The results of a large FDA-funded study evaluating the risk of serious cardiovascular events in adults using stimulants and other medications for attention-deficit/hyperactivity disorder (ADHD) have been published early online in the Journal of the American Medical Association (JAMA).  These show no evidence of an increased risk of heart attack, sudden cardiac death or stroke associated with use of these medicines. 

The authors note that over 1.5 million adults in the US were taking stimulants in 2005; the increased prescribing rate was likely due to an increase in ADHD diagnoses (although these medicines may also be used for narcolepsy and off-label indications).  Placebo-controlled studies have suggested that stimulants and atomoxetine elevate blood pressure and heart rate but they have not been large enough to assess risk of resultant clinical events (e.g. myocardial infarction [MI]); cardiovascular safety data from epidemiological studies are limited and inconsistent. 

The aim of this retrospective, population-based cohort study was to examine whether current use of medications used primarily to treat ADHD is associated with increased risk of MI, sudden cardiac death (SCD) or stroke in adults.  It was conducted in parallel with a study in children and young adults – the results of this were recently reported in the New England Journal of Medicine (see link below to view NeLM summary).

Researchers used data from electronic health records from four study sites in the US.  The analysis included 150,359 eligible adults (aged 25-64 years) who were dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline; each was matched to two non-users according to study site, age, sex, and calendar year.  The main outcome measure was a composite of serious cardiovascular events, including MI, SCD or stroke.  A summary cardiovascular risk score was constructed for each patient to control for differences in CVD risk between exposed and unexposed individuals.

The main findings reported, from a total of 806,182 person-years of follow-up, are as follows:
  

• Current use of ADHD medications was associated with a crude incidence of 1.34 (95% CI 1.14-1.57) per 1000 person-years for MI, 0.30 (0.20-0.42) for SCD and 0.56 (0.43-0.72) for stroke

• Current use was not associated with an increased risk of serious CV events versus non-use (multivariable-adjusted rate ratio [RR] of 0.83; 95% CI 0.72-0.96).  This was also true for new users of ADHD medications (adjusted RR 0.77; 0.63-0.94).

The researchers additionally compared current use to remote use (defined as >364 days since the end of the last days supply) to account for potential selection bias or unmeasured confounding that could arise from users being more or less health than non-users.  They note the following:

• The adjusted RR for current use vs. remote use was 1.03 (95% CI 0.86-1.24); for new use vs. remote use it was 1.02 (95% CI 0.82-1.28).  The authors note that the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years.

The authors conclude that current use of ADHD medications was not associated with an increased risk of serious CV events compared to remote use or no use in their studied population.  They do however caution that a modestly elevated risk cannot be ruled out due to the limited power and lack of complete information on potential confounders. 

The FDA has issued an updated communication regarding its ongoing safety review of stimulant medications, noting the results of the study and stating that patients should continue to use their medicine for the treatment of ADHD as prescribed by their healthcare professional.  It also reminds healthcare professionals that stimulant products and atomoxetine should generally not be used in patients with serious heart problems, or for whom an increase in blood pressure or heart rate would be problematic.