CanJPsychiatry 2014;59(11):597–608
Original Research
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With Attention-Deficit Hyperactivity Disorder in Quebec Jean Lachaine, PhD1; Gourab De, PhD2; Vanja Sikirica, PharmD, MPH3; Judy van Stralen, MD, FRCPC4; Paul Hodgkins, PhD, MSc5; Hongbo Yang, PhD2; Julie Heroux, MSc6; Leila Ben Amor, MD, MSc7 1
Professor, Faculty of Pharmacy, University of Montreal, Montreal, Quebec. Correspondence: Faculty of Pharmacy, University of Montreal, 2900 Edouard Montpetit Boulevard Montreal, QC H3T 1J4; [email protected].
2
Manager, Analysis Group Inc, Boston, Massachusetts.
3
Senior Director, Head of Global Outcomes Research, Shire, Wayne, Pennsylvania.
4
Consulting Pediatrician, Centre for Pediatric Excellence, Ottawa, Ontario.
5
Senior Director, Global Health Economics and Outcomes Research, Shire, Wayne, Pennsylvania.
6
Health Economist, Analysis Group Inc, Boston, Massachusetts.
7
Associate Professor, Department of Psychiatry, University of Montreal, Montreal, Quebec; Head, Department of Psychiatry, Sainte-Justine Research Centre, Montreal, Quebec.
Key Words: attention-deficit hyperactivity disorder, atypical antipsychotic, discontinuation, augmentation, switching, treatment patterns, costs Received February 2014, revised, and accepted June 2014.
Objective: To assess treatment patterns, health care resource utilization (HRU), and costs among previously stimulant-treated children and adolescents with attention-deficit hyperactivity disorder (ADHD) receiving atypical antipsychotic (AAP) prescriptions in Quebec. Methods: Health care claims data extracted from Quebec’s provincial health plan database between March 2007 and February 2012 were analyzed. Children and adolescents (6 to 17 years) with ADHD who were taking a stimulant and either switched to, or augmented with, an AAP (with the first AAP defined as the index AAP) without a documented diagnosis for which AAPs are Health Canada–approved were included. Discontinuation, augmentation, and switching of the index AAP during the 12-month, follow-up period were estimated using Kaplan–Meier survival analysis. HRU and costs for the 6 months before (baseline period) and after initiation of the index AAP were compared. Results: A total of 453 children and adolescents with ADHD, mostly male (74.6%) and aged 6 to 12 years (73.7%), met the inclusion criteria. The 12-month discontinuation, augmentation, and switching rates were 45.5%, 68.2%, and 80.7%, respectively. Patients had, on average, more all-cause prescription fills (22.2, compared with 13.3) and incurred more all-cause pharmacy ($889, compared with $710), total medical ($1096, compared with $644), and total health care ($1985, compared with $1354) costs during the 6-month study period than during the 6-month baseline period (all P < 0.05). Similarly, ADHD-related total health care costs were higher during the study period ($1269, compared with $835; P < 0.05); all-cause and ADHD-related total health care costs increased by 46.6% and 52.0%, respectively. Conclusion: Use of an AAP among stimulant-treated children and adolescents with ADHD in Quebec was associated with high rates of therapy changes and increased HRU and costs. WWW
Modèles de traitement, utilisation des ressources, et résultats économiques associés aux prescriptions d’antipsychotiques atypiques aux enfants et adolescents souffrant du trouble de déficit d’attention avec hyperactivité au Québec Objectif : Évaluer les modèles de traitement, l’utilisation des ressources de santé (URS), et les coûts chez les enfants et les adolescents souffrant du trouble de déficit d’attention avec hyperactivité (TDAH) précédemment traités par stimulants et recevant maintenant des prescriptions d’antipsychotiques atypiques (APA) au Québec. www.TheCJP.ca
The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 597
Original Research
Méthodes : Des données des fiches soins extraites de la base de données du régime d’assurance-maladie provincial québécois entre mars 2007 et février 2012 ont été analysées. Ont été inclus les enfants et les adolescents (de 6 à 17 ans) souffrant de TDAH qui prenaient un stimulant et qui ont soit changé pour un APA, soit augmenté leur médication avec un APA (le premier APA étant défini comme l’APA index) sans un diagnostic documenté qu’exige Santé Canada pour approuver les APA. L’interruption, l’augmentation, et le changement de l’APA index durant la période de suivi de 12 mois ont été estimés à l’aide de l’analyse de survie de Kaplan-Meier. L’URS et les coûts ont été comparés pour les 6 mois avant (période de départ) et après l’initiation de l’APA index. Résultats : Un total de 453 enfants et adolescents souffrant de TDAH, la plupart de sexe masculin (74,6 %) et âgés de 6 à 12 ans (73,7 %) satisfaisaient aux critères d’inclusion. Les taux d’interruption, d’augmentation, et de changement sur 12 mois étaient de 45,5 %, 68,2 %, et 80,7 %, respectivement. Les patients avaient, en moyenne, plus d’ordonnances remplies (22,2 comparé à 13,3) toutes causes confondues, plus de dépenses de pharmacies (889 $ comparé à 710 $) toutes causes confondues, et plus de coûts totaux des soins de santé (1985 $ comparé à 1354 $) durant la période de 6 mois de l’étude que durant la période de 6 mois de départ (tous les P < 0,05). De même, le total des coûts de santé liés au TDAH était plus élevé durant la période de l’étude (1269 $ comparé à 835 $; P < 0,05); le total des coûts de santé toutes causes confondues et le total des coûts de santé liés au TDAH ont augmenté de 46,6 % et de 52,2 %, respectivement. Conclusion : L’utilisation des APA chez les enfants et les adolescents souffrant de TDAH traités par stimulants au Québec était associée à des taux plus élevés de changements de thérapie ainsi qu’à une URS et des coûts accrus.
A
ttention-deficit hyperactivity disorder is a common psychiatric disorder in children, affecting 2.6% of children in Canada.1 Children and adolescents with ADHD are often diagnosed with psychiatric comorbidities, such as conduct disorders (30% to 50%), mood disorders (15% to 75%), and anxiety disorders (about 25%).2,3
Treatment for ADHD is often multi-modal, including both behavioural and pharmacologic options. Stimulants, such as amphetamines and methylphenidate, are recommended by the CADDRA guidelines and other guidelines as first-line pharmacotherapy with or without behavioural interventions for children (aged 6 years and older), adolescents, and adults.4,5 The estimated number needed to treat (that is, number of patients that need to be treated to achieve the desired outcome for 1 patient) has been reported as about 2 for lisdexamfetamine dimesylate and 3 for methylphenidate.6,7 Patients who are unresponsive
or intolerant to their initial stimulant monotherapy may require an adjunctive or alternative drug therapy.8 Two nonstimulants are currently approved by Health Canada for the treatment of ADHD: ATX (Strattera, Eli Lilly, Indianapolis, IN), a selective norepinephrine reuptake inhibitor approved for monotherapy for children (aged 6 to 12 years), adolescents (aged 13 to 17 years), and adults, and guanfacine extended release (Intuniv, Shire, Wayne, PA), a selective alpha-2A adrenergic receptor agonist approved for monotherapy for children and as adjunctive therapy to stimulants for the subgroup of children with a suboptimal response to stimulants. In addition, certain psychotropic and nonpsychotropic medications are often prescribed off label for the treatment of ADHD, including clonidine immediate release and AAPs. Among off-label drugs, AAPs have received special attention. ADHD is among the top diagnoses associated with
Abbreviations
Clinical Implications
AAP
atypical antipsychotic
•
ADHD
attention-deficit hyperactivity disorder
In clinical practice, the HRU or cost consequences of treatment decisions are often poorly understood.
ATX
atomoxetine HCl
•
High rates of therapy changes, increased HRU, and costs were observed in stimulant-treated children and adolescents with ADHD using AAPs in Quebec.
•
This indicates a need for informed decision making and further research on alternative treatment options when stimulant monotherapy is insufficient.
CADDRA Canadian ADHD Resource Alliance ED
emergency department
HRU
health care resource utilization
ICD
International Classification of Diseases
KM
Kaplan–Meier
LA
long acting
RAMQ
Régie de l’assurance maladie du Québec
SA
short acting
SD
standard deviation
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Limitations •
Common limitations inherent to retrospective claims analysis may apply (for example, lack of clinical information on patients and treatments).
•
Limitations specific to use of the RAMQ database also apply to our study, as described within the article.
www.LaRCP.ca
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With ADHD in Quebec
AAP prescriptions, which increased 5-fold from 1999 to 2008.9 Risperidone is one of the most frequently prescribed AAPs in this population.10–12 In 2004, an international expert panel for child and adolescent psychiatry recommended augmenting stimulants with risperidone as a second-line treatment for children and adolescents who had persistent and marked aggression or impulsivity and were diagnosed with ADHD and disruptive behaviour disorders.12 However, published evidence supporting the efficacy and safety of AAPs for treating ADHD is currently limited.13,14 Clinical trials of AAPs have been conducted on specific ADHD subpopulations, including patients with comorbidities, such as bipolar disorder or mental retardation,11,15 or on specific symptoms, such as treatment-resistant aggression.10 The effectiveness of AAPs in controlling core ADHD symptoms was variable in these trials. Serious side effects associated with AAP use, such as extrapyramidal symptoms, tardive dyskinesia, metabolic syndrome including hyperprolactinemia, type-2 diabetes, and weight gain, are of concern.14,16–22 A recent study in the province of Quebec found that the 1-year period prevalence of combination therapy and switching among 9431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were AAPs (10.8%), atomoxetine (5.5%), and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAPs (5.5%), and ATX (4.7%).23 However, to our knowledge, costs associated with AAP use among children and adolescents with ADHD in Canada have not been assessed. Given the high prevalence of AAP use in this population, it is important to understand the treatment patterns, HRU, and economic impact associated with AAP use. Such information can help clarify the economic impact of initiating AAPs in children and adolescents with ADHD. In our retrospective observational study, we evaluated the treatment patterns, HRU, and health care costs after initiation of AAPs among children and adolescents with ADHD in Quebec who received AAPs either as an augmenting drug or as an alternative therapy to stimulants.
Methods Data and Patient Selection
A retrospective analysis of health care claims data from Quebec’s provincial health plan database, the RAMQ, was conducted. The RAMQ database contains information on medical services for the entire Quebec population (more than 7.5 million people covered annually) and prescription drug claims from the RAMQ prescription drug plan (about 3.3 million people). Enrollees in the drug plan include recipients of last-resort financial assistance, people who are not eligible for a private insurance plan and their dependents, and people who are 65 years or older. For the purpose of our study, medical and prescription drug claims data for children and adolescents with ADHD who had at least 1 prescription for a stimulant between March 1, www.TheCJP.ca
2007, and February 29, 2012, were extracted. Patients were required to have their first prescription fill of their first AAP (see list of AAPs in online eAppendix A), defined as the index AAP, after a stimulant fill, and had to have augmented with or switched (as defined below) to the index AAP from a stimulant (defined as the index stimulant). The date on which the index AAP prescription was filled was defined as the index date, with the 6 months preceding the index date and the 12 months following the index date, defined as the baseline period and the follow-up period, respectively. Patients were also required to have at least 1 documented ADHD diagnosis (ICD-9 codes: 314.0 to 314.9) during the baseline or follow-up periods, continuous enrolment in both medical and prescription drug plans throughout these 2 periods, and at least 30 days’ supply of a stimulant before the index date. To protect patient confidentiality, patients’ ages were reported in groups of 2- to 3-year intervals. Based on these age groups, patients were required to be between 6 and 17 years of age as of January 1st of the year of the index date. Finally, patients who had a documented psychiatric diagnosis for which AAPs are indicated (according to the approved product labels by Health Canada summarized in online eAppendix B) during the baseline or follow-up periods were excluded from this study.
Study Measures
The following outcomes were measured in our study: treatment patterns after AAP initiation, including discontinuation, augmentation, and switching; HRU; and health care costs. Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill, and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest. The discontinuation date was defined as the last day of supply of the index AAP before the gap. Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period.24 Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply of less than 30 days with the index AAP or a gap of less than 30 days between the end of supply of the index AAP and the initiation of the new treatment. Stimulants, ATX, clonidine, or other AAPs (online eAppendix A) were considered psychotropics that could be used for augmentation or switching. Assessment of HRU included medical services and prescription drugs. Medical services included inpatient admissions, inpatient days, ED visits, outpatient visits (all outpatient and office visits, excluding psychiatric department visits), psychiatric department visits, and other medical services (for example, visits to local community service centres, chronic pain centres, foster care establishments, or laboratories). Because the number of inpatient admissions The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 599
Original Research
Figure 1 Flow chart of patient selection Patients with >18 months of continuous eligibility: N = 13 850 Patients with >1 AAP prescription fill and >1 stimulant prescription fill: n = 1894 Patients with >1 AAP prescription fill, >1 stimulant prescription fill, and >30 days of supply of a stimulant during the 6-month period prior to an AAP prescription fill: n = 1737 Patients with a documented diagnosis of ADHD, without any documented psychiatric diagnosis for which AAPs are indicated, and continuously enrolled in both medical and drug plans during the 6-month period prior to and the 12-month period after an AAP prescription fill: n = 1255 Patients 6 andfill,17>1 years old asprescription of January 1st of the year of of ansupply AAP of a Patients with > aged 1 AAPbetween prescription stimulant fill and >30 days prescription stimulant fill, and who augmented with period or switched to an theAAP first prescription AAP drug (index during the 6-month prior to fill: AAP) used: n = 453 Augmenters with an AAP:
Switchers to an AAP:
n = 206
n = 247
and lengths of stay were not directly available in the data, the number of inpatient admissions and inpatient days were estimated from the RAMQ medical claims using a published algorithm developed and validated to replicate hospitalization episodes, which first identifies all claims for services delivered in hospitals (from variables describing the date and the location of the billed service) and then identifies hospitalizations from the temporal sequence of the inpatient claims.25 The medical services and prescription claims were further categorized into all-cause, ADHD-related (services associated with an ADHD diagnosis or pharmacy claims for medications that could be used for ADHD, listed in online eAppendix A) and mental health-related HRU (services associated with a diagnosis of mental health disorder or pharmacy claims for mental health-related medications within the therapeutic classes listed in online eAppendix C). ADHD and mental HRU were not mutually exclusive. ADHD diagnoses (ICD-9 codes: 314.0 to 314.9) were a subgroup of mental health-related diagnoses (ICD-9: 290 to 319), and ADHD medications were a subgroup of mental health-related medications. Medical service costs included costs charged by physicians to the RAMQ for inpatient, ED, outpatient, psychiatric, and other medical services. In addition, as the RAMQ database Services médicaux rémunérés à l’acte only includes information on physician costs, hospitalization costs for inpatient admissions and ED visits were imputed based on average costs charged for an inpatient day and an ED day using data provided by the Ministère de la Santé et des Services Sociaux of Quebec (that is, Quebec’s Ministry of Health and Social Services). Prescription drug costs reported were amounts charged by pharmacists to the 600 W La Revue canadienne de psychiatrie, vol 59, no 11, novembre 2014
RAMQ. Total health care costs were defined as the sum of medical service costs and prescription drug costs. Each type of health care cost was further categorized into all-cause, ADHD-related, and mental health-related costs. Similar to resource use, ADHD-related costs were a component of mental health-related costs. Costs were calculated from the Quebec public payer’s perspective. All costs were inflated to 2012 Canadian dollars using the Quebec consumer price index for health and personal care, published by Statistics Canada.
Statistical Analysis
Mean, median, and SD were reported for continuous variables. Frequency and percentage were reported for categorical variables. Patients’ demographics (for example, age, sex, index year, and enrolment type), treatment (for example, class of index stimulant and number of stimulants used during baseline), comorbidities, and other baseline characteristics (for example, physician specialty) were summarized using descriptive statistics. Time from the index date to AAP treatment discontinuation, augmentation, or switching during the 12-month follow-up period were estimated using KM survival analyses. Patients were censored at discontinuation of the index AAP when analyzing treatment switching, and at discontinuation or switching when evaluating treatment augmentation. A pre–post design was used to evaluate the HRU and health care costs associated with initiation of the index AAP. To ensure comparable duration of time between the pre and post periods, the proportion of patients with at least 1 visit or at least 1 drug prescription was compared between the 6-month baseline period and the 6-month study period www.LaRCP.ca
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With ADHD in Quebec
(defined as the first 6 months of the 12-month follow-up period) using McNemar’s tests. HRU and health care costs were summarized for the 6-month baseline period, the 6-month study period, and the entire 12-month follow-up period. The mean HRU and costs were compared between the 6-month baseline period and the 6-month study period using Wilcoxon signed-rank tests. For comparison purposes, statistical significance was evaluated at the 0.05 significance level (2-sided).
Sensitivity Analysis
Several sensitivity analyses were undertaken to evaluate the robustness of the study findings. An alternative definition for treatment discontinuation, which required a gap of at least 60 consecutive days between the end of a prescription supply and the beginning of the next fill of the index AAP, was used. Additionally, switching was alternatively defined as an overlap in days of supply of the index AAP and the new drug of less than 30 consecutive days, or a gap of less than 60 days.
Results
Table 1 Patient demographics and baseline characteristics Baseline characteristics Demographics Age, years, mean (SD) [median]
As shown in Table 1, the mean age of patients was 10.4 (SD 2.5) years, with the majority (73.7%) of them being children (that is, aged 6 to 12 years) and male (74.6%). The index stimulants used by these patients were LA methylphenidate (50.3%), LA amphetamines (25.4%), SA methylphenidate (22.3%), and SA amphetamines (2.0%) (online eTable 2). The index AAPs were predominantly risperidone (81.7%), followed by quetiapine (16.3%) (online eTable 3). About 33.5% of patients had at least 1 documented comorbidity during the 6-month baseline period. The most frequently documented psychiatric or neurologic comorbidities were adjustment reaction (7.1%), anxiety disorder (5.1%), and learning disability (4.4%). Index AAPs were most commonly prescribed by psychiatrists (41.1%) (Table 1).
Treatment Patterns
Pharmacologic therapy regimen changes occurred in 92.1% of patients during the 12-month, follow-up period. The KM survival curves of treatment discontinuation, augmentation, switching (not mutually exclusive), or any one of these www.TheCJP.ca
10.42 (2.5) [10.0]
Children (≤12 years)
334 (73.7)
Adolescents (>12 years)
119 (26.3)
Female
115 (25.4)
Enrolment type Employment assistance recipient
173 (38.22)
Subscriber
280 (61.78)
Class and formulation of index stimulant Amphetamines, short acting
9 (2.0)
Amphetamines, long acting
115 (25.4)
Methylphenidate, short acting
101 (22.3)
Methylphenidate, long acting Number of distinct stimulants, mean (SD) [median]
228 (50.3) 1.39 (0.5) [1.0]
Comorbidity profile Mental comorbidities
Baseline Characteristics
A total of 13 850 children and adolescents with ADHD who received stimulant prescriptions during the 5-year period from March 2007 to February 2012 were identified in the RAMQ database. Among these 13 850 patients, 1894 (13.7%) filled an AAP prescription. After applying additional inclusion criteria, 453 children and adolescents with ADHD aged 6 to 17 years were identified as having initiated their first AAP, either as an augmenting drug or as alternative therapy to a stimulant. Among these patients, 206 (45.5%) augmented a stimulant with an AAP and 247 (54.5%) switched from a stimulant to an AAP. The sample selection flow chart is shown in Figure 1.
Patients, n = 453 n (%)
Adjustment reaction
32 (7.1)
Anxiety disorder
23 (5.1)
Learning disability
20 (4.4)
Physical comorbidities Accidents and injuries
43 (9.5)
Asthma
11 (2.4)
Number of comorbidities Patients with 1 comorbidity
117 (25.8)
Patients with 2 comorbidities
26 (5.7)
Patients with ≥3 comorbidities
9 (2.0)
Physician specialtya Physician prescribing the index AAP Psychiatry
186 (41.1)
Pediatrics
162 (35.8)
Neurology
30 (6.6)
Missing
74 (16.3)
Physician prescribing ≥1 stimulant Pediatrics
236 (52.1)
Psychiatry
128 (28.3)
Neurology Missing
28 (6.2) 143 (31.6)
Physician providing ≥1 ADHD diagnosisb
a
Pediatrics
144 (31.8)
Psychiatry
125 (27.6)
Neurology
21 (4.6)
Missing
63 (13.9)
Only the most common physician specialties are reported.
Numbers are not mutually exclusive as patients could have been seen by >1 specialist during the baseline period. AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder b
The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 601
Original Research
Figure 2 Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: a) treatment discontinuationa; b) treatment augmentationb a. 3-month rate: (95% CI) 24.7 (21.0–29.0)
6-month rate: (95% CI) 35.5 (31.3–40.1)
12-month rate: (95% CI) 45.5 (41.0–50.2)
90 80 70 60 50 40 30 20 10 0 0
30
60
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120
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330
Number of patients, n 453
Augmentation 100 Proportion of patients with a treatment augmentation, %
Proportion of patients with a treatment discontinuation, %
Discontinuation 100
360
90 80 70 60 50 40 30 20 10 0 0
30
Time from index date, days
b.
month rate: (95% CI) 7 (58.0–67.4)
330
c. Augmentation Switch 100 100
360
Number of patients with a 1-month rate: treatment augmentation, Number of Number 3-month rate: 6-month rate: 12-month rate: of patients with a (95%rate: CI) n (%) patients, (95%rate: CI) (95%rate: CI) 1-month (95% rate: CI) treatment switch, Number of n 3-month 6-month 12-month 14.6 (11.5–18.5) 191 (42.2) 453 n 51.3 (45.6–57.3) 65.4 (59.2–71.5) (95% CI) 68.2 (61.9–74.3) n (%) patients, (95% CI) (95% CI) (95% CI) 15.9 (12.8–19.6) 42.9 (38.4–47.8) 321 (70.9) 453 62.7 (58.0–67.4) 80.7 (76.5–84.6)
80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 30 30
d.
Number of Health Care Resource Utilization patients, n
12-month rate: (95% CI) 80.7 (76.5–84.6)
60 60
90 90
120 150 180 210 240 120 150 180 210 240 Time from index date, days Time from index date, days
Number of patients with a treatment change, n (%) 417 (92.1)
453
30 Consistent with all-cause outpatient visits, a higher proportion of patients with at least 1 mental health-related 20
602 W La Revue canadienne de psychiatrie, vol 59, no 11, novembre 2014 10 0
270 270
300 300
330 330
90 80 70 60 50 40 30 20 10 0
360 360
0
3-month in rate:the 6-month rate: 12-month rate: changes index AAP treatment are presented in Figure (95% CI) (95% CI) (95% CI) 75.7 (71.7–79.6) 87.6 (84.4–90.5) 92.1 (89.3–94.3) 2. The 12-month KM rates of treatment discontinuation, treatment augmentation, and treatment switching were 45.5%, 68.2%, and 80.7%, respectively. For most patients with pharmacologic therapy regimen changes, the changes occurred in the first 6 months after the index AAP was initiated (6-month KM rate of 87.6%).
1-month rate: (95% CI) 38.0 (33.7–42.6)
A significantly higher proportion of patients had at least 1 100 all-cause outpatient visit in the 6-month study period after 90 initiating the index AAP, compared with baseline (92.3%, 80 compared with 87.4%, P = 0.01) (Table 4). There were no significant differences (P > 700.05) in the proportion of patients with at least 1 psychiatric department visit, the 60 proportion of patients with at least 1 inpatient admission, and the proportion of patients50with at least 1 ED visit between the baseline and study periods. 40 Treatment change
Number of patients, n 453
Treatment change
100
90 90
0 0 0 0
d.
Proportion of patients with a treatment change, %
Proportion of patients with a treatment switch, % Proportion of patients with a treatment augmentation, %
300
12-month rate: (95% CI) 45.5 (41.0–50.2)
Proportion of patients with a treatment change, %
month rate: (95% CI) 5 (31.3–40.1)
270
b. Number of patients with a Number of treatment discontinuation, 1-month rate: (95% CI) n (%) patients, n 14.4 (11.4–17.9) 206 (45.5) 453
Results of the sensitivity analyses that used alternative definitions of discontinuation and switching were similar, with the 12-month KM rates of treatment discontinuation, augmentation, and switching estimated at 35.1%, 67.0%, and 78.0%, respectively (online eFigure 3). www.LaRCP.ca
30
Nu tr
0
30
60
90
120
150
180
210
240
270
300
330
360
10 0 0
30
Time from index date, days
Figure 2 Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: c) treatment switchingc; d) any therapy regimen change b.
330
Augmentation Switch 100 100 90 90
360
12-month rate: (95% CI) 80.7 (76.5–84.6)
Number of patients with a treatment augmentation, Number of Number 3-month rate: of patients with a 1-month rate: (95% rate: CI) n (%) patients,ofn (95% rate: CI) 1-month treatment switch, Number 3-month 14.6 (11.5–18.5) 191 (42.2) 453 n 51.3 (45.6–57.3) (95% CI) n (%) patients, (95% CI) 15.9 (12.8–19.6) 42.9 (38.4–47.8) 321 (70.9) 453
c.
6-month rate: 12-month rate: (95% CI) (95% CI) 6-month rate: 12-month rate: 65.4 (59.2–71.5) 68.2 (61.9–74.3) (95% CI) (95% CI) 62.7 (58.0–67.4) 80.7 (76.5–84.6)
d. 100
80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 0
d.
30 30
Number of patients, n 453
Treatment change
60 60
90 90
120 150 180 210 240 120 150 180 210 240 Time from index date, days Time from index date, days
Number of patients with a treatment change, n (%) 417 (92.1)
1-month rate: (95% CI) 38.0 (33.7–42.6)
3-month rate: (95% CI) 75.7 (71.7–79.6)
270 270
300 300
6-month rate: (95% CI) 87.6 (84.4–90.5)
330 330
360 360
12-month rate: (95% CI) 92.1 (89.3–94.3)
Proportion of patients with a treatment change, %
100 90 80 70 60 50 40 30 20 10 0 300
330
360
0
30
60
90
120
150
180
210
240
270
300
330
360
Time from index date, days
AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder a Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest. b Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period. c Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply
Original Research
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With Attention-Deficit Hyperactivity Disorder in Quebec Jean Lachaine, PhD1; Gourab De, PhD2; Vanja Sikirica, PharmD, MPH3; Judy van Stralen, MD, FRCPC4; Paul Hodgkins, PhD, MSc5; Hongbo Yang, PhD2; Julie Heroux, MSc6; Leila Ben Amor, MD, MSc7 1
Professor, Faculty of Pharmacy, University of Montreal, Montreal, Quebec. Correspondence: Faculty of Pharmacy, University of Montreal, 2900 Edouard Montpetit Boulevard Montreal, QC H3T 1J4; [email protected].
2
Manager, Analysis Group Inc, Boston, Massachusetts.
3
Senior Director, Head of Global Outcomes Research, Shire, Wayne, Pennsylvania.
4
Consulting Pediatrician, Centre for Pediatric Excellence, Ottawa, Ontario.
5
Senior Director, Global Health Economics and Outcomes Research, Shire, Wayne, Pennsylvania.
6
Health Economist, Analysis Group Inc, Boston, Massachusetts.
7
Associate Professor, Department of Psychiatry, University of Montreal, Montreal, Quebec; Head, Department of Psychiatry, Sainte-Justine Research Centre, Montreal, Quebec.
Key Words: attention-deficit hyperactivity disorder, atypical antipsychotic, discontinuation, augmentation, switching, treatment patterns, costs Received February 2014, revised, and accepted June 2014.
Objective: To assess treatment patterns, health care resource utilization (HRU), and costs among previously stimulant-treated children and adolescents with attention-deficit hyperactivity disorder (ADHD) receiving atypical antipsychotic (AAP) prescriptions in Quebec. Methods: Health care claims data extracted from Quebec’s provincial health plan database between March 2007 and February 2012 were analyzed. Children and adolescents (6 to 17 years) with ADHD who were taking a stimulant and either switched to, or augmented with, an AAP (with the first AAP defined as the index AAP) without a documented diagnosis for which AAPs are Health Canada–approved were included. Discontinuation, augmentation, and switching of the index AAP during the 12-month, follow-up period were estimated using Kaplan–Meier survival analysis. HRU and costs for the 6 months before (baseline period) and after initiation of the index AAP were compared. Results: A total of 453 children and adolescents with ADHD, mostly male (74.6%) and aged 6 to 12 years (73.7%), met the inclusion criteria. The 12-month discontinuation, augmentation, and switching rates were 45.5%, 68.2%, and 80.7%, respectively. Patients had, on average, more all-cause prescription fills (22.2, compared with 13.3) and incurred more all-cause pharmacy ($889, compared with $710), total medical ($1096, compared with $644), and total health care ($1985, compared with $1354) costs during the 6-month study period than during the 6-month baseline period (all P < 0.05). Similarly, ADHD-related total health care costs were higher during the study period ($1269, compared with $835; P < 0.05); all-cause and ADHD-related total health care costs increased by 46.6% and 52.0%, respectively. Conclusion: Use of an AAP among stimulant-treated children and adolescents with ADHD in Quebec was associated with high rates of therapy changes and increased HRU and costs. WWW
Modèles de traitement, utilisation des ressources, et résultats économiques associés aux prescriptions d’antipsychotiques atypiques aux enfants et adolescents souffrant du trouble de déficit d’attention avec hyperactivité au Québec Objectif : Évaluer les modèles de traitement, l’utilisation des ressources de santé (URS), et les coûts chez les enfants et les adolescents souffrant du trouble de déficit d’attention avec hyperactivité (TDAH) précédemment traités par stimulants et recevant maintenant des prescriptions d’antipsychotiques atypiques (APA) au Québec. www.TheCJP.ca
The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 597
Original Research
Méthodes : Des données des fiches soins extraites de la base de données du régime d’assurance-maladie provincial québécois entre mars 2007 et février 2012 ont été analysées. Ont été inclus les enfants et les adolescents (de 6 à 17 ans) souffrant de TDAH qui prenaient un stimulant et qui ont soit changé pour un APA, soit augmenté leur médication avec un APA (le premier APA étant défini comme l’APA index) sans un diagnostic documenté qu’exige Santé Canada pour approuver les APA. L’interruption, l’augmentation, et le changement de l’APA index durant la période de suivi de 12 mois ont été estimés à l’aide de l’analyse de survie de Kaplan-Meier. L’URS et les coûts ont été comparés pour les 6 mois avant (période de départ) et après l’initiation de l’APA index. Résultats : Un total de 453 enfants et adolescents souffrant de TDAH, la plupart de sexe masculin (74,6 %) et âgés de 6 à 12 ans (73,7 %) satisfaisaient aux critères d’inclusion. Les taux d’interruption, d’augmentation, et de changement sur 12 mois étaient de 45,5 %, 68,2 %, et 80,7 %, respectivement. Les patients avaient, en moyenne, plus d’ordonnances remplies (22,2 comparé à 13,3) toutes causes confondues, plus de dépenses de pharmacies (889 $ comparé à 710 $) toutes causes confondues, et plus de coûts totaux des soins de santé (1985 $ comparé à 1354 $) durant la période de 6 mois de l’étude que durant la période de 6 mois de départ (tous les P < 0,05). De même, le total des coûts de santé liés au TDAH était plus élevé durant la période de l’étude (1269 $ comparé à 835 $; P < 0,05); le total des coûts de santé toutes causes confondues et le total des coûts de santé liés au TDAH ont augmenté de 46,6 % et de 52,2 %, respectivement. Conclusion : L’utilisation des APA chez les enfants et les adolescents souffrant de TDAH traités par stimulants au Québec était associée à des taux plus élevés de changements de thérapie ainsi qu’à une URS et des coûts accrus.
A
ttention-deficit hyperactivity disorder is a common psychiatric disorder in children, affecting 2.6% of children in Canada.1 Children and adolescents with ADHD are often diagnosed with psychiatric comorbidities, such as conduct disorders (30% to 50%), mood disorders (15% to 75%), and anxiety disorders (about 25%).2,3
Treatment for ADHD is often multi-modal, including both behavioural and pharmacologic options. Stimulants, such as amphetamines and methylphenidate, are recommended by the CADDRA guidelines and other guidelines as first-line pharmacotherapy with or without behavioural interventions for children (aged 6 years and older), adolescents, and adults.4,5 The estimated number needed to treat (that is, number of patients that need to be treated to achieve the desired outcome for 1 patient) has been reported as about 2 for lisdexamfetamine dimesylate and 3 for methylphenidate.6,7 Patients who are unresponsive
or intolerant to their initial stimulant monotherapy may require an adjunctive or alternative drug therapy.8 Two nonstimulants are currently approved by Health Canada for the treatment of ADHD: ATX (Strattera, Eli Lilly, Indianapolis, IN), a selective norepinephrine reuptake inhibitor approved for monotherapy for children (aged 6 to 12 years), adolescents (aged 13 to 17 years), and adults, and guanfacine extended release (Intuniv, Shire, Wayne, PA), a selective alpha-2A adrenergic receptor agonist approved for monotherapy for children and as adjunctive therapy to stimulants for the subgroup of children with a suboptimal response to stimulants. In addition, certain psychotropic and nonpsychotropic medications are often prescribed off label for the treatment of ADHD, including clonidine immediate release and AAPs. Among off-label drugs, AAPs have received special attention. ADHD is among the top diagnoses associated with
Abbreviations
Clinical Implications
AAP
atypical antipsychotic
•
ADHD
attention-deficit hyperactivity disorder
In clinical practice, the HRU or cost consequences of treatment decisions are often poorly understood.
ATX
atomoxetine HCl
•
High rates of therapy changes, increased HRU, and costs were observed in stimulant-treated children and adolescents with ADHD using AAPs in Quebec.
•
This indicates a need for informed decision making and further research on alternative treatment options when stimulant monotherapy is insufficient.
CADDRA Canadian ADHD Resource Alliance ED
emergency department
HRU
health care resource utilization
ICD
International Classification of Diseases
KM
Kaplan–Meier
LA
long acting
RAMQ
Régie de l’assurance maladie du Québec
SA
short acting
SD
standard deviation
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Limitations •
Common limitations inherent to retrospective claims analysis may apply (for example, lack of clinical information on patients and treatments).
•
Limitations specific to use of the RAMQ database also apply to our study, as described within the article.
www.LaRCP.ca
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With ADHD in Quebec
AAP prescriptions, which increased 5-fold from 1999 to 2008.9 Risperidone is one of the most frequently prescribed AAPs in this population.10–12 In 2004, an international expert panel for child and adolescent psychiatry recommended augmenting stimulants with risperidone as a second-line treatment for children and adolescents who had persistent and marked aggression or impulsivity and were diagnosed with ADHD and disruptive behaviour disorders.12 However, published evidence supporting the efficacy and safety of AAPs for treating ADHD is currently limited.13,14 Clinical trials of AAPs have been conducted on specific ADHD subpopulations, including patients with comorbidities, such as bipolar disorder or mental retardation,11,15 or on specific symptoms, such as treatment-resistant aggression.10 The effectiveness of AAPs in controlling core ADHD symptoms was variable in these trials. Serious side effects associated with AAP use, such as extrapyramidal symptoms, tardive dyskinesia, metabolic syndrome including hyperprolactinemia, type-2 diabetes, and weight gain, are of concern.14,16–22 A recent study in the province of Quebec found that the 1-year period prevalence of combination therapy and switching among 9431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were AAPs (10.8%), atomoxetine (5.5%), and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAPs (5.5%), and ATX (4.7%).23 However, to our knowledge, costs associated with AAP use among children and adolescents with ADHD in Canada have not been assessed. Given the high prevalence of AAP use in this population, it is important to understand the treatment patterns, HRU, and economic impact associated with AAP use. Such information can help clarify the economic impact of initiating AAPs in children and adolescents with ADHD. In our retrospective observational study, we evaluated the treatment patterns, HRU, and health care costs after initiation of AAPs among children and adolescents with ADHD in Quebec who received AAPs either as an augmenting drug or as an alternative therapy to stimulants.
Methods Data and Patient Selection
A retrospective analysis of health care claims data from Quebec’s provincial health plan database, the RAMQ, was conducted. The RAMQ database contains information on medical services for the entire Quebec population (more than 7.5 million people covered annually) and prescription drug claims from the RAMQ prescription drug plan (about 3.3 million people). Enrollees in the drug plan include recipients of last-resort financial assistance, people who are not eligible for a private insurance plan and their dependents, and people who are 65 years or older. For the purpose of our study, medical and prescription drug claims data for children and adolescents with ADHD who had at least 1 prescription for a stimulant between March 1, www.TheCJP.ca
2007, and February 29, 2012, were extracted. Patients were required to have their first prescription fill of their first AAP (see list of AAPs in online eAppendix A), defined as the index AAP, after a stimulant fill, and had to have augmented with or switched (as defined below) to the index AAP from a stimulant (defined as the index stimulant). The date on which the index AAP prescription was filled was defined as the index date, with the 6 months preceding the index date and the 12 months following the index date, defined as the baseline period and the follow-up period, respectively. Patients were also required to have at least 1 documented ADHD diagnosis (ICD-9 codes: 314.0 to 314.9) during the baseline or follow-up periods, continuous enrolment in both medical and prescription drug plans throughout these 2 periods, and at least 30 days’ supply of a stimulant before the index date. To protect patient confidentiality, patients’ ages were reported in groups of 2- to 3-year intervals. Based on these age groups, patients were required to be between 6 and 17 years of age as of January 1st of the year of the index date. Finally, patients who had a documented psychiatric diagnosis for which AAPs are indicated (according to the approved product labels by Health Canada summarized in online eAppendix B) during the baseline or follow-up periods were excluded from this study.
Study Measures
The following outcomes were measured in our study: treatment patterns after AAP initiation, including discontinuation, augmentation, and switching; HRU; and health care costs. Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill, and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest. The discontinuation date was defined as the last day of supply of the index AAP before the gap. Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period.24 Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply of less than 30 days with the index AAP or a gap of less than 30 days between the end of supply of the index AAP and the initiation of the new treatment. Stimulants, ATX, clonidine, or other AAPs (online eAppendix A) were considered psychotropics that could be used for augmentation or switching. Assessment of HRU included medical services and prescription drugs. Medical services included inpatient admissions, inpatient days, ED visits, outpatient visits (all outpatient and office visits, excluding psychiatric department visits), psychiatric department visits, and other medical services (for example, visits to local community service centres, chronic pain centres, foster care establishments, or laboratories). Because the number of inpatient admissions The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 599
Original Research
Figure 1 Flow chart of patient selection Patients with >18 months of continuous eligibility: N = 13 850 Patients with >1 AAP prescription fill and >1 stimulant prescription fill: n = 1894 Patients with >1 AAP prescription fill, >1 stimulant prescription fill, and >30 days of supply of a stimulant during the 6-month period prior to an AAP prescription fill: n = 1737 Patients with a documented diagnosis of ADHD, without any documented psychiatric diagnosis for which AAPs are indicated, and continuously enrolled in both medical and drug plans during the 6-month period prior to and the 12-month period after an AAP prescription fill: n = 1255 Patients 6 andfill,17>1 years old asprescription of January 1st of the year of of ansupply AAP of a Patients with > aged 1 AAPbetween prescription stimulant fill and >30 days prescription stimulant fill, and who augmented with period or switched to an theAAP first prescription AAP drug (index during the 6-month prior to fill: AAP) used: n = 453 Augmenters with an AAP:
Switchers to an AAP:
n = 206
n = 247
and lengths of stay were not directly available in the data, the number of inpatient admissions and inpatient days were estimated from the RAMQ medical claims using a published algorithm developed and validated to replicate hospitalization episodes, which first identifies all claims for services delivered in hospitals (from variables describing the date and the location of the billed service) and then identifies hospitalizations from the temporal sequence of the inpatient claims.25 The medical services and prescription claims were further categorized into all-cause, ADHD-related (services associated with an ADHD diagnosis or pharmacy claims for medications that could be used for ADHD, listed in online eAppendix A) and mental health-related HRU (services associated with a diagnosis of mental health disorder or pharmacy claims for mental health-related medications within the therapeutic classes listed in online eAppendix C). ADHD and mental HRU were not mutually exclusive. ADHD diagnoses (ICD-9 codes: 314.0 to 314.9) were a subgroup of mental health-related diagnoses (ICD-9: 290 to 319), and ADHD medications were a subgroup of mental health-related medications. Medical service costs included costs charged by physicians to the RAMQ for inpatient, ED, outpatient, psychiatric, and other medical services. In addition, as the RAMQ database Services médicaux rémunérés à l’acte only includes information on physician costs, hospitalization costs for inpatient admissions and ED visits were imputed based on average costs charged for an inpatient day and an ED day using data provided by the Ministère de la Santé et des Services Sociaux of Quebec (that is, Quebec’s Ministry of Health and Social Services). Prescription drug costs reported were amounts charged by pharmacists to the 600 W La Revue canadienne de psychiatrie, vol 59, no 11, novembre 2014
RAMQ. Total health care costs were defined as the sum of medical service costs and prescription drug costs. Each type of health care cost was further categorized into all-cause, ADHD-related, and mental health-related costs. Similar to resource use, ADHD-related costs were a component of mental health-related costs. Costs were calculated from the Quebec public payer’s perspective. All costs were inflated to 2012 Canadian dollars using the Quebec consumer price index for health and personal care, published by Statistics Canada.
Statistical Analysis
Mean, median, and SD were reported for continuous variables. Frequency and percentage were reported for categorical variables. Patients’ demographics (for example, age, sex, index year, and enrolment type), treatment (for example, class of index stimulant and number of stimulants used during baseline), comorbidities, and other baseline characteristics (for example, physician specialty) were summarized using descriptive statistics. Time from the index date to AAP treatment discontinuation, augmentation, or switching during the 12-month follow-up period were estimated using KM survival analyses. Patients were censored at discontinuation of the index AAP when analyzing treatment switching, and at discontinuation or switching when evaluating treatment augmentation. A pre–post design was used to evaluate the HRU and health care costs associated with initiation of the index AAP. To ensure comparable duration of time between the pre and post periods, the proportion of patients with at least 1 visit or at least 1 drug prescription was compared between the 6-month baseline period and the 6-month study period www.LaRCP.ca
Treatment Patterns, Resource Use, and Economic Outcomes Associated With Atypical Antipsychotic Prescriptions in Children and Adolescents With ADHD in Quebec
(defined as the first 6 months of the 12-month follow-up period) using McNemar’s tests. HRU and health care costs were summarized for the 6-month baseline period, the 6-month study period, and the entire 12-month follow-up period. The mean HRU and costs were compared between the 6-month baseline period and the 6-month study period using Wilcoxon signed-rank tests. For comparison purposes, statistical significance was evaluated at the 0.05 significance level (2-sided).
Sensitivity Analysis
Several sensitivity analyses were undertaken to evaluate the robustness of the study findings. An alternative definition for treatment discontinuation, which required a gap of at least 60 consecutive days between the end of a prescription supply and the beginning of the next fill of the index AAP, was used. Additionally, switching was alternatively defined as an overlap in days of supply of the index AAP and the new drug of less than 30 consecutive days, or a gap of less than 60 days.
Results
Table 1 Patient demographics and baseline characteristics Baseline characteristics Demographics Age, years, mean (SD) [median]
As shown in Table 1, the mean age of patients was 10.4 (SD 2.5) years, with the majority (73.7%) of them being children (that is, aged 6 to 12 years) and male (74.6%). The index stimulants used by these patients were LA methylphenidate (50.3%), LA amphetamines (25.4%), SA methylphenidate (22.3%), and SA amphetamines (2.0%) (online eTable 2). The index AAPs were predominantly risperidone (81.7%), followed by quetiapine (16.3%) (online eTable 3). About 33.5% of patients had at least 1 documented comorbidity during the 6-month baseline period. The most frequently documented psychiatric or neurologic comorbidities were adjustment reaction (7.1%), anxiety disorder (5.1%), and learning disability (4.4%). Index AAPs were most commonly prescribed by psychiatrists (41.1%) (Table 1).
Treatment Patterns
Pharmacologic therapy regimen changes occurred in 92.1% of patients during the 12-month, follow-up period. The KM survival curves of treatment discontinuation, augmentation, switching (not mutually exclusive), or any one of these www.TheCJP.ca
10.42 (2.5) [10.0]
Children (≤12 years)
334 (73.7)
Adolescents (>12 years)
119 (26.3)
Female
115 (25.4)
Enrolment type Employment assistance recipient
173 (38.22)
Subscriber
280 (61.78)
Class and formulation of index stimulant Amphetamines, short acting
9 (2.0)
Amphetamines, long acting
115 (25.4)
Methylphenidate, short acting
101 (22.3)
Methylphenidate, long acting Number of distinct stimulants, mean (SD) [median]
228 (50.3) 1.39 (0.5) [1.0]
Comorbidity profile Mental comorbidities
Baseline Characteristics
A total of 13 850 children and adolescents with ADHD who received stimulant prescriptions during the 5-year period from March 2007 to February 2012 were identified in the RAMQ database. Among these 13 850 patients, 1894 (13.7%) filled an AAP prescription. After applying additional inclusion criteria, 453 children and adolescents with ADHD aged 6 to 17 years were identified as having initiated their first AAP, either as an augmenting drug or as alternative therapy to a stimulant. Among these patients, 206 (45.5%) augmented a stimulant with an AAP and 247 (54.5%) switched from a stimulant to an AAP. The sample selection flow chart is shown in Figure 1.
Patients, n = 453 n (%)
Adjustment reaction
32 (7.1)
Anxiety disorder
23 (5.1)
Learning disability
20 (4.4)
Physical comorbidities Accidents and injuries
43 (9.5)
Asthma
11 (2.4)
Number of comorbidities Patients with 1 comorbidity
117 (25.8)
Patients with 2 comorbidities
26 (5.7)
Patients with ≥3 comorbidities
9 (2.0)
Physician specialtya Physician prescribing the index AAP Psychiatry
186 (41.1)
Pediatrics
162 (35.8)
Neurology
30 (6.6)
Missing
74 (16.3)
Physician prescribing ≥1 stimulant Pediatrics
236 (52.1)
Psychiatry
128 (28.3)
Neurology Missing
28 (6.2) 143 (31.6)
Physician providing ≥1 ADHD diagnosisb
a
Pediatrics
144 (31.8)
Psychiatry
125 (27.6)
Neurology
21 (4.6)
Missing
63 (13.9)
Only the most common physician specialties are reported.
Numbers are not mutually exclusive as patients could have been seen by >1 specialist during the baseline period. AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder b
The Canadian Journal of Psychiatry, Vol 59, No 11, November 2014 W 601
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Figure 2 Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: a) treatment discontinuationa; b) treatment augmentationb a. 3-month rate: (95% CI) 24.7 (21.0–29.0)
6-month rate: (95% CI) 35.5 (31.3–40.1)
12-month rate: (95% CI) 45.5 (41.0–50.2)
90 80 70 60 50 40 30 20 10 0 0
30
60
90
120
150
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210
240
270
300
330
Number of patients, n 453
Augmentation 100 Proportion of patients with a treatment augmentation, %
Proportion of patients with a treatment discontinuation, %
Discontinuation 100
360
90 80 70 60 50 40 30 20 10 0 0
30
Time from index date, days
b.
month rate: (95% CI) 7 (58.0–67.4)
330
c. Augmentation Switch 100 100
360
Number of patients with a 1-month rate: treatment augmentation, Number of Number 3-month rate: 6-month rate: 12-month rate: of patients with a (95%rate: CI) n (%) patients, (95%rate: CI) (95%rate: CI) 1-month (95% rate: CI) treatment switch, Number of n 3-month 6-month 12-month 14.6 (11.5–18.5) 191 (42.2) 453 n 51.3 (45.6–57.3) 65.4 (59.2–71.5) (95% CI) 68.2 (61.9–74.3) n (%) patients, (95% CI) (95% CI) (95% CI) 15.9 (12.8–19.6) 42.9 (38.4–47.8) 321 (70.9) 453 62.7 (58.0–67.4) 80.7 (76.5–84.6)
80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 30 30
d.
Number of Health Care Resource Utilization patients, n
12-month rate: (95% CI) 80.7 (76.5–84.6)
60 60
90 90
120 150 180 210 240 120 150 180 210 240 Time from index date, days Time from index date, days
Number of patients with a treatment change, n (%) 417 (92.1)
453
30 Consistent with all-cause outpatient visits, a higher proportion of patients with at least 1 mental health-related 20
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270 270
300 300
330 330
90 80 70 60 50 40 30 20 10 0
360 360
0
3-month in rate:the 6-month rate: 12-month rate: changes index AAP treatment are presented in Figure (95% CI) (95% CI) (95% CI) 75.7 (71.7–79.6) 87.6 (84.4–90.5) 92.1 (89.3–94.3) 2. The 12-month KM rates of treatment discontinuation, treatment augmentation, and treatment switching were 45.5%, 68.2%, and 80.7%, respectively. For most patients with pharmacologic therapy regimen changes, the changes occurred in the first 6 months after the index AAP was initiated (6-month KM rate of 87.6%).
1-month rate: (95% CI) 38.0 (33.7–42.6)
A significantly higher proportion of patients had at least 1 100 all-cause outpatient visit in the 6-month study period after 90 initiating the index AAP, compared with baseline (92.3%, 80 compared with 87.4%, P = 0.01) (Table 4). There were no significant differences (P > 700.05) in the proportion of patients with at least 1 psychiatric department visit, the 60 proportion of patients with at least 1 inpatient admission, and the proportion of patients50with at least 1 ED visit between the baseline and study periods. 40 Treatment change
Number of patients, n 453
Treatment change
100
90 90
0 0 0 0
d.
Proportion of patients with a treatment change, %
Proportion of patients with a treatment switch, % Proportion of patients with a treatment augmentation, %
300
12-month rate: (95% CI) 45.5 (41.0–50.2)
Proportion of patients with a treatment change, %
month rate: (95% CI) 5 (31.3–40.1)
270
b. Number of patients with a Number of treatment discontinuation, 1-month rate: (95% CI) n (%) patients, n 14.4 (11.4–17.9) 206 (45.5) 453
Results of the sensitivity analyses that used alternative definitions of discontinuation and switching were similar, with the 12-month KM rates of treatment discontinuation, augmentation, and switching estimated at 35.1%, 67.0%, and 78.0%, respectively (online eFigure 3). www.LaRCP.ca
30
Nu tr
0
30
60
90
120
150
180
210
240
270
300
330
360
10 0 0
30
Time from index date, days
Figure 2 Kaplan–Meier analyses of treatment patterns after atypical antipsychotic use: c) treatment switchingc; d) any therapy regimen change b.
330
Augmentation Switch 100 100 90 90
360
12-month rate: (95% CI) 80.7 (76.5–84.6)
Number of patients with a treatment augmentation, Number of Number 3-month rate: of patients with a 1-month rate: (95% rate: CI) n (%) patients,ofn (95% rate: CI) 1-month treatment switch, Number 3-month 14.6 (11.5–18.5) 191 (42.2) 453 n 51.3 (45.6–57.3) (95% CI) n (%) patients, (95% CI) 15.9 (12.8–19.6) 42.9 (38.4–47.8) 321 (70.9) 453
c.
6-month rate: 12-month rate: (95% CI) (95% CI) 6-month rate: 12-month rate: 65.4 (59.2–71.5) 68.2 (61.9–74.3) (95% CI) (95% CI) 62.7 (58.0–67.4) 80.7 (76.5–84.6)
d. 100
80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 0
d.
30 30
Number of patients, n 453
Treatment change
60 60
90 90
120 150 180 210 240 120 150 180 210 240 Time from index date, days Time from index date, days
Number of patients with a treatment change, n (%) 417 (92.1)
1-month rate: (95% CI) 38.0 (33.7–42.6)
3-month rate: (95% CI) 75.7 (71.7–79.6)
270 270
300 300
6-month rate: (95% CI) 87.6 (84.4–90.5)
330 330
360 360
12-month rate: (95% CI) 92.1 (89.3–94.3)
Proportion of patients with a treatment change, %
100 90 80 70 60 50 40 30 20 10 0 300
330
360
0
30
60
90
120
150
180
210
240
270
300
330
360
Time from index date, days
AAP = atypical antipsychotic; ADHD = attention-deficit hyperactivity disorder a Discontinuation of the index AAP was defined as a gap of at least 30 consecutive days between the end of the supply of a prescription fill and either the beginning of the following fill for the index AAP or the end of the study period, whichever occurred earliest. b Augmentation of the index AAP was defined as the event in which a new psychotropic (see list in online eAppendix A) was initiated after the index AAP and was used concomitantly with the index AAP for at least 30 consecutive days during the study period. c Switching was defined as a prescription fill of a new psychotropic that could be used for the treatment of ADHD that had an overlap in supply
