December 12, 2011 — Stimulants and other medications used to treat attention-deficit hyperactivity disorder (ADHD) confer no increased risk for serious cardiovascular events, according to a study published online December 12 in the Journal of the American Medical Association.

"This is one of the first studies, and the largest in adults, to examine the cardiovascular safety of ADHD medications," first author Laurel A. Habel, PhD, of the Division of Research, Kaiser Permanente Northern California, Oakland, told Medscape Medical News.

"We did not see any evidence that these medications were associated with an increase in risk of myocardial infarction, sudden cardiac death, or stroke," she said. "This was true when comparing current users to nonusers, or when looking just at the users of ADHD medications and comparing periods of current use to periods a year or more after discontinuation. We also did not see an increase in any patient subgroup, such as those with a history of cardiovascular disease," Dr. Habel noted.

"Solid Evidence"

In an accompanying editorial, Philip Shaw, MD, PhD, of the National Human Genome Research Institute, Bethesda, Maryland, writes that the study's greatest clinical influence lies in "how clinicians counsel patients regarding the risks and benefits of ADHD medications. Now there is solid evidence — perhaps even some heartening news — that physicians can use to address concerns about cardiovascular risk."

During roughly the last decade, the use of ADHD medications increased more rapidly in adults than in children, with an estimated 1.5 million adults in the United States taking these medications. Because these drugs raise heart rate and blood pressure, concerns have been raised about their cardiovascular safety in adults.

Clinical trials have provided "limited information" on the cardiovascular safety of ADHD medications, largely because the trials have been too small to evaluate serious events, such as myocardial infarction, sudden cardiac death, and stroke, the investigators note.

The retrospective, population-based cohort study used electronic healthcare records at 4 different sites. The study included a total of 443,198 adults aged 25 to 64 years, of whom 150,359 were users of ADHD medications at baseline. Methylphenidate accounted for 45% of current use, amphetamine for 44%, atomoxetine for 8%, and pemoline for 3%.

Cardiovascular disease was generally uncommon and was similar or modestly more prevalent in users than in nonusers. As expected, ADHD was more common among users; other psychiatric conditions were also more common among users.

During 806,182 person-years of follow-up (median, 1.3 years per person), 1357 cases of myocardial infarction, 296 cases of sudden cardiac death, and 575 cases of stroke were recorded.

The researchers say the multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medication was 0.83 (95% confidence interval [CI], 0.72 - 0.96).

Among new users of ADHD medications (study participants who did not use ADHD medications in the year before baseline), the adjusted RR was 0.77 (95% CI, 0.63 - 0.94). The adjusted RR for current use vs remote use (ie, >364 days since the day on which the supply of medication would be expected to run out) was 1.03 (95% CI, 0.86 - 1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82 - 1.28).

The investigators note that the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25 to 44 years and 0.77 events per 1000 person-years at ages 45 to 64 years. The "apparent protective associations likely represent healthy-user bias," they note.

"We also found little support for an increased risk with any specific medication or with longer duration of current use. Rate ratios did not appear to be influenced by prior cardiovascular disease or by prior non-ADHD psychiatric conditions," the authors write.

Focus on Adults "Welcome"

In his commentary, Dr. Shaw notes that this is the most comprehensive study to date that assesses the cardiovascular safety of ADHD medications and that the focus on adults is "welcome." ADHD affects about 4% of adults, and these individuals often struggle with it in their personal, academic, and work lives, he notes.

It is estimated that 30% of psychostimulant prescriptions are written for adults; the proportion is likely to increase, and the duration of treatment may be longer in adults than in children, Dr. Shaw notes. "Thus, data on cardiovascular safety of these medications are as relevant to adults as to children."

A limitation of the study, Dr. Shaw says, is its focus on the most severe cardiac events (ie, myocardial infarction, sudden cardiac death, and stroke). "These are very rare events; thus, even with this large sample size, study power was limited," he writes.

There are other possible adverse cardiac events associated with ADHD medications, such as palpitations and dyspnea, "which, although less severe, are nonetheless alarming to patients and can consume substantial health care resources," he points out.

Dr. Habel agrees. "Less severe events are also important, and studies of ventricular arrhythmias and other events could be worthwhile," she told Medscape Medical News.

"As with any study such as ours, there are limitations to the data, and we cannot completely rule out a modestly elevated risk," Dr. Habel added.

The investigators note in their report that the study did not take into consideration the dose of ADHD medication and therefore could not examine whether risk varied by this factor. The study does not provide information on the safety of ADHD medications in adults older than 65 years.

The current findings, Dr. Habel and colleagues note, are similar to those of another study published recently the New England Journal of Medicine (N Engl J Med. 2011;365:1896-1904) and reported by Medscape Medical News at that time. This study, by some of the same researchers, found no increased risk for serious cardiovascular events with ADHD medication use in a cohort of patients aged 2 to 24 years.

Thorough Assessment Still Warranted

Dr. Shaw notes that the current study raises several clinically important issues.

"First, the findings support the final decision by the US Food and Drug Administration in 2006 not to place a black box warning of serious cardiovascular events on ADHD medications for all children and adults but to pursue further research. The findings, however, do not directly inform the current black box warning for psychostimulants, which is confined to patients with structural heart lesions," he writes.

"In addition, the study provides no evidence to support routine obtaining of electrocardiograms before starting treatment, certainly insofar as this recommendation was driven by concerns about serious cardiovascular events," Dr. Shaw writes.

However, the study "does not obviate either the need for a thorough history and examination of all patients prior to starting any ADHD medications or the need for ongoing evaluations. Psychostimulants have many noncardiovascular adverse effects that must be monitored, including weight loss, appetite suppression, and insomnia," he points out.

The study was funded in part by the Agency for Healthcare Research and Quality (AHRQ), the US Department of Health and Human Services, the US Food and Drug Administration, and the National Institute on Aging.

Dr. Habel discloses receiving research grants from Merck, Takeda, and Sanofi-aventis. A complete list of author disclosures is listed with the original article. Dr. Shaw reports having received an unrestricted travel grant from Jannsen-Cilag to attend ADHD conferences in 2010 and 2011. He received no honorarium or other compensation.

JAMA. 2011. Published online December 12, 2011. Full article, Editorial