New Study Answers Questions About Cardiac Risk of ADHD Drugs

The parents and physicians of children who need medications for attention-deficit/hyperactivity disorder (ADHD) likely breathed a collective sigh of relief when an online May 16 Pediatrics report stated that the rate of cardiovascular events and death in children who take those medications is no greater than in children who do not take them.

Credit: University of Pennsylvania

Sean Hennessy, Pharm.D., Ph.D., an associate professor of epidemiology and pharmacology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues evaluated a large cohort of children (241,417) aged 3 to 17 who were listed in one of two administrative databases: a five-state Medicaid database (1999-2003) and a 14-state Health-Core Integrated Research Database (2001-2006).

All children with a prescription for an amphetamine, atomoxetine, or methylphenidate were included and matched with up to four nonusers on the basis of data source, gender, state of residence, and age. Cardiovascular events were validated using medical records. The study was funded by Shire, which makes Adderall XR and Intuniv (guanfacine), which are approved for treatment of ADHD.

"The rate of cardiovascular events in exposed children was very low and in general no higher than that in unexposed control subjects," the study's authors concluded.

The study debuted in April on the heels of the most recent update from the Food and Drug Administration (FDA) of its ongoing study with the Agency for Healthcare Research and Quality of potential serious cardiovascular risks associated with medications used to treat ADHD in children and adults. The FDA update provided no new information, but said that the FDA "had received and is currently reviewing preliminary results" and planned to update the public after the results of the final analyses are evaluated.

The FDA first announced that joint study, known as the Multicenter Observational Cohort Study to Assess the Cardiovascular Risks of Medications Prescribed for ADHD, in October 2007. In February 2006, the FDA's Drug Safety and Risk Management Advisory Committee recommended that black-box warnings be added to ADHD drug labels regarding the risks of heart attacks and other cardiovascular events. In March 2006, an FDA Pediatric Advisory Committee concluded that the available safety data from clinical trials and postmarketing surveillance did not warrant black-box warnings and instead recommended revisions to the drug labels concerning use in patients with "known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at an increased vulnerability to the sympathomimetic effects of a stimulant drug" and a medication guide for patients; these recommendations were subsequently carried out in 2006 (Psychiatric News, April 21, 2006).

In 2008, Madelyn Gould, Ph.D., M.P.H., a professor of clinical psychiatry at Columbia University College of Physicians and Surgeons, and colleagues presented, and later published, results of a study of sudden death and the use of stimulant medications in youth. The study, a matched case-control design, compared mortality data from 1985-1996 state vital statistics to identify 564 cases of sudden death occurring at ages 7 through 19 with a matched group of 564 young people who died as passengers in motor vehicle traffic accidents. Ten of the sudden unexplained deaths were of youth taking stimulants, specifically methylphenidate; in contrast, use of stimulants was found in only two subjects in the motor vehicle accident comparison group, with only one involving methylphenidate use, leading Gould and colleagues to conclude that their work lent support to an association between the use of stimulants and sudden unexplained death among children and adolescents.

Though the results of the FDA's study—which is expected to include data from more than 500,000 ADHD medication users and 1 million nonusers across 12 health plans—have not yet been made public, the work of Hennessy and colleagues brings new information to the table regarding children and ADHD medications. "We really didn't have any predictions at the outset about whether or not we would find association between ADHD medications and cardiovascular events," said Hennessy, who became interested in the safety of ADHD medications as a result of the 2006 FDA meeting, where he was one of those who opposed a black-box warning about cardiovascular risks on stimulant medications.

"The FDA/AHRQ study is being performed by an excellent research team, and I expect that it's being done very carefully," Hennessy told Psychiatric News. "With those results coming out soon, we expect to see a revision to the warnings on the label. Especially if their study results are consistent with ours, such a revision would seem appropriate."

David Fassler, M.D., a child and adolescent psychiatrist and a clinical professor of psychiatry at the University of Vermont, agrees the study brings valuable information to the conversation: "This is a large-scale study utilizing data from diverse populations," he told Psychiatric News. "Consistent with previous findings, the authors report a very low rate of cardiovascular events in children and adolescents taking amphetamine, atomoxetine, or methylphenidate. However, they also note that the minimal frequency of such incidents precludes definitive conclusions regarding the relative risk of such rare but potentially serious side effects. Nonetheless, the study provides useful information and additional reassurance for physicians and parents of children with ADHD."

"Cardiovascular Events and Death in Children Exposed and Unexposed to ADHD Agents" is posted at <http://pediatrics.aappublications.org/content/early/2011/05/11/peds.2010-3371.full.pdf+html>. The FDA's April 2 "Communication About an Ongoing Safety Review of Stimulant Medications Used in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)" is posted at <www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165858.htm>.