Case reports that have raised concerns about a possible link between drugs used to treat attention-deficit/hyperactivity disorder and an increased risk of serious cardiovascular events, but no evidence of such a link was found in a large retrospective cohort study involving data from more than 1.2 million children and young adults.

Although case reports from adverse-event reporting systems are important for helping to identify safety signals, they cannot be relied upon to quantify risk, and the findings of the current study, which are consistent with several other studies, suggest that risk is low, according to Dr. William O. Cooper of Vanderbilt University, Nashville, Tenn., and his colleagues.

The findings also raise questions about regulatory and policy decisions that followed a number of adverse-event reports in the United States and Canada.

"In Canada, Health Canada removed and then reinstated marketing of extended-release mixed amphetamine salts. In the United States, three different [Food and Drug Administration] advisory committees considered the issue and recommended a black-box warning for stimulants, as well as a medication guide for patients," the investigators wrote online in the Nov. 1 issue of the New England Journal of Medicine.

These and others policies, they wrote, "led to concern and confusion among health care providers, patients, and families about the risks of these drugs."

The current study involved nearly 2.6 million person-years of follow-up, including more than 373,000 person-years of current use of ADHD drugs. Neither current use nor former use was associated with an increased risk for serious cardiovascular events, compared with non-use. The adjusted hazard ratios were 0.75 for current use and 1.03 for former use (N. Engl. J. Med. 2011 Nov. 1 [doi:10.1056/NEJMoa1110212]).

Furthermore, current use was not associated with an increased risk for any individual end points in the study, including sudden cardiac death, acute myocardial infarction, and stroke. The investigators also saw no increase in risk in current users when former users (rather than nonusers) served as the reference group. That yielded an adjusted hazard ratio of 0.70.

The study cohort included participants aged 2 to 24 years in four large health plans. The investigators matched data from computerized health records to state death certificates and the National Death Index to identify serious cardiovascular events. They compared event rates in users of the ADHD drugs methylphenidate, dexmethylphenidate, dextroamphetamines, amphetamine salts, atomoxetine, and pemoline, and up to two nonuser controls subjects. In all, there were 3.1 serious cardiovascular events per 100,000 person-years.

The point estimates of the relative risks for ADHD drugs in this study did not indicate increased risk, but the upper limit of the 95% confidence interval suggested that a doubling in the risk could not be ruled out. However, several alternative analyses to test the robustness of the findings supported those of the primary analysis, the investigators explained, concluding that "the absolute magnitude of any increased risk would be low."

The Agency for Healthcare Research and Quality, the Department of Health and Human Services, and the Food and Drug Administration funded the study. Some authors reported disclosures other than grant funding from these organizations, including receiving grant funding or owning stock or stock options from various pharmaceutical companies.