Electrocardiographic Screening in Children With Attention-Decit Hyperactivity Disorder

William T. Mahle, MDa,b,*, Camden Hebson, MDa,b, and Margaret J. Strieper, DOa,b
Some investigators have suggested that children receiving stimulant medications to manage attention-decit hyperactivity disorder should undergo screening electrocardiography to identify asymptomatic cardiac disease. However, no study to date has examined the efcacy and costs of this strategy. In the present study we sought to determine the utility of electrocardiographic screening in children with attention-decit hyperactivity disorder. We reviewed the clinical experience of electrocardiographic screening of subjects with attention-decit hyperactivity disorder <21 years of age from April to September 2008. Additional cardiac care and testing that resulted from an abnormal initial electrocardiogram were recorded. Screening electrocardiograms were obtained in 1,470 children with attention-decit hyperactivity disorder and were interpreted as abnormal in 119 subjects (8.1%). Further evaluation of these 119 subjects included 63 transthoracic echocardiograms, 5 stress tests, and 9 Holter monitor studies. Cardiac disease was identied in 5 subjects (0.3% of entire cohort), yielding a positive predictive value of 4.2%. Cardiac diagnoses included ventricular pre-excitation syndrome (n 2), bicuspid aortic valve (n 2), and moderate secundum atrial septal defect (n 1). The mean cost of electrocardiographic screening including further testing for subjects with abnormal initial screen results was $58 per child. The mean cost to identify a true-positive result was $17,162. In conclusion, electrocardiographic screening for children with attention-decit hyperactivity disorder can successfully identify cardiac disease in otherwise asymptomatic subjects, although the positive predictive value is low. Ongoing studies are needed to know what role electrocardiographic screening should play in the management of children with attention-decit hyperactivity disorder. 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:1296 1299) A recent American Heart Association (AHA) statement concluded that screening with electrocardiogram may be helpful to assess for cardiac disease in children with attention-decit disorder who are treated with stimulant medication.1 This statement suggested that, It is reasonable to consider adding an ECG [electrocardiogram], which is of reasonable cost, to the history and physical examination in the cardiovascular evaluation of children who need to receive treatment with drugs for ADHD [attention-decit hyperactivity disorder]. Although these recommendations are intriguing, to date it is unknown whether such a strategy might be successful in detecting occult cardiac disease. In the present study we analyzed the efcacy of electrocardiographic screening in an attention-decit hyperactivity disorder population that resulted from changes in clinical practice because of the AHA recommendations. In particular we paid attention to the impact of false-positive studies that result because of this strategy and report the economic costs of such an approach. Methods With the approval of the institutional review board of Childrens Healthcare of Atlanta (Atlanta, Georgia), we analyzed data from a cohort of children who underwent electrocardiography performed for the purpose of cardiac screening for stimulant medication. The study population included children 5 to 21 years of age who obtained an electrocardiogram from April 21 to September 21, 2008. A start date of April 21 was chosen because the AHA consensus guideline was published at that time. We assumed that electrocardiograms ordered after that date would represent a response to the AHA guidelines. Although the AHA statement did not explicitly recommend electrocardiographic screening, many clinicians (psychiatrists and primary care providers) began to refer children receiving or likely to receive stimulants for this test. Electrocardiograms from 3 major sources were included, namely outpatient cardiology practices, a hospital-based laboratory performing outpatient electrocardiography, and community hospitals that perform the studies and then forward them to the Sibley Heart Center (Atlanta, Georgia). Those subjects who were identied as having attentiondecit hyperactivity disorder screening or stimulant medication screening were included in the analysis. Those subjects who were identied as having an abnormal initial electrocardiogram were dened as positive screens. Findings that were considered variants of normal such as sinus arrhythmia or early repolarization were considwww.AJConline.org

a Sibley Heart Center, Childrens Healthcare of Atlanta, and bDepartment of Pediatrics, Emory University School of Medicine, Atlanta, Georgia. Manuscript received April 29, 2009; revised manuscript received and accepted June 19, 2009. *Corresponding author: Tel: 404-315-2672; fax: 404-325-6021. E-mail address: mahlew@kidsheart.com (W.T. Mahle).

0002-9149/09/$ see front matter 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.06.052

Miscellaneous/Electrocardiographic Screening for Stimulant Medications Table 1 Most common abnormalities on initial electrocardiogram Abnormality Left ventricular hypertrophy Right ventricular hypertrophy Prolonged QT interval Right bundle branch block Left-axis deviation Right-axis deviation Left atrial enlargement Premature ventricular complexes Premature atrial complexes Ventricular pre-excitation Subjects (%) 34 (28.2%) 24 (20.5%) 22 (18.5%) 17 (14.2%) 7 (5.9%) 7 (5.9%) 3 (2.5%) 2 (1.7%) 2 (1.7%) 2 (1.7%)

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Results During the 5-month study period 1,470 children had electrocardiography performed for purposes of screening for attention-decit hyperactivity disorder medications. The mean age of this population was 9.8 2.9 years. Those undergoing electrocardiographic screening were primarily boys (1,237 of 1,470, 84%). The primary payers for children screened with electrocardiogram were private payers in 55%, governmental in 44%, and self pay in 1%. Of the screened cohort of 1,470, there were 119 subjects (8.1%) who were found to have an abnormal electrocardiogram. Electrocardiographic abnormalities were found more commonly in children undergoing testing at community hospitals than in pediatric cardiology ofces or children hospitals (11.2% vs 7.5%, respectively, p 0.04). The most common abnormalities are listed in Table 1. The median interval from rst electrocardiogram to cardiology consultation was 11 days (range 1 to 49). Most subjects referred to cardiology evaluation (78 of 119, 65%) were already receiving stimulant medications at the time of screening electrocardiogram; the remaining subjects were referred in anticipation of starting stimulant medications. Of the 119 with abnormal electrocardiograms, 97 subjects had a second electrocardiogram obtained at the time of cardiology consultation. More than 35% of subjects who had repeat electrocardiography were thought to have a normal electrocardiogram when the study was repeated (Figure 1). The most common original diagnoses that were reinterpreted as normal were prolonged QT interval and left ventricular hypertrophy, respectively. Physical examination performed by a cardiologist demonstrated abnormalities in 14 subjects. These abnormalities included systolic ejection murmur (n 7), systolic ejection click (n 3), irregular heart rhythm (n 5), and prominent precordial impulse (n 1). Seven subjects were thought to have an innocent heart murmur. Additional ancillary testing included complete echocardiography in 63 subjects, Holter monitoring in 9 subjects, and exercise stress testing in 5 subjects. Indications for echocardiograms were early systolic ejection click in 2, heart murmur in 5, and abnormal electrocardiograms with a variety of ndings (n 56), the 3 most common being left ventricular hypertrophy, right ventricular hypertrophy, and right bundle branch block. Indications for Holter monitors were prolonged QT interval in 5, ventricular pre-excitation in 2, and premature ventricular complexes in 2. Indication for exercise stress testing was prolonged QT interval in all 5 patients. Final diagnoses included no cardiac disease in 114, ventricular pre-excitation syndrome in 2, bicuspid aortic valve in 2, and moderate secundum atrial septal defect in 1. Therapeutic interventions undertaken because of new diagnoses included transcatheter closure of an atrial septal defect (n 1) and ablation of an accessory pathway (n 2). Therefore, the proportion of children with cardiac disease identied with an electrocardiographic screening strategy was 0.003 (95% condence interval 0.001 to 0.008). The positive predictive value was 4.2%. Total cost for testing in the entire cohort of 1,470 children was $85,868. Therefore, the cost to screen a single child is $58. The calculated cost to identify a child with

Entire Cohort N=1470 1st ECG Normal N=1351 2nd ECG Performed N=97 1st ECG Abnormal N=119 2nd ECG Not Performed N=22 2nd ECG Abnormal N=61 2nd ECG Normal N=36

Figure 1. Results of electrocardiographic testing in study cohort. ECG electrocardiogram.

ered negative screens. Based on the AHA statement, these ndings would be classied as category 1 (normal or normal variants). The outcome for those with positive initial electrocardiograms (AHA category II and III readings) was determined. For those subjects with a positive initial screening electrocardiogram who presented for further cardiology consultation, records were reviewed to determine results of repeat electrocardiogram if performed and physical examination ndings. Ancillary testing that was performed in the diagnostic work-up was also recorded. Final cardiac diagnosis was reported. To analyze the added cost of an electrocardiographic screening program for attention-decit hyperactivity disorder, we included the cost of the initial electrocardiogram. Subsequent evaluation such as cardiology consultation, echocardiography, and stress testing were included in the model. Costs for all tests were determined based on Current Procedural Terminology codes and 2008 Medicare reimbursement rates.2 The cost model assumed that the rst electrocardiogram did not result in any lost parental wages. The model did assume that follow-up cardiac consultation might result in lost wages.3 The proportion of positive initial electrocardiographic screens was reported, as were 95% condence intervals. The positive predictive value of electrocardiographic screen was reported. Because the number of true-positive results in the population could not be determined, we were unable to calculate the sensitivity and specicity of electrocardiographic screening.

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some form of heart disease is $17,162. If one were to assume that the additive risk of stimulant medication is negligible in mild congenital heart lesions, such as bicuspid aortic valve and atrial septal defect, the cost to identify a child with complex congenital heart disease or potential life-threatening arrhythmias is $42,904. Discussion This study in a small, contemporary cohort of children receiving stimulant medications demonstrates electrocardiographic screening can identify otherwise asymptomatic heart disease. Electrocardiographic screening can prompt additional testing and ultimately diagnosis of cardiac disease that might be life-threatening and that may represent a contraindication to the administration of stimulant medications. Conversely, the positive predictive value of electrocardiographic screening is low, meaning that a signicant number of children without heart disease will likely be subjected to additional testing. Recent recommendations from the AHA have engendered considerable controversy. The American Academy of Pediatrics writing group stated that, the harm outweighs the benet of recommending routine ECGs [electrocardiograms] for healthy children starting stimulant medication for ADHD [attention-decit hyperactivity disorder].4 These investigators raised concerns about the sensitivity and specicity of the electrocardiogram as a general screening test. Much of the resistance to routine electrocardiographic screening relates to the concern that this strategy will produce many false-positive results. Studies of electrocardiographic screening in other populations have generally reported that 5% to 10% of children will have an abnormal electrocardiogram on initial testing.5,6 Findings from our analysis are very much in agreement with these previous publications because we reported that 8.1% had an abnormal screen on rst examination. Many quality initiatives could decrease the number of false-positive results. For example, we found that electrocardiograms obtained in community hospitals generally had a higher rate of abnormalities than those obtained in pediatric cardiology clinics and childrens hospitals. This may result from improper lead placement in centers that care for primarily for adults.7 Also, there may be signicant inconsistencies among interpretations by pediatric cardiologists.8 Previous investigators have suggested that there is considerable variability in the interpretation of QT interval in pediatric cardiologists and that reinterpretation by specialists at large referral centers can demonstrate 30% discordance.9 A key assumption of any screening strategy is that early detection of the disorder might improve outcome. To date, however, the link between stimulant medications used to treat attention-decit disorder and an increased cardiovascular risk is tenuous. The original Health Canada warning suggested a possible association between congenital heart defects even mild defects such as bicuspid aortic valve and sudden death while receiving Adderall XR (Shire US, Inc., Florence, Kentucky).10 Therefore, the discovery of congenital heart disease with minimal or mild hemodynamic signicance may be a valuable nding of electrocar-

diographic screening. However, it should be recognized that in the 2 subjects with bicuspid aortic valve identied in this series, the minor electrocardiographic abnormalities were not thought to be related to valvar disease. The balance of risks and benets of stimulants in children with heart disease and attention-decit hyperactivity disorder continues to be evaluated by the Food and Drug Administration and other organizations. However, use of stimulant medications in children with known structural heart disease is controversial. Even with more complex structural heart lesions, practitioners may believe that the benets of medical management of attention-decit hyperactivity disorder may outweigh any cardiovascular risks. As such, the advantage of identication of these predominantly mild forms of congenital heart disease through electrocardiographic screening remains speculative. In contrast, many cardiologists would likely agree that stimulant medications may pose a risk in children with potentially life-threatening arrhythmias such as supraventricular tachycardia, long QT syndrome, and hypertrophic cardiomyopathy.11,12 Importantly, with diseases such as Wolff-Parkinson-White syndrome (or ventricular pre-excitation), ablation procedures can effectively treat the disorder and decrease any potential risk. For other entities that cannot be cured, such as long QT syndrome, further diagnostic testing and risk stratication might allow clinicians to weigh the risks and benets of stimulant medications. With any screening strategy cost-effectiveness is an important issue. To calculate cost-effectiveness one needs to be able to quantify the economic benets of early detection, such quantiable decrease in morbidity or mortality. Given the very limitedand controversial data regarding the risk of sudden death related to the use of stimulant medications, one cannot say with certainty whether an electrocardiographic screening program has the potential of saving any lives. The cost of a single electrocardiogram is relatively lowapproximately $22. However, one must consider the additional costs incurred from added testing. The cost per subject increased approximately threefold due to the added diagnostic work-up that is required when the initial electrocardiogram is abnormal. Assuming that in the United States approximately 2.5 million children receive stimulant medication for attention-decit hyperactivity disorder, the total cost of a screening electrocardiographic program for a single screen per child would be $146 million.13 In addition to nancial costs associated with false-positive electrocardiograms, concerns have been raised about the adverse psychological impact of screening programs. One of the factors in weighing the adverse consequences of a false-positive test result is the length of time to takes to make a nal diagnosis. In our series, the median interval from initial electrocardiogram to evaluation by a pediatric cardiologist was relatively short2 weeks. However, one might imagine that wait times could be potentially longer in underserved areas. Although most of the time a single visit with a pediatric cardiologist allowed a denitive diagnosis, there were 13 subjects who required additional testing, thus prolonging the diagnostic process and potentially adding to the anxiety of a false-positive screen. There are several limitations to the present study. First, because this is not a population-based study, it is unknown

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what proportion of children receiving stimulant medications in metropolitan Atlanta were referred for electrocardiographic screening. Primary physicians may have selectively referred for electrocardiographic testing. Second, the sample is relatively small. The 95% condence interval for the positive detection rates varies from 0.001 to 0.008. Such variability would dramatically alter the utility of screening and our cost estimates.
1. Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, Webb CL. Cardiovascular monitoring of children and adolescents with heart disease receiving stimulant drugs: a scientic statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation 2008;117:24072423. 2. 2008 Medicare physician fee schedule. Available at: www.cms.hhs. gov/center/physician.asp. Accessed October 10, 2008. 3. U.S. Department of Labor, Bureau of Labor Statistics. Employment and earnings, 2007 annual averages and the monthly labor review. Available at: www.dol.gov/wb/stats/main.htm. Accessed November 1, 2007. 4. Perrin JM, Friedman RA, Knilans TK. Cardiovascular monitoring and stimulant drugs for attention-decit/hyperactivity disorder. Pediatrics 2008;122:451 453. 5. Pelliccia A, Culasso F, Di Paolo FM, Accettura D, Cantore R, Castagna W, Ciacciarelli A, Costini G, Cuffari B, Drago E, Federici V, Gribaudo CG, Iacovelli G, Landol L, Menichetti G, Atzeni UO, Parisi A, Pizzi AR, Rosa M, Santelli F, Santilio F, Vagnini A, Casasco M, Di LL. Prevalence of abnormal electrocardiograms in a large, unselected population undergoing pre-participation cardiovascular screening. Eur Heart J 2007;28:2006 2010.

6. Haneda N, Mori C, Nishio T, Saito M, Kajino Y, Watanabe K, Kijima Y, Yamada K. Heart diseases discovered by mass screening in the schools of Shimane Prefecture over a period of 5 years. Jpn Circ J 1986;50:13251329. 7. Garson AJ, Bricker J, Fisher D, Neish S, eds. Electrocardiography in the Science and Practice of Pediatric Cardiology. Baltimore: Williams and Wilkins, 1998. 8. Chiu CC, Hamilton RM, Gow RM, Kirsh JA, McCrindle BW. Evaluation of computerized interpretation of the pediatric electrocardiogram. J Electrocardiol 2007;40:139 143. 9. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007;115: 26132620. 10. Health Canada suspends the market authorization of ADDERALL XR, a drug prescribed for attention decit hyperactivity disorder (ADHD) in children. Available at: http://www.hc-sc.gc.ca/ahc-asc/ media/advisories-avis/_2005/2005_01-eng.php. Accessed February 9, 2005. 11. Gracious BL. Atrioventricular nodal re-entrant tachycardia associated with stimulant treatment. J Child Adolesc Psychopharmacol 1999;9: 125128. 12. Lehnart SE, Ackerman MJ, Benson DW Jr, Brugada R, Clancy CE, Donahue JK, George AL Jr, Grant AO, Groft SC, January CT, Lathrop DA, Lederer WJ, Makielski JC, Mohler PJ, Moss A, Nerbonne JM, Olson TM, Przywara DA, Towbin JA, Wang LH, Marks AR. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Ofce of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 2007;116:23252345. 13. Mayes R, Bagwell C, Erkulwater J. ADHD and the rise in stimulant use among children. Harv Rev Psychiatry 2008;16:151166.