Adults with attention-deficit/hyperactivity disorder (ADHD) who received long-acting combination therapy had significantly lower adherence and persistence compared with those who received long-acting monotherapy.
Objectives: To evaluate the treatment patterns among commercially insured adults in the United States with attention-deficit/hyperactivity disorder (ADHD) who received long-acting (LA) combination therapy (CT) or monotherapy for ADHD.
Study Design: Retrospective observational study.
Methods: Adults with at least 1 ADHD diagnosis and at least 1 LA ADHD medication were identified from the MarketScan claims database (April 1, 2009, to March 31, 2014). The index date was randomly selected among LA medication initiation dates (index treatment). CT was identified if a different ADHD medication was filled within 30 days of the index date and the 2 medications overlapped by 30 days or more; otherwise, the treatment was considered monotherapy. Adherence was measured using proportion of days covered (PDC) during the 1 year post index date and was defined as a PDC of 0.8 or greater. Persistence was defined as time to discontinuation (TTD) (ie, ≥30-day supply gap). Adherence and persistence were compared between CT and monotherapy using multivariable logistic and Cox models, respectively, adjusting for baseline characteristics.
Results: Of 225,600 eligible patients, 7.3% received LA CT and 92.7% received LA monotherapy (mean age, 29 vs 31 years, respectively). Patients receiving LA CT had significantly lower adherence than those receiving LA monotherapy (mean PDC, 0.33 vs 0.41; adherence rate, 7% vs 16%, respectively; adjusted odds ratio, 0.38; P <.001). They also demonstrated significantly lower persistence than patients receiving LA monotherapy (median TTD, 59 vs 79 days, respectively; adjusted hazard ratio, 1.32; P <.001).
Conclusions: Among US adults with ADHD treated with LA medications, LA CT was associated with significantly lower adherence and persistence compared with LA monotherapy.
Am J Manag Care. 2018;24(Spec Issue No. 8):SP329-SP337Takeaway Points
Medication adherence is the extent to which patients follow a medication regimen as prescribed by their healthcare provider. It is an important part of the optimal management of health conditions, disorders, and diseases.1 Prior studies have demonstrated that adherence is influenced by several factors, including dose frequency.2 Issues with adherence are more prevalent and impactful among those with chronic conditions that require ongoing management compared with acute conditions.3,4 In particular, poor adherence is prominent among patients withpsychiatric conditions,5,6 including attention-deficit/hyperactivity disorder (ADHD),7 which is a lifespan disorder characterized by symptoms of persistent inattention, hyperactivity, and impulsivity.8 Although ADHD is primarily diagnosed in children and adolescents, approximately 50% of patients diagnosed in childhood experience symptoms that persist into adulthood.9 The prevalence of ADHD was estimated in 2006 at up to 5% among adults in the United States.10 ADHD is associated with a high burden of illness among affected adults and was estimated to account for 3.5% of all adult mental health visits from 1996 to 2003.11 If left untreated or undertreated, ADHD can cause significant personal, social, and economic burdens, which may impair patients’ quality of life during adulthood.12
ADHD symptoms can often be effectively treated with pharmacotherapy. The 2 main classes of ADHD medications are stimulants and nonstimulants.13,14 Stimulant medications, such as methylphenidate and amphetamine (AMPH), are commonly used as the first-line treatment for adults with ADHD,14 which generally complies with the recommendations for treating ADHD in childhood and adolescence. Nonstimulant medications include atomoxetine (ATX) or off-label use of clonidine hydrochloride extended release (ER), guanfacine ER, or antihypertensive agents such as clonidine instant release (IR) and guanfacine IR.15 Depending on the average duration of action, ADHD medications are classified as long-acting (LA; up to 12-14 hours of activity) or short-acting (SA; up to 4-6 hours of activity).16,17
The duration of action affects the dosing frequency of ADHD medications and thus may affect adherence and persistence (ie, whether patients follow prescribed treatment regimens and remain on treatment, respectively).18-21 As other chronic diseases do, ADHD requires long-term pharmacotherapy to control symptoms. Poor medication adherence and persistence are common challenges in ADHD treatment and can negatively impact the optimal management of ADHD and increase healthcare costs.7 For example, a literature review by Gajria et al of 91 studies (1990-2013) reporting ADHD medication adherence and persistence among adults or children with ADHD found adherence to be low in both groups (medication possession ratio <0.7 in both groups).21 Adverse effects (AEs), lack of symptom control, inconvenient dosing, and social stigma associated with ADHD medications were reported to be common reasons for treatment discontinuation in that review.
Previous study findings have suggested that patients with ADHD have better adherence and persistence if they use LA versus SA stimulants.18-21 A recent study of ADHD medication use in European countries reported an increase in the use of LA stimulants to treat ADHD in adults.22 However, if available LA medications cannot provide sufficient symptom control throughout the day, combination therapy (LA medications in combination with other ADHD medications) may be used.16 Results from a US study using retrospective claims data among adult patients with ADHD between 2007 and 2008 showed that 8.3% of patients augmented their LA medications.23
However, no studies to date have assessed how adherence and persistence with LA ADHD medications is impacted by using combination therapy compared with monotherapy. To address this gap in the literature, the present study compared the real-world treatment patterns (medication adherence and persistence) of US adults with ADHD who received either LA combination therapy or monotherapy.
Commercial administrative claims data from the Truven Health MarketScan and Medicare Supplemental databases (April 1, 2009, to March 31, 2014) were used in this study. The data represent the medical claims of insured employees and their dependents from more than 40 national employers, as well as Medicare-eligible retirees with employer-provided Medicare Supplemental plans. These databases contain eligibility information (ie, enrollment dates), medical service claims (provider and institutional), and pharmacy claims from approximately 100 insurance providers and third-party administrators in the United States, representing approximately 50 million covered lives. Data were deidentified and complied with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act and the most recent amendment to the Declaration of Helsinki. Because the data were anonymized, no institutional review was required.
Patients were eligible if they had at least 1 diagnosis for ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification codes 314.0 or 314.9) in the databases and initiated atleast 1 LA ADHD medication within 30 days prior to or any time after the first ADHD diagnosis. The list of ADHD medications is provided in the eAppendix Table (eAppendix available at ajmc.com). For each patient, continuous treatment episodes were constructed for each LA medication initiated. Discontinuation of a treatment episode was defined as no prescription fill of a medication within 30 days from the last day of supply of the previous fill. Each initiation date of a unique treatment episode was defined as a potential index date. Patients were further required to be 18 years or older on any potential index date and continuously enrolled in a health plan during the 6 months before (baseline period) and 12 months after the potential index date (study period). The final index date was randomly selected from among all potential index dates for each patient. The treatment prescribed on the index date was defined as the first index treatment.
Patients were classified into either the LA combination therapy cohort (LA CT cohort) or LA monotherapy cohort (LA mono cohort), as defined below.
LA CT cohort. Patients were classified into the LA CT cohort if they had (1) a prescription for a different LA or SA ADHD medication within 30 days of the index date and (2) 30 or more days of overlap in medication supply between the first index treatment and the additional treatment. The index treatments for patients in the LA CT cohort included the 2 treatments in combination. Drugs of the same molecule but of different brands were considered 2 different treatments. Patients who used more than 2 ADHD treatments in combination were not considered in the study.
LA mono cohort. Patients not meeting the criteria for inclusion in the LA CT cohort were classified into the LA mono cohort. The first index treatment was the only index treatment for patients in the LA mono cohort.
Study Measures: Baseline Characteristics
Baseline patient characteristics were measured on the index date or during the 6-month baseline period. These included age, sex, US geographic region, insurance type, prior ADHD-related psychotherapies, and prior ADHD medication use at drug class level. Comorbidities included a composite assessment of physical comorbidities using the Deyo-Charlson Comorbidity Index (DCCI).24 In addition, the 5 most prevalent neurological and psychiatric comorbid conditions25 and the 5 most prevalent physical comorbidconditions based on the literature were reported.26
Study Measures: Treatment Patterns
The following outcomes assessing the treatment patterns of the 2 cohorts were measured during the 1-year study period.
Adherence. Adherence to the index treatment(s) was measured using the proportion of days covered (PDC; ie, the proportion of days with medication on hand). The PDC was calculated as the sum of days that are “covered” by the index treatment (for the LA mono cohort) or both agents in the combination therapy (for the LA CT cohort) during the study period, divided by the number of days in the study period. Patients were considered adherent if their PDC was 0.8 or greater and nonadherent if their PDC was less than 0.8, based on the threshold defined by Haynes.27
Persistence. Persistence was measured using treatment discontinuation, which was defined as a gap of 30 or more consecutive days between the last day of supply of a prescription fill for the index treatment and the next prescription fill date of the same drug or the end of continuous healthcare plan enrollment, whichever occurred first. For the LA CT cohort, the date of treatment discontinuation was the earlier discontinuation date of either agent.
Treatment switch. A treatment switch was defined as initiation of a different ADHD medication from the index treatment(s) within 30 days before or after the discontinuation date. The new medication filled was the switched-to treatment. The date of a treatment switch was defined as the date of the first prescription fill of the switched-to treatment.
Patient baseline characteristics were compared between the 2 cohorts using Wilcoxon rank-sum tests for continuous variables and χ2 tests for categorical variables. Fisher’s exact tests were used if 25% or more of the cells had expected counts less than 5 for categorical variables.
For the comparison of treatment adherence, the mean PDC was summarized and compared between cohorts using univariate and multivariable linear regression models. Unadjusted and adjusted mean differences were reported. In addition, univariate and multivariable logistic regression models were constructed and unadjusted and adjusted odds ratios (ORs) of being adherent to treatment were reported. Treatment discontinuation and treatment switch were assessed using Kaplan-Meier analyses and compared between cohorts using log-rank tests. For the analysis of treatment discontinuation, patients who did not discontinue the index treatment(s) during the study period were censored at the end of the study period. For the analysis of time to treatment switch, patients were censored at 30 days after the discontinuation dates or the end of study period, whichever occurred earlier. In addition, Cox proportional hazards models were used to compare the hazards of treatment discontinuation and treatment switch between cohorts controlling for baseline covariates. Proportional hazards assumption was tested on the cohort variable.
All multivariable models controlled for the following baseline characteristics: age, sex, US geographic region, insurance plan type,year of the index date, any prior ADHD-related psychotherapy, any prior ADHD medication use, DCCI score, and neurological, mental, and physical comorbid conditions that were significantly different (P <.05) between the cohorts. All tests were 2-sided and the significance was assessed based on a P value of .05. All analyses were conducted using SAS version 9.3 (SAS Institute; Cary, North Carolina).
Of the 225,968 adults who fulfilled all of the sample selection criteria, 16,401 (7.3%) were classified into the LA CT cohort and 209,199 (92.6%) were classified into the LA mono cohort. A total of 368 (0.2%) patients using more than 2 ADHD treatments in combination were excluded from the analysis (Figure 1). Among the LA CT cohort, the majority of patients (55.9%) used dextroamphetamine and AMPH mixed salts (LA and SA) in combination (Table 1 [part A and part B]). Among the LA mono cohort, about two-thirds of patients (65.8%) used dextroamphetamine and AMPH mixed salts. The 5 most prevalent neurological and psychiatric comorbid conditions were mood disorders, anxiety disorders, adjustment disorders, substance-related disorders, and other conditions that may be a focus of clinical attention; the 5 most prevalent physical comorbid conditions were hypertension (uncomplicated and complicated), chronic pulmonary disease, hypothyroidism, diabetes (uncomplicated), and obesity.
Patients in the LA CT cohort were younger than those in the LA mono cohort (mean age, 29.0 vs 31.0 years, respectively), and that cohort had a higher proportion of males than the LA mono cohort (51.0% vs 49.1%, respectively; both P <.001) (Table 1). Compared with the LA mono cohort, patients in the LA CT cohort had a lower baseline comorbidity burden (DCCI score 0.10 vs 0.12, respectively; P <.001) and higher rates of prior ADHD medication use (68.2% vs 54.5%) and prior ADHD-related psychotherapy (25.1% vs 17.1%; both P <.001).
The PDC was significantly lower among patients in the LA CT cohort (mean [SD] = 0.33 [0.25]) compared with those in the LA mono cohort (mean [SD] = 0.41 [0.30]; adjusted mean difference, —0.08; P <.001) (Table 2). In addition, patients in the LA CT cohort were less likely to be adherent to the index combination compared with those in the LA mono cohort (6.5% vs 16.2%, respectively; adjusted OR, 0.38; P <.001).
Persistence and Treatment Switch
In the unadjusted analysis, the median time to treatment discontinuation was 59 days for the LA CT cohort and 79 days for the LA mono cohort (log-rank P <.001) (Figure 2). The LA CT cohort had a significantly higher risk of treatment discontinuation than the LA mono cohort (adjusted hazard ratio [HR], 1.32 [95% CI, 1.30-1.33] over the entire study period; 1.49 [95% CI, 1.47-1.54] over the period from 2 months after the index date to the end of study period). However, patients in the LA CT cohort were less likely to switch to a new ADHD treatment compared with patients in the LA mono cohort (adjusted HR, 0.77 [95% CI, 0.74-0.81]) (Figure 3), although the risk of switching was similar between the 2 cohorts from 2 months after the index date to the end of study period. At the end of the study period, a higher proportion of patients in the LA CT cohort had discontinued the index treatment(s) compared with the LA mono cohort (12-month rate, 93.1% vs 83.1%, respectively), while a lower proportion switched treatments (12-month rate,12.7% vs 19.6%, respectively).
This real-world study found that approximately 7% of US adults with ADHD who received LA medications used combination therapy with another LA or SA agent. Patients using LA combination therapy had significantly lower rates of treatment adherence and persistence compared with those using LA monotherapy. Moreover, a relatively small proportion of patients on combination therapy switched to a new treatment, in contrast with the high proportion that discontinued treatment.
Previous research has primarily focused on comparing the treatment patterns of adults with ADHD by the class of LA medications, instead of comparison between combination therapy and monotherapy. The patients in the current study who were receiving combination therapy were younger and had higher rates of use of prior ADHD-related medications and psychotherapies compared with patients receiving monotherapy. Few studies have compared the characteristics of these patient populations, although Clemow et al28 similarly noted that adult patients with ADHD receiving combination ATX therapy had higher rates of prior use of ADHD medications compared with those receiving monotherapy (76% vs 28%, respectively). However, that study, unlike the present study, reported that the patients receiving monotherapy were younger than those who received combination therapy (mean age, 32 vs 36 years, respectively). Patients receiving LA combination therapy may represent a group with greater unmet needs. Improvements in our understanding of the treatment patterns in this specific group may help improve the overall treatment and outcomes in adult patients with ADHD. The proportion of patients using LA combination therapy identified in the current study (7%) is consistent with the literature. A previous claims-based analysis conducted by Hodgkins et al in 2012 reported an augmentation rate of 8.3% over 6 months among adults with ADHD.23 In addition, the adherence and persistence results from our study are comparable with those of other studies using similar outcome definitions. In 3 studies by Setyawan et al, the reported mean PDC for LA monotherapy ranged from 0.30 to 0.49, which was similar to our estimates of 0.33 for LA combination therapy and 0.41 for LA monotherapy.29-31 Similarly, Setyawan et al reported 1-year discontinuation rates of 76% to 91% in those 3 studies, comparable with the current results (93% for LA combination therapy and 83% for LA monotherapy). Other claims-based studies used different definitions for adherence and persistence, which makes it difficult to compare them with the current study.23,32-35 For example, Hodgkins et al and Christensen et al defined persistence as the number of days that the patient remained on treatment until the date of the last filled prescription during a 1-year study period.23,32,35 Treatment adherence was measured during time on treatment. Those definitions may have led to higher observed rates of treatment persistence and adherence.
An abundance of literature has discussed the issues of nonadherence and nonpersistence among patients with chronic psychiatric conditions. Certain ADHD symptoms, such as disorganization and difficulties with planning, may contribute to the poor treatment adherence and/or persistence rates.36 According to a 2014 systematic literature review, treatment ineffectiveness/suboptimal response and dosing inconvenience are the 2 most commonly reported reasons for discontinuation in ADHD studies of adults.21 In addition, the AEs of stimulant medications, which are dose dependent, may contribute to poor rates of adherence, especially in patients using combination therapy. Common AEs related to stimulants include insomnia, anorexia, headache, abdominal pain, nausea, decreased appetite, increases in heart rate and blood pressure, and changes in mood.16 Moreover, patients receiving LA combination therapy are likely to be nonresponders to their regimen,37 resulting in a higher rate of nonadherence compared with patients receiving LA monotherapy.
Although previous studies' results have demonstrated that, among patients with ADHD, use of LA medications is associated with higher treatment adherence compared with use of SA medications,32,33 the rates of treatment adherence and persistence with LA medications observed in the present study may be suboptimal. Additionally, although it is difficult to know how long patients should persist on combination therapy, this regimen is attempted for certain adult patients, and these patients were observed to have shorter persistence (by approximately 2 months) compared with patients who received LA monotherapy. Reasons for poorer persistence among adultsreceiving LA combination therapy may include inadequate symptomatic coverage, a need for temporary relief, or factors associated with pill burden (ie, requiring multiple daily doses or medications). Current LA medications provide a maximum of only 12 to 14 hours of coverage. Thus, patients in need of longer durations of coverage are required to augment their therapy. A single medication providing more than 12 to 14 hours of coverage may benefit these patients by improving their treatment adherence and persistence on monotherapy.
This study was subject to the common limitations inherent to retrospective observational studies using claims data. First, the treatment patterns defined in this study may not be completely accurate. For example, combination therapy was identified using prespecified algorithms in claims databases, which may not reflect physicians’ prescribed dosing regimens for how patients should take their medication. Although using a 30-day overlap to define combination therapy is consistent with the literature,38 it may misclassify some “switchers” as “combination therapy patients.” Second, adherence was measured based on days of supply information in claims, assuming patients take the medication as long as it is supplied. This may not reflect the actual drug-taking behavior of patients. Third, reasons underlying treatment patterns, including the use of combination therapy and treatment nonadherence, nonpersistence, and switching, were not available in the claims databases. Moreover, as the analysis was not stratified by specific medications, it is unknown whether poor adherence or persistence were more pronounced within any particular class of ADHD medication. Fourth, the current study estimated ADHD medication use among the commercially insured adult population in the United States. The present results apply to commercially insured US adults diagnosed with ADHD and who had ADHD medication usage. They may not be generalizable to the general US adult population with ADHD, such as those without commercial insurance coverage.
This study found that some adults with ADHD who received LA treatment used the medication in combination with another ADHD medication. Both adherence (6.5% [CT] vs 16.2% [mono]) and persistence (12-month discontinuation rate, 93.1% [CT] vs 83.1% [mono]) were observed to be low among LA medication patients overall, and patients who used LA combination therapy were less likely to be adherent and persistent on their ADHD therapy compared with patients receiving LA monotherapy. The findings suggest unmet needs among adults with ADHD who use LA medications, particularly those who use LA combination therapy. Although the reasons for nonadherence and nonpersistence cannot be assessed using the current data, some patients receive LA combination therapy due to the need for longer coverage of symptoms. Thus, a single medication providing longer duration of coverage may be beneficial due to reduced dosing frequency. Future research is warranted to investigate whether a single medication providing longer duration of coverage may be beneficial due to reduced dosing frequency, as well as to investigate the underlying reasons for poor adherence and persistence in adult LA medication patients.
Editorial assistance was provided by Shelley Batts, PhD, a professional medical writer employed by Analysis Group, Inc.Author Affiliations: Analysis Group, Inc, Boston, MA (ZZ), New York, NY (Z-YZ, SSK), Los Angeles, CA (JX); Shire (VS, RG), Chesterbrook, PA.
Source of Funding: Funding for this research was provided by Shire Human Genetic Therapeutics, Inc. The sponsor was involved in all stages of the study research and manuscript preparation.
Author Disclosures: Ms Zhou, Dr Zhou, Ms Kelkar, and Dr Xie are employees of Analysis Group, Inc, which received consulting fees from Shire related to this work. Dr Sikirica and Dr Grebla were employees of Shire during the conduct of the study and own Shire stock and/or stock options.
Authorship Information: Concept and design (ZZ, Z-YZ, VS, JX, RG); analysis and interpretation of data (ZZ, Z-YZ, SSK); drafting of the manuscript (ZZ, SSK); critical revision of the manuscript for important intellectual content (ZZ, SSK, VS, JX, RG); statistical analysis (SSK); obtaining funding (VS, RG); and supervision (JX).
Address Correspondence to: Zhou Zhou, MS, Analysis Group, Inc, 111 Huntington Ave, Fl 14, Boston, MA 02199. Email: email@example.com.REFERENCES
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