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CVD risk upped by long-term use of ADHD drugs

A case-control study by Swedish scientists suggests that longer use of attention deficit-hyperactivity disorder (ADHD) medication is associated with an increased risk of cardiovascular disease, particularly hypertension and arterial disease.

Risk of cardiovascular disease rose with longer cumulative exposure to the drugs, peaking at three to five years of use (adjusted odds ratio [AOR] 1.27, 95% CI 1.17-1.39), Le Zhang of the Karolinska Institute in Stockholm and colleagues reported in JAMA Psychiatry.

When looking at the risk for specific diseases, only two were consistently elevated: hypertension (AOR 1.72, 95% CI 1.51-1.97, for 3 to ≤5 years; and AOR 1.80, 95% CI 1.55-2.08, for >5 years) and arterial disease (AOR 1.65, 95% CI 1.11-2.45, for 3 to ≤5 years), they reported.

“Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment with ADHD medications,” Zhang told MedPage Today.

As use of ADHD drugs has increased, so too have concerns about their cardiovascular side effects, as meta-analyses of randomised controlled trials have revealed increases in heart rate and blood pressure for both stimulant and non-stimulant ADHD medications.

Findings from longitudinal observational studies have been mixed, the researchers noted. Their own meta-analysis of observational studies showed no significant association between ADHD drugs and cardiovascular risk, however, they wrote “the possibility of a modest risk increase cannot be ruled out due to several methodological limitations in these studies”.

So they turned to Sweden’s nationwide health registers to assess data on 258 835 people aged six to 64 with a diagnosis of ADHD or ADHD medication dispensation from 2007 to 2020.

A total of 10 388 had a diagnosis of cardiovascular disease and were included in the final assessment. They were matched with 51 672 controls with ADHD but without cardiovascular disease.

The median age was 34.6, the majority were male (59.2%), and the median follow-up time was 4.1 years in both groups.

They found that through the entire follow-up period, each one-year increase in use of ADHD drugs was tied to a 4% increased risk of CVD (95% CI 1.03-1.05), and the corresponding increase for the first three years was 8% (95% CI 1.04-1.11).

They said they saw similar results when looking at children or youth and adults separately.

When looking by condition, the study didn’t show a significant increased risk for arrhythmias, heart failure, ischaemic heart disease, thromboembolic disease, or cerebrovascular disease.

However, they warned that an absence of association in this study “does not rule out an increased risk for mild arrhythmias or subclinical symptoms”.

When looking by medication, they found that long-term use of methylphenidate was associated with an increased risk of cardiovascular disease compared with no use (AOR 1.20, 95% CI 1.10-1.31, for 3 to ≤5 years; and AOR 1.19, 95% CI 1.08-1.31, for >5 years).

Lisdexamfetamine was also associated with an elevated risk of cardiovascular disease (AOR 1.23, 95% CI 1.05-1.44, for 2 to ≤3 years; and AOR 1.17, 95% CI 0.98-1.40, for >3 years).

Zhang noted that the study was limited by its observational nature and thus could not prove causality, and results by type of ADHD medication and type of cardiovascular disease need to be replicated by studies with larger sample sizes.

“Also, it is important to note the results were shown for individuals without pre-existing (cardiovascular disease), so the results may not be applicable to those with underlying (cardiovascular disease),” Zhang told MedPage Today.

In an accompanying editorial, Dr Samuele Cortese of the University of Southampton in the UK, and Dr Cristiano Fava of Lund University in Sweden, said the study fills an important gap in the understanding of the long-term effects of these drugs.

“Rigorously addressing the cardiovascular effects of ADHD medications has been challenging due to the limited availability of methodologically sound long-term studies,” they wrote.

Zhang and colleagues “addressed this gap by assessing the association between cumulative long-term use of ADHD medications up to 14 years and the risk of CVD”.

The results support current clinical guidance for preventing or managing cardiovascular-related adverse effects from ADHD medications, they wrote, and it “should remind us that clinical decision-making is often based on tricky trade-offs that should be considered at the individual patient level, rather than straightforward one-size-fits-all recommendations”.

Study details

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases

Le Zhang, Lin Li,   Henrik Larsson,  Zheng Chang.

Published in JAMA Psychiatry on 22 November 2023

Key Points

Question Is long-term use of attention-deficit/hyperactivity disorder (ADHD) medication associated with an increased risk of cardiovascular disease (CVD)?
Findings In this case-control study of 278 027 individuals in Sweden aged 6 to 64 years who had an incident ADHD diagnosis or ADHD medication dispensation, longer cumulative duration of ADHD medication use was associated with an increased risk of CVD, particularly hypertension and arterial disease, compared with nonuse.
Meaning Findings of this study suggest that long-term exposure to ADHD medications was associated with an increased risk of CVD; therefore, the potential risks and benefits of long-term ADHD medication use should be carefully weighed.

Abstract

Importance
Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear.

Objective
To assess the association between long-term use of ADHD medication and the risk of CVD.

Design, Setting, and Participants
This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up.

Exposure
Cumulative duration of ADHD medication use up to 14 years.

Main Outcomes and Measures
The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs.

Results
Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years).

Conclusions and Relevance
This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

 

JAMA Psychiatry article – Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases (Open access)

 

JAMA Psychiatry accompanying editorial – Long-Term Cardiovascular Effects of Medications for Attention-Deficit/Hyperactivity Disorder—Balancing Benefits and Risks of Treatment (Open access)

 

MedPage Today article – Longer Use of ADHD Meds May Boost Heart Risk (Open access)

 

See more from MedicalBrief archives:

 

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

 

Childhood ADHD medicines not linked to higher substance use later – US study

 

Benefits of long-term use of ADHD medications questioned

 

 

 

 

 

 

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