
Country
USA
23,862
n
Mean, 17.82 (12.9); range, 6 to >65
Sample age (SD) years
Claims analysis of a managed care population
Design
SA-, IA- and LA-MPH
Medication(s) examined
Claims analysis: Adherence estimated by calculating MPR – percentage of the number of days of therapy supplied to the total number of days persistent Persistence based on gap between prescription refills and the end of the follow-up period.
Adherence/ persistence measures
Adherence: Not dichotomized, MPR percentages reported as continuous variables Persistence: Number of days that the patient remained on initial therapy without a ‡30-day gap between end of last prescription claim and the end of the follow-up period (366-day duration).
Adherence/ persistence definitions
The mean adherence (MPR) rate of patients using any type of MPH formulation was 53% and mean persistence was 219 days. Further analyses were conducted for LAMPH where it was determined that mean adherence ranged from 49% (adolescents) to 59% (children). Persistence to LA-MPH varied between 183 (adults) and 256 days (children). No specific adherence/ persistence comparisons were conducted between the different groups of medication
Results
[80]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
Hodgkins et al. (2011)
Studies including adults (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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805
806
Country
USA
15,055
n
Mean, 11.3 (6.1); range, 6–63
Sample age (SD) years
Prescription and medical claims analysis from a Medicaid population
Design
SA-MPH, LA-MPH, SA-AMPH, LA-AMPH
Medication(s) examined
Claims analysis: Adherence estimated by calculating DPR – proportion of days the patient was in possession of index drug during 180-day observation period Persistence based on gap between prescription refills
Adherence/ persistence measures
Adherence: Adherence indicated by DPR ‡0.8; nonadherence indicated by DPR
ISSN: 1473-7167 (Print) 1744-8379 (Online) Journal homepage: http://www.tandfonline.com/loi/ierp20
Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults Rana Ahmed & Parisa Aslani To cite this article: Rana Ahmed & Parisa Aslani (2013) Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults, Expert Review of Pharmacoeconomics & Outcomes Research, 13:6, 791-815 To link to this article: http://dx.doi.org/10.1586/14737167.2013.841544
Published online: 09 Jan 2014.
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Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults Expert Rev. Pharmacoecon. Outcomes Res. 13(6), 791–815 (2013)
Rana Ahmed and Parisa Aslani* Room N502, Pharmacy Building (A15), The University of Sydney, NSW, 2006 Australia *Author for correspondence: Tel.: +61 290 366 541 Fax: +61 293 514 391 [email protected]
Suboptimal adherence to treatment regimens is a major obstacle to treatment efficacy and positive outcomes for patients. While poor adherence is common across a variety of chronic conditions, an area which presents unique challenges to clinicians and researchers is non-adherence among pediatric populations. These challenges are well illustrated by the management of attention-deficit/hyperactivity disorder (ADHD), a pervasive pediatric psychiatric condition. The average rates of non-adherence in children and adults ranged between 15 and 87%. Factors predicting increased adherence/persistence included the use of long-acting formulations, younger age, Caucasian background, family structure and the presence and treatment of comorbidities. Decreased adherence/persistence were predicted by multiple daily dosing, family history of ADHD, experiences of adverse effects, stigma and treatment inefficacy. The broad range of non-adherence rates identified reflects the complexities of adherence research in ADHD, and highlights the need for better standardization of adherence/persistence definitions and measurement approaches. KEYWORDS: attention-deficit/hyperactivity disorder • medication adherence • medication compliance • medication persistence • psychostimulant • review
The multi-faceted dimensions of chronic health conditions are reflected in the complexity of their management practices, which stipulate the utilization of multiple treatment modalities and interventions, often over a prolonged period of time and across multiple settings. While this approach allows for more holistic management, it nevertheless presents several challenges to those affected [1]. Perhaps the most apparent of these challenges is adherence, with figures from developed countries highlighting that only 50% of patients with chronic disease are adherent to their treatments [2]. As medication adherence has a central role in predicting morbidity and mortality associated with chronic illness [3], deviations from prescribed regimens can be expected to lead to a range of undesirable outcomes [4–6]. In the short term, non-adherence can affect treatment efficacy and tolerability while in the long term it can lead
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to poor therapeutic outcomes and increased economic disease burden [7,8]. Comparatively, adherence to treatment regimens has been associated with positive health outcomes, patient safety and improvements in quality of life [9–13] even when the treatment used is a placebo [14,15]. By extension, improving adherence can reduce medical expenditure and overall disease burden [4]. Non-adherence is considered to be a serious public health issue [13], presenting challenges not only to affected individuals, but to clinicians and policy makers alike. The gravity of this issue is heightened by the recognition that the prevalence of medication non-adherence is approaching ‘crisis proportions’ [16]. This, coupled with the steady rise in the incidence of chronic conditions [17] has catalyzed significant interest in investigating the underlying issues associated with non-adherence and developing ways to remedy this.
2013 Informa UK Ltd
ISSN 1473-7167
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While extensive research has been conducted exploring these issues in a variety of conditions and populations, an area which poses unique challenges is medication adherence in pediatric populations [18,19]. Depending on the chronic condition in question, medication adherence rates among pediatric populations can be as low as 11% [20]. What is of great interest in the pediatric setting is that the traditional patient–clinician dynamic is complicated as the parent becomes an intermediary between their child and the clinician [21]. Children may have limited involvement in the treatment decisions made during consultations and can often be unaware of the purpose of prescribed treatments [18]. In turn, medication adherence does not necessarily depend on the patient (child) alone, but also on the parent or caregiver who will often assume sole responsibility for administering the medication [18,22]. This parental involvement has the potential to introduce a number of factors which could influence adherence to treatment regimens. With regard to chronic illnesses in particular, parents often discontinue medications upon perceived resolution of symptoms, lack of effectiveness or observation of adverse effects [18]. These issues are particularly apparent in pediatric psychiatric disorders [19] which often require pharmacological intervention well into adolescence and even adulthood [23–26]. Public resistance to biomedical conceptualizations for such disorders [27], and negative attitudes toward their treatment using medications may encourage premature termination of treatment. These issues are exemplified in attention-deficit/hyperactivity disorder (ADHD) which is a common chronic psychiatric disorder of childhood characterized by persistent and impairing symptoms of inattention, hyperactivity and impulsivity. The disorder is believed to affect between 5.9 and 7.1% of children and adolescents [28], with prevalence peaking during middle childhood and declining over time. The prevalence of ADHD among adults has been estimated to be approximately 2.5% [29]. The experience of ADHD symptoms during adolescence and adulthood has been associated with impaired academic, occupational and social performance in addition to strained family relationships [30,31]. Current ADHD treatment guidelines recommend a multifaceted approach to treatment [32,33] incorporating the use of medications in conjunction with psychological and behavioral interventions where appropriate [34,35]. Stimulant medications such as methylphenidate (MPH) are considered first-line therapy for ADHD [36,37] as they have been shown to significantly improve symptoms [38–41] and are efficacious in approximately 80% of users [38]. Due to the chronicity and nature of the impairing symptoms associated with ADHD, the use of such medications is often required over extended periods of time. Hence, adherence to these long-term medication regimens is important in the treatment of ADHD [1,42,43]. Despite strong empirical evidence supporting their safety and efficacy [44,45], adherence rates to stimulant medications for ADHD are poor [46] and persistence rates of 15% 1 year after treatment initiation have been reported [47]. These suboptimal figures are believed to be a major barrier to positive treatment 792
outcomes [1]. Poor medication adherence in ADHD not only leads to symptomatic relapse [48], but it can also affect clinicians’ ability to determine treatment efficacy and to assess the need for dose or medication changes [49,50]. The severity of this predicament is emphasized by the understanding that ADHD is as prevalent as asthma in school-aged populations [51] and accounts for greater annual healthcare expenditure [52]. Hence, although this area hasn’t traditionally been the focus of much interest, over the past 5 years there has been a surge in research examining the extent and causes of non-adherence to ADHD medications. By reviewing the findings of recent research, this article aimed to explore the prevalence of non-adherence to ADHD medications and to provide insight into why users of ADHD medications cease treatment despite the persistence of symptoms and impairments. Users were defined as children, adolescents and adults with ADHD. The article begins with background information about the adherence measures used in the retrieved studies and is followed by the summarized findings of the literature search. Adherence & persistence Definitions
Adherence is a multi-faceted construct which at the core level is founded upon a patient’s understanding of the severity of their illness, their belief in the efficacy of a chosen intervention and in their ability to control their symptoms using this intervention [53]. While differences exist in how adherence is defined between studies, the term is generally understood to reflect the extent to which a patient’s actions correspond with the agreed recommendations of healthcare providers (HCPs) [54]. Medication adherence more specifically, is defined as the act of conforming to HCPs’ recommendations about the timing, dosage and administration frequency of the medication [53]. Comparatively, medication persistence is a measure of treatment continuity, defined as the length of time from the initiation of therapy to its discontinuation [53]. Therefore, although these two terms are often used interchangeably in the literature it is important to recognize that they are unique and are at times two mutually exclusive constructs. Saying patients are adherent to their medication regimens does not necessarily imply that they are persistent, and the opposite is also true. To clarify, patients who purposefully skip some of their prescribed daily doses of medication would not be considered to be adherent, however they may be persistent provided that they continue treatment for the agreed period of time specified by their HCPs. In this way, it is often simpler to view adherence as whether or not patients takes their medication as prescribed for the duration of time that they are persistent with treatment [55]. Measurement
Owing to these definitional differences, adherence and persistence are measured differently, as will be demonstrated in the included studies, although both can be determined by prospective and retrospective approaches. In prospective examinations, Expert Rev. Pharmacoecon. Outcomes Res. 13(6), (2013)
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adherence is measured over a specified period of time and reported as a percentage of the doses taken by the patient against the doses prescribed. In these studies, adherence can be determined using direct or indirect methods of measurement, each with their individual advantages and disadvantages. Direct methods of investigation include observation of therapy and measurement of drug or metabolite concentrations in samples of a patient’s saliva, urine or blood. While these approaches provide the most objective assessments of adherence, direct observation can be impractical and burdensome for clinicians in practice while the analysis of biological samples can be a costly and invasive process for patients. Comparatively, indirect measures of adherence are generally easier to implement but may be more prone to error and distortion. These include patient or parent self-reports/questionnaires, pill counts and the use of electronic medication monitors [8]. The use of patient questionnaires is a relatively simple approach to measuring adherence however there is much controversy surrounding the accuracy and reliability of patients’ reports, which often lead to an overestimation of adherence levels [56]. Pill counting which involves determining the number of pills remaining in patients’ medication bottles or blister packs, may be perceived to provide a more accurate measure of adherence. However, this too is subject to distortion as patients may switch pills between medication bottles or even discard a certain amount of pills prior to clinic visits in an attempt to appear adherent [57–59]. Further, these approaches do not provide insight into the specific timing of dosages whereas the use of electronic monitoring devices such as the medication event management system (MEMS) allows such information to be obtained. These devices are increasingly becoming known as the gold standard for medication adherence measurement [60]. They generally consist of a computer chip inserted into the cap of the medication bottle which is capable of recording the dates and times that the container was opened. This information can then be downloaded from the chip directly into a computer program for analysis. While this information is useful in providing insight into the timing and frequency of medication use, it does not document whether a patient actually took the correct dose of the medication or whether it was taken at all. It is also important to note that MEMS data may be inaccurate in instances where patients remove their total daily dose (or additional doses) from the pill bottle, rather than opening the bottle on every occasion that a dose is required. Nevertheless these devices are still considered to provide the most accurate measures of adherence, although they are not routinely used in clinical practice due to their cost. Adherence can also be determined through retrospective examinations which generally involve the study of pharmacy claims databases for information about how frequently patients refill their prescriptions. The time between the initial dispensing of the medication and when the prescription would run out without further refills is used as a proxy for adherence. The most commonly reported outcome measure in these studies is the medication or drug possession ratio (MPR/DPR) which is www.expert-reviews.com
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a reflection of the dispensed doses in relation to the dispensing period being examined [61]. The MPR is generally calculated as the total days’ medication supply issued to a patient divided by the number of days the patient should have been taking the medication, which in most cases is equivalent to the number of days between prescription refills. MPR values ‡0.8 are taken to reflect adequate treatment adherence. These studies do not provide the detailed insight into patients’ medication-taking behaviors provided by MEMS for example, however their strength lies in their inclusion of prescription information of thousands of patients from community settings, allowing for strong insight into real-world medication utilization. Persistence can also be measured in both prospective and retrospective studies, although unlike adherence, it is reported as a continuous variable in terms of the number of days of continuous therapy from the point of initiation until the end of the observation period. A number of studies also report persistence as a dichotomy where patients are classified as persistent or non-persistent at the conclusion of the study period [62]. In retrospective studies, a permissible gap between consecutive refills of a prescription is pre-specified based on the specific properties and dosing regimen of the medication being examined. As long as patient records indicate that prescription refills were obtained within this ‘gap’, that patient is considered to be persistent. There are, therefore, numerous approaches to conducting studies of adherence and varying definitions of the term itself. It is for this reason that a meta-analysis of the studies identified in this review was not possible. Instead, the studies have been categorized according to whether they have adopted prospective or retrospective examinations of adherence and persistence. A summary of their findings is presented in light of the definitions they have used and in comparison with those of other studies where possible. Methods Literature search & search strategy
The electronic databases Medline, PsycINFO and Embase were searched for articles between January 2008 and April 2013. Combinations of the following search terms and key words were used to identify appropriate studies: medication adherence, medication compliance, medication persistence, patient compliance, patient adherence, medication nonadherence, medication noncompliance, patient noncompliance, treatment refusal, patient acceptance of healthcare, attention deficit disorder with hyperactivity, ADHD, treatment, stimulant, medication, drug therapy. Search terms within similar categories were combined with OR and then combined with the results of other categories using AND. The reference lists of review articles and relevant studies were also examined for further potentially appropriate studies. Studies were limited to those published in peer-reviewed journals and in the English language. The titles and abstracts of the articles obtained through these systematic literature searches were screened for eligibility. Only those articles which appeared relevant were examined in detail for inclusion. 793
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Inclusion & exclusion criteria
Eligible studies met the following criteria: study sample included children, adolescents or adults with an official diagnosis of ADHD and who were being treated using medication; ADHD medication(s) under examination clearly identified; empirical data on rates of adherence/persistence to ADHD medications obtained through direct or indirect measures presented and adherence/persistence clearly defined. The presence of any of the following was used to ascertain the inclusion of participants with an official ADHD diagnosis in the reviewed articles: structured diagnostic assessments based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or its Text Revision (DSM-IV-TR); record of ADHD diagnosis according to DSM-IV or DSM-IV-TR criteria in patient medical records and record of diagnostic codes for ADHD in retrospective databases. The following types of studies were excluded: those that used patient records of ADHD medication use as a proxy for a diagnosis of ADHD; those that examined adherence to alternative ADHD treatments, for example, behavioral therapy; those that reported only on patient treatment preferences without reference to treatment adherence and those that did not report specific adherence measures. Data extraction
The following information was extracted from each retrieved study: country where the study was conducted; number and age of participants; study design; study duration; medications examined; adherence/persistence definition, measures and outcomes. Studies were categorized according to whether they adopted prospective or retrospective approaches to measuring adherence/persistence to ADHD medications. Results Study selection
The search strategy yielded a total of 940 citations (FIGURE 1). After title and abstract screening, 860 of these were excluded and the full text of the remaining 80 articles was obtained. Of these, 19 articles met the inclusion criteria and were included in the final review. The excluded articles either presented the findings of non-primary research (reviews and editorial articles) Medline (203 citations)
940 citations
860 excluded on the basis of title and abstract review
80 citations
61 excluded after full-text analysis: – No inclusion of adherence measures (n = 9) – Examined treatment preferences only (n = 13) – Non-primary research (review, editorial) (n = 21) – Factors influencing treatment initiation only (n = 3) – Related to non-pharmacological ADHD treatments (n = 8) – Patient medication use as proxy for ADHD diagnosis (n = 7)
19 citations
Included in review (16,546 adults; 161,828 children/adolescents)
PsycINFO (109 citations) Embase (628 citations) Ref. list (9 citations)
(n = 21), did not include specific adherence measures (n = 9), examined ADHD treatment preferences without reference to adherence (n = 13), explored adherence to non-pharmacological ADHD treatments (n = 8), utilized participants’ ADHD medication use as a proxy for ADHD diagnosis (n = 7) or looked at factors influencing initiation of treatment only (n = 3). Of the 19 retrieved articles, 2 [63,64] reported on alternate findings from the same investigation. However, for ease of reference henceforth, the total number of studies will be referred to as 19. The 19 studies report on findings related to a total of 16, 546 adults and 161, 828 children and adolescents treated with medications for the management of their ADHD. Most of the studies were conducted in the USA (n = 9), followed by England (n = 2), Taiwan (n = 3), Canada (n = 1), Germany (n = 1), Italy (n = 1), Korea (n = 1) and Spain (n = 1). Just under half of these studies involved prospective assessments of adherence [63–71] and of these, six included child and adolescent participants [63–68] while the remaining three studies examined only adult populations (TABLE 1) [69–71]. In these studies, medication adherence was assessed through the use of indirect measures including pill counts [67–69,71], parent/patient reports [63–65,68,69], clinician interviews/assessments [63,66,68,70] and electronic monitoring devices such as MEMS [68,69]. The remaining 10 studies adopted a retrospective approach to explore treatment adherence and persistence [72–81] generally by analyzing claims data from large health databases (TABLE 2). Only one included direct measures of adherence, whereby participant saliva samples were obtained and assayed to measure levels of the medication used [72]. Six of these retrospective studies included children and adolescents [72–77] while adult participants were additionally included in the remaining four studies [78–81]. It is important to note that although some of these studies have conducted their investigations using similar methods, they do not necessarily use the same criteria for defining adequate adherence or persistence levels. Therefore, to avoid ambiguity or inaccuracies, a summary of the investigative approaches, outcome-of-interest measures and definitions used in these studies is provided in TABLES 1 & 2 and should be referred to when examining the key findings presented below.
Figure 1. Results of search strategy and process for the identification of studies included for review. Please note that the 19 included citations report on the findings of 18 investigations. Ref. list = Citations sourced from the reference lists of relevant articles.
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Prevalence of non-adherence & treatment cessation in ADHD Prospective assessments of adherence & persistence Studies of children & adolescents
Of the six prospective studies (TABLE 1) exploring medication adherence and persistence in children and adolescents with ADHD [63– 68], three explored adherence to both immediate-release (IR) and osmotic release oral system (OROS)-MPH [63–65]; one focused on adherence to a non-OROS extended-release (XR)-MPH preparation called Equasym XL1 (EXL) [66]; one examined adherence to IR-MPH only [67] and one measured adherence to OROS-MPH only [68]. The findings of a large open-label observational study conducted in Taiwan are presented by Gau et al. [63] and Chou et al. [64]. Daily parent/patient reports of missed doses and clinician interviews were used to measure adherence rates to IR and OROS-MPH. Gau et al. focused on determinants of adherence to IR-MPH [63]. From an initial sample of 607 children initiated on IR-MPH, 240 (39.5%) were observed to have poor adherence (i.e., overall IR-MPH adherence rate, 60.5%) and of these, 137 were switched to OROS-MPH, with only 124 completing the assessment period [63]. After initiating the switch, more than 80% of these children demonstrated improved adherence and reduced symptom severity. Chou et al. provided insight into the determinants of adherence to OROS-MPH among the 137 children switched to OROS-MPH [64]. Of those with available data (124), only 38 (27.7%) were observed to have poor adherence (i.e., overall adherence rate to OROS-MPH, 72.3%). It is important to note that the authors of both studies have not included details about how or why the 137 children were selected to be switched to OROS-MPH, other than the fact that they were considered to have poor adherence to IR-MPH. However, when considering that the remaining 103 children who also had poor adherence remained on IR-MPH, it becomes apparent that there may be potential selection biases which may influence the results presented. Similar findings were seen in another observational study conducted by Tzang et al., where parent reports were also used to measure and compare adherence rates with IR and OROSMPH [65]. The study was conducted over a comparatively longer 48-week period and involved a total of 757 children diagnosed with ADHD who were allocated to either IR-MPH (n = 265), OROS-MPH (n = 293), IR and OROS-MPH (n = 129) or no treatment (n = 70) depending on their clinical needs. A total of 67.2% of the children on OROS-MPH were deemed to have good adherence compared with only 36.2% of children who exhibited good adherence to IR-MPH (p < 0.0001). Rothenberger et al. used clinician rating scales to determine adherence rates to the XR-MPH preparation [66], EXL in a post-marketing, open-label observational study. The study involved 822 children newly initiated on EXL and monitored over a 6- to 12-week period to determine treatment satisfaction and adherence. The treating physician graded adherence to treatment using a scale ranging from 1 (very good adherence), www.expert-reviews.com
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to 6 (inadequate adherence). Mean adherence scores improved from 2.1 ± 1.2 to 1.5 ± 1.0, and of the 773 children with adherence ratings available on the final clinic visit, 67.9 and 22.6% had very good (1) or good (2) adherence, respectively. Adherence was continually superior with EXL in comparison with adherence to prior treatments and especially among children previously treated using multiple doses of IR-MPH, with 57.7% of them exhibiting better adherence to EXL. Atzori et al. used pill counts to assess adherence to treatment among 134 children treated with IR-MPH [67]. Pill counts were conducted by the clinician at the conclusion of each month for 36 months. At the end of the 36-month study period, 46% (n = 62) of children remained on treatment, 24% (n = 32) ceased treatment due to functional remission and 30% (n = 40) due to other reasons. Of these 40 children, 50% suspended treatment for poor adherence, that is, approximately 15% of the total sample exhibited poor adherence that led to treatment discontinuation during the study period. The authors, however, did not specify whether those who remained on treatment met criteria for good adherence. Importantly, treatment discontinuation in this study was also as a result of symptomatic remission. Yang et al. used pill counts in conjunction with parental reports, clinician rating scales and the MEMS to measure adherence to OROS-MPH in a sample of 39 children over an 8-week period [68]. Adherence rates as determined by pill counts, parent report, MEMS and the clinician rating scale were 87.2, 82.1, 53.8 and 68.3%, respectively. Therefore, using MEMS as the reference standard, 46.2% of the children did not meet criteria for adherence within the 8-week study period. In comparison with MEMS, the other measures overestimated patient adherence. Studies of adults
A total of three studies examined medication adherence in adults diagnosed with ADHD [69–71] using a prospective approach. Two of these studies explored adherence to both IRand OROS-MPH [70,71] while the remaining study focused on adherence to IR- and XR-mixed amphetamine salts (MAS) [69]. Adler et al. conducted a randomized crossover study in which patient reports, pill counts and MEMS were used to determine adherence rates to IR- and XR-MAS [69]. The study involved 49 adults who received treatment with either IR-MAS (requiring three daily doses) or XR-MAS (requiring one morning dose daily) for 3 weeks. At the conclusion of the 3-week period and following a 7-day washout period, participants were switched onto the alternate MAS preparation for another 3 weeks. Daily self-reports of adherence were collected during weekly follow-up clinic visits where clinicians also conducted pill counts. The information obtained through MEMS was used to determine the following: dosage adherence which required that ‡75% of prescribed doses to be taken; time adherence which required that ‡80% of prescribed doses to be taken at the correct time and regimen adherence which required that the complete daily dosing regimen to be taken on ‡90% of days. 795
796
Country
Taiwan
Taiwan
Chou et al. (2009)
Tzang et al. (2012)
757
137
607
n
Mean, 10.1 (2.7); range, 6–18
Mean, 10.7 (2.5)
Mean, 10.4 (2.6)
Sample age years (SD)
Parent/patient reports: Verbal feedback about frequency of missed doses
Parent reports: Feedback about adherence during final clinic visit
OROS-MPH
IR and OROS-MPH
Open-label prospective observational study
Prospective observational study
Adherence measures
Parent/patient reports: Yes/no responses to questions (unspecified) Clinician interviews: Standard interview (unspecified content)
Medication(s) examined
IR and OROS-MPH
Open-label prospective observational study
Design
[63]
[64]
[65]
Of the 124 children who completed the assessment period after being switched onto OROS-MPH, 27.7% had poor adherence based on parental/patient global adherence reports, i.e., overall adherence rate = 72.3% Parent adherence reports were provided for 621 children at the final clinic visit (week 48). 67.2% of children using OROS-MPH were considered to have ‘good adherence’ compared with 36.2% of children using IR-MPH.
Poor adherence: ‡1 doses missed on ‡2 school days per week for 3 weeks OR parents/patients report poorer adherence to OROS-MPH than IR-MPH Adherence via parent reports not clearly defined
Ref.
Among the initial study sample of 607 children treated with IR-MPH, 240 (39.5%) had poor adherence, i.e., overall adherence rate = 60.5%. Of the 137 children switched onto OROS-MPH, ‡80% had their adherence evaluated as ‘a little’ or ‘much’ better compared with previous use of IRMPH.
Results
Poor adherence: ‡1 doses missed on ‡2 school days per week for 4 school weeks
Adherence definitions
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Taiwan
Gau et al. (2008)
Child and adolescent studies
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults.
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Country
n
Italy
Atzori et al. (2009)
134
822
Mean, 9 (2); range, 4–16
Mean, 10.1 (2.5); range, 6–17
Sample age years (SD)
EXL
IR-MPH
Medical chart review
Medication(s) examined
Open-label prospective observational study
Design
Pill counts: Number of unused pills counted by treating physician at the end of each month
Clinician rating scale: Grade provided by treating physician to reflect patient adherence
Adherence measures
The mean adherence score (SD) improved from 2.1 (1.2) to 1.5 (1.0) while subjects were using EXL and adherence was consistently superior to prior treatment. 57.7% of patients previously on multi-dose IR-MPH had better adherence on EXL. At 36 months, 46% of the initial population remained on IR-MPH, 24% stopped for functional remission and 30% stopped for other reasons. Of these, 50% did not satisfy the criteria for ‘good’ adherence, i.e., approximately 15% of the total sample did not adhere to treatment.
‘Good’ adherence: ‡80% of prescribed pills taken monthly for ‡8 months
Results
Adherence grades: Scale ranged from 1 (very good adherence) to 6 (inadequate adherence)
Adherence definitions
[67]
[66]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Germany
Rothenberger et al. (2011)
Child and adolescent studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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797
798
Country
n
Korea
39
Mean, 10.4 (2.2)
Sample age years (SD)
Prospective observational study
Design
OROS-MPH
Medication(s) examined
Parent reports: Global adherence estimated by parents using a value between 0 and 100% Pill counts: Unused pills counted by research assistant at follow-up clinic visits. Actual pill count calculated as a percentage of prescribed pills. MEMS: Number of doses taken on schedule (container opened within 3-h time frame) as a percentage of prescribed doses Clinician rating scale: Grade provided by treating physician to reflect patient adherence
Adherence measures
Good adherence: Values ‡80% as determined by parent reports, pill counts and MEMS Values >5 as determined by clinician rating scale where 1 reflects complete treatment refusal and 7 reflects active responsibility for treatment
Adherence definitions
When reported as continuous variables, mean adherence values (SD) for OROS-MPH were as follows; parentreport: 90.1% (16.25); pill count: 94.1% (8.62); MEMS: 77.58% (19.13) and clinician rating: 4.58 (0.99). When dichotomized at the ‡80% and >5 (clinician rating) thresholds, the percentage of adherent patients according to each measure were as follows; 82.1% (parent reports); 87.2% (pill count); 53.8% (MEMS) and 68.3% (clinician rating)
Results
[68]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Yang et al. (2012)
Child and adolescent studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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USA
Country
49
n
Mean, 35.7 (10.3)
Sample age years (SD)
Randomized crossover study
Design
IR- and XR-MAS
Medication(s) examined
Patient reports: Patients record whether medication was taken within 30 min of waking (morning dose) and at 5-h intervals (±30 min) (subsequent doses) Pill counts: Conducted by clinician weekly to determine percentage of pills taken MEMS: Number of doses taken at the prescribed dose and within the prescribed time
Adherence measures
Adherence: Taking all doses (±20%) as prescribed by measurement criteria for patient reports and pill counts For MEMS measures, dosage adherence was defined as ‡75% of prescribed doses taken and time adherence defined as ‡80% of doses taken at the correct time
Adherence definitions
According to patient reports and pill counts, 92.6 and 90.4% of patients were adherent to IR-MPH, respectively. When treated using XR-MAS, 98.8 and 96.9% of patients were adherent to treatment based on patient reports and pill counts, respectively. No significant differences were observed between these two adherence measures According to MEMS measures, 42.7% satisfied the criteria for dosage adherence and only 4.5% for time adherence while being treated with IR-MAS. Comparatively, 66.2% met criteria for dosage adherence and 43.7% for time adherence when treated with XR-MAS. These differences were statistically significant
Results
[69]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Adler et al. (2011)
Adult studies
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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799
800
Country
USA
Spencer et al. (2011)
53
70
n
Mean, 37.4 (9.7)
Mean, 30 (9.6)
Sample age years (SD)
Single-blind, randomized, parallel study
Naturalistic chart review
Design
Clinician interview: Brief adherence assessment questionnaire used during follow-up clinic visits at 3 and 6 months after treatment initiation
Pill counts: Conducted on a weekly basis by physicians to determine percentage of pills taken
IR and OROS-MPH
Adherence measures
IR and OROS-MPH
Medication(s) examined
[70]
[71]
Adherence was better among users of OROSMPH with 46% measured to have complete adherence compared with 17% of those treated with IR-MPH. Statistically significant differences in the number of missed doses between the two treatment groups was observed, with approximately twice missed pills being reported among IR-MPH users Adherence: Patients dichotomized as having either complete adherence or missed doses
Ref.
Non-adherence rates among those treated using IR-MPH were as follows: 37.1% (mildly); 11.4% (moderately) and 4.7% (highly). Comparatively, only 2.9% of patients treated using OROS-MPH were mildly non-adherent and none met the criteria for moderate or high nonadherence.
Results
Non-adherence: Patient not taking medication (over 3-month period) for: ‡5 days: mildly non-adherent ‡10 days: moderately nonadherent ‡20 days: highly non-adherent
Adherence definitions
ADHD: Attention-deficit/hyperactivity disorder; EXL: Equasym XL1; IR: Immediate release; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MEMS: Medication event management system; OROS: Osmotic release oral system; XR: Extended release.
Spain
RamosQuiroga et al. (2008)
Adult studies (cont.)
Study (year)
Table 1. Summary of prospective studies examining adherence to ADHD medications in children, adolescents and adults (cont.).
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Country
www.expert-reviews.com
USA
Winterstein et al. (2008)
40,052
254
n
Range: 5–20
Mean, 7.8 (0.8); range, 7–9.9
Sample age (SD) years
Crosssectional analysis of Medicaid beneficiaries cohort
Retrospective comparison of MTA study data on adherence
Design
[72]
[73]
Allowing for a 3-month gap between prescription refills, the percentage of patients who were persistent were as follows: 49.9% after 1 year; 32.8% after 2 years; 17.2% after 5 years and 15.4% after 9 years. Comparatively, allowing for a 1-month gap only 47.4% persisted after 6 months and 26.9% after 1 year. No differences in persistence between the different medications were presented Persistence: Continuous refills of index treatment without a 1- or 3-month gap between drug claims Claims analysis: Persistence based on gap between prescription refills
Stimulant medications and ATX
Ref.
According to parent reports, only 3.1% of the children did not meet criteria for verbal adherence to IR-MPH. Comparatively, physiological adherence results indicated that 24.8% of the children were non-adherent, indicating that parent reports may overestimate adherence levels
Results
Verbal adherence: At ‡80% of monthly visits, parents report child has taken the medication on the day and has good overall adherence Physiological adherence: MPH detectable in ‡50% of child saliva samples
Adherence/ persistence definitions
Parent reports: Verbal feedback given about global adherence and whether child took medication on day of clinic visit Saliva assays: Four assays conducted over treatment period to detect MPH levels
Adherence/ persistence measures
IR-MPH
Medication(s) examined
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Pappadopulos et al. (2009)
Child and adolescent studies
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults.
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801
802
Country
n
UK
Wong et al. (2009)
983
9559
Range: 15– 21
Range: 6–12
Sample age (SD) years
Cohort study using data from GPRD database
Pharmacy and medical claims analysis
Design
Claims analysis: Persistence based on length of stimulant treatment episodes
Claims analysis: Persistence based on gap between prescription refills
MPH, DEX, ATX
Adherence/ persistence measures
IR and OROS-MPH, IR- and XR-MAS
Medication(s) examined
[74]
[75]
The percentages of patients who persisted with treatment were as follows: 83% after 1 year; 54% after 2 years; 36% after 3 years; 24% after 4 years; 22% after 5 years and 17% after 6 years. No differences in persistence between the different medications were presented Persistence: Continuous refills of the same medication without a ‡6 month gap between successive refills
Ref.
The mean stimulant treatment episodes for each medication were as follows: 145.4 ± 37.5 days (IR-MPH); 160.8 ± 32.3 days (OROSMPH); 150.8 ± 36.2 days (IR-MAS) and 158.0 ± 36.2 days (XR-MAS).
Results
Persistence: Continuous refills of the same stimulant without a ‡30-day gap between successive refills Stimulant treatment episode: Date of first stimulant script to date of last supply OR 180 days after first stimulant prescription (whichever came first)
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Olfson et al. (2009)
Child and adolescent studies (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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Country
n
www.expert-reviews.com
USA
Palli et al. (2012)
46,135
610
Mean, 9.2; range: 6–19
Range, 6–28
Sample age (SD) years
Longitudinal claims analysis of Medicaid extract
Descriptive populationbased cohort study using THIN data
Design
Claims analysis: Persistence based on gap between prescription refills
Claims analysis: Persistence based on gap between prescription refills
SA-S, IA-S, LA-S
Adherence/ persistence measures
MPH, DEX, ATX
Medication(s) examined
[76]
[77]
The mean persistence values for each stimulant type were as follows: 79.97 days (SA-S); 76.59 days (IA-S) and 104.96 days (LA-S). Overall, children who received index LA-S medications had 29% longer persistence than those on SA/IA-S Persistence: Sum of days the patient remained on stimulant therapy from the first prescription date without a ‡30-day gap between successive refills of the same stimulant
Ref.
Of the 213 children who initiated treatment between 6 and 12 years of age, 61.5% did not persist beyond 18 years. The median treatment duration for this group was 5.9 years. Comparatively, 57.2% of the 397 who began treatment between 13 and 17 years of age did not persist beyond 18 years. The median treatment duration was 1.6 years. No differences in persistence between the different medications were presented
Results
Persistence: Continuous refills of the same medication without a >6-month gap between successive refills Treatment duration: Date of first script to the calculated end date of the last script in the database where criteria for persistence were satisfied
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
UK
McCarthy et al. (2012)
Child and adolescent studies (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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803
804
Country
Canada
Lachaine et al. (2012)
15,838
60,010
n
Mean, 14 (8); range, 2.5–90
Mean, 20.7; range, 6 to >65
Sample age (SD) years
Claims analysis: Adherence calculated by determining ratio of number of days’ therapy supplied to the total number of days persistent Persistence based on gap between prescription refills and the end of the follow-up period
Claims analysis: Adherence calculated as the ratio of the number of days’ therapy received to the number of days treatment expected to last (365 days) Persistence based on gap between prescription refills
SA-S, LA-S, LA-NS
Crosssectional retrospective prescription claims analysis
Adherence/ persistence measures
SA-S, IA-S, LA-S, ATX
Medication(s) examined
Claims analysis of a managed care population
Design
[78]
[79]
The adherence rates for the different medication categories were as follows: 39.4% (SAS); 63% (LA-S) and 60.2% (LA-NS). Persistence rates at 12 months were as follows: 59.6% (SAS); 81.1% (LA-S) and 61.7% (LA-NS) Adherence: Values >80% indicate adherence Persistence: Continuation of treatment without a ‡90 day gap between end date of last prescription duration and new prescription claim
Ref.
Persistence and adherence were significantly greater for patients: using SA/IA/LA-S compared with ATX; using amphetamine rather than methylphenidate stimulant preparations; and those using LA medications compared with SA/IA medications irrespective of the specific agent
Results
Adherence: Not dichotomized, reported as continuous variable ranging from 0 to 1 (complete adherence) Persistence: Number of days that the patient remained on initial therapy without a ‡30-day gap between end of last prescription claim and the end of the follow-up period (366-day duration)
Adherence/ persistence definitions
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
USA
Christensen et al. (2010)
Studies including adults
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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Country
USA
23,862
n
Mean, 17.82 (12.9); range, 6 to >65
Sample age (SD) years
Claims analysis of a managed care population
Design
SA-, IA- and LA-MPH
Medication(s) examined
Claims analysis: Adherence estimated by calculating MPR – percentage of the number of days of therapy supplied to the total number of days persistent Persistence based on gap between prescription refills and the end of the follow-up period.
Adherence/ persistence measures
Adherence: Not dichotomized, MPR percentages reported as continuous variables Persistence: Number of days that the patient remained on initial therapy without a ‡30-day gap between end of last prescription claim and the end of the follow-up period (366-day duration).
Adherence/ persistence definitions
The mean adherence (MPR) rate of patients using any type of MPH formulation was 53% and mean persistence was 219 days. Further analyses were conducted for LAMPH where it was determined that mean adherence ranged from 49% (adolescents) to 59% (children). Persistence to LA-MPH varied between 183 (adults) and 256 days (children). No specific adherence/ persistence comparisons were conducted between the different groups of medication
Results
[80]
Ref.
ADHD: Attention-deficit/hyperactivity disorder; AMPH: Amphetamine; ATX: Atomoxetine; DEX: Dexamphetamine; DPR: Drug possession ratio; IA: Intermediate acting; IR: Immediate release; LA: Long acting; MAS: Mixed amphetamine salts; MPH: Methylphenidate; MPR: Medication possession ratio; NS: Non-stimulant; OROS: Osmotic release oral system; S: Stimulant; SA: Short acting; XR: Extended release.
Hodgkins et al. (2011)
Studies including adults (cont.)
Study (year)
Table 2. Summary of retrospective studies examining adherence and persistence to ADHD medications in children, adolescents and adults (cont.).
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805
806
Country
USA
15,055
n
Mean, 11.3 (6.1); range, 6–63
Sample age (SD) years
Prescription and medical claims analysis from a Medicaid population
Design
SA-MPH, LA-MPH, SA-AMPH, LA-AMPH
Medication(s) examined
Claims analysis: Adherence estimated by calculating DPR – proportion of days the patient was in possession of index drug during 180-day observation period Persistence based on gap between prescription refills
Adherence/ persistence measures
Adherence: Adherence indicated by DPR ‡0.8; nonadherence indicated by DPR
