Farhat, Luis C., Lannes, Alice, Del Giovane, Cinzia, Parlatini, Valeria, Garcia-Argibay, Miguel, Ostinelli, Edoardo G, Tomlison, Anneka, Chang, Zheng, Larsson, Henrik, Fava, Cristiano, Montastruc, François, Cipriani, Andrea, Revet, Alexis and Cortese, Samuele (2025) Comparative cardiovascular safety of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry, 12 (5), 355-365. (doi:10.1016/S2215-0366(25)00062-8).
Abstract
Background: concerns about the cardiovascular safety of medications used for the treatment of attention-deficit/hyperactivity disorder (ADHD) remain. We aimed to compare the effects of pharmacological treatments for ADHD on haemodynamic values and electrocardiogram (ECG) parameters in children, adolescents, and adults.
Methods: for this systematic review and network meta-analysis, we searched 12 electronic databases, including Cochrane CENTRAL, Embase, PubMed, and the WHO ICTRP, until 18 January 2024 for published and unpublished randomised controlled trials (RCTs) comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, lisdexamfetamine, methylphenidate, modafinil, or viloxazine against each other or placebo. Primary outcomes included change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), measured in mmHg, as well as pulse, measured in beats per minute, at timepoints closest to 12, 26, and 52 weeks. Summary data were extracted and pooled in random-effects network meta-analyses. Certainty of evidence were assessed with the Confidence in Network Meta-Analysis (CINeMA) framework. The protocol was pre-registered in PROSPERO (CRD42021295352). We contacted representatives of the ADHD Foundation to confirm the relevance of the topic, the appropriateness of the outcomes chosen, and their willingness to the dissemination of the study findings.
Findings: 102 RCTs with short-term follow-up (median 7 weeks; interquartile range 5-9) were included, encompassing 13,315 children and adolescents (aged ≥ 5 years and < 18 years, mean [standard deviation] 11 years [3]; 9,635 [73%] male and 3,670 [27%] female; 289 [2%] Asian, 1,719 [15%] Black, and 8,303 [71%] White) and 9,387 adults (≥ 18 years, 35 years [11]; 5,064 [57%] male and 3,809 [43%] female; 488 [6%] Asian, 457 [6%] Black, and 6,372 [79%] White). Amphetamines, atomoxetine, lisdexamfetamine, methylphenidate, and viloxazine led to increments in haemodynamic values in children and adolescents, adults, or both. In children and adolescents, mean increase against placebo ranged from: 1·07 (95% confidence interval 0·36, 1·79; CINeMA moderate confidence) with atomoxetine to 1·81 (1·05, 2·57; moderate) with methylphenidate for SBP; 1·93 (0·74, 3·11; high) with amphetamines to 2·42 (1·69, 3·15; low) with methylphenidate for DBP; 2·79 (1·05, 4·53; moderate) with viloxazine to 5·58 (4·67, 6·49; high) with atomoxetine for pulse. In adults, mean increase against placebo ranged from: 1·66 (0·38, 2·93; very low) with methylphenidate to 2·3 (0·66, 3·94; very low) with amphetamines for SBP; 1·6 (0·29, 2·91; very low) with methylphenidate to 3·07 (0·69, 5·45; very low) with lisdexamfetamine for DBP; 4·37 (3·16, 5·59; very low) with methylphenidate to 5·8 (2·3, 9·3, very low) with viloxazine for pulse. Amphetamines, lisdexamfetamine, or methylphenidate were not associated with larger increments in haemodynamic values compared to atomoxetine or viloxazine in either children and adolescents or adults. In contrast, guanfacine was associated with decrements in haemodynamic values in children and adolescents (mean decrease against placebo SBP: -2·83 [95% confidence interval -3·8, -1·85], low; DBP: -2·08 [-3, -1·17], low; pulse -4·06 [-5·45, -2·68], moderate) and adults (mean decrease against placebo SBP -10·1 [-13·76, -6·44], very low; DBP -7·73 [-11·88, -3·58], very low; pulse -6·83 [-10·85, -2·81], very low).
Interpretation: practitioners should monitor blood pressure and heart rate in patients with ADHD treated with any pharmacological intervention, and not stimulants only.
Funding: National Institute for Health and Care Research (NIHR).
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