Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.

Epidemiology of Treatment for Preschoolers on Kentucky Medicaid Diagnosed with Attention-Deficit/Hyperactivity Disorder.

Objectives: The National Survey of Children's Health reported a concerning increase in children 2-5 years being diagnosed with attention-deficit/hyperactivity disorder (ADHD) in 2016. Concerns include both the increase in diagnosing and potential deviations from published guidelines for the treatment of ADHD in preschoolers. The present study aims to describe the epidemiology and factors associated with receiving the diagnosis and treatment types for low-income preschoolers. Methods: Using Kentucky Medicaid claims from 2012 to 2017, a retrospective cohort study of children 2-5 years of age (n = 337,631) with a diagnosis of ADHD (n = 11,712) was completed. Trends in demographics, comorbidities, and treatment and provider types are presented. Multinomial logistic regression was used to determine predictors of receipt of the diagnosis and treatment type (a stimulant only, an alpha-2 agonist [A2A] only, both, or neither) based on nonmissing 2017 data (n = 2394). Results: The number of children in the cohort diagnosed with ADHD and receiving a stimulant decreased from 2012 to 2017, but the use of A2As increased. Primary care physicians were the most frequent prescribers of both medications. The adjusted odds ratios (AORs) of receipt of an A2A alone, stimulant alone, or both medications over receiving no ADHD medication were associated with specific demographics and comorbid conditions for each medication regimen. Race/ethnicity is associated with receiving the diagnosis of ADHD and treatment with A2A. Comorbid mental health conditions and provider type are associated with treatment type. Conclusion: Use of stimulants for preschoolers in Kentucky has decreased and A2A use has increased since 2012. Continued vigilance and long-term follow-up of preschoolers with ADHD are warranted. The appropriateness of the diagnosis and treatment type could not be determined.

The use of off-label medications in substance abuse treatment programs.

Background: Substance use disorder (SUD) treatment centers serve a population of clients who have diverse needs, and may desire or require access to varied treatments while seeking care for their SUDs. While pharmacotherapies have increased in popularity for the treatment of SUDs, adoption rates do remain quite low. But a wider array of pharmacotherapies has become available in recent years which may shift the trend. This article helps shed light on how variations in SUD treatment centers develop and persist with regard to the adoption and delivery of off-label medications. Methods: We use a nationally representative and longitudinal sample of SUD treatment centers in the US (N = 196). We use a logistic regression to analyze the relationship between organizational characteristics and offering any medications, off-label. We also use a negative binomial regression to analyze the relationship between organizational characteristics and the number of medications that were used off-label. Results: Our findings reveal that older centers, accredited centers, and centers that offer mental health screenings are all positively associated with the provision of off-label medication in SUD treatment. We also find a positive relationship between private funding and offering a greater number of off-label medications. Conclusions: Our results suggest that SUD clients who seek treatment from centers that offer medications off-label, may have access to a greater number of medication-assisted treatment options.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

BACKGROUND: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. OBJECTIVES: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. DATA SOURCES: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. RESULTS: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). LIMITATIONS: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. CONCLUSIONS: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101. FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Assessment of dexmedetomidine and other agents for emesis induction in cats: 43 cases (2009-2014).

OBJECTIVE: To compare the use of dexmedetomidine hydrochloride, xylazine hydrochloride, and hydrogen peroxide for emesis induction in cats. DESIGN: Retrospective case series. ANIMALS: 43 client-owned cats for which emesis induction was attempted because of known or suspected toxicant ingestion or recent ingestion of a string foreign body. PROCEDURES: Data collected from the cats' medical records included type, dose, and route of administration of emetic agent; outcome of attempted emesis induction; time until emesis or postemesis administration of a reversal agent (to counter sedative effects of the emetic agent); and adverse events. RESULTS: Emesis induction was attempted by oral administration of hydrogen peroxide (n = 3) or IM or IV administration of xylazine (25 [including 1 cat that had already received hydrogen peroxide]) or dexmedetomidine (16). No cat that received hydrogen peroxide vomited. Emesis was induced in 11 of 25 xylazine-treated cats and in 13 of 16 dexmedetomidine-treated cats. Dexmedetomidine was more likely to cause vomiting than xylazine (OR, 5.5; 95% confidence interval, 1.1 to 36). The median dose of dexmedetomidine that caused emesis was 7.0 µg/kg (3.2 µg/lb; range, 0.96 to 10.0 µg/kg [0.44 to 4.55 µg/lb]). The elapsed time until emesis or postemesis reversal agent administration was recorded for 5 xylazine-treated cats (median interval, 10 minutes [range, 5 to 175 minutes]) and 10 dexmedetomidine-treated cats (median interval, 5 minutes [range, 1 to 12 minutes]). Sedation was the only adverse effect, occurring in 2 xylazine-treated cats and 1 dexmedetomidine-treated cat. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dexmedetomidine can be used successfully to induce emesis in cats.

Impact of a Step Therapy for Guanfacine Extended-Release on Medication Utilization and Health Care Expenditures Among Individuals Receiving Treatment for ADHD.

BACKGROUND: While step therapy (ST) policies are generally effective at reducing cost through the managed utilization of targeted medications, the clinical implications of ST policies are not clear and may vary across therapeutic areas. Guanfacine extended-release (GXR) is approved by the FDA for the treatment of attention-deficit/hyperactivity disorder (ADHD) as both monotherapy and adjunctive to stimulant treatment. At the introduction of GXR to the market, Humana implemented an ST policy on GXR requiring the documentation of previous treatment, intolerance, or contraindication to generic clonidine or guanfacine. OBJECTIVE: To examine the impact of a GXR ST coverage determination (i.e., approved vs. denied) on medication utilization and health care costs among members of a commercial health plan with an ST policy for GXR.  METHODS: This study was a retrospective cohort study of administrative claims data. Humana commercial members prescribed GXR who had an ST coverage determination review were identified. All members included in this analysis were required to be aged 6-17 years, have a diagnosis of ADHD or be receiving stimulant medication, have an ST coverage determination (index event) between September 1, 2009, and May 30, 2012, and have 6 months of pre- and post-index continuous enrollment. Members were assigned to either the approved or denied group based on the outcome of the ST coverage determination. Medical and pharmacy claims data were used to measure baseline demographic and clinical characteristics and to measure medication utilization and health care costs. Outcomes assessed during follow-up included ADHD medication use, proportion of days covered (PDC) with any ADHD medication treatment, time to first observed post-index ADHD treatment, and all-cause and mental health (MH)-related health care costs. Administrative costs associated with the coverage determination process were also estimated. Bivariate and multivariable adjusted analyses were conducted to compare medication utilization and health care costs between the approved and denied groups. RESULTS: A total of 642 members were included in the analysis (denied group n = 395 [61.5%], approved group n = 247 [38.5%]). The approved and denied groups were similar in terms of baseline demographics, provider characteristics, and baseline MH diagnoses, with the exception of anxiety disorders being more prevalent in the approved group compared with the denied group (18.2% vs. 10.6%, P = 0.006). A denied GXR coverage determination was associated with a greater percentage of members receiving no ADHD treatment post-index (13.9% vs. 3.2%, P less than 0.001), greater mean [SD] number of days between index and first observed post-index ADHD medication claim (44.5 [59.6] vs. 17.6 [33.4], P less than 0.001), and lower mean [SD] PDC with any ADHD medication post-index (0.59 [0.33] vs. 0.75 [0.26], P less than 0.001). These findings remained statistically significant in multivariable regression models. Unadjusted pre-index median total health care costs and MH-related costs were greater among the approved group compared with the denied group (total health care: $1,582 vs. $1,465, P = 0.033; MH-related: $993 vs. $981, P = 0.020). Likewise, post-index median total health care and MH-related costs were greater among the approved group compared with the denied group (total: $2,056 vs. $1,420, P less than 0.001; MH-related: $1,543 vs. $946, P less than 0.001). After adjustment for potentially confounding covariates including pre-index costs, there were no statistically significant differences between the approved and denied groups in all-cause total health care (P = 0.393) or MH-related health care costs (P = 0.054).  CONCLUSIONS: The current study found that GXR coverage denial was associated with lower rate of ADHD medication utilization, greater delay in receiving ADHD medication, and lower PDC with ADHD medication. There were no differences observed between the approved and denied group in terms of all-cause total health care or MH-related total health care costs after controlling for potentially confounding variables. Prior to implementation in the ADHD therapeutic area and others, payers should consider the potentially unintended consequences of ST policies, including delay in treatment and undertreatment.

Erythema of Rosacea: Validation of Patient's Self-Assessment Grading Scale.

BACKGROUND: Facial erythema is a primary feature of rosacea. Currently, no validated scales exist that can accurately capture a patient's self-assessment of their own facial erythema. During phase 2 studies for brimonidine tartrate gel, a 5-point numeric rating scale was developed as a tool to allow subjects to provide an independent assessment of visible changes to the facial erythema associated with their rosacea. OBJECTIVE: The objective of this study was to validate the revised patient's self-assessment (PSA) scale and evaluate it for statistical reliability and validity in quantification of facial erythema of rosacea. METHODS: The validity of the PSA scale was evaluated by assessing the test-retest reliability, construct validity, and known-groups validity based on the data collected during a Phase 2b study on brimonidine gel for the treatment of persistent facial erythema of rosacea. RESULTS: Based on the results of this evaluation, this PSA scale demonstrated test-retest reliability, construct validity, and known-groups validity. LIMITATIONS: Study results are most generalizable to those with moderate to severe erythema. CONCLUSION: The PSA is an appropriate scale to assess facial erythema associated with rosacea.

Brimonidine for erythema caused by rosacea.

Brimonidine gel (Mirvaso-Galderma) became available in February of this year for the symptomatic treatment of facial erythema associated with rosacea in adults.1 Here, we review the evidence on brimonidine gel and consider its place in the management of erythema associated with rosacea.

Aggregometric assessment of clonidine's impact on the efficacy of dual platelet inhibition.

BACKGROUND: Clonidine is commonly used as a calmative and antihypertensive agent in perioperative care. Due to the drug's alpha-2-agonistic effects, it has recently been hypothesised that clonidine may affect platelet aggregability. The present investigation aimed to study the potential impact of clonidine on the efficacy of dual antiplatelet therapy. METHODS: In this prospective, observational, single-centre study, patients treated with dual antiplatelet therapy were screened for eligibility. The patients were enrolled in the study if ex vivo thrombin-induced (TRAPtest), arachidonic acid-induced (ASPItest) and adenosine diphosphate-induced (ADPtest) platelet aggregation, as measured using multiple electrode aggregometry (MEA; Multiplate, Roche AG, Grenzach, Germany), confirmed efficient dual platelet inhibition. Ex vivo induced platelet aggregation was assessed before (baseline) and 3 minutes after (T1) spiking blood samples with either 1 ng/mL clonidine or sodium chloride 0.9% (control group). RESULTS: In total, 34 patients were finally enrolled in the study. Compared with baseline, platelet aggregation in the ASPItest and ADPtest was significantly increased at T1 in both groups. Platelet aggregation in the TRAPtest remained unchanged between baseline and T1 in both groups. Comparing platelet aggregation at T1, we detected no differences between blood samples that were spiked with clonidine and blood samples that were spiked with sodium chloride 0.9% in the TRAPtest, the ASPItest, or the ADPtest. CONCLUSIONS: The results of this study indicate that clonidine does not affect platelet aggregability in patients treated with dual antiplatelet therapy. The findings of the study also indicate that ex vivo induced platelet aggregation in the ASPItest and ADPtest increases with the duration between blood drawing and MEA analyses.

Optical coherence tomography imaging of erythematotelangiectatic rosacea during treatment with brimonidine topical gel 0.33%: a potential method for treatment outcome assessment.

BACKGROUND: Patients with moderate to severe rosacea often seek treatment to reduce erythema and vascular markings. Few studies have looked at the effectiveness of the novel treatment, brimonidine topical gel 0.33%, trademark name Mirvaso®, in the treatment of rosacea. We report the use of optical coherence tomography (OCT) scanning to monitor the effectiveness of Mirvaso® on in vivo skin. OCT is a non-invasive optical imaging technique that can provide high-resolution imaging of vessel and cellular morphology. OCT may be useful as a pre-treatment assessment tool for identifying possible morphologic features in the skin that may serve as outcome predictors. OCT may also serve as a monitoring tool in the treatment of rosacea. OBJECTIVE: To examine and describe how OCT skin morphology changes when exposed to brimonidine topical gel 0.33% in the treatment of erythematotelangiectatic rosacea. METHODS: Normal in vivo telangiectasias and erythematous patches and papules were examined prior to treatment clinically, dermatoscopically, and through OCT scans. Brimonidine topical gel 0.33% was applied to the face and OCT images were acquired at defined time intervals: baseline; immediately (<5 minutes) after application; 4 hours after application; and after 2 weeks' once daily application. OCT morphology was then described. RESULTS: OCT imaging showed an increase in the mean gray value (MGV), a measure of dermal reflectivity, corresponding to a decrease in dermal edema. MGV measurements for the nasal telangiectasia were: baseline, MGV 10,471 (standard deviation [SD] 6,847); immediate, MGV 15,634 (SD 8,983); after 4 hours, MGV 16,357 (SD 7,647); and after 2 weeks, MGV 15,505 (SD 6,870). MGV measurements for the chin erythema were: baseline, MGV 8,850 (SD 4,969); immediate, MGV 10,799 (SD 5,266); after 4 hours, MGV 12,419 (SD 6,714); and after 2 weeks, MGV 13,395 (SD 6,170). No significant change in vessel lumen diameter was appreciated. Vessel lumen diameter for the facial papule ranged from 0.13 mm at baseline, 0.09 mm immediately after treatment, 0.09 mm after 4 hours, and 0.11 mm after 2 weeks. CONCLUSIONS: OCT scanning showed a decrease in the dermal hyporeflectivity of the dermis consistent with a decrease in dermal edema. The OCT scans obtained did not show any significant change in vessel lumen diameter. These results may reflect an increase in vascular tone, which can be attributable to the clinical improvement and decreased erythema noted in the patient. This technology could potentially be used for the non-invasive in vivo monitoring of other topical treatments.

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Cost effectiveness of guanfacine extended-release versus atomoxetine for the treatment of attention-deficit/hyperactivity disorder: application of a matching-adjusted indirect comparison.

BACKGROUND: About 7% of children and adolescents are diagnosed with attention-deficit/hyperactivity disorder (ADHD) in the US. Patients with ADHD who are intolerant of or do not have an optimal response to stimulants often use non-stimulants as alternative therapies. Guanfacine extended-release (GXR) and atomoxetine (ATX) are the only non-stimulants approved by the US Food and Drug Administration for once-daily use in the treatment of children and adolescents with ADHD in the US. ATX has been on the market since 2002 while GXR was recently approved in 2009. To date, there is no comparative effectiveness or cost-effectiveness study comparing the two drugs. OBJECTIVES: The aim of this study was to assess the cost effectiveness of GXR versus ATX for the treatment of ADHD in children and adolescents, using the comparative efficacy results from a matching-adjusted indirect comparison (MAIC). METHODS: The MAIC method was used to compare the efficacy between GXR (target dose and lower doses) and ATX (target dose) in the absence of head-to-head clinical trials. Individual patients in the GXR trials were weighted such that the summary baseline characteristics and the efficacy of the placebo arm of the GXR trials matched exactly with those from published ATX trials. After weighting, the efficacy (i.e. change in the ADHD rating scale, fourth edition [ADHD-RS-IV] total score from baseline) was compared between each GXR dosing group and the ATX group. The results from the MAIC analyses were used to populate a 1-year Markov model that is used to compare the cost effectiveness of GXR versus ATX from a US third-party payer perspective. Effectiveness outcomes for each treatment group were estimated as the proportion of responders, defined as patients with ≥25% reduction in ADHD-RS-IV total score from baseline, and average quality-adjusted life years (QALYs). Utilities associated with response/non-response and disutilities due to adverse events were applied in the model. Costs included drug and medical service costs and were inflated to 2011 US dollars ($US). Incremental cost/QALY and incremental cost/responder were estimated. Univariate sensitivity analyses were conducted by varying all model parameters, including costs, utilities, and response rate. RESULTS: The target dose of GXR was 0.12 mg/kg/day. In match-adjusted populations with balanced baseline characteristics, patients receiving GXR at the dose of 0.09-0.12(p = 0.0016) [DOSAGE ERROR CORRECTED] and 0.075-0.09 mg/kg/day (p = 0.0248) had better efficacy, while those receiving GXR at the dose of 0.046-0.075 mg/kg/day had comparable efficacy (p = 0.0699), compared with patients receiving ATX at the target dose of 1.2 mg/kg/day. In the base case of the cost-effectiveness analysis (CEA), GXR had incremental cost-effectiveness ratios of $US10 637/QALY and $US853/responder, compared with ATX (incremental costs: $US74; incremental effectiveness: 0.007 QALYs and 86 responders per 1000 patients treated). Results of all univariate sensitivity analyses showed that the model results were robust to changes in model inputs. CONCLUSIONS: To our knowledge, this is the first application of the novel comparative efficacy method of MAIC to a CEA model. The MAIC results indicate that GXR (0.075-0.12 mg/kg/day) was more effective than ATX (1.2 mg/kg/day) in the trial population. The CEA results indicate that GXR is cost effective compared with ATX for the treatment of ADHD in children and adolescents.

Combination therapy patterns and predictors of ADHD in commercially insured and Medicaid populations.

OBJECTIVES: Several stimulant and nonstimulant medications are used alone or in combination to treat attention-deficit/hyperactivity disorder (ADHD). Little is known about the current prevalence and predictors of combination therapy. This analysis describes ADHD medication use focusing on combination versus monotherapy. METHODS: Health insurance claims from the Truven Health MarketScan® Commercial Database and Multi-State Medicaid Database were analyzed for patients with an ADHD diagnosis (International Classification of Diseases, Ninth Revision codes 314.0x). Patients included were aged ≥ 6 years as of January 2010, continuously enrolled from July 2009 through December 2010, and had a claim for an ADHD medication in 2010. Medication use was measured in treatment months during 2010. Baseline demographic and clinical predictors of combination therapy (> 1 ADHD medication class in the same month) involving atomoxetine, long-acting stimulants, and α2-adrenergic agonists were explored using logistic regression, with generalized estimating equations to account for within-patient correlation between months. RESULTS: Commercially insured patients with ADHD (N = 211 226) were primarily aged 6 to 17 years (58.4%) and male (61.5%). Attention-deficit/hyperactivity disorder with hyperactivity was present in 15.8% of these patients. Combination therapy was used in 10.3% of 1 125 119 treatment months. Short-acting stimulants and α2-adrenergic agonists had the highest combination use (45.3% and 54.0%, respectively). Patients with ADHD insured through Medicaid (N = 125 104) were primarily aged 6 to 17 years (94.4%) and male (69.5%). Hyperactivity was present in 39.7% of these patients. Combination therapy was used in 24.0% of 721 986 treatment months. Short-acting stimulants, α2-adrenergic agonists, and intermediate-acting stimulants had the highest combination use (70.0%, 63.8%, and 51.8%, respectively). In multivariate models for both data sources, female patients were less likely to use combination therapy. Patients with hyperactivity were more likely to use combination therapy. Tics/Tourette's syndrome was associated with combination therapy for atomoxetine and long-acting stimulants. CONCLUSION: In commercially insured and Medicaid ADHD populations, combination therapy rates differed by medication class, as did the demographic and clinical characteristics statistically significantly associated with combination therapy. This suggests that these medications may be used differently in clinical practice.

Cost effectiveness of guanfacine extended release as an adjunctive therapy to a stimulant compared with stimulant monotherapy for the treatment of attention-deficit hyperactivity disorder in children and adolescents.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood, affecting 3-7% of school-age children in the US and imposing substantial economic burden. Stimulants are considered first-line pharmacological treatment and are the most prescribed treatment for ADHD. However, approximately 30% of children with ADHD do not have an optimal response to a single stimulant and may require adjunctive therapy. OBJECTIVE: Our objective was to conduct a cost-effectiveness analysis (CEA) of adding a non-stimulant, guanfacine extended release (GXR), to stimulants versus maintaining existing stimulant monotherapy in the treatment of ADHD in children and adolescents with suboptimal response to stimulant monotherapy. METHODS: A 1-year Markov model was developed to estimate costs and effectiveness from a US third-party payer perspective. Effectiveness was measured by the QALY. The model assumed that patients transitioned among four health states (normal, mild, moderate and severe), defined by the Clinical Global Impression-Severity (CGI-S) scale. Transition probabilities were estimated in an ordered logit model using patient-level data from a multicentre, 9-week, double-blind, placebo-controlled, dose-optimization study, where subjects (n = 461) continued their stable morning stimulant and were randomized to GXR administered in the morning, GXR administered in the evening, or placebo. The model assumed that patients in moderate/severe health states after week 8 would discontinue ADHD treatment and remain in that state for the rest of the study period. Direct costs included drug wholesale acquisition costs and health state costs, all in $US, year 2010 values. Utility associated with each health state was obtained from the literature and disutilities associated with adverse events were applied for the first 4 weeks. One-way sensitivity analyses and probabilistic sensitivity analysis (PSA) were conducted by varying costs, utilities, adverse-event duration, and transition probabilities. RESULTS: Compared with maintaining existing stimulant monotherapy, adding GXR to existing stimulant monotherapy was associated with an incremental drug cost of $US1016 but a lower medical cost of $US124, resulting in a total incremental cost of $US892 at 1 year. The addition of GXR to stimulants led to an incremental QALY of 0.03 and an incremental cost-effectiveness ratio (ICER) of $US31,660/QALY. In one-way sensitivity analysis, ICER values ranged from $US19,723, when 100% of patients were assumed to be severe in their initial health state, to $US46,631, when the last observed states from the clinical trial were carried forward to the end of the 1-year analysis period. PSA demonstrated a 94.6% likelihood that the ICER falls below $US50,000/QALY. CONCLUSIONS: The impairment associated with residual ADHD symptoms after stimulant therapy is becoming increasingly recognized. This is the first analysis of the cost effectiveness of stimulants combined with an adjunctive medication. This study suggests that the adjunctive therapy of GXR with stimulants is a cost-effective treatment based on a willingness-to-pay threshold of $US50,000/QALY. This may address an unmet need among patients with suboptimal response to stimulant monotherapy.