PHARMACOLOGICAL TREATMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: EFFICACY AND SAFETY EVIDENCES META-ANALYSIS OF DIRECTLY DRUGS COMPARISON FROM RANDOMIZED CONTROLLED TRIALS Suzane Virtuoso1,2 -
[email protected]/
[email protected], Helena Hiemisch Lobo Borba1, Fernanda Stumpf Tonin1; Roberto Pontarolo1 1Pharmaceutical
Sciences Postgraduate Program, Federal University of Parana, Curitiba, Parana, Brazil
2Professor
of Pharmacy, West of Paraná State University, Cascavel, Parana, Brazil
Introduction and Objective The Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms became an obstacle to academic, professional and personal relationships development and may trigger negative behaviors. Thus, appropriate treatment is important for patients and society. In this context, the search for better therapy evidences should be grounded, whenever possible, in direct comparisons studies (head-tohead). For children from six years old, pharmacological treatment is the most recommended intervention. Currently there are no evidences on efficacy and safety meta-analysis from head-to-head studies for drugs available to ADHD treatment. In this context, the aim of this study was to perform a meta-analysis exclusively from randomized controlled trials (RTC`s) headto-head in order to evaluate the efficacy and safety of drugs used to treat ADHD.
Methods We conducted a systematic review of all double-blind RTC`s that evaluated the efficacy and safety of allopathic agents in the treatment of ADHD in children and adolescents. The electronic search was performed in MEDLINE (Pubmed), The Cochrane Library, International Pharmaceutical Abstracts, EMBASE, Science Direct, Scopus, Web of Science, Scielo, Lilacs and PsycINFO and updated in September 2014. No filters or time limits were applied. The meta-analysis was conducted using relative risk and inverse variance for dichotomous variables and effect size for continuous variables with a confidence interval of 95%. The random effects model was applied and heterogeneity was estimated by I2 values.
Results Initially 9352 studies were selected. After screening 239 RTC`s were included of which 246 (83.9%) compared drugs versus placebo. It was possible to perform direct meta-analysis with 17 studies (5.8%) for the following comparisons: methylphenidate versus seleginine, atomoxetine, buspirone, bupropion, dextroamphetamine and mixed amphetamine salts. The efficacy meta-analysis was obtained to methylphenidate versus atomoxetine in three outcomes. Methylphenidate was superior in the CGI ADHD Severity Scale, SMD = 0.20 [0.06, 0.34], p=0.006, I2=0%. As for ADHD Rating Scale and Conners Parent Rating Scale no statistical difference between the drugs was identified. In a 3 studies meta-analysis (n=940 patients) methylphenidate caused more insomnia than atomoxetine and buspirone (0.41 [0.24, 0,70], p = 0,001, I2=1%) and (0,09 [0.02, 0.45], p = 0.003, I2=0%), respectively. Atomoxetine induced more fatigue (2.62 [1.40, 4.89], p = 0,003, I2=0%), cough (2.62 [1.40, 4.89], p = 0,003, I2=0%) and somnolence (5.16 [2.88, 9.22], p = 0,00001, I2=0%) than methylphenidate. There was no statistically significant difference between interventions for some adverse events as shown in Table 1. TABLE 1 – DIRECT SAFETY COMPARISONS BETWEEN DRUGS USED TO TREAT ADHD ADVERSE EVENTS
DRUGS
Abdominal pain
Methylphenidate vs. Atomoxetine Methylphenidate vs. Seleginine Methylphenidate vs. MASb Methylphenidate vs. Dextroamphetamine Methylphenidate vs. Bupropion Methylphenidate vs. Seleginine Methylphenidate vs. Atomoxetine Methylphenidate vs. Atomoxetine Methylphenidate vs. MASb Methylphenidate vs. Dextroamphetamine
Headache
Irritability Decreased appetite
aEffect
NUMBER OF STUDIES 2 2 4 2 2 2 3 3 4 3
NUMBER OF PATIENTS 610 68 221 294 70 68 940 940 221 360
STD MEAN DIFFERENCE (95% CI)a 1.31 [0.70, 2.45] 0.33 [0.06, 1.95] 1.70 [0.63, 4.57] 2.32 [0.35, 15.58] 0.36 [0.13, 1.02] 0.17 [0.04, 0.69] 0.86 [0.53, 1.37] 0.88 [0.49, 1.58] 1.25 [0.92, 1.69] 1.04 [0.88, 1.23]
p VALUE
I2
.40 .22 .30 .39 .05 .01 .52 .68 .15 .67
23% 0% 0% 0% 0% 0% 0% 75% % 0%
estimate for methylphenidate vs dextroamphetamine expressed as risk ratio (95% CI); bMAS = Mixed Amphetamine Salts.
Conclusion Despite the significant number of publications, a direct comparison was only possible with few RTC`s. However, the efficacy and safety of ADHD drugs compared in this meta-analysis may be considered similar. Further, in the clinical setting, it is important to ensure for each patient a drug that presents the best tolerable adverse events profile considering the efficacy benefits. ACKNOWLEDGES: To UFPR Pharmaceutical Sciences Postgraduate Program and UNIOESTE
