, cerebrovascular disease (9%), and cardiovascular disease not otherwise specified (40%).
The study also showed an important, complex dose-response relationship, with ADHD children who were treated with high doses of stimulants (>30 mg methylphenidate) 12 months prior to the cardiovascular event showing a significantly higher risk (HR, 2.24) for cardiovascular events compared with those treated with lower doses (< 15 mg methylphenidate; HR, 1.43, compared with no stimulant use) 12 months before the event.
The authors pointed out that an inverse dose-response relationship was seen when looking at the dosage of stimulants at the time of the cardiovascular event: Among patients with ADHD who used stimulants and who experienced a cardiovascular event, more than half (57%) had reductions in their stimulant dose in the 12 months prior to the event.
Among stimulant users who did not have cardiovascular events, the rate of dose reduction in the previous 12 months was lower ― only 30% (P = .01).
“Our data suggest that high doses of methylphenidate followed by a lower dose may contribute to an increased long-term risk of adverse cardiovascular events,” the authors note.
“A possible biological mechanism for the time-dose-response relationship in our study may involve alterations to cardiac sympathetic function via altered striatal dopamine transporter levels in the brain, mediated through treatment and discontinuation of treatment with stimulants,” they write.
Key limitations of the study include the possibility that cardiovascular symptoms may have been more likely to have been identified in children receiving pharmacologic treatment and that minor cardiovascular symptoms may have led to a reduction in stimulant dose.
With previous studies linking stimulant use among ADHD patients with increases in blood pressure and heart rate, concern about the ever-expanding use of the drugs has grown in recent years.
A recent review of 10 population-based observational studies on cardiovascular risks with psychostimulant medications (Westover and Halm et al, BMC Cardiovasc Disord.2012;12:41 ) showed an increased risk in 1 of 7 studies in children and adolescents and in 2 of 3 studies involving adults.
Dr. Dalsgaard and colleagues report that although their new findings are consistent with the 1 study in the review showing an increased risk (Winterstein et al. 2007), their observation period was significantly longer (9.5 vs 2.3 years), which likely explains the finding of a higher risk (HR, 2.2 vs 1.2).
Commenting on the study’s findings for Medscape Medical News, Arthur N. Westover, MD, of the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, and lead author on the 10-study review, suggested that another explanation for the higher risk could be the inclusion of a broad scope of cardiovascular events.
“The investigators used a very broad outcome, essentially any kind of cardiovascular event, whether serious or not,” he said.
“When you broaden the outcome to include any kind of cardiovascular event, you are more likely to find a signal, but less able to determine whether it is clinically meaningful,” he said.
“For example, in the study, 40% of the cases were ‘cardiovascular disease not otherwise specified,’ ” he noted. “For a clinician or patient, it may be hard to interpret what that means.”
In contrast, he noted, another prominent study that looked at only serious cardiovascular events, including stroke, heart attack, and sudden death (Cooper, et al, N Engl J Med. 2011;365:1896-1904 ), which was reported by Medscape Medical News, did not find an increased risk.
Likewise, the new study also did not show an increased risk for death or serious cardiovascular events among stimulant users, Dr. Westover pointed out.
Mark Olfson, MD, MPH, professor of psychiatry at Columbia University Medical Center in New York City, and lead author on another of the studies included in Dr. Westover’s review ( J Am Acad Child Adolesc Psychiatry. 2012;51:147-56 ), added that an important limitation of the new study is a lack of informa