First-line stimulant class medications, such as methylphenidate and amphetamine formulations are FDA approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. It is estimated that 4.4% of US adults experience some symptoms and disabilities of ADHD. However adults receive 32% of all issued stimulant prescriptions.¹ Off-label treatment for conditions including weight management, fatigue related to depression, stroke, traumatic brain injury, or hyper-somnolence due to Obstructive Sleep Apnea (OSA) may account for the high prevalence of stimulant use in adults. Such conditions are frequently associated with history or risk of cardiovascular disease. Of note, OSA and other forms of sleep-disordered breathing have unfavorable effects on cardiovascular physiology, predisposing affected individuals to cardiovascular disease and cardiac arrhythmias.^2,3

Due to reports of cardiovascular adverse events and observed physiological effects, the package inserts for stimulant drugs warn against use in patients with preexisting heart disease or cardiac structural abnormalities due to risk of sudden death, stroke, and myocardial infarction (MI).^4-6 Furthermore, the FDA issued a safety announcement in 2011 stating that stimulant products and atomoxetine should not be used in patients with serious heart problems, or for whom an increase in blood pressure (BP) or heart rate (HR) would be problematic.⁷ Table 1 summarizes the available stimulant and stimulant-like medications, including those referenced by the FDA. Debate remains on the safety of stimulants in the cardiovascular population. Specifically, the use of stimulants in patients with history of or susceptible to arrhythmias has not been studied. In an effort to elucidate risk, interpretation of current evidence surrounding stimulant and stimulant-like drugs is offered.

Table 1: Stimulant and Stimulant-like Medications
Stimulants
Medication	Trade Names	FDA-labeled Indications
Methylphenidate	Concerta, Daytrana, Metadate CD, Metadate ER, Ritalin, Ritalin-LA, Ritalin-SR, Methylin, Methylin ER, Quillivant XR	ADHD
Dexmethylphenidate HCl	Focalin, Focalin XR	ADHD
Dextroamphetamine sulfate	Dexedrin, Dexedrin Spansules, Dextrostat, Liquadd, ProCentra, Zenzedi	ADHD, narcolepsy
Lisdexamphetamine	Vyvanese	ADHD, binge-eating disorder
Amphetamine, mixed salts	Adderall, Adderall XR	ADHD, narcolepsy
Methamphetamine	Desoxyn	ADHD, simple obesity
Stimulant-like (non-amphetamine containing)
Medication	Trade Names	FDA-labeled Indications
Atomoxetine	Strattera	ADHD
Modafinil*	Provigil	Excessive sleepiness associated with narcolepsy, OSA, SWD
Armodafinil*	Nuvigil	Excessive sleepiness associated with narcolepsy, OSA, SWD
*Not included in the 2011 FDA Safety Communication

CNS stimulants exert their action on the brainstem ascending arousal system and cortex, blocking the reuptake of norepinephrine and dopamine into the presynaptic neuron and increasing their release into the extraneuronal space. An increase in circulating catecholamines can activate cardiovascular beta-1 adrenoreceptors resulting in increased inotropy and HR, while activation of alpha-adrenoreceptors causes vasoconstriction and a rise in BP. Studies have indicated small, but statistically significant increases in BP (1-6 mmHg) and HR (2-5 bpm) with short-term stimulant use, as well as similar findings with once-daily methylphenidate up to one year of use.^8-11 The nonstimulant medication, atomoxetine is a selective norepinephrine reuptake inhibitor indicated for ADHD which appears to be free of effects on other noradrenergic receptors and neurotransmitter systems.¹² Nonetheless, it is has been shown to have similar increases in BP and HR with short term use compared to stimulants.^13,14 The aforementioned studies excluded subjects with clinically significant chronic medical conditions or did not offer description of comorbidities, such as cardiovascular disease. In addition, the studies were not powered due to inadequate sample size or follow-up duration to determine risk of clinical cardiovascular events.

The observed effects of stimulants on BP and HR would be expected to increase cardiovascular risk. Schelleman et al. found a 1.8-fold increase in risk of sudden death or ventricular arrhythmia in adult patients who initiated methylphenidate therapy.¹⁷ Methylphenidate dosage was inversely associated with risk, suggesting that the association may not be directly causal. Limitations of this study include unmeasured confounding variables due to the nonrandomized design, that methylphenidate users (n=43,999) were more likely to have preexisting cardiovascular disease than nonusers (n=175,955), and limited duration of follow-up with a median of 60 days. Even so, the findings are of concern and should not be disregarded.

Conversely, a retrospective, population-based study of more than 150,000 adults with prescriptions for methylphenidate, amphetamine, or atomoxetine matched to non-users demonstrated a lack of association between stimulant use and incidence of MI, sudden cardiac death (SCD), and stroke.¹⁵ Individuals with cardiovascular disease were included and potential confounding variables were adjusted for in the analysis. However, the study had several limitations and the authors did indicate that a modestly elevated risk could not be ruled out given the limited power and lack of a complete data set of risk factors. A similar study found no evidence of increased risk of serious cardiovascular events in adult initiators of amphetamines or atomoxetine, but could not rule out modest elevated risk due to limitations of unmeasured confounders and lack of stratified analyses.¹⁶

In analyzing safety of drug use in arrhythmia patients, potential for QT prolongation and risk of torsades de pointes (TdP) should be considered. Trials have found no statistically or clinically significant changes in QT intervals over short and long-term treatment with methylphenidate and amphetamine drugs.^10-12,18 Alternatively, there is evidence that atomoxetine may prolong the QT interval. Scherer et al demonstrated that atomoxetine inhibits cardiac hERG potassium channel currents which in turn can cause action potential prolongation and increase risk of development of acquired long-QT syndrome.¹⁹ When studied in healthy CYP2D6 poor metabolizers, atomoxetine was not associated with a clinically significant change in corrected QT (QTc) which is similar to findings of a pooled analysis to determine cardiovascular safety of atomoxetine.^20,13 However, there are few published reports of atomoxetine-induced life-threatening long QT syndrome.^21,22 CredibleMeds® is a nationally-recognized site which classifies potential QT prolonging drugs according to risk. As a result of recent literature and case reports of atomoxetine, it was recently added to the category of drugs that have possible risk of TdP. Methylphenidate and amphetamine-containing drugs are recommended to be avoided in patients with congenital long QT syndrome.

Modafinil and its R-enantiomer armodafinil are novel nonamphetamine psychostimulants indicated for improved wakefulness in adult patients with excessive sleepiness associated with narcolepsy, OSA, or shift-work disorder (SWD). Both medications have similar wake-promoting actions to sympathomimetic stimulant agents, yet differ in pharmacological profile and are thought to have lower potential for abuse and adverse cardiovascular events. Nonetheless, package labels have similar cardiovascular warnings to the stimulant drugs. Exclusive to modafinil and armodafinil is the warning against use in patients with history of left ventricular hypertrophy or in those with mitral valve prolapse who have experienced mitral valve prolapse with previous CNS stimulant use. This recommendation is based on minimal evidence of 3 patients of such history with observed adverse events of ischemic T-wave changes, dyspnea and palpitations in clinical studies.^23,24

To date, no studies have been published on the safety of modafinil and armodafinil specifically in cardiovascular patients with or without arrhythmias. The safety and tolerability of modafinil was evaluated in six randomized, double-blind, placebo-controlled studies in patients with hypersomnolence and showed infrequent (<1%) clinically significant increases in BP or HR and similar electrocardiogram (ECG) changes to placebo.²⁵ All trials were of short duration of 4-12 weeks. Rare treatment-related cardiovascular events were noted in a longer duration trial of 478 patients with narcolepsy over 40-weeks of modafinil therapy.²⁶ Most common were palpitations (1.5%), hypertension (1.0%), and tachycardia (1.0%). Schwartz et al. conducted a 12-month trial of armodafinil in 328 patients with OSA, SWD, or narcolepsy.²⁷ Cardiovascular disease, mostly hypertension, was prevalent in 139 (43%) of the patients. History of arrhythmia was noted in five patients. Only minimal changes in HR and BP were observed overall, however 6% of patients experienced hypertension and three serious cardiovascular adverse events (pulmonary embolism, MI, chest pain) were considered to be possibly related to armodafinil treatment. Two patients had clinically significant ECG changes of long QT syndrome and QRS complex prolongation, and three patients had changes in baseline QTc of > 60 msec. No correlation of adverse events with patients who had cardiovascular disease was described.

Few reports have been made of arrhythmic events associated with modafinil use. One published case report details a 54-year old male who developed premature ventricular contractions (PVCs) with modafinil usage that resolved after discontinuation.²⁸ Upon rechallenge with modafinil, the PVCs returned after 10-days of treatment, and resolved once again after re-discontinuation.

Although the cardiovascular impact of stimulant use is minimal in healthy populations, with minor elevations in HR and BP, concern remains regarding use in patients with preexisting cardiovascular conditions. The adrenergic activation caused by stimulants and stimulant-like drugs may have a larger impact on autonomic regulation in patients with compromised cardiovascular function. Even modest elevations in HR and BP may exacerbate preexisting cardiovascular conditions, particularly arrhythmias.

Studies to date evaluating cardiovascular safety of stimulant drugs have several limitations that may confound outcomes. Data has been retrospective and limited to less than two years, thus longer-term safety and cumulative effect of stimulants is unknown. Due to lack of inclusion of patients with history of cardiovascular disease, particularly arrhythmias, results should not be extrapolated to such populations. Furthermore, study outliers and case reports indicate the possibility of greater cardiovascular risk than observed, especially in vulnerable populations. Until further evidence of safety is demonstrated by large-scale, long-term, standardized trials, the avoidance of stimulant use in arrhythmia patients is prudent. Assessment of clinical benefits and risks should be made on an individualized basis when therapy is warranted. If initiated, caution must be exercised as detailed in regulatory warnings, with monitoring of cardiovascular parameters and use limited to short durations and lowest effective doses.

References

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2. Shahar E, Whitney C, Redline S, et al. Sleep-disordered Breathing and Cardiovascular Disease. Am J Respir Crit Care Med 2001; 163: 19-25.
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Keywords: Action Potentials, Adrenergic Agents, Adult, Amphetamine, Amphetamines, Attention Deficit Disorder with Hyperactivity, Benzhydryl Compounds, Binge-Eating Disorder, Blood Pressure, Brain Injuries, Brain Stem, Cardiovascular Diseases, Catecholamines, Chest Pain, Comorbidity, Confounding Factors, Epidemiologic, Cytochrome P-450 CYP2D6, Death, Sudden, Death, Sudden, Cardiac, Depression, Dexmethylphenidate Hydrochloride, Dextroamphetamine, Disorders of Excessive Somnolence, Dopamine, Double-Blind Method, Dyspnea, Electrocardiography, Follow-Up Studies, Heart Rate, Humans, Hypertension, Hypertrophy, Left Ventricular, Incidence, Long QT Syndrome, Male, Methamphetamine, Methylphenidate, Mitral Valve Prolapse, Myocardial Infarction, Narcolepsy, Neurons, Neurotransmitter Agents, Norepinephrine, Obesity, Potassium Channels, Prevalence, Product Labeling, Propylamines, Pulmonary Embolism, Retrospective Studies, Risk Assessment, Risk Factors, Salts, Sample Size, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Stroke, Sympathomimetics, Torsades de Pointes, Trimeprazine, Vasoconstriction, Ventricular Premature Complexes, Vulnerable Populations, Wakefulness

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