Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison

Eur Child Adolesc Psychiatry DOI 10.1007/s00787-017-0962-6 REVIEW Comparative efficacy and safety of attention‑deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison Alain Joseph1 · Rajeev Ayyagari2 · Meng Xie2 · Sean Cai3 · Jipan Xie3 · Michael Huss4 · Vanja Sikirica5 Received: 1 September 2015 / Accepted: 13 February 2017 © The Author(s) 2017. This article is published with open access at Springerlink.com Abstract This study compared the clinical efficacy and safety of attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in children and adolescents 6–17 years of age. A systematic literature review was conducted to identify randomized controlled trials (RCTs) of pharmacologic monotherapies among children and adolescents with ADHD. A Bayesian network meta-analysis was conducted to compare change in symptoms using the ADHD Rating Scale Version IV (ADHD-RS-IV), Clinical Global Impression–Improvement (CGI-I) response, all-cause discontinuation, and adverse event-related discontinuation. Thirtysix RCTs were included in the analysis. The mean (95% credible interval [CrI]) ADHD-RS-IV total score change from baseline (active minus placebo) was −14.98 (−17.14, −12.80) for lisdexamfetamine dimesylate (LDX), −9.33 (−11.63, −7.04) for methylphenidate (MPH) extended release, −8.68 (−10.63, −6.72) for guanfacine extended release (GXR), and −6.88 (−8.22, −5.49) for atomoxetine (ATX); data were unavailable for MPH immediate release. The relative risk (95% CrI) for CGI-I response (active versus placebo) was 2.56 (2.21, 2.91) for LDX, 2.13 (1.70, 2.54) for MPH extended release, 1.94 (1.59, 2.29) for GXR, 1.77 (1.31, 2.26) for ATX, and 1.62 (1.05, 2.17) for MPH immediate release. Among non-stimulant pharmacotherapies, GXR was more effective than ATX when comparing ADHD-RS-IV total score change (with a posterior probability of 93.91%) and CGI-I response (posterior probability 76.13%). This study found that LDX had greater efficacy than GXR, ATX, and MPH in the treatment of children and adolescents with ADHD. GXR had a high posterior probability of being more efficacious than ATX, although their CrIs overlapped. Keywords Attention-deficit/hyperactivity disorder · Efficacy · Meta-analysis · Mixed treatment comparison · Children · Adolescents Background Electronic supplementary material The online version of this article (doi:10.1007/s00787-017-0962-6) contains supplementary material, which is available to authorized users. * Rajeev Ayyagari 1 Shire, Zug, Switzerland 2 Analysis Group, Inc., Economic, Financial, and Strategy Consulting, 111 Huntington Avenue, 14th Floor, Boston, MA 02199, USA 3 Analysis Group, Inc., New York, NY, USA 4 University Medicine, Department of Child and Adolescent Psychiatry, Mainz, Germany 5 Shire, Wayne, PA, USA The current UK National Institute for Health and Care Excellence (NICE) guidelines for attention-deficit/hyperactivity disorder (ADHD) recommend medication for patients with severe impairment or for those patients with moderate impairment who have refused non-drug treatments or whose symptoms have not responded to other, non-drug interventions [1]. Monotherapy with stimulants, including amphetamines and methylphenidate (MPH), is the mainstay of pharmacologic treatment for ADHD in children and adolescents; however, about 20–35% of patients are refractory or intolerant to stimulants [2–5]. In these cases, alternative options include non-stimulants and behavioral therapies. These treatments may be in the form of monotherapy or, in case of refractoriness or intolerance to monotherapy, 13 Eur Child Adolesc Psychiatry adjunctive therapy (e.g., add-on therapy) to existing stimulants to help improve symptoms that cannot be controlled by stimulants alone. European guidelines for the management of ADHD in children and adolescents [6] include monotherapy with stimulants, such as dexamphetamine (d-AMPH), lisdexamfetamine dimesylate (LDX), and MPH, either immediate release (IR) or extended release (ER)/osmotic-release oral system (OROS). For those children and adolescents refractory or intolerant to stimulants, alternative options include non-stimulants, such as atomoxetine (ATX), clonidine immediate release (CIR), and guanfacine immediate release (GIR). The NICE guidelines [1] recommend ATX and MPH for the management of ADHD in children and adolescents aged 6–17 years. Guanfacine extended release (GXR) is a non-stimulant approved for both monotherapy and adjunctive therapy in children and adolescents (6–17 years) in the USA and Canada. In addition, GXR was approved by the European Medicines Agency (EMA) for children and adolescents (6–17 years) in September 2015. The availability of treatments with different mechanisms of action provides opportunities for additional treatment strategies when patients do not adequately respond to prior therapies. The objective of this study was to compare the clinical efficacy and safety of ADHD pharmacotherapies in children and adolescents aged 6–17 years. A number of randomized clinical trials have compared the efficacy and safety of these pharmacotherapies with each other or with placebo in children and adolescents. A recently published study conducted a meta-analysis incorporating published data from randomized controlled trials (RCTs) containing GXR and placebo [7]. However, the present study has a broader scope, performing a mixed treatment comparison (MTC) of EMA-approved pharmacotherapies and GXR in a network meta-analysis framework. It incorporates both direct and indirect evidence, from a wider range of sources. from the American Academy of Child and Adolescent Psychiatry (AACAP) annual meeting were included for 2012– 2014; 2015 abstracts could not be accessed. The search included articles indexed through May 2016. No time restriction was applied to database searches of the drugs. Detailed search criteria are available in Online Resource 1. Inclusion and exclusion criteria were designed to broadly identify available information on treatments for ADHD in children and adolescents. Studies were eligible if they satisfied the following conditions: • A placebo or active comparator RCT. • Included children or adolescents aged 6–17 years with ADHD. • Interventions included monotherapy with at least one drug of interest (i.e., d-AMPH, ATX, CIR, GIR, GXR, LDX, MPH-IR, or MPH-ER/OROS). • Reported efficacy or safety outcomes after a treatment duration of ≤16 weeks. • Included ˃25 patients. Methods Trials were excluded if all patients had a comorbid condition in addition to ADHD. In addition, as the comparison with non-stimulants was a novel element of this study, trials were excluded if they could not be connected to GXR and ATX in an evidence network via a chain of common comparators. As a consequence, only parallel-arm studies were included—crossover studies were excluded if they did not report results for the parallel phase (just prior (...truncated)