Clinical Context

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder characterized by developmentally inappropriate inattention and/or hyperactivity-impulsivity symptoms starting in childhood and often persisting into adulthood. Recommended pharmacological treatment, including stimulants and nonstimulants, has increased substantially in many countries.

Findings have been conflicting from longitudinal observation studies evaluating serious cardiovascular outcomes associated with ADHD medication use. An updated evidence synthesis is needed to address methodological limitations of previous studies and to include several new original studies published after previous meta-analyses.

Study Synopsis and Perspective

A new study provides some reassurance regarding the cardiovascular safety of medications used to treat attention-deficit/hyperactivity disorder (ADHD).

A large meta-analysis showed no statistically significant association between use of stimulant or nonstimulant ADHD medications and any cardiovascular disease (CVD) outcome across age groups.

However, a “modest” increase in risk could not be ruled out, especially with regard to risk for cardiac arrest or tachyarrhythmias and among women and those with preexisting heart disease.

“Overall, the meta-analysis provides reassuring data on the putative cardiovascular risk with ADHD medications, but the possible associations with cardiac arrest or tachyarrhythmias, among female patients, and among those with preexisting CVD warrant further investigation,” Dr Zheng Chang, PhD, with Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

The study was published online November 23 in JAMA Network Open.^[1]

ADHD medications can increase heart rate and blood pressure, making it biologically plausible that they could increase the risk for CVD, including arrhythmias, especially in susceptible people.

Yet the literature has been mixed, and an updated synthesis is needed to address limitations of prior studies, the investigators note in their article.

To that end, they analyzed 19 studies from the United States, South Korea, Canada, Denmark, Spain, and Hong Kong. The studies involved roughly 3.9 million children, adolescents, and adults (61% male; median follow-up time, 1.5 years).

The results showed no statistically significant association between ADHD medication use and any CVD outcome among children and adolescents (pooled adjusted relative risk [RR], 1.18; 95% CI, 0.91-1.53), young or middle-aged adults (RR, 1.04; 95% CI, 0.43-2.48), older adults (RR, 1.59; 95% CI, 0.62-4.05), or overall (RR, 1.22; 95% CI, 0.88-1.68).

By medication type, there were no significant associations for stimulant medications (RR, 1.24; 95% CI, 0.84-1.83) or nonstimulant medications (RR, 1.22; 95% CI, 0.25-5.97).

Regarding specific CVD outcomes, no statistically significant association was suggested for 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).

The risk for CVD outcomes associated with ADHD medications seemed to be higher in those with preexisting CVD (RR, 1.31; 95% CI, 0.80-2.16) compared with those without prior CVD, although the association did not reach the threshold of statistical significance.

Point estimates for risk for CVD with ADHD medications also trended higher among female compared with male patients (RR, 1.88; 95% CI, 0.43-8.24).

“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,” the authors say.

They also say that further studies with rigorous methods are needed to evaluate the long-term risk for CVD associated with ADHD medication use.

In only 2 of the 19 studies was follow-up time sufficient to examine the long-term CVD risk associated with ADHD medication, but these studies were only of moderate quality.

Other limitations include high heterogeneity between studies and an inability to compare the associations between specific ADHD medications. Also, few studies had information on dosage and duration of medication use.

“Importantly,” Dr Chang told Medscape Medical News, “the findings are presented at the population level; in clinical practice, clinicians should make individual-level assessment of the patient’s risk for cardiovascular outcomes and weigh it with other risks and benefits of ADHD medications.”

In an invited commentary, Roy Ziegelstein, MD, with Johns Hopkins University School of Medicine, Baltimore, Maryland, says the investigators are “appropriately cautious in the stated conclusions of this study. Clinicians should be similarly cautious in reaching conclusions about the safety of ADHD medications, especially in older adults with established CVD.”^[2]

Dr Ziegelstein also notes that as ADHD medication use increases among older adults, the likelihood that individuals with preexisting CVD will be exposed to these medications increases as well.

Of note, he pointed to a study published last year that showed that older adults exposed to amphetamines were at increased risk for CVD events compared with those who did not take amphetamines (odds ratio, 6.16; 95% CI, 4.22-8.99).^[3]

A separate study of older adults found that the use of prescription stimulants was associated with an increased risk for a CVD event at 30 days, with a hazard ratio of 3.0 (95% CI, 1.1-8.7) for ventricular arrhythmias and 1.6 (95% CI, 1.1-2.1) for stroke or transient ischemic attack.^[4]

It should also be noted that polypharmacy is common among older individuals, and the potential for drug-drug interactions is therefore greater, Dr Ziegelstein writes.

“Every treatment decision is a balance of potential harm and potential benefit, and that balance is different for every individual patient based on their biological variability. . .and other important differences in psychological, social, cultural, behavioral, and economic factors and each individual’s unique life circumstances,” Dr Ziegelstein advises.

Although the study by Chang and colleagues is “reassuring in many ways, health care professionals must carefully weigh these factors when prescribing ADHD medications, especially to older adults, individuals with established CVD, and those with other comorbidities that increase CVD risk,” Dr Ziegelstein concludes.

The study was supported by grants from the Swedish Research Council for Health, Working Life, and Welfare and the European Union’s Horizon 2020 research and innovation program. Dr Chang has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article. Dr Ziegelstein has disclosed no relevant financial relationships.

JAMA Netw Open. Published online November 23, 2022.

Clinical Implications

• The most comprehensive meta-analysis to date suggested no statistically significant association between ADHD medications and CVD risk across age groups.
• However, it could not exclude a modest risk increase, especially for risk for cardiac arrest or tachyarrhythmias.
• Implications for the Health Care Team: The healthcare team should carefully weigh and discuss possible cardiovascular risks for ADHD medication and rigorously follow guidelines for blood pressure and heart rate monitoring at baseline and follow-up.

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