Skip to main content
Top
Published in: Neurology and Therapy 4/2022

Open Access 26-08-2022 | Sudden Cardiac Death | Original Research

Risk of Major Cardiovascular and Cerebrovascular Events in Users of Lisdexamfetamine and Other Medications for Attention-Deficit/Hyperactivity Disorder in Denmark and Sweden: A Population-Based Cohort Study

Authors: Joan Forns, Elena Dudukina, David Hägg, Péter Szentkúti, Karin Gembert, Estel Plana, Alicia Gilsenan, Erzsébet Horváth-Puhó, Vera Ehrenstein, Johan Reutfors, Cristina Rebordosa

Published in: Neurology and Therapy | Issue 4/2022

Login to get access

Abstract

Introduction

This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine).

Methods

This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months’ data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6–24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression.

Results

From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85–3.14]) and previous users (1.61 [1.28–2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09–1.79) in LDX users and 1.17 (1.00–1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48–2.13) in Denmark, 1.13 (0.75–1.71) in Sweden, and 1.10 (0.77–1.58) in the pooled analysis.

Conclusion

Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.
Appendix
Available only for authorised users
Literature
1.
go back to reference Fayyad J, Sampson NA, Hwang I, et al. The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord. 2017;9(1):47–65.CrossRef Fayyad J, Sampson NA, Hwang I, et al. The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Atten Defic Hyperact Disord. 2017;9(1):47–65.CrossRef
2.
go back to reference Kooij JJS, Bijlenga D, Salerno L, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56:14–34.CrossRef Kooij JJS, Bijlenga D, Salerno L, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56:14–34.CrossRef
3.
go back to reference Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23(6):534–41.CrossRef Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23(6):534–41.CrossRef
4.
go back to reference Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727–38.CrossRef Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727–38.CrossRef
5.
go back to reference Elliott J, Johnston A, Husereau D, et al. Pharmacologic treatment of attention deficit hyperactivity disorder in adults: a systematic review and network meta-analysis. PLoS ONE. 2020;15(10):e0240584.CrossRef Elliott J, Johnston A, Husereau D, et al. Pharmacologic treatment of attention deficit hyperactivity disorder in adults: a systematic review and network meta-analysis. PLoS ONE. 2020;15(10):e0240584.CrossRef
6.
go back to reference Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013;27(1):15–30.CrossRef Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013;27(1):15–30.CrossRef
7.
go back to reference Liu H, Feng W, Zhang D. Association of ADHD medications with the risk of cardiovascular diseases: a meta-analysis. Eur Child Adolesc Psychiatry. 2019;28(10):1283–93.CrossRef Liu H, Feng W, Zhang D. Association of ADHD medications with the risk of cardiovascular diseases: a meta-analysis. Eur Child Adolesc Psychiatry. 2019;28(10):1283–93.CrossRef
8.
go back to reference Westover AN, Halm EA. Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review. BMC Cardiovasc Disord. 2012;12:41.CrossRef Westover AN, Halm EA. Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review. BMC Cardiovasc Disord. 2012;12:41.CrossRef
9.
go back to reference Schelleman H, Bilker WB, Kimmel SE, et al. Amphetamines, atomoxetine and the risk of serious cardiovascular events in adults. PLoS ONE. 2013;8(1):e52991.CrossRef Schelleman H, Bilker WB, Kimmel SE, et al. Amphetamines, atomoxetine and the risk of serious cardiovascular events in adults. PLoS ONE. 2013;8(1):e52991.CrossRef
10.
go back to reference Holick CN, Turnbull BR, Jones ME, Chaudhry S, Bangs ME, Seeger JD. Atomoxetine and cerebrovascular outcomes in adults. J Clin Psychopharmacol. 2009;29(5):453–60.CrossRef Holick CN, Turnbull BR, Jones ME, Chaudhry S, Bangs ME, Seeger JD. Atomoxetine and cerebrovascular outcomes in adults. J Clin Psychopharmacol. 2009;29(5):453–60.CrossRef
11.
go back to reference Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178–85.CrossRef Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178–85.CrossRef
12.
go back to reference Liang EF, Lim SZ, Tam WW, et al. 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. Int J Environ Res Public Health. 2018;15(8):1789. Liang EF, Lim SZ, Tam WW, et al. 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. Int J Environ Res Public Health. 2018;15(8):1789.
13.
go back to reference Mosholder AD, Taylor L, Mannheim G, Ortendahl L, Woodworth TS, Toh S. Incidence of heart failure and cardiomyopathy following initiation of medications for attention-deficit/hyperactivity disorder: a descriptive study. J Clin Psychopharmacol. 2018;38(5):505–8.CrossRef Mosholder AD, Taylor L, Mannheim G, Ortendahl L, Woodworth TS, Toh S. Incidence of heart failure and cardiomyopathy following initiation of medications for attention-deficit/hyperactivity disorder: a descriptive study. J Clin Psychopharmacol. 2018;38(5):505–8.CrossRef
14.
go back to reference Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673–83.CrossRef Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673–83.CrossRef
15.
go back to reference Coghill DR, Caballero B, Sorooshian S, Civil R. A systematic review of the safety of lisdexamfetamine dimesylate. CNS Drugs. 2014;28(6):497–511.CrossRef Coghill DR, Caballero B, Sorooshian S, Civil R. A systematic review of the safety of lisdexamfetamine dimesylate. CNS Drugs. 2014;28(6):497–511.CrossRef
16.
go back to reference Adler LA, Goodman DW, Kollins SH, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364–73.CrossRef Adler LA, Goodman DW, Kollins SH, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364–73.CrossRef
17.
go back to reference Adler LA, Dirks B, Deas PF, et al. Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(7):694–702.CrossRef Adler LA, Dirks B, Deas PF, et al. Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(7):694–702.CrossRef
20.
go back to reference Laugesen K, Ludvigsson JF, Schmidt M, et al. Nordic Health Registry-based research: a review of health care systems and key registries. Clin Epidemiol. 2021;13:533–54.CrossRef Laugesen K, Ludvigsson JF, Schmidt M, et al. Nordic Health Registry-based research: a review of health care systems and key registries. Clin Epidemiol. 2021;13:533–54.CrossRef
21.
go back to reference Schmidt M, Schmidt SAJ, Adelborg K, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91.CrossRef Schmidt M, Schmidt SAJ, Adelborg K, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91.CrossRef
22.
go back to reference Schmidt M, Pedersen L, Sørensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014;29(8):541–9.CrossRef Schmidt M, Pedersen L, Sørensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014;29(8):541–9.CrossRef
24.
go back to reference Nguyen TL, Collins GS, Spence J, et al. Double-adjustment in propensity score matching analysis: choosing a threshold for considering residual imbalance. BMC Med Res Methodol. 2017;17(1):78.CrossRef Nguyen TL, Collins GS, Spence J, et al. Double-adjustment in propensity score matching analysis: choosing a threshold for considering residual imbalance. BMC Med Res Methodol. 2017;17(1):78.CrossRef
25.
go back to reference McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32(19):3388–414.CrossRef McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32(19):3388–414.CrossRef
26.
go back to reference Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat. 2005;30(3):261–93.CrossRef Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat. 2005;30(3):261–93.CrossRef
27.
go back to reference Kittel-Schneider S, Arteaga-Henriquez G, Vasquez AA, et al. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity? Neurosci Biobehav Rev. 2022;132:1157–80.CrossRef Kittel-Schneider S, Arteaga-Henriquez G, Vasquez AA, et al. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity? Neurosci Biobehav Rev. 2022;132:1157–80.CrossRef
28.
go back to reference Jeong HE, Lee H, Lai EC, et al. Association between methylphenidate and risk of myocardial infarction: a multinational self-controlled case series study. Pharmacoepidemiol Drug Saf. 2021;30(10):1458–67.CrossRef Jeong HE, Lee H, Lai EC, et al. Association between methylphenidate and risk of myocardial infarction: a multinational self-controlled case series study. Pharmacoepidemiol Drug Saf. 2021;30(10):1458–67.CrossRef
Metadata
Title
Risk of Major Cardiovascular and Cerebrovascular Events in Users of Lisdexamfetamine and Other Medications for Attention-Deficit/Hyperactivity Disorder in Denmark and Sweden: A Population-Based Cohort Study
Authors
Joan Forns
Elena Dudukina
David Hägg
Péter Szentkúti
Karin Gembert
Estel Plana
Alicia Gilsenan
Erzsébet Horváth-Puhó
Vera Ehrenstein
Johan Reutfors
Cristina Rebordosa
Publication date
26-08-2022
Publisher
Springer Healthcare
Published in
Neurology and Therapy / Issue 4/2022
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI
https://doi.org/10.1007/s40120-022-00396-y

Other articles of this Issue 4/2022

Neurology and Therapy 4/2022 Go to the issue