Children With ADHD Should be Screened for Potential Heart Problems Before Initiating Treatment With Stimulant Medication

Fran Lowry

June 22, 2010

June 22, 2010 (Boca Raton, Florida) — Stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) can increase heart rate, blood pressure, and QT interval. Because of these effects, children should be screened for occult disease and get a baseline electrocardiogram (ECG) whenever possible, according to new research presented at the New Clinical Drug Evaluation Unit 50th Anniversary Meeting.

Up to 8% of children and adolescents are affected by ADHD. Stimulant medications, specifically methylphenidate and mixed amphetamine salt (MAS) formulations, are the 2 basic treatments, but concerns about their cardiotoxic effects have been raised.

Even though the cardiotoxic effects are thought to be mild, concern about cardiovascular events has led the American Heart Association (AHA) to issue guidelines for cardiac monitoring of all children with ADHD before starting treatment.

However, the American Academy of Pediatrics has responded by stating that there is no evidence to support the AHA's recommendation, said lead study author Raul R. Silva, MD, from the Department of Child & Adolescent Psychiatry, New York University Langone Medical Center in New York City.

"There has been a big brouhaha about the safety, particularly the cardiovascular safety, of stimulant medications for ADHD in kids, and at one point, the cardiac folks put a very big scare into people," he told Medscape Psychiatry.

"We wanted to get a sense of what has actually happened over the last ten years in 2 different kinds of studies — the double-blind, placebo-controlled studies and the longer studies, the open-label extension trials, because often, that is where you will see problems emerge."

Dr. Silva and colleagues reviewed all such trials published after 2000 that reported data on heart rate, blood pressure, and QT interval in children, adolescents, or adults with ADHD who were treated with methylphenidate or MASs and compared the cardiovascular data on all treated subjects across all the studies.

In their review of 3 placebo-controlled trials of MASs, which comprised a total of 659 patients who were treated with the medication for 3 to 6 weeks, they found that 1 trial reported significant increases in mean heart rate from baseline (5.0 beats per minute; P < .05).

None of the placebo-controlled trials with MASs showed significant blood pressure or QT interval changes.

When they reviewed 4 open-label extension trials of MASs, which comprised 3087 subjects who were treated for 15 weeks to 2 years, they found that that all of these trials reported significant increases in heart rate from baseline (1.5 to 4.4 beats per minute; P < .001).

The 4 MAS extension trials also reported significant increases in both systolic and diastolic blood pressure from baseline, ranging from 0.6 to 3.5 mm Hg for systolic blood pressure (P < .05) and from 0.7 to 2.6 mm Hg for diastolic blood pressure (P < .001). Three MAS extension trials noted QT interval increases ranging from 2.7 to 7.2 milliseconds (P < .05).

In their review of 3 placebo-controlled trials of 4 to 6 weeks of methylphenidate treatment in a total of 253 patients, they found that 2 of the trials reported significant heart rate increases ranging from 4.5 to 7.0 beats per minute (P < .001). One trial reported increases in systolic blood pressure of 1.5 mm Hg (P < .05), diastolic blood pressure of 4.0 mm Hg (P < .001), and QT interval (7.0 milliseconds; P < .05).

Of 2 open-label extension trials evaluating 6 to 12 months of methylphenidate treatment in 602 subjects, the investigators found that 1 trial showed significant increases in heart rate (3.9 beats per minute; P < .001), systolic blood pressure (3.3 mm Hg; P < .001), and diastolic blood pressure (1.5 mm Hg; P < .001).

There were no deaths or hospitalizations due to cardiovascular adverse events reported in any of the studies.

"At the end of the day, the real issues with safety have to do with what underlying cardiac conditions the patient may have," said Dr. Silva. "I think the cardiovascular recommendations are well intended, but you have to balance those with the doctor's ability and the patient's ability to actually get the baseline information and the screening studies, because if you prohibit kids from being treated for ADHD because they don't have access to an ECG, that's not going to be good for them."

He added that he always screens his pediatric patients. "The parents appreciate my doing this, and I have found some very interesting things, such as arrhythmias. When I go back to the pediatric cardiologist, they often tell me that it's nothing to worry about. So the take-home message here is monitor when you can, ask baseline questions, but also be reassured, because the data really [don't] show a heck of a lot of problems with cardiovascular side effects."

Richard P. Malone, MD, professor of psychiatry at Drexel University, Philadelphia, Pennsylvania, agrees that the moderate elevation in blood pressure and heart rate seen with stimulant drugs are not, for the most part, clinically relevant. He told Medscape Psychiatry that this study confirms what has been shown in smaller clinical trials.

"These drugs are associated with a moderate but probably not clinically significant increase in heart rate and blood pressure. This meta-analysis is confirmation of that, so these effects are to be expected, but in general won't be clinically significant. The real problem would be if you took large quantities in overdose, then you might have significant increases in blood pressure, but for usual clinical use in general, these are mild increases."

This study was sponsored by Novartis Pharmaceuticals Corporation. Dr. Silva has disclosed no relevant financial relationships. Dr. Malone has reported financial relationships with Bristol Meyers Squibb, Johnson & Johnson, and Eli Lilly.

New Clinical Drug Evaluation (NCDE) Unit 50th Anniversary Meeting: Abstract 12, Session I. Presented June 15, 2010.

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