The debate over whether or not stimulant medications like methylphenidate raise the risk of cardiovascular diseases and events has been going back and forth for years. Many clinicians will remember the famous comment of Dr. Steven Nissan in a New England Journal of Medicine editorial in 2006 when he hoped that a physician’s hand would “tremble” before writing a stimulant prescription. Then there was the American Heart Association’s recommendation in 2008 that all children get an ECG before stimulants are started only to have the group backtrack on this shortly thereafter.
Lately the question has been raised again with this report published in the Journal of Child and Adolescent Psychopharmacology. To address some limitation of previous studies, the authors not only compared cardiovascular risk in stimulant users versus non-users but also did this analysis among patients who have received an ADHD diagnosis. The study used a Danish registry to follow prospectively a group of over 700,000 children. The main outcome variable was the presence of a cardiovascular disease or event. This was a somewhat broad designation with the most common diagnoses coded being cardiovascular disease not otherwise specified (40%) followed by an arrhythmia (23%). Hypertension was the diagnosis in 8% of those identified as having a cardiovascular event.
Overall, the use of stimulants was found to roughly double the risk of a cardiovascular events both among ADHD patients (hazard ratio=2.20) and compared to the general population (hazard ratio=1.83). Cardiovascular events were rare, with 170 events occurring among ADHD patients per 100,000 person years compared to 84 events per 100,000 person years for the overall population.
The association between risk and dose was a bit odd. When looking at the dose taken 12 months prior to the cardiac “event,” higher doses (defined as over 30mg/day of methylphenidate) were found to be associated with higher risk. When looking at doses taken more closely around the event, however, lower doses (less than 15mg perday) were associated with increased risk. In addition, among children with known cardiovascular risk, stimulant treatment did not convey significantly increased risk beyond these other factors. The authors also note that among the 5 ADHD children that experienced a serious cardiovascular event, none had been treated with stimulants.
In trying to put this all together, the authors concluded that stimulant treatment is associated with an increased risk of cardiovascular events compared both to the general population and to patients with ADHD who do not receive stimulant treatment.
The authors did try to sort out some of their puzzling findings with regard to dose. While admitting that this was speculative, they wondered if there might be a slight danger in dropping someone from a high stimulant dose to a low one, perhaps via a shortening of the QTc interval via which in turn might be mediated through dopamine transporters that are found on the myocardium.
While the study is important in documenting this association with stimulant even among individuals with ADHD, many questions remain about clinical significance. It is difficult to know exactly what is meant by “cardiovascular disease not otherwise specified” and other broad terms, especially since some prior studies that used more serious cardiac outcomes have not supported a link with stimulants. In addition, the nagging questions about increased screening also are not answered with these data. Of course, one could simply not prescribe stimulants, but then there are also studies linking stimulant treatment with reduced emergency department admissions. This will very likely not be the last chapter in this important issue.
Dalsgaard S, et al. Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study. J Child Adolsc Psychopharmacology 2014; 24(6):302-310.