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No conclusive CVD risk link to ADHD medicines – Swedish meta-analysis

With the increase of medication prescribed for Attention-deficit/hyperactivity disorder (ADHD) in recent years, concern has grown about the possible link with cardiac problems. However, recent research dispelled any obvious associations, said the scientists involved in the study.

Their extensive systematic review and meta-analysis based on 19 observational studies with more than 3.9m participants suggested that there was no statistically significant association between ADHD medications and the risk of cardiovascular events among children and adolescents, young and middle-aged adults, or older adults.

The symptoms of ADHD often persist into adulthood, and even into older age for a substantial number of patients. The various medications, including both stimulants and non-stimulants, are recommended for pharmacological treatment of the disorder, and the prevalence of ADHD medication use among both children and adults has increased substantially in many countries.

While evidence from randomised clinical trials (RCTs) suggests the drugs are efficacious in reducing the disorder’s symptoms, there are concerns about their cardiovascular safety. As ADHD medications are sympathomimetic agents that exert dopaminergic and noradrenergic effects, increasing heart rate and blood pressure is biologically plausible.

A previous Cochrane review of RCTs found that the stimulant methylphenidate was associated with increased pulse or heart rate. However, as these RCTs could only evaluate short-term effects, it remains uncertain whether these changes led to a clinically significant risk of cardiovascular disease (CVD) over time. Longitudinal observation studies evaluating serious cardiovascular outcomes associated with ADHD medication use have emerged during the past decade, but with mixed findings.

A review paper incorporating five large population-based studies in the US reported no association between stimulants and serious cardiovascular events in children. A meta-analysis of only three studies found no increased risk of arrhythmic and ischaemic cardiac events but a decreased risk of stroke.

A more recent meta-analysis of 10 studies showed a positive association between ADHD medications and risk of sudden death or arrhythmia but not for stroke, myocardial infarction, or all-cause mortality. However, it had several methodology limitations (e.g. not preregistered, narrow outcome definition, and missing several important studies). Moreover, several new original studies have been published after these meta-analyses.

Thus, an updated synthesis is needed to address those limitations as well as to include a broader range of cardiovascular events (e.g., hypertension, heart failure and transient ischaemic attack that have not been included in previous meta-analyses) and conduct sub-analyses by type of cardiovascular events and ADHD medications.

In addition, observational studies that evaluate the benefits or risks of medical treatments are prone to bias (e.g. immortal time bias, prevalent user bias, confounding by indication) if not conducted appropriately. It is therefore critical to make a rigorous quality assessment of the available studies and discuss common problems that future studies need to address.

Understanding whether, and to what extent, ADHD medications are associated with CVD is highly relevant from both clinical and public health perspectives, as an increasing number of individuals are receiving ADHD medications globally. Findings of any significant association would prompt research on underlying causal mechanisms (e.g. dopaminergic dysfunction and alterations in cytochrome P450 2D6 metabolism).

The most recent study, by scientists from the Karolinska Institute, Sweden, and published in JAMA Open Network, aimed to provide a comprehensive and updated systematic review and meta-analysis to assess the associations between ADHD medications and risks of a broad range of cardiovascular events. It also examined whether there was any difference in the associations by types of ADHD medication, types of cardiovascular events, sex, age and pre-existing CVD conditions.

Study details

Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis

Le Zhang, Honghui Yao, Lin Li, Ebba Du Rietz, Pontus Andell, Miguel Garcia-Argibay, Brian M. D’Onofrio, Samuele Cortese, Henrik Larsson, Zheng Changh.

Published in JAMA Network Open on 23 November 2022

Key Points

Question
Are attention-deficit/hyperactivity disorder (ADHD) medications associated with the risk of cardiovascular disease (CVD)?

Findings
This systematic review and meta-analysis based on 19 observational studies with more than 3.9 million participants suggested that there was no statistically significant association between ADHD medications and the risk of cardiovascular events among children and adolescents, young and middle-aged adults, or older adults.

Meaning
Despite no statistically significant association between ADHD medications and CVD, more evidence is needed for the potential risk of cardiac arrest and tachyarrhythmias, the cardiovascular risk in female patients and in those with preexisting CVD, and long-term risk.

Abstract

Importance
Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades, but there are concerns regarding their cardiovascular safety.

Objective
To provide an updated synthesis of evidence on whether ADHD medications are associated with the risk of a broad range of cardiovascular diseases (CVDs).

Main Outcomes and Measures
The outcome was any type of cardiovascular event, including hypertension, ischemic heart disease, cerebrovascular disease, heart failure, venous thromboembolism, tachyarrhythmias, and cardiac arrest.

Results
Nineteen studies (with 3 931 532 participants including children, adolescents, and adults; 60.9% male), of which 14 were cohort studies, from 6 countries or regions were included in the meta-analysis. Median follow-up time ranged from 0.25 to 9.5 years (median, 1.5 years). Pooled adjusted relative risk (RR) did not show a statistically significant association between ADHD medication use and any CVD among children and adolescents (RR, 1.18; 95% CI, 0.91-1.53), young or middle-aged adults (RR, 1.04; 95% CI, 0.43-2.48), or older adults (RR, 1.59; 95% CI, 0.62-4.05). No significant associations for stimulants (RR, 1.24; 95% CI, 0.84-1.83) or nonstimulants (RR, 1.22; 95% CI, 0.25-5.97) were observed. For specific cardiovascular outcomes, no statistically significant association was found in relation to cardiac arrest or arrhythmias (RR, 1.60; 95% CI, 0.94-2.72), cerebrovascular diseases (RR, 0.91; 95% CI, 0.72-1.15), or myocardial infarction (RR, 1.06; 95% CI, 0.68-1.65). There was no associations with any CVD in female patients (RR, 1.88; 95% CI, 0.43-8.24) and in those with preexisting CVD (RR, 1.31; 95% CI, 0.80-2.16). Heterogeneity between studies was high and significant except for the analysis on cerebrovascular diseases.

Conclusions and Relevance
This meta-analysis suggests no statistically significant association between ADHD medications and the risk of CVD across age groups, although a modest risk increase could not be ruled out, especially for the risk of cardiac arrest or tachyarrhythmias. Further investigation is warranted for the cardiovascular risk in female patients and patients with preexisting CVD as well as long-term risks associated with ADHD medication use.

 

JAMA Network article –Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder (Open access)

 

See more from MedicalBrief archives:

 

Benefits of long-term use of ADHD medications questioned

 

 

Adult-onset ADHD may not exist, study suggests

 

 

Prescription ‘smart drugs’ have opposite effect in healthy adults – Australian study

 

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