Gainesville, FL - A retrospective cohort study shows that incidence rates of fatal or serious manifestations of heart disease for children with attention-deficit/hyperactivity disorder (ADHD) treated with central nervous system (CNS) stimulants were low and similar to national background rates [1].

Stimulant use was, however, associated with an increase in emergency department (ED) and physician visits for cardiac symptoms, the researchers, with first author Dr Almut G Winterstein (University of Florida at Gainesville), conclude.

Given that clinical trial data have shown an effect of stimulants on heart rate and blood pressure, they note, "it is not surprising that our analysis finds an association between stimulant use and ED visits for similar types of symptoms. Whether these symptoms manifest in heart disease is unclear, but our data suggest that such a manifestation is likely rare within the age group and follow-up time period studied."

"The message of this study is really ambivalent," Winterstein said. "It is pretty clear from our study that stimulants don't have such an increased risk that we will see very large populations being affected."

The number of deaths and hospital admissions was so small that they were not able to make any inferences, she added. "They were rare, which is good news; it means if there is a risk for manifestation of severe heart disease attributable to stimulants, it's not so pronounced that it would show in a small population. A 10-fold risk, for example, would have been picked up in our study. However, our study was inconclusive in terms of being able to rule out a subtler risk." Of note, the study included more than 50 000 children with ADHD.

Their report appears in the December 2007 issue of Pediatrics.

In February 2006, the FDA Drug Safety and Risk Management Advisory Committee voted to recommend a black-box warning describing the cardiovascular risks of stimulant drugs for ADHD, the authors write. In response, the FDA's Pediatric Advisory Committee suggested the warning may not be warranted, arguing that "a black box is meant for situations where the risk/benefit analysis would suggest not using the medication, which is not applicable to stimulants, given the strong evidence on treatment effectiveness and the weak evidence on risk."

The Drug Safety Advisory Committee's decision had been based on the known propensity of sympathomimetic agents to raise blood pressure and heart rate and the history of serious adverse effects seen with other members of this drug class, such as methamphetamine and phenylpropanolamine, as well as the rapid increase in stimulant use, exposing a large population of children and adolescents to these possible risks.

The clinical evidence of cardiac risk from stimulants approved for ADHD consists of placebo-controlled trial data showing an increase in BP and heart rate, they note, "which is typically described as mild, of short duration, and responsive to dosing or timing adjustments, and several case reports of stroke, myocardial infarction, and sudden death to the FDA Adverse Event Reporting System."

Some 20 international reports of sudden death resulted in the withdrawal of the extended-release formulation of a single-entity amphetamine product (Adderall XR, Shire Pharmaceuticals) from the Canadian market in February 2005, the authors add. That decision, they write, "was reached despite the concern that case reports deliver questionable proof of causality, especially since some case subjects showed on autopsy evidence of undiagnosed congenital heart disease. The Canadian regulatory body revoked its decision six months later, which reflects the intensity of the current debate in the absence of solid clinical evidence."

The lack of evidence becomes even more urgent considering that stimulants are now used chronically in about 5% of American children and a growing number of adults, they write. The aim of the present study was to look at the cardiac safety of CNS stimulants in children and adolescents treated for ADHD.

The retrospective cohort study included data from 10 years of Florida Medicaid claims, between July 1994 and June 2004, cross-linked to Vital Statistics Death Registry data. The cohort included all youths three to 20 years old who were newly diagnosed with ADHD during that time period.

Each month of follow-up was classified according to stimulant claims for methylphenidate (Ritalin, Novartis Pharmaceuticals), amphetamines, and pemoline (Cylert, Abbott Laboratories) as "current use," having an active stimulant claim; "former use," the time after periods of current use; or "nonuse," the time preceding the first stimulant claim, including follow-up of subjects who were never exposed to stimulants.

Study end points were cardiac death, first hospital admission for cardiac causes, or first ED visit for cardiac causes. Risks were then compared with time-dependent Cox regression analysis, adjusted for various cardiac risk factors.

In their study population of 55 383 subjects with 124 932 person-years of observation, 73 young people died, for an all-cause mortality rate of 58.4 per 100 000 person-years. The rank order of prevalent causes for death was accidents in 21, CNS disease in eight, homicide in seven, and disease of the circulatory system in five.

The rate of death due to circulatory causes was 4.0 per 100 000 person-years. No sudden cardiac death occurred during 42 612 person-years of current stimulant use, they note.

Hospital admissions for cardiac causes occurred in 27 children, for a rate of 21.6 per 100 000 person-years. Of these, eight occurred during stimulant use, 11 during 35 671 person-years of former use, and eight during 46 649 person-years of nonuse. Because of the small number of fatal and serious events requiring hospital admission, they note, they did not attempt to compare incidence rates among the groups.

They did find a 20% increase in the risk for emergency-department visits with current stimulant use compared with nonuse. No increased risk was seen comparing former use with nonuse.

The most common reasons for ED visits related to circulatory causes were syncope in 33.7%, cardiac dysrhythmia in 32.6%, tachycardia and palpitation in 15.7%, and hypertensive disease in 14.7%.

The association between stimulant use and physician office visits for a cardiac cause or symptoms was similar, with a 21% increase during current use periods vs nonuse periods, they write.

"Two important findings emerge from this study," the authors conclude. "First, the use of stimulants was associated with an increased incidence of ED and physician office visits for cardiac symptoms. Second, the incidence of fatal and serious events because of circulatory causes in the study population was low and seemed similar to national background rates."

In September 2007, the FDA and the Agency for Health Research and Quality (AHRQ) announced they would collaborate on "the most comprehensive study to date" of potential cardiovascular risks associated with prescription medications used to treat ADHD. The study will examine clinical data on some 500 000 children and adults who have taken medications for ADHD, looking specifically at cardiovascular risks, including MI and stroke. The analysis will focus on all drugs currently marketed for ADHD, looking at the overall risks, and then with drugs grouped by class.

The study will be coordinated by Vanderbilt University researchers, with principal investigator Dr William D Cooper on contract through AHRQ's Effective Health Care Program, and data analysis will be performed at Vanderbilt, Kaiser Permanente of California, the HMO Research Network, and i3 Drug Safety, as well as the FDA and AHRQ. The results are expected in about two years.

Winterstein said that she shared their results with the FDA at the International Conference of Pharmacoepidemiology. The design of the new AHRQ/FDA study is very similar to their own, she noted, but larger.

"What I'm curious about is patient populations who are at higher risk, and I'm wondering whether their sample size is even large enough to find these populations," she said. Among these populations are adults, who may already have other cardiac risk factors, and patients treated concomitantly with antidepressant and/or antipsychotic medications.

"We had about 20% to 25% of children concomitantly using an antidepressant and antipsychotic, both of which are associated with cardiac problems as well, and nobody really knows what the concomitant use is doing," she said.

Finally, the effect of chronic use also requires more study. "There literally are no data, not in a clinical trial or other fashion, that evaluate whether chronic use has any effect on children," she said.