New Findings Regarding Cardiovascular Adverse Events with ADHD Medications

By: Aleena Cherian, Co-Copy Editor [Graphics-Focused]

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Attention deficit/hyperactivity disorder (ADHD) is a chronic neurological behavior characterized by persistent patterns of inattention and/or hyperactive behavior, resulting in a wide range of emotional, functional, and neurocognitive impairments.^1,2 First line therapy for ADHD consists of stimulant medications together with non-pharmacologic interventions, and has been shown to improve health related quality of life, brain dysfunction, and academic achievement.³ In the US, over 2.8 million children and 1.5 million adults use stimulants and other medications annually for the treatment of ADHD.^3,4,5

Stimulant medications for ADHD include methylphenidate and amphetamines, which facilitate the release of norepinephrine and dopamine in the prefrontal cortex.³ The most frequently reported adverse events with these agents are decreased appetite, stomachache, nausea, headache, insomnia and nervousness, and less commonly, emotional lability, irritability, and cardiovascular effects.³ The sympathomimetic effects of stimulants have been reported to cause an increase in systolic blood pressure by 1-4 mm Hg and an increase in heart rate by 3-8 bpm at therapeutic doses, which while insignificant, has potential long-term complications.^1,6 An FDA Summary also reported cardiac arrest, MI, and sudden unexplained death among the top 50 adverse events after use of amphetemines and methylphenidate.⁷

Various retrospective cohort studies have been conducted to better evaluate the potential cardiovascular consequences of stimulant agents in children and adults, with most studies finding no increased risk of serious cardiovascular events with the use of these medications. ^6,8,9 However, one matched case-control study of sudden deaths in youths ages 7-19 did find a significant association with stimulant use and sudden unexplained death.¹⁰

In May 2013, the results of a meta-analysis of studies that examined the cardiovascular effects of ADHD were published online. Reviewers included studies with at least 100 ADHD patients with follow up longer than 1 year. Three studies were included in the analysis with a total of over 2 million patients, the largest patient population to date, assessing the primary endpoint as rates of sudden cardiac death and the secondary endpoint as rates of MI or stroke. The researchers confirmed the findings of most of the earlier studies, that the use of ADHD medications did not increase a patient’s risk of sudden death and did not cause adverse cardiovascular outcomes.² Even after excluding the results of the only study that included middle aged patients,⁵ the findings still did not show an increased risk of sudden death or stroke.

While this analysis did not demonstrate an increased risk of adverse cardiac events, pharmacists still have a role to play in monitoring the use of ADHD medication, especially given the widespread use of stimulants. Practitioners should be advised against administering or prescribing these agents to patients with severe heart problems, arrhythmias, or uncontrolled blood pressure. Pharmacists can also advise and educate patients to regularly monitor their blood pressure and heart rate while on stimulant medications to check for any changes that could warrant medical attention.

SOURCES:

1. Donner R, Michaels MA, Ambrosini PJ. Cardiovascular effects of mixed amphetamines salts extended release in the treatment of school-aged children with attention-defecit/hyperactivity disorder. Biol Psychiatry 2007;61:706-712.
2. Mazza M, D’Ascenzo F, Frati CD et al. Drugs for attention defecit-hyperactivity and the midterm risk of sudden death in children: a meta-analysis of observational studies. Int J Card 2013. Epub ahead of print.
3. Shier AC, Reichenbacher T, Ghuman HS, Ghuman JK. Pharmacologic treatment of attention defecit hyperactivity disorder in children and adolescents: clinical strategies. J Cent Nerv Syst Dis 2013;5:1-17
4. Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children — United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep 2010;59:1439-1443
5. Habel LA, Cooper W, Sox CM et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;206(24):2673-83
6. Schelleman H, Bilker WB, Strom BL, et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics. 2011;127(6):1102-1110
7. Food and Drug Administration. Drug Safety and Risk Management Advisory Committee meeting. http://www.fda.gov/ohrms/dockets/ac/cder06.html#DrugSafetyRiskMgmt. Food and Drug Administration Web site. February 9-10, 2006. Accessed July 17 2013
8. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-1904
9. Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2007;120(6):e1494-e1501
10. Gould MS, Walsh BT, Munfakh JL, et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009;166(9):992-1001
11. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med 2006;354:1445-1448.