Are Amphetamines Associated with Adverse Cardiovascular Events Among Elderly Individuals?

Discussion

These data suggest that patients with a diagnosis of ADHD who are aged 65 years and older may be at elevated risk of a negative cardiovascular outcome if exposed to amphetamines. This risk may be mediated through known ASCVD metrics such as blood pressure; however, events may also be due to acute vasoconstriction and stress on a vulnerable cardiovascular system. Table 3 demonstrates that the mean SBP and HDL levels among individuals with amphetamine exposure were a fraction higher than those in the control group. On an individual level, these differences may not be clinically significant; however, this shows that population-level intermediate endpoints (HDL, LDL, A1c) are nearly equivalent (or favorable) for individuals with amphetamine exposure. Still, cardiovascular events are increased in this group. Further investigation regarding the relationship between intermediate endpoints (HDL, LDL, A1c, SBP, DBP) and cardiovascular events is warranted on an individual level.

Although previous studies have assessed cardiovascular risks associated with amphetamines and demonstrated increased heart rate and blood pressure in younger individuals, few studies have assessed risk specific to older populations. This is important to consider given the changes in cardiovascular physiology during the aging process. Most notably, as individuals age, they experience changes in myocardial elasticity and chemoelectrical conduction. In addition, elevated levels of circulating catecholamines and decreased β-adrenergic cellular receptor sensitivity are common.¹⁸ Atherosclerosis constitutes another significant age-related variation.¹⁹ All these age-related changes independently enhance the risk of adverse cardiovascular events, and it is plausible that the presence of amphetamines—which have innate characteristics that increase blood pressure and heart rate²⁰—creates complications for vulnerable cardiovascular systems in this age cohort.

A systematic review of cardiovascular outcomes related to amphetamines was published in 2012 and described studies among both adult and pediatric patients.²¹ They concluded that “stimulant use in children and adolescents likely did not result in negative cardiovascular outcomes, but found that there was a potential increased risk in adults.”²¹ While this review surmised that there was no increased risk of negative cardiovascular outcomes in young and middle-aged adults (categorized as individuals between 25 and 64 years old), it did not involve data focused on individuals older than 65 years of age. Similarly, a retrospective study by Michielsen et al suggested that stimulants are a “safe treatment for older adults with ADHD, under the condition that the cardiovascular parameters are monitored and appropriately managed during treatment.”²² It is important to note that this was a single-site study in the Netherlands limited by sample size (n = 113) and included patients aged 55 to 79 years. A small sample will bias results toward the null, and a heterogeneous population inclusive of people as young as 55 years may also mask the risk of amphetamines among older individuals. The data presented in our study represent a larger sample (n = 13,233) across 40 health care organizations and are exclusive to individuals older than 65 years. Given our data suggest significantly increased odds of negative cardiovascular outcomes, there is concern that smaller studies and those that do not adequately control for age may not detect significant cardiovascular risks among older individuals.

Even though our study focuses on a vulnerable population that has not been explored sufficiently, there are several important limitations to consider. First, the study was specific to patients with a diagnosis of ADHD. As such, the findings may not generalize to those treated with a stimulant for other conditions such as narcolepsy, depression, or dementia. Moreover, in this retrospective cohort, we cannot assess the level of amphetamine exposure, so we cannot comment on the influence of amphetamine dose or duration on cardiovascular outcomes. In addition, individuals in the control group who may have been exposed to amphetamines before the 3-year “washout” period could not be accounted for, which may create an underestimate of total amphetamine exposure. A prospective study or longitudinal data would better elucidate this relationship.

In addition, our study relied on the International Classification of Diseases, Version 10 (ICD-10) system for medical coding and billing. There are systemic challenges in establishing a diagnosis of ADHD,²³ which may result in misclassification of both cases and controls in this study. Moreover, there are inherent errors in medical diagnosis codes that can lead to misclassification bias. These study data cannot be accessed by chart review to determine what level of misclassification may exist. Some ICD-10 diagnoses, such as “arrhythmia,” may be vague or include benign conditions such as premature atrial contractions, which may not be clinically relevant indicators of risk.

Older individuals may be prescribed other, non-stimulant medication for ADHD, such as atypical antipsychotics. These may independently increase the risk of adverse cardiovascular events via their impact on cholesterol and QT intervals. We attempted to mitigate the risk of confounding by matching cohorts based on cholesterol levels and limiting the analysis to individuals with ADHD for both the exposed and control group. However, the potential impact of QT segment prolongation was not captured with these data. A recent study using the National Health and Nutrition Examination Survey dataset found that the use of antipsychotics for ADHD was too rare to include in their threshold for analysis²⁴ (which suggests this variable is unlikely to influence the inferences of our study). However, we believe assessing the relationship between QT-prolonging medications, amphetamines, and cardiovascular events in older adults is worth evaluating.

Despite these limitations, we believe these data are worth considering when evaluating the risks and benefits of stimulant prescriptions in elderly patients, especially given that stimulants are categorically listed on the American Geriatrics Society's Beers Criteria as a medication class to “Avoid.”²⁵ There is evidence they may offer therapeutic value for the treatment of depression,^{26⇓⇓⇓–30} dementia^31,32 and ADHD,^33,34; however, benefits should always be considered in the context of potential risks. This study raises concerns that the geriatric population may have a different risk profile than adolescents and young adults treated with amphetamines.