Is the cardiovascular risk of stimulants in Excessive Daytime Sleepiness (EDS) dose-dependent?

From the Guidelines

The cardiovascular risk of stimulants in Ehlers-Danlos Syndrome (EDS) appears to be dose-dependent, and patients should start with the lowest effective dose and gradually increase if needed, with careful monitoring of blood pressure, heart rate, and cardiac symptoms. According to the clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents 1, stimulant medications can increase patient heart rate (HR) and blood pressure (BP) to a mild and clinically insignificant degree, but higher doses may be linked to more substantial increases in HR and BP in a subset of individuals (5%–15%).

Key Considerations

• Stimulants can raise heart rate and blood pressure, which is particularly concerning for EDS patients who may already have cardiovascular manifestations such as mitral valve prolapse, aortic root dilation, or dysautonomia 1.
• Higher doses of stimulants generally correlate with greater cardiovascular effects, and regular monitoring of blood pressure, heart rate, and cardiac symptoms is essential, especially during dose adjustments 1.
• Some EDS patients may need to avoid stimulants entirely if they have significant cardiac involvement, arrhythmias, or severe autonomic dysfunction.

Monitoring and Precautions

• Clinicians should obtain the child or adolescent’s history of specific cardiac symptoms in addition to the family history of sudden death, cardiovascular symptoms, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy, and long QT syndrome before initiating therapy with stimulant medications 1.
• If any of these risk factors are present, clinicians should obtain additional evaluation to ascertain and address potential safety concerns of stimulant medication use by the child or adolescent 1.

From the FDA Drug Label

In the placebo-controlled clinical trials which compared doses of 200,300, and 400 mg/day of modafinil tablets and placebo, the following adverse reactions were dose related: headache and anxiety Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm), and individuals may have larger increases.

The answer to whether the cardiovascular risk of stimulants in EDS is dose-dependent is not directly supported by the provided drug labels. However, the labels do mention that certain adverse reactions, such as headache and anxiety, are dose-related for modafinil 2, and that stimulant medications can cause increases in blood pressure and heart rate 3.

• Key points:
  • Dose-related adverse reactions: headache and anxiety for modafinil
  • Cardiovascular effects: increases in blood pressure and heart rate for stimulant medications However, the labels do not provide a clear answer to the question of whether the cardiovascular risk is dose-dependent.

From the Research

Cardiovascular Risk of Stimulants in EDS

The relationship between the cardiovascular risk of stimulants in Excessive Daytime Sleepiness (EDS) and dosage is complex and not directly addressed in the provided studies. However, we can explore the available information on stimulants, EDS, and cardiovascular risk:

• Stimulants and EDS: Stimulants like modafinil, methylphenidate, and amphetamines are used to treat EDS in conditions such as narcolepsy 4. Modafinil, in particular, has been shown to be effective in reducing EDS with a relatively low risk of abuse and withdrawal phenomena 4.
• Cardiovascular Risk and EDS: EDS has been associated with an increased risk of cardiovascular events, including myocardial infarction, stroke, and heart failure 5, 6, 7. This risk appears to be independent of the presence of sleep disorders, suggesting that EDS itself may be a marker of cardiovascular risk 6, 7.
• Dose-Dependent Effects: While the provided studies do not directly address the dose-dependent effects of stimulants on cardiovascular risk in EDS, they do suggest that the pharmacokinetics of modafinil are linear and dose-dependent 4. However, the incidence or severity of adverse events associated with modafinil did not appear to be dose-related in one study 4.

Key Findings

• EDS is associated with an increased risk of cardiovascular events 5, 6, 7.
• Stimulants like modafinil can effectively reduce EDS in conditions such as narcolepsy 4.
• The relationship between the dosage of stimulants and cardiovascular risk in EDS is not clearly established in the provided studies.

Relevant Studies

• 5: Excessive daytime sleepiness is associated with increased residual cardiovascular risks among coronary artery disease patients with obstructive sleep apnea.
• 4: Modafinil is effective in the treatment of EDS in patients with narcolepsy, with a relatively low risk of abuse and withdrawal phenomena.
• 6: EDS may be an independent marker of cardiovascular risk, even in the absence of sleep disorders.
• 7: EDS is an independent prognostic factor of adverse outcome in post-myocardial infarction patients with moderate to severe sleep-disordered breathing.