EDITORIAL

Cautious Reassurance: Cardiovascular Risk in theContext of Stimulant Use

Laurence L. Greenhill, M.D.

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B ased on insurance claims data, 3.6 millionchildren took stimulant medications forattention-deficit/hyperactivity disorder

(ADHD) in 2008.1 Historically, stimulants havebeen considered safe for long-term use. How-ever, the Food and Drug Administration’s Ad-verse Event Reporting System, which collectspostmarketing reports of adverse events, hasidentified cases of myocardial infarction, stroke,and sudden unexplained death in patients takingstimulant medication.2 Although dependent onuncontrolled, spontaneous reports, postmarket-ing surveillance is sensitive to rare or unusualadverse events. Although it cannot really identifycausal links or quantify risk,3 it can providecompelling information. For example, postmar-keting surveillance identified a number of casesof hepatic damage with pemoline,4 leading to thedrug’s removal from the market.

In this issue of the Journal, Olfson and col-leagues5 report on the association of cardiovas-cular events to stimulant treatment (i.e., methyl-phenidate and amphetamines salts) based onclaims of privately insured youth 6 to 21 yearsold with ADHD (N � 171,126). This study isunique in its large size, its focus on youth, and,importantly, its controlling for pre-existing car-diovascular risk factors. The adjusted odds ratiosfor current stimulant use (0.69, 95% confidenceinterval 0.42–1.12) and for past stimulant use(1.18, 95% confidence interval 0.83–1.66) werenonsignificant. There were also no significantdifferences in the risk of vascular events orsymptoms when comparing methylphenidatewith amphetamine use.

Olfson and colleagues5 note that the incidenceof a single cardiovascular adverse event identi-fied in their data (0.3 per 100,000 person-years offollow-up) is comparable to the rate of cardiovas-cular adverse events in youth not taking stimu-

lants (0.5 per 100,000) derived in another large i

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N � 241,417) epidemiologic claims-based study.6

The limitations of working with claims data arenoted by the investigators, including vascularevents not receiving medical treatment were notcounted as outcomes, leading to possible under-reporting; some outcomes may not have beenvascular in origin, resulting in possible over-reporting; the inability to confirm adherence tostimulant prescription status, leading to possiblefalse-positive associations; and only private in-surance claims were included, limiting what canbe known about children whose care is fundedby public medical insurance.

Despite the study’s limitations, no signal ofadverse cardiac events associated with stimulantuse in youth with ADHD was detected. Thefindings of Olfson and colleagues are consistentwith a larger epidemiologic study3 involvingcomputerized health records of four health plansand 1,200,438 children and adults (mean age, 11.1years) followed for 2.1 years, yielding a total of2,579,104 person-years, which reported 3.1 per100,000 serious cardiovascular events in childrenand young adults.

The conclusions drawn by Olfson and col-leagues and those of other epidemiologic studiesare in keeping with some, but not all, otherstudies. Vitiello and colleagues7 prospectivelyollowed, with periodic assessments during 12ears, 579 children with ADHD combined typefter they had been randomized into a naturalis-ic 14-month treatment (the National Institute of

ental Health’s Multimodal Treatment Study ofDHD). They reported increases in pulse only in

he children randomized to stimulant medicationompared with those assigned to behavioralreatment, but no consistent increases in systoliclood pressure, diastolic blood pressure, or ad-erse cardiovascular events such as tachycardia.ollowing up on preliminary epidemiologic stud-

es that suggested a “signal” of adverse cardiovas-

AL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY

VOLUME 51 NUMBER 2 FEBRUARY 2012

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EDITORIAL

cular events might be occurring in children onstimulants, the Food and Drug Administration’sPediatric Advisory Committee in 2006 reviewedthe data and concluded that the rate of suddencardiac death with stimulant medication wasbelow national rates for unmedicated youth.2

Winterstein and colleagues8 studied 10 years ofFlorida Medicaid claims that showed an increasein stimulant-treated youth visits to an emergencyroom but not an increase in deaths. However,increased death rates associated with stimulantuse were detected by Gould and colleagues9 whoconducted a case-control study using reports ofunexplained sudden death in youth from 50 statecoroners compared with a set of age-matchedcontrols who died as passengers in car accidents.Ten children in the unexplained death group of564 cases had been treated with stimulants ver-sus only two unmedicated cases in the controlgroup, leading to the conclusion that an associa-tion exists between stimulant use and suddenunexplained death. Despite the specter of riskidentified by Gould and colleagues, the Food andDrug Administration resisted changing their es-timate of the overall risk: the benefit profile ofstimulants based on the study’s limitations, in-cluding significant time lags between deaths andcollection of data, the low overall use of stimu-lant medication, and the different circumstancesof death.

Where does this leave us? Cautiously reas-sured. The work of Olfson and colleagues and of

two other large epidemiologic studies have es-

events in youth with attention-deficit/hyperactivity disorder. JAm Acad Child Adolesc Psychiatry. 2012;51:147-156.

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VOLUME 51 NUMBER 2 FEBRUARY 2012

ablished a risk of 0.3 to 3.1 serious cardiovascu-ar events per 100,000 person-years—no differentrom the risk in unmedicated youth. Althoughhe data support the conclusion that stimulantsre safe for long-term use, for any given child, thelinician must be vigilant, assess children forardiac risk, and monitor them closely duringreatment. The American Heart Association, themerican Academy of Pediatrics, and the Ameri-

an Academy of Child and Adolescent Psychiatryave come to the consensus that a good personalnd family cardiac history should be conductednd that electrocardiograms and other cardiaccreening approaches should be used only beforetarting stimulants if, based on history and physicalxamination, there is suspicion of high-risk condi-ions such as Wolf-Parkinson-White syndrome, hy-ertrophic cardiomyopathy, or long QT syndrome.hese recommendations are fully outlined in the011 American Pediatric Associations Guidelinesor the Treatment of ADHD.10 &

Accepted November 23, 2011.

Dr. Greenhill is with the New York State Psychiatric Institute andColumbia University.

Disclosure: Dr. Greenhill receives research funding from the NationalInstitute of Mental Health, Rhodes Pharmaceuticals, and Shire.

Correspondence to Laurence L. Greenhill, M.D., NYSPI/ColumbiaUniversity, 1051 Riverside Drive, New York, NY 10032; e-mail:llg2@columbia.edu

0890-8567/$36.00/©2012 American Academy of Child andAdolescent Psychiatry

DOI: 10.1016/j.jaac.2011.11.013

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2. Hammerness PG, Perrin JM, Shelly-Abrahamson R, Wilens TE.Cardiovascular risk of stimulant medication in pediatric ADHD:update and clinical recommendations. J Am Acad Child AdolescPsychiatry. 2011;50:978-990.

3. Cooper WO, Habel LA, Sox CM et al. ADHD drugs and seriouscardiovascular events in children and young adults. N Engl JMed. 2011;365:1896-1904.

4. Safer DJ, Zito DM, Gardner JE. Pemoline hepatotoxicity andpostmarketing surveillance. J Am Acad of Child Adolesc Psychi-atry. 2001;40:622-629.

5. Olfson M, Huang C, Gerhard T et al. Stimulants and vascular

6. Schelleman H, Bilker WB, Simm BL et al. Cardiovascular eventsand death in children exposed and unexposed to ADHD agents.Pediatrics. 2011;127:1102-1110.

7. Vitiello B, Elliot GR, Swanson JM et al. Blood pressure andheart rate over 10 years in the Multimodal Treatment Study ofADHD [published online ahead of print September 2, 2011].Am J Psychiatry. doi:10.1176/appi.ajp.2011.10111705.

8. Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Car-diac safety of central nervous system stimulants in children with att-ention-deficit/hyperactivity disorder. Pediatrics. 2007;120:e1491-e1501.

9. Gould MS, Walsh BT, Munfakh JL et al. Sudden death and the use ofstimulant medications in youths. Am J Psychiatry. 2009;166:992-1001.

10. American Academy of Pediatrics, Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvementand Management. ADHD: clinical practice guideline for the diagnosis,

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