May 17, 2011 — Children and adolescents who take medication for attention-deficit/hyperactivity disorder (ADHD) are not at increased risk for cardiovascular events and death, according to results of a large observational cohort study.
"There has been concern that there might be a cardiovascular risk associated with ADHD medications. These drugs increase blood pressure and heart rate, and there are case reports of cardiovascular events in kids getting ADHD medication," senior study author Sean Hennessy, PharmD, PhD, an associate professor of epidemiology at University of Pennsylvania School of Medicine, Philadelphia, told Medscape Medical News.
"Our study provides reassurance that parents shouldn't let the potential risk of cardiovascular events keep them from treating their kids if they would otherwise benefit from it," he said.
The study was published online May 16 in Pediatrics . It was funded by Shire, a manufacturer of ADHD medications.
Low Event Rates in Users and Nonusers
Using 2 administrative databases, the researchers identified 241,417 children 3 to 17 years old with a prescription for an amphetamine, atomoxetine, or methylphenidate and matched each of them with up to 4 nonusers of ADHD medications (n = 965,668).
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| Dr. Sean Hennessy |
Specific outcomes included sudden cardiac death, myocardial infarction (MI), stroke, and cardiac arrhythmias. Median follow-up time was 135 days in users of ADHD medication and 609 days in nonusers.
The incidence of all these events was "very low" in both groups, the researchers report. As a result, they write many of the hazard ratios were inestimable, and those that were estimable had very wide 95% confidence intervals.
There were 28 deaths in the group exposed to ADHD medications (incidence 1.79 per 10,000 person-years) and 607 in the control group (incidence 3.00 per 10,000 person-years). There were no validated cases of MI or stroke in the exposed group and 11 cases in the unexposed group.
"The fact that the rates of cardiovascular events that could be identified were very low is of interest because at least we can tell that we do not have an epidemic of such events in kids receiving ADHD drugs," Dr. Hennessy noted in a prepared statement. "If ADHD medications were causing an epidemic of cardiovascular events, we would expect to see it in this study."
For the study, the researchers defined incident ADHD users as those with at least 180 days of observation before their first ADHD medication prescription and prevalent users as those with fewer than 180 days of observation before a first ADHD medication.
They found no statistically significant difference between incident users and nonusers in the rate of sudden death or ventricular arrhythmia or death from any cause.
Table 1. Cardiovascular Events in Incident Users vs Nonusers of ADHD Medications
| Endpoint | Hazard Ratio (95% CI) |
| Sudden death or ventricular arrhythmia | 1.60 (0.91 – 13.60) |
| Death from any cause | 0.76 (0.52 – 1.12) |
ADHD = attention-deficit/hyperactivity disorder; CI = confidence interval
Similarly, they did not find any statistically significant difference between prevalent users and nonusers in sudden death or ventricular arrhythmia, stroke/MI, or all-cause death.
Table 2. Cardiovascular Events in Prevalent Users vs Nonusers of ADHD Medications
| Endpoints | Hazard Ratio (95% CI) |
| Sudden death or ventricular arrhythmia | 1.43 (0.31 – 6.61) |
| Stroke/MI | 0.72 (0.11 – 7.11) |
| All-cause death | 0.77 (0.56 – 1.07) |
ADHD = attention-deficit/hyperactivity disorder; CI = confidence interval; MI = myocardial infarction
End of the Story?
Although this study is "reassuring," Dr. Hennessy added, "whether it puts the nail in the coffin" of concern about cardiovascular risks with these drugs "is really up for others to determine.
"This is an observational study; it's nonexperimental, but it does show a low rate of events, and we know that we have complete capture or close to complete capture for death and that the risk of death is certainly no higher in the group of kids using ADHD medications than in the population controls," Dr. Hennessy noted.
He also noted that results of a study on cardiovascular risks of ADHD medications in children sponsored by the US Food and Drug Administration and the Agency for Healthcare Research and Quality are due to be released soon.
"I think that together those results and our results are going to be able to reassure a lot of people," he told Medscape Medical News.
Long-Term Effects Still in Question?
Not everyone is reassured, however. Reached for comment, Almut Winterstein, PhD, from the College of Pharmacy, University of Florida in Gainesville, who was not involved in the study, noted that "none of the stimulant safety studies that has been published or that is under way will be able to address the long-term effect of stimulant exposure on cardiovascular morbidity and mortality.
…I don't think this study is reassuring.
"We will need to wait another decade to understand whether even only slightly increased blood pressure and heart rate over several years during childhood results in increased cardiovascular risk in later life," she added.
"Thus, I don’t think that this study is reassuring. Stimulants have side effects that may or may not be fatal. Until we know, risk-benefit considerations should include the potential for severe arrhythmia or sudden cardiac death."
The study was funded by Shire, a manufacturer of ADHD medications. All authors received funding from Shire through their employers. Two of the authors are employed by HealthCore Inc, which conducts research for and receives funding from pharmaceutical manufacturers for research services. A complete list of author disclosures is available with the original article. Dr. Winterstein has disclosed no relevant financial relationships.
Pediatrics. Published online May 16, 2011. Abstract
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