This review of the cardiovascular effects of attention-deficit/hyperactivity disorder (ADHD) medications focuses on stimulants, which we define as amphetamine and methylphenidate compounds, and the nonstimulant selective norepinephrine reuptake inhibitor (SNRI) atomoxetine hydrochloride. Therefore, discussion of both the epidemiology of ADHD and outcomes associated with ADHD treatment is limited to these pharmacological agents.
Epidemiology of ADHD and ADHD Treatment among Adults in the United States
The prevalence of ADHD among adults in the United States is between 2% and 5%, with the most common estimate of prevalence from the National Comorbidity Survey Replication being 4.4%, meaning that between 8 and 9 million adults (age 18–44 years) in the US are affected.1–3 The estimated prevalence of ADHD in adults older than age 50 years is approximately 3%.4,5 Among those diagnosed as children, 36% will continue to meet full diagnostic criteria for ADHD, whereas up to 60% will have significant persistent impairment from ADHD.6,7 According to observational data from Habel et al.,8 amphetamines and methylphenidate account for approximately 90% of medications prescribed and used for the treatment of ADHD, with another 8% of adults treated with atomoxetine, which has physiological effects similar to central nervous system (CNS) stimulants. Given stable prevalence rates, an increase in the general rate of stimulant prescription,9 and a growing adult population,10 the number of adults taking prescription stimulants for ADHD will continue to rise; currently, primary care clinicians identify, diagnose, and prescribe 58% of stimulant medications in the US.11
The US Food and Drug Administration (FDA) has approved five sustained-release stimulant formulations for adult ADHD. The formulations of methylphenidate and amphetamines include racemics, isomers, prodrugs, and one nonstimulant medication (atomoxetine hydrochloride). Both stimulant and nonstimulant medications have similar effects on blood pressure (BP) and heart rate, and, as stated previously, nearly all adults taking pharmacological agents for ADHD use stimulants or atomoxetine.
Concerns Regarding Long-Term Pharmacological Treatment
Given the increasing use of prescription medication in the treatment of ADHD, and an increase in the use of these medications throughout adulthood, concerns regarding the long-term health outcomes have risen. Specifically, people in the medical community are interested in whether ADHD medications increase a person's risk for developing cardiovascular disease (CVD).
The concern for chronic hypertension and tachycardia secondary to prolonged stimulant or atomoxetine use arises from these agents' mechanism of action. Both methylphenidate and amphetamines are stimulants with central and peripheral effects. These medications function by increasing the release of monoamines, specifically dopamine and norepinephrine, into the synaptic space by competitively inhibiting the reuptake of these monoamines.12–14 It should be noted that although amphetamines and methylphenidate have similar effects on monoamine transport, amphetamines also cause increased vesicular release into the synaptic space, making them slightly more potent than methylphenidate.15 Increased dopamine release in the brains of people with ADHD leads to decreased impulsivity/hyperactivity and increased attention. However, norepinephrine also binds to adrenergic receptors located on cardiac muscle, increasing both the contractility of the heart and heart rate.16 Atomoxetine has similar systemic effects because it functions as an SNRI.17 Preventing the reuptake of norepinephrine should theoretically increase heart rate due to increased binding of norepinephrine to the adrenergic receptors of the heart. Daily use of these medications might, therefore, induce a pathological increase in resting heart rate and/or increase a person's risk for developing chronic hypertension. Both hypertension and tachycardia are independently positively correlated with cardiovascular mortality.18,19 The possibility of increased cardiovascular mortality secondary to medication use has led to a substantial body of research assessing the long-term cardiovascular outcomes in people treated for ADHD with medication.
This article presents a review of the literature of the cardiovascular effects of ADHD medication in adults. Our methods included a PubMed search for the terms “adult,” “ADHD,” “cardiovascular outcomes,” “medication,” “treatment,” “epidemiology,” “blood pressure,” and “heart rate,” and cross-referencing appropriate articles. By design, we focused on potential effects on blood pressure, pulse, stroke, myocardial infarction (MI), and sudden death. Individual articles are presented first, followed by summary meta-analyses when available. Space limitations prevent us from discussing all individual studies; therefore, this review is not exhaustive.
There are multiple cardiovascular endpoints that researchers have examined in assessing the impact of ADHD medication; specifically resting BP, resting heart rate, risk of heart failure, and risk of cardiovascular events such as MI or stroke. The question these researchers have proposed is whether these medications cause pathological changes in any of these endpoints over an extended period of time. This question has been answered by a combination of both experimental and observational research, and the findings for these endpoints are discussed in the following text.
Individual clinical trials, with durations ranging from 10 weeks to 2 years, have reported a 2 to 5 mm Hg increase in systolic BP in response to amphetamine medication at doses between 20 and 60 mg.20,21 Spencer et al.22 conducted a study evaluating the safety of dexmethylphenidate and observed a minor elevation in systolic BP of approximately 2.5 mm Hg for both treatment and placebo, with no significant difference between the two groups. A randomized, placebo-controlled trial of 24 weeks by Rosler et al.23 found no differences in BP among participants treated with extended-release methylphenidate versus placebo. It should be noted that in this study, participants were started on 10 mg daily of methylphenidate but were titrated up to a maximum of 60 mg daily depending on individual efficacy. Atomoxetine has demonstrated levels of safety equivalent to amphetamine and methylphenidate. Adler et al.24 conducted an open-label study over the course of 4 years and found an average increase of 2 mm Hg for systolic BP. The changes in BP reported in these individual studies are supported by larger meta-analyses.
Mick et al.25 reviewed 20 clinical trials (N = 2,665) that were as long as 24 weeks and found a statistically significant increase in systolic BP of approximately 1.2 mm Hg for both methylphenidate and amphetamine across the studies they reviewed. A meta-analysis by Fredriksen et al.26 found that use of atomoxetine increased systolic BP by 1 to 3 mm Hg across multiple randomized controlled trials. A large meta-analysis conducted by Hammerness et al.27 that evaluated the cardiovascular consequences of atomoxetine, methylphenidate, and amphetamine reported changes in BP equivalent to those reported in the individual clinical trials and meta-analyses discussed thus far.
Amphetamine, methylphenidate, and atomoxetine have been shown to increase heart rate in adults. Weisler et al.20 reported that use of mixed amphetamine salts increased heart rate by an average of 2.1 beats per minute (bpm) over the course of 24 months. Spencer et al.22 conducted a 5-week clinical trial assessing the safety of dexmethylphenidate, reporting increases in heart rate of 3 to 6 bpm. It should be noted that this study reported an apparent dose-dependent relationship, as participants who received 30 mg of dexmethylphenidate exhibited a 3 bpm increase in heart rate, whereas those who received a dose of 40 mg showed increases of 6 bpm.22 A study summarizing two randomized, placebo-controlled trials each lasting 10 weeks found that atomoxetine caused an increase in heart rate of 3.8 to 6.7 bpm, and that this increase was significant compared to the changes observed in the placebo group.28
The changes found in these individual studies are supported by meta-analyses as well. In the assessment by Mick et al.25 of 12 different randomized controlled trials that evaluated the effects of CNS stimulants, the CNS stimulants were found to induce an average heart rate increase of approximately 5.7 bpm. Across these studies, each of which was placebo-controlled, changes in heart rate in the placebo groups were on average 0.5 bpm, which was statistically significant when compared to changes in the CNS-stimulant groups.25 A second meta-analysis conducted by Fredriksen et al.26 concluded that atomoxetine causes a chronic increase in heart rate ranging from 3 to 5 bpm, suggesting that both atomoxetine and CNS stimulants induce equivalent changes in heart rate.
Risk for Cardiovascular Events
Aside from risk factors such as hypertension and resting tachycardia, previous research had sought to evaluate the risk for adverse cardiovascular events such as MI or stroke associated with the use ADHD medication. Habel et al.8 conducted the largest study to date assessing these outcomes, analyzing medical records from more than 440,000 people age 25 to 64 years (approximately 150,000 medication users). Approximately 97% of these people were prescribed atomoxetine, amphetamine, or methylphenidate. Analysis of the medical histories of the participants revealed that people taking CNS stimulants or atomoxetine for ADHD had an approximately equal risk of experiencing an MI or stroke when compared to nonusers.8 However, the study is limited by its observational nature, mean stimulant exposure of only 0.33 years, and the populations it compares. Because rates of cardiovascular incidence were not studied longitudinally in treated and untreated ADHD populations, this study cannot evaluate whether initiation of CNS or atomoxetine use is associated with greater cardiac mortality within the ADHD patient population. The study is also limited because it estimates use based on prescription history, which may not equate to use as patients might not have taken their medication as prescribed.
A review by Hammerness et al.27 of placebo-controlled clinical trial evidence suggests that cardiovascular side effects such as palpitations occur more frequently among patients treated with active medication versus placebo. However, more serious cardiovascular events such as MI, arrhythmia, or cerebrovascular accident are rarely seen in large-scale clinical trials.27 These findings provide preliminary support for the safety of ADHD medication, but, given the limitations of the epidemiological research conducted thus far, further work is required to conclusively establish the long-term safety of these medications.
The existing body of literature asserts that stimulant and nonstimulant ADHD medications can cause statistically significant elevations in both BP and heart rate. These findings are reproduced consistently across a multitude of studies, but although they are statistically significant, the clinical significance remains unclear.
There are limitations to the findings of these studies that need to be considered in regard to clinical applicability. Drug studies typically exclude participants with cardiovascular issues such as hypertension (treated or not), structural/electrical abnormalities, cardiac medications, and age older than 65 years. In addition, there is generally no assessment or monitoring of caffeine consumption or smoking, which can cause BP variation throughout the day. Also, stressors the participants encounter during day may have an impact on BP/pulse readings in a clinical trial. In clinical practice, all of these factors are important in interpreting BP/pulse readings. Having the patient monitor BP/pulse at home in the morning before taking medication and again later in the day may provide more meaningful day-to-day readings; however, inconsistent or improper technique BP measurement can produce variations as large as 5 to 10 mm Hg.29,30 The inherent precision of BP monitors and manual-measurement devices are also ±5 mm Hg and ±3.6 mm Hg, respectively.31 Because of this variability, attempting to apply differences as small as 2 to 5 mm Hg, which is what the clinical trials studying ADHD medication report as a guideline for clinically significant changes in BP, would be ill advised.
A review of observational data does show that increases in BP of more than 10 mm Hg have been shown to significantly increase a person's risk for cardiac death; however, the magnitude of changes in group data observed with ADHD medication falls well below that threshold.32 Although group data may be reassuring, clinical prudence requires paying attention to outlying patients with elevated BP/pulse while using these medications.
The observed elevations in heart rate, although statistically significant, should also be treated cautiously. Sustained heart rates of higher than 10 bpm have been shown to significantly increase a person's risk of cardiac death, but this is greater than the elevation in resting heart rate observed across multiple studies evaluating the safety of ADHD medication.33
This is not to say that ADHD medications are devoid of risk and should be prescribed without caution. The studies discussed in this review evaluated ADHD medications in the context of proper use, and both amphetamine and methylphenidate have significant abuse potential.34 These studies also report mean changes, meaning that although people on average experienced small changes in BP and heart rate, some patients treated with these medications experienced larger elevations in these vital signs. Chronic resting heart rate above 90 bpm can increase a person's risk for CVD.33 Hypertension and borderline-hypertensive BP also significantly increase one's risk for CVD.32 There is also an element of unpredictability in patients who begin with high BP, treated or not. The current research does not evaluate whether these patients regress to the mean in terms of increases in BP and exhibit relatively small changes, or if they instead experience greater increases in BP possibly due to their predisposition to hypertension. Based on these factors, we recommend, in accordance with previous research, that screening should include a baseline assessment of heart rate, BP, and family history of CVD and sudden death.35–37 Assessment of both heart rate and BP during the course of treatment also seems prudent.35–38 In conjunction with these initial screening procedures, we advise routine reassessment of blood pressure, pulse, and patient-reported exercise tolerance throughout the course of treatment to ensure the stability of the patient's condition.
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