Our study supports previous findings confirming the safety of central nervous system stimulants in the treatment of attention-deficit/hyperactivity disorder and other mental disorders in children and young people. Similar to the report by Cooper and colleagues, most point estimates were below 1, indicating a small chance for excess risk associated with stimulant use and suggesting a residual healthy user bias.14
The upper confidence limits for the full cohort suggest that the maximum increase in risk should be no be higher than 44% for sudden cardiac death, acute myocardial infarction, or stroke and 46% for these events or ventricular arrhythmia, respectively, a lower upper risk boundary than reported in the study by Cooper and colleagues (hazard ratio 0.75, 0.31 to 1.85).14
With a baseline incidence rate of less than three events per 100
000 patient years of stimulant use, the absolute increase in risk, if any, can be expected to be small.
Stratified analysis did not support a differential effect of stimulants in young people at high risk and emphasised, as observed by others, that these events are extremely rare in healthy children.10
A small fraction of high risk patients, however, accounted for close to half of all events, suggesting a profound difference in risk. Of note, our ability to identify high risk status was dependent on respective diagnoses in automated claims data and some high risk patients might have been missed. Finally, inclusion of admissions to hospital for ventricular arrhythmia did not change our results. We conducted additional analyses with expanded definitions of admission for arrhythmia and cardiomyopathy, resulting in several hundred events, but risk estimates remained essentially the same and incidence rates were consistently low (results not shown). Because the claims based definitions of these endpoints have not been sufficiently validated in children our results should be interpreted with caution.
On the basis of US census estimates our study cohort was drawn from a population that represented more than a quarter of all children in the US. Nevertheless, in common with the previous studies, it struggled with small event rates, despite a massive sample size, and further emphasises periods of use of stimulants in this population. Because of its focus on children eligible for public health insurance (providing coverage for low income families, children in foster care, or children with disabilities and over-representing minorities) our study allowed evaluation of a more vulnerable population when compared with children with private insurance. Rather than excluding high risk groups, we present stratified risk estimates for high risk conditions associated with frequent stimulant use. The overall incidence rate for the primary endpoint (2.8 per 100
000 patient years) was similar to that in the study by Cooper and colleagues (3.1 events for 100
000 patient years).14
Our slightly lower event rates might be because of restriction to children with select mental health diagnoses, which was not required by Cooper and colleagues.14
That study also used a broader claims based screening algorithm to ascertain events if patient charts and autopsy reports were retrievable for verification, while our study relied on their validated automated case definitions.
Study strength and limitations
Our study has several distinct strengths. Firstly, we used a new user design because of our concern that immediate sympathomimetic effects such as tachycardia might cause early discontinuation of treatment in children more susceptible to cardiac events.26
Secondly, several features aided in establishing a balanced comparison group, including the requirement for diagnoses of mental disorder with high propensity for treatment with stimulants and the broad selection of variables for propensity score adjustment. Our comparison of baseline characteristics suggests that non-users had slightly more cardiovascular risk factors, but the magnitude of confounding was small, which is reflected in well overlapping propensity score distributions among stimulant users and non-users (see appendix, fig A). Use was largely associated with demographic variables and psychiatric parameters, which is consistent with previous reports.27
We might not have been able to capture the full range of cardiac risk factors from claims data and stimulant users might have been generally healthier. Our observation that the presence of even severe cardiac risk factors did not preclude treatment with stimulants, however, increases our confidence that the impact of residual confounding is probably limited—that is, that odds ratios are reversed because of its effects. Furthermore, our previous analysis in young people eligible for Florida Medicaid, a subpopulation of this study cohort, found a 20% increase in emergency department visits for mild cardiac causes, congruent with clinical trial reports of increased heart rate and blood pressure.10
The fact that these mild effects were captured in that analysis reduces the likelihood that a healthy user effect masked stimulant cardiac effects. Thirdly, even though our study was not designed to examine risks associated with antipsychotic use, it showed a significant cardiac risk for these agents of similar size as reported previously in adults.28
Finally, we aimed to exclude alternative causes, which could bias results, especially when event rates are as low as we observed. For example, the study by Schelleman and colleagues, which had included admissions to hospital and emergency department visits with a primary diagnosis of cardiac arrest, found low positive predictive values for their composite endpoint.13
When we examined causes of death attributed to these events in death records we noted a large proportion with non-cardiovascular causes, especially trauma. Thus, we relied on a validated claims based definition for our primary endpoint. We further confirmed our findings with a sensitivity analysis that censored children when claims indicated severe injury and acute infections.
As with all claims based studies, we cannot exclude non-adherence, which would result in misclassification of users and underestimate the risk of stimulants. Because most states permit only 30 days’ supply for controlled substances, however, exposure information was often updated according to prescription refills. We furthermore did not see any impact when we changed the definition of our grace period that defined the lengths of each prescription (data not shown). We also examined whether the use of majority rules in assigning drug exposure to the 15 day increments in our analysis might have introduced misclassification. For this, we examined the attribution of all adverse events to exposure status on the basis of definitions of daily versus 15 day exposure. The attribution for all events matched the exposure status that was assigned based on the 15 day period majority rules. We also ran sensitivity analyses that excluded time periods when participants were admitted to hospital in the short term (less than 30 days) for reasons other than the study endpoints, which our primary analysis ignored. Results were virtually identical. Finally, illicit use of stimulants in non-users might have contributed to misclassification.
With a median follow-up time of about two years our study is not able to examine the safety of long term use of stimulants. A possible pathway of severe short term effects is cardiomyopathy induced by tachycardia, a reversible form of cardiomyopathy that has been described in children and adults.30
Control of arrhythmias, which usually present as supraventricular or ventricular arrhythmia, and heart rate usually results in rapid improvement in cardiac function with normalisation of the ejection fraction within one to two weeks.32
The effect of even slight increases in heart rate or blood pressure over many years, however, is unclear. Likewise, it is unclear whether the effect of such subtle increases could manifest many years after use of stimulants.
Finally, because of sample size constraints we could not provide comparative safety estimates for different doses of stimulants or for methylphenidate and mixed amphetamine salts separately, but, given the small overall incidence of severe cardiac events, differences are expected to be subtle. We also did not find indications for differential effects in our previous analysis of emergency department visits resulting from cardiac symptoms.10
We examined a different, more vulnerable population than previous studies, and have confirmed earlier findings that treatment of children with central nervous stimulants is not associated with an increase in risk of severe cardiac events. Even if general concerns about bias in observational studies are considered, the observed incidence rates provide assurance for minimal absolute risk. It is important to note, however, that stimulant use was short term and the results might not generalise to children who use stimulants over many years. Furthermore, long term effects of slight increases on heart rate or blood pressure, even after discontinuation of use, are unknown and require ongoing monitoring for safety.
What is already known on this topic
- Case reports, concerns about a drug class effect, and a potential pharmacological pathway substantiated concerns about cardiac safety of central nervous system stimulants used in the treatment of children with psychiatric disorders
- Only one of several observational studies was sufficiently powered to investigate the risk for major cardiovascular events and found no association
What this study adds
- In a vulnerable population of children eligible for public insurance in the United States there was no significant association between use of stimulants for the treatment of mental health conditions and the outcomes of stroke, acute myocardial infarction, or sudden cardiac death
- Even in children with congenital heart and other cardiac disease receiving stimulant treatment for conditions such as attention-deficit/hyperactivity disorder there was no increased cardiovascular risk, but study power was limited
- Several additional sensitivity analyses confirmed no appreciable association between stimulant treatment and major cardiovascular events, but effect of long term use or long term consequences of even small increases in blood pressure or heart rate were not evaluated