The Safety of Stimulant Use in Cardiovascular and Arrhythmic Patients - American College of Cardiology (2023)

Frontline stimulant drugs such as methylphenidate and amphetamine formulations are FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. An estimated 4.4% of American adults experience some ADHD symptoms and impairments. However, adults receive 32% of all stimulant prescriptions issued.¹Off-label treatment for conditions such as weight management, depression-related fatigue, stroke, traumatic brain injury, or hypersomnolence due to obstructive sleep apnea (OSA) may explain the high prevalence of stimulant use in adults. Such conditions are often associated with a history or risk of cardiovascular disease. It is important to note that 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 adverse cardiovascular events and observed physiological effects, the package inserts for stimulant medications warn against use in patients with pre-existing heart disease or structural heart abnormalities due to the risk of sudden death, stroke, and myocardial infarction (MI). .^4-6Additionally, the FDA issued a safety announcement in 2011 stating that stimulant products and atomoxetine should not be used in patients with serious heart conditions or for whom an increase in blood pressure (BP) or heart rate (HR) would be problematic.⁷Table 1 summarizes available stimulants and similar medications, including those listed by the FDA. Debate continues over the safety of stimulants in the cardiovascular population. Specifically, the use of stimulants in patients with a history of or susceptible to arrhythmias has not been studied. In an effort to elucidate the risk, interpretation of current evidence on stimulants and similar drugs is offered.

CNS stimulants exert their action on the ascending excitation system of the brainstem and cortex, blocking the reuptake of norepinephrine and dopamine in the presynaptic neuron and increasing their release into the extraneuronal space. An increase in circulating catecholamines can activate cardiovascular beta-1 adrenoceptors, increasing inotropy and heart rate, whereas activation of alpha adrenoceptors causes vasoconstriction and increased 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 for up to one year of use.^8-11The nonstimulant medication atomoxetine is a selective norepinephrine reuptake inhibitor indicated for ADHD that appears to have no effect on other noradrenergic receptors and neurotransmitter systems.¹²However, it has been shown to have similar increases in BP and HR with short-term use compared to stimulants.^13,14The aforementioned studies excluded subjects with clinically significant chronic medical conditions or did not provide a description of comorbid conditions such as cardiovascular disease. Furthermore, the studies were insufficient due to inadequate sample size or duration of follow-up to determine the risk of clinical cardiovascular events.

The observed effects of stimulants on BP and HR are expected to increase cardiovascular risk. Schelleman et al. found a 1.8-fold increase in the risk of sudden death or ventricular arrhythmia in adult patients who started methylphenidate therapy.¹⁷Methylphenidate dose 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 non-randomized design, that methylphenidate users (n = 43,999) were more likely to have pre-existing cardiovascular disease than non-users (n = 175,955), and a longer duration. limited follow-up with a median of 60 days. Still, the results are worrisome and should not be ignored.

In contrast, a retrospective population-based study of more than 150,000 adults with prescriptions of methylphenidate, amphetamine, or atomoxetine combined with non-users demonstrated a lack of association between stimulant use and the incidence of myocardial infarction, sudden cardiac death (SCD) and stroke.¹⁵People with cardiovascular disease were included and possible confounding variables were adjusted in the analysis. However, the study had several limitations and the authors stated that a moderately elevated risk cannot be ruled out due to limited power and lack of a comprehensive dataset of risk factors. A similar study found no evidence of an increased risk of serious cardiovascular events in adults who started using amphetamines or atomoxetine, but could not rule out a moderately increased risk due to limitations of unmeasured confounding factors and lack of stratified analyses.^sixteen

When considering the safety of using the drug in patients with arrhythmia, the potential for QT prolongation and the risk of torsades de pointes (TdP) should be considered. The trials found no statistically or clinically significant changes in QT intervals during short-term and long-term treatment with methylphenidate and amphetamines.^10-12,18Alternatively, there is evidence that atomoxetine can prolong the QT interval. Scherer et al demonstrated that atomoxetine inhibits cardiac hERG potassium channel currents, which in turn may cause action potential prolongation and increase the risk of developing acquired long QT syndrome.¹⁹When studied in healthy CYP2D6 poor metabolisers, atomoxetine was not associated with a clinically significant change in corrected QT (QTc), which is similar to findings from a pooled analysis to determine the cardiovascular safety of atomoxetine.^20,13However, there are few published reports on atomoxetine-induced life-threatening long QT syndrome.^21,22CredibleMeds® is a nationally recognized website that ranks potential QT prolongation medications based on risk. As a result of recent literature and case reports of atomoxetine, it has recently been added to the category of drugs that carry a possible risk of TdP. It is recommended to avoid drugs containing methylphenidate and amphetamines in patients with congenital long QT syndrome.

Modafinil and its R-enantiomer armodafinil are new non-amphetamine psychostimulants indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, OSA or shift work disorder (SWD). Both drugs have stimulant actions similar to those of stimulant sympathomimetic agents, but differ in pharmacological profile and are believed to have less potential for abuse and adverse cardiovascular events. However, package labels carry cardiovascular warnings similar to those for stimulant medications. Unique to modafinil and armodafinil is the warning against use in patients with a history of left ventricular hypertrophy or those with mitral valve prolapse who have experienced mitral valve prolapse with prior use of CNS stimulants. This recommendation is based on minimal evidence from 3 patients with such a history with observed adverse events of ischemic T-wave changes, dyspnoea, and palpitations in clinical trials.^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 were evaluated in six randomized, double-blind, placebo-controlled studies in patients with hypersomnia and showed infrequent (<1%) clinically significant increases in BP or HR and electrocardiographic (ECG) changes similar to those of o placebo.²⁵All trials were of short duration, from four to 12 weeks. Rare treatment-related cardiovascular events were observed in a longer study of 478 patients with narcolepsy during 40 weeks of modafinil therapy.²⁶The most frequent were palpitations (1.5%), hypertension (1.0%) and tachycardia (1.0%). Schwartz et al. conducted a 12-month study of armodafinil in 328 patients with OSA, SWD, or narcolepsy.²⁷Cardiovascular disease, mainly hypertension, was prevalent in 139 (43%) of the patients. History of arrhythmia was observed in five patients. In general, only minor changes in heart rate and blood pressure were observed; however, 6% of patients had hypertension and three serious cardiovascular adverse events (pulmonary embolism, myocardial infarction, chest pain) were considered possibly related to armodafinil treatment. Two patients had clinically significant electrocardiographic changes of long QT syndrome and QRS complex prolongation, and three patients had baseline QTc interval changes >60 msec. No correlation of adverse events with patients with cardiovascular disease has been described.

There have been few reports of arrhythmic events associated with modafinil use. A published case report details a 54-year-old man who developed premature ventricular contractions (PVCs) with modafinil use that resolved after discontinuation.²⁸After reintroduction with modafinil, PVCs returned after 10 days of treatment and resolved again after further discontinuation.

Although the cardiovascular impact of stimulant use is minimal in healthy populations with small elevations in HR and BP, concerns remain regarding their use in patients with pre-existing cardiovascular conditions. Adrenergic activation caused by stimulants and stimulant-like drugs may have a greater impact on autonomic regulation in patients with compromised cardiovascular function. Even modest elevations in heart rate and blood pressure can exacerbate pre-existing cardiovascular conditions, particularly arrhythmias.

The studies carried out to date evaluating the cardiovascular safety of stimulant drugs have several limitations that may confound the results. Data were retrospective and limited to less than two years, so the long-term safety and cumulative effect of stimulants are unknown. Due to the lack of inclusion of patients with a history of cardiovascular disease, especially arrhythmias, the results should not be extrapolated to these populations. In addition, study outliers and case reports indicate the possibility of greater than observed cardiovascular risk, especially in vulnerable populations. Until more evidence of safety is demonstrated by standardized large-scale, long-term studies, it is prudent to avoid the use of stimulants in patients with arrhythmia. Assessment of clinical benefits and risks should be done on an individual basis when therapy is warranted. If initiated, caution should be exercised as detailed in the regulatory warnings, with monitoring of cardiovascular parameters and use limited to short durations and lower effective doses.

References

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