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As you know, most research papers begin with an introduction, which in addition to providing a big picture view of the issue at hand also builds up to “Why this study? What was missing after earlier research? What’s the remaining question?” For this new review by Le Zhang and colleagues, the question was: Are the medications used for attention-deficit/hyperactivity disorder (ADHD) really free of any cardiac risk? Most are adrenergic stimulants, which can raise heart rate and induce arrhythmias or even myocardial infarction. After all, the FDA labeling in the United States includes a warning on stimulant use among individuals with structural cardiac abnormalities or other serious heart problems. So, treatment guidelines generally recommend assessing cardiac risk, such as with a personal and family history of cardiovascular disease, a physical examination, and perhaps an electrocardiogram.
Hi! Jim Phelps here for the Psychopharmacology Institute. Among previous meta-analyses on this question of cardiac risk for ADHD medications, older reviews tend to conclude no risk, but a larger, more recent review found an association between ADHD medications and the risk of sudden death or arrhythmia—although not for MI or stroke. Since then, there have been 13 new studies with data relevant to this risk evaluation. So, Dr. Zhang and colleagues have prepared a new updated meta-analysis. This is a huge issue. Well, I’ll ask you: What percentage of children between 3 and 17 years old have been given the diagnosis of attention-deficit/hyperactivity disorder, at least according to 2022 data from the United States Centers for Disease Control and Prevention? It’s big—10% here in the United States. By adulthood, how many still warrant a diagnosis? Well, several worldwide studies have found a rate of persistent ADHD, meaning it was present before adulthood and then continued of around 3% of the adult population. With that big a population potentially at risk, we’d better be as certain as possible. Is there any cardiac risk from stimulant medications?
This review from Zhang et al. examines 19 data sets with a total of nearly 4 million participants from 6 countries. Well, that ought to be enough to detect even an extremely small signal. Indeed, this could be so sensitive an assay as to reveal a statistically significant result but not clinically significant result. On the other hand, even a tiny, tiny cardiovascular risk might still be relevant. Well, depending on how you answer that question, you can interpret the results of this new meta-analysis either way—that is, overall, “we found no statistically significant association between ADHD medication use and cardiovascular disease among children and adolescents, young and middle-aged adults or older adults.”
But now, the hedging starts. First, “although the confidence interval could not exclude an increased risk.” That’s because as the authors make clear heterogeneity between studies was high and significant. In other words, the results from those 19 different studies were all over the place—some suggesting risk and some even suggesting reduced risk. Well, there’s more hedging around relative and absolute risk in this paper. The authors finally conclude “our meta-analysis provides reassuring data on the putative cardiovascular risk with ADHD medications”, followed by some highly cautious caveats that actually maintain concern. So, what are you supposed to do with this? Answer: Follow the existing guidelines about assessing cardiovascular risk before you start a stimulant. There are not enough data to do otherwise. However, there’s no new risk to report either. There. Done.
For more on this, I think the most interesting part is the hedging and the cautious caveats.
Abstract
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 Chang
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).
Data Sources PubMed, Embase, PsycINFO, and Web of Science up to May 1, 2022.
Study Selection Observational studies investigating the association between ADHD medications (including stimulants and nonstimulants) and risk of CVD.
Data Extraction and Synthesis Independent reviewers extracted data and assessed study quality using the Good Research for Comparative Effectiveness (GRACE) checklist. Data were pooled using random-effects models. This study is reported according to the Meta-analyses of Observational Studies in Epidemiology guideline.
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.
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Reference
Zhang, L., Yao, H., Li, L., Du Rietz, E., Andell, P., Garcia-Argibay, M., … & Chang, Z. (2022). Risk of cardiovascular diseases associated with medications used in Attention-Deficit/Hyperactivity Disorder: A systematic review and meta-analysis. JAMA Network Open, 5(11), e2243597-e2243597.
