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and the WHO International Clinical Trials Registry Platform, from database inception to Jan 18, 2024, for published and unpublished randomised controlled trials comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, lisdexamfetamine, methylphenidate, modafinil, or viloxazine against each other or placebo. Primary outcomes were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), measured in mm Hg, and pulse, measured in beats per minute, at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. Summary data were extracted and pooled in random-effects network meta-analyses. Certainty of evidence was assessed with the Confidence in Network Meta-Analysis (CINeMA) framework. This study was registered with PROSPERO, CRD42021295352. Before study initiation, we contacted representatives of a UK-based charity of people with lived experience of ADHD-the ADHD Foundation-regarding the relevance of the topic and the appropriateness of the outcomes chosen. Findings 102 randomised controlled trials with short-term follow-up (median 7 weeks [IQR 5-9]) were included, encompassing 13 315 children and adolescents (aged >= 5 years and <18 years; mean age 11 years [SD 3]; of available data, 9635 [73%] were male and 3646 [27%] were female; of available data, 289 [2%] were Asian, 1719 [15%] were Black, and 8303 [71%] were White) and 9387 adults (>= 18 years, mean age 35 years [11]; of available data, 5064 [57%] were male and 3809 [43%] were female; of available data, 488 [6%] were Asian, 457 [6%] were Black, and 6372 [79%] were 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 107 (95% CI 036-179; moderate CINeMA confidence) with atomoxetine to 181 (105-257; moderate) with methylphenidate for SBP; from 193 (074-311; high) with amphetamines to 242 (169-315; low) with methylphenidate for DBP; and from 279 (105-453; moderate) with viloxazine to 558 (467-649; high) with atomoxetine for pulse. In adults, mean increase against placebo ranged from 166 (95% CI 038-293; very low) with methylphenidate to 23 (066-394; very low) with amphetamines for SBP; from 160 (029-291; very low) with methylphenidate to 307 (069-545; very low) with lisdexamfetamine for DBP; and from 437 (316-559; very low) with methylphenidate to 58 (23-93; very low) with viloxazine for pulse.Amphetamines, lisdexamfetamine, or methylphenidate were not associated with larger increments in haemodynamic values compared with atomoxetine or viloxazine in either children and adolescents or adults. Guanfacine was associated with decrements in haemodynamic values in children and adolescents (mean decrease against placebo of-283 [95% CI-38 to-185; low CINeMA confidence] in SBP, -208 [-3 to-117; low] in DBP, and-406 [-545-268; moderate] in pulse) and adults (mean decrease against placebo of-101 [-1376 to-644; very low] in SBP, -773 [-1188 to-358; very low] in DBP, and-683 [-1085 to-281; very low] in pulse). Only four RCTs informed on effects in the medium term and none on the long term. Interpretation Practitioners should monitor blood pressure and pulse in patients with ADHD treated with any pharmacological intervention, and not stimulants only. Given the short duration of available randomised controlled trials, new research providing insights on the causal effects of ADHD medications on cardiovascular parameters in the longer term should be funded. Funding National Institute for Health and Care Research. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Comparative cardiovascular safety of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis
Fava, Cristiano;Cipriani, Andrea;Cortese, Samuele
2025-01-01
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 International Clinical Trials Registry Platform, from database inception to Jan 18, 2024, for published and unpublished randomised controlled trials comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, lisdexamfetamine, methylphenidate, modafinil, or viloxazine against each other or placebo. Primary outcomes were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), measured in mm Hg, and pulse, measured in beats per minute, at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. Summary data were extracted and pooled in random-effects network meta-analyses. Certainty of evidence was assessed with the Confidence in Network Meta-Analysis (CINeMA) framework. This study was registered with PROSPERO, CRD42021295352. Before study initiation, we contacted representatives of a UK-based charity of people with lived experience of ADHD-the ADHD Foundation-regarding the relevance of the topic and the appropriateness of the outcomes chosen. Findings 102 randomised controlled trials with short-term follow-up (median 7 weeks [IQR 5-9]) were included, encompassing 13 315 children and adolescents (aged >= 5 years and <18 years; mean age 11 years [SD 3]; of available data, 9635 [73%] were male and 3646 [27%] were female; of available data, 289 [2%] were Asian, 1719 [15%] were Black, and 8303 [71%] were White) and 9387 adults (>= 18 years, mean age 35 years [11]; of available data, 5064 [57%] were male and 3809 [43%] were female; of available data, 488 [6%] were Asian, 457 [6%] were Black, and 6372 [79%] were 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 107 (95% CI 036-179; moderate CINeMA confidence) with atomoxetine to 181 (105-257; moderate) with methylphenidate for SBP; from 193 (074-311; high) with amphetamines to 242 (169-315; low) with methylphenidate for DBP; and from 279 (105-453; moderate) with viloxazine to 558 (467-649; high) with atomoxetine for pulse. In adults, mean increase against placebo ranged from 166 (95% CI 038-293; very low) with methylphenidate to 23 (066-394; very low) with amphetamines for SBP; from 160 (029-291; very low) with methylphenidate to 307 (069-545; very low) with lisdexamfetamine for DBP; and from 437 (316-559; very low) with methylphenidate to 58 (23-93; very low) with viloxazine for pulse.Amphetamines, lisdexamfetamine, or methylphenidate were not associated with larger increments in haemodynamic values compared with atomoxetine or viloxazine in either children and adolescents or adults. Guanfacine was associated with decrements in haemodynamic values in children and adolescents (mean decrease against placebo of-283 [95% CI-38 to-185; low CINeMA confidence] in SBP, -208 [-3 to-117; low] in DBP, and-406 [-545-268; moderate] in pulse) and adults (mean decrease against placebo of-101 [-1376 to-644; very low] in SBP, -773 [-1188 to-358; very low] in DBP, and-683 [-1085 to-281; very low] in pulse). Only four RCTs informed on effects in the medium term and none on the long term. Interpretation Practitioners should monitor blood pressure and pulse in patients with ADHD treated with any pharmacological intervention, and not stimulants only. Given the short duration of available randomised controlled trials, new research providing insights on the causal effects of ADHD medications on cardiovascular parameters in the longer term should be funded. Funding National Institute for Health and Care Research. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
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