In this very large cohort study conducted in 2 distinct populations, we found that the incidence of validated sudden death or ventricular arrhythmia, stroke, and MI was very low. In analyses of validated events, many of the HRs were inestimable because of low numbers of events, and those that were estimable had very wide 95% CIs. Thus, although the low incidence of events does not permit us to exclude the existence of moderate or even large relative associations, the absolute risk of cardiovascular events in children and adolescents receiving ADHD medications in this very large cohort was still very low. Also arguing against an important increase in risk is the observation that neither all-cause death, nonaccidental death, nor nonsuicide death was more common in those receiving ADHD medications than unexposed subjects. In addition, baseline cardiovascular diagnoses and risk factors seemed to be more prevalent in the treated than the control group.
From a methodologic perspective, a low PPV is understandable, given that PPV is directly proportional to incidence in the population studied, and the incidence of cardiovascular events in children and adolescents is very low. If the PPVs were lower in the exposed than unexposed subjects, it might suggest that exposure may have made it more likely that diagnostic codes for cardiovascular events appeared incorrectly on the discharge record, which could artificially inflate the rate of (unvalidated) events in the exposed group. However, there was an insufficient number of validated events to make a definitive conclusion about differential PPVs. For example, the PPV of ventricular arrhythmia or sudden death was 33% (95% CI: 11–62) in users and 42% (95% CI: 30–55) in nonusers. Although these numbers are somewhat different, both are too low to rely on, and there is considerable overlap in their 95% CIs. Such ascertainment bias might have been responsible for the few associations observed in the secondary analyses of claims-based cardiovascular events.
The low rate of validated sudden death or ventricular arrhythmia found in this study is lower than the rate found in an earlier study. In particular, Wren et al23
found an incidence rate of sudden death of 0.33 per 10 000 per year in those aged 1 to 20 years. If we assume that the PPV in the unavailable records in our study was the same as those for whom records were obtained, the incidence rate of sudden death or ventricular arrhythmia in our study would have been 0.21 to 0.28 per 10 000 per person-years in nonusers, which is very similar to these previous findings. Our incidence rate of all-cause death is squarely within the range of the rate of all-cause death in the United States, which ranges from 1.37 to 6.19 per 10 000 subjects aged 5 to 19 years.24
Three previous studies have tried to evaluate the rate of cardiovascular events in children and adolescents. In 2 smaller studies, no sudden cardiac death events were found among 32 807 and 5351 stimulant users.5,7
Nonetheless, in 1 of these 2 studies, stimulant users had a 1.20-fold (95% CI: 1.04–1.38) hazard for emergency-department visits for an outcome that included less severe cardiac events and symptoms than we studied (eg, angina, hypertensive disease, syncope, and palpitations) compared with unexposed patients with ADHD.5
A higher degree of clinical vigilance for cardiac events in the treated groups might explain this very weak association. In the third study, a case-control study using US mortality data, subjects aged 7 to 19 years who died suddenly had a 7.4-fold (95% CI: 1.4–74.9) odds of having used stimulants compared with those who died in a motor-vehicle crash.6
However, given the small number of stimulant-exposed case (n
= 10) and control (n
= 2) subjects, a delay of 1 to 23 years between time of death and collection of data, possible recall bias for stimulant use, and possible higher likelihood of postmortem inquiries into the cause of death in those who died suddenly compared with those who died in a car crash, its results may have been biased away from the null.
An important strength of this study is our very large and diverse study population. Another strength is the validation of our study outcomes. We assessed the validity of study events rather than relying on claims-based diagnoses, which we found to be unreliable. An additional strength is inclusion of all-cause death, which should be recorded completely and nondifferentially.
One limitation of our study is the low retrieval rate of medical records, which reduced our power to detect associations with validated events. However, the retrieval rate was very similar in unexposed and exposed groups, which should not have caused a bias toward the null. Furthermore, the low retrieval rate did not affect our analyses of death outcomes, which were also consistent with no increased cardiovascular risk. Another limitation is the potential for residual confounding. Because of the small number of events, we were unable to adjust simultaneously for multiple potential confounding factors. In addition, not all factors that one would like to evaluate as potential confounders are recorded in administrative data, including baseline blood pressure and BMI. Also, patients may have undiagnosed diseases (eg, congenital heart disease). In addition, there is underreporting of diagnoses of psychiatric conditions (eg, ADHD) in administrative databases, which most likely resulted in lower frequency of these diagnoses of psychiatric conditions than expected a priori.