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Longer use of attention deficit-hyperactivity disorder (ADHD) medication was associated with an increased risk of cardiovascular disease, particularly hypertension and arterial disease, a nested case-control study from Sweden showed.

Risk of cardiovascular disease rose with longer cumulative exposure to the drugs, peaking at 3 to 5 years of use (adjusted odds ratio [AOR] 1.27, 95% CI 1.17-1.39), Le Zhang, PhD, of the Karolinska Institute in Stockholm, and colleagues reported in .

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 乌鸦传媒 in an email.

As use of ADHD drugs has increased, so too have concerns about their cardiovascular side effects, as meta-analyses of randomized 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. Indeed, 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 ages 6 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 1-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 3 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, ischemic 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 乌鸦传媒 in an email.

In , Samuele Cortese, MD, PhD, of the University of Southampton in the U.K., and Cristiano Fava, MD, PhD, 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."

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