Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine

Abstract

BackgroundMany children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or increase the risk for serious cardiovascular adverse events such as stroke or sudden death.ObjectivesTo evaluate potential cardiovascular effects of these treatments, we conducted a systematic review and meta-analysis of the effects of methylphenidate (MPH), amphetamines (AMP), and atomoxetine (ATX) on diastolic and systolic blood pressure (DBP, SBP) and heart rate (HR) in children and adolescents with ADHD.MethodsWe conducted systematic searches in electronic databases (PsychINFO, EMBASE and Medline) to identify published trials which involved individuals who were (i) diagnosed with ADHD and were aged between 0–18 years; (ii) treated with MPH, AMP or ATX and (iii) had their DBP and SBP and/or HR measured at baseline (pre) and the endpoint (post) of the study treatment. Studies with an open-label design or a double-blind randomised control design of any duration were included. Statistical analysis involved calculating differences between pre- and post-treatment measurements for the various cardiovascular parameters divided by the pooled standard deviation. Further, we assessed the percentage of clinically relevant increased BP or HR, or documented arrhythmias.ResultsEighteen clinical trials met the inclusion criteria (10 for MPH, 5 for AMP, and 7 for ATX) with data from 5837 participants (80.7% boys) and average duration of 28.7 weeks (range 4–96 weeks). All three medications were associated with a small, but statistically significant pre–post increase of SBP (MPH: standard mean difference [SMD] 0.25, 95% confidence interval [CI] 0.08–0.42, p < 0.01; AMP: SMD 0.09, 95% CI 0.03–0.15, p < 0.01; ATX: SMD 0.16, 95% CI 0.04–0.27, p = 0.01). MPH did not have a pre–post effect on DBP and HR. AMP treatment was associated with a small but statistically significant pre–post increase of DBP (SMD 0.16, CI 0.03–0.29, p = 0.02), as was ATX treatment (SMD 0.22, CI 0.10–0.34, p < 0.01). AMP and ATX were associated with a small to medium statistically significant pre–post increase of HR (AMP: SMD 0.37, CI 0.13–0.60, p < 0.01; ATX: SMD 0.43, CI 0.26–0.60, p < 0.01). The head-to-head comparison of the three medications did not reveal significant differences. Sensitivity analyses revealed that AMP studies of <18 weeks reported higher effect sizes on DBP compared with longer duration studies (F(1) = 19.55, p = 0.05). Further, MPH studies published before 2007 reported higher effect sizes on SBP than studies after 2007 (F(1) = 5.346, p = 0.05). There was no effect of the following moderators: type of medication, doses, sample size, age, gender, type of ADHD, comorbidity or dropout rate. Participants on medication reported 737 (12.6%) other cardiovascular effects. Notably, 2% of patients disc...

The Effect of Methylphenidate and Atomoxetine on Heart Rate and Systolic Blood Pressure in Young People and Adults with Attention-Deficit Hyperactivity Disorder (ADHD): Systematic Review, Meta-Analysis, and Meta-Regression

“…This meta-analysis has confirmed that there were significant increases in post- vs. pre-treatment HR and SBP in children/adolescents and adults receiving methylphenidate or atomoxetine as compared to placebo, which is consistent with recent meta-analysis that reported similar findings in children and adolescents [17]. We further clarified these risks in children/adolescents and adults taking atomoxetine and found atomoxetine caused significant and larger increases in post- vs. pre-treatment HR and SBP as compared to methylphenidate.…”

Vitamin‐mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo‐controlled trial

“…Those on micronutrients nominally grew more during the 10‐week trial than those on placebo, although the group difference was not significant ( p = .06, ES = 0.40). These results are relevant in view of the adverse effects that stimulants can have on height and blood pressure, both in the short term and long term (Hennissen et al., ; Swanson et al., ; Thapar & Cooper, ). Further, there were few reports among participants of loss of appetite, increased irritability and nausea, side effects frequently associated with stimulant medication (Thapar & Cooper, ).…”

Long‐term study of lisdexamfetamine dimesylate in Japanese children and adolescents with attention‐deficit/hyperactivity disorder

“…Notwithstanding, our study provides important evidence of the safety and efficacy of LDX in Japanese pediatric patients with ADHD. Additional studies, or pharmacovigilance assessments, would be appropriate in this population to confirm that LDX lacks major potential to cause growth retardation or adverse cardiovascular effects (eg, QTcF prolongation), or to be linked with abuse liability. Further studies specifically in Japanese patients with ADHD would also be useful to clearly define the overall place in therapy of LDX.…”