No mortality, CV-event hazard with ADHD drugs: Cohort study

Megan Brooks

May 18, 2011

Philadelphia, PA - Children and adolescents who take medication for attention-deficit/hyperactivity disorder (ADHD) are not at increased risk of cardiovascular events and death, according to results of a large observational cohort study [1] that are at odds with some prior reports.

"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 author Dr Sean Hennessy (University of Pennsylvania School of Medicine, Philadelphia) said in an interview.

"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."

The study, with first author Dr Hedi Schelleman (University of Pennsylvania), was funded by ADHD drug manufacturer Shire and published online May 16, 2011 in Pediatrics.

Using two administrative databases, the researchers identified 241 417 children three to 17 years old with a prescription for an amphetamine, atomoxetine, or methylphenidate and matched each of them with up to four nonusers of ADHD medications (n=965 668).

Specific outcomes included sudden cardiac death, MI, stroke, and cardiac arrhythmias. Median follow-up time was 135 days in ADHD-drug users and 609 days in nonusers.

The incidence of all the events was "very low" in both groups, the researchers report. As a result, they write, many of the hazard ratios couldn't be determined, and those that were 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.

"At least we can tell that we do not have an epidemic . . . "

"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," 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 significant difference between incident users and nonusers in the rate of sudden death or ventricular arrhythmia or death from any cause.

Cardiovascular events in incident users vs nonusers of ADHD medications

End point
Hazard r atio (95% CI)
Sudden death or ventricular arrhythmia
1.60 (0.91-13.60)
Death from any cause
0.76 (0.52-1.12)

Similarly, they did not find a significant difference between prevalent users and nonusers with respect to sudden death or ventricular arrhythmia, stroke/MI, or death from any cause.

Cardiovascular events in prevalent users vs nonusers of ADHD medications

End point
Hazard r atio (95% CI)
Sudden death or ventricular arrhythmia
1.43 (0.31-6.61)
0.72 (0.11-7.11)
All- cause death
0.77 (0.56-1.07)

While this study is "reassuring," Hennessy added, "whether it puts the nail in the coffin" regarding concern about cardiovascular risks with these drugs "is really up to others to determine."

The study was observational, he said, "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."

He also noted that results of a study on cardiovascular risks of ADHD medications in children sponsored by the US Food and Drug Administration (FDA) and the Agency for Healthcare Research and Quality (AHRQ) 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."

"I don't think this study is reassuring"

Dr Al mut Winterstein (University of Florida, Gainesville), who was not involved in the study, said when interviewed 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.

"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 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, from which all authors received funding through their employers. Two of the authors are employed by HealthCore , which conducts research for and receiv es funding from pharmaceutical manufacturers for research services. Disclosures for the coauthors are listed in the paper. Winterstein has no relevant disclosures .


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