ADHD Stimulant Medication and the Risk of Sudden Cardiac Death

Marc Lerner, M.D. CHOC Childrens Hospital University of California, Irvine

Attention Deficit Hyperactivity Disorder

„ Neurobehavioral disorder marked by one or more of the following: Š Inattention (poor focus / distractibility) Š Hyperactivity (excessive motor activity) Š Impulsivity (no “brakes”) „ Prevalence rates Š 33--8%8% of the school-school-ageage population Š Clinically presents more often in boys than in girls (3:1) Š Three quarters of children retain ADHD symptoms in adolescence, and up to one half as adults

http://www.cdc.gov/ncbddd/adhd/ Froehlich TE, Lanphear BP, et al. Arch Pediatr Adolesc Med. 2007 Sep;161(9):857-64.

January 14-15, 2011 SCA Conference Molecular Genetics of ADHD

„ Specific genes associated with ADHD Š Dopamine receptor D4 gene (DRD4) on chromosome 11 Š Dopamine transporter gene (DAT1) on chromosome 5 Š D2 dopamine receptor gene Š DopamineDopamine--betabeta--hydroxylasehydroxylase gene Š Possible association of noradrenergic genes Š Most recently identidentified:ified: Latrophilin 3 gene (LPHN3), may contribute sign ifican tltly

„ Association suggested between ADHD, parenting characteristics and serotonergic genotypes Swanson et al, 1998,

NikolasSunohara M et al, G, Beh et al. and J Am Brain Acad Func Adolesc2010 Psychiatry. (6) 23 2000;39:1537-1592. Giros B, et al. Nature. 1996;379:606-612. ArcosArcos--BurgosBurgos M, Jain M , et al Mol Psychiatry 2/16/10

ADHD and Copy Number Variants

„ Comparison of genomegenome--widewide analysis in children with ADHD (366) and controls (1047)

„ CNVs were found twice as often in children with ADHD

„ Rate 5X higher in individuals with ADHD and MR

„ More than 1/3rd of children with ADHD and intellectual disability carried a large rare CNV

„ Significantly enriched for loci previously implicated in patients with ASDs and schizophrenia

„ Among the genes spanned by CNV on 16p is NDE1 (nuclear distribution gene E homologue 1) which interacts with DISC1, which is disrupted in schizophrenia

Williams, N, ZaharievaZaharieva,, I, et al Lancet published on line on 9/30/2010

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January 14-15, 2011 SCA Conference 5

ADHD Treatments

1. Medications

2. Behavioral/Psychological Interventions

3. Educational Interventions

4. Alternative and Complementary Treatments

January 14-15, 2011 SCA Conference ADHD Medications

Long-Acting Long-Acting Immediate-Release Formulated Prodrug Stimulants Stimulants Non-stimulant Stimulant Dexmethylphenidate HCl Dexmethylphenidate HCl XR Atomoxetine HCl Lisdexamfetamine dimesy la te (FOCALIN) (FOCALIN XR) (STRATTERA) (VYVANSE) Methylphenidate HCl Methylphenidate HCl CD Guanfacine XR (RITALIN) (METADATE CD) (INTUNIV) Mixed salts of a Methylphenidate HCl LA Clonidine LA singlesingle--entityentity (RITALIN LA) (KAPVAY) amphetamine product (ADDERALL) DD--amphetamineamphetamine Methylphenidate transdermal system (DAYTANA) (DEXEDRINE) Mixed salts of a singlesingle--entityentity amphetamine product XR (ADDERALL XR) OROS methylphenidate HCl (CONCERTA)

Modification of ADHD Medication Impact by Use of Use of Extended Release Systems

„ Oral osmotic system

„ Timed beads

„ Use of propro--drugdrug

„ Transcutaneous patch technology

„ Delayed disintegration via use of incipients

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January 14-15, 2011 SCA Conference ADHD

Plasma Profiles Following MPH -IR tid and OROS MPH OROS MPH 18mg (n=27) MPH – IR 5 mg TID (n=27) 6

5

4

3 ntration (ng/ml) methylphenidate 2 e a

1 Conc Plasm 0 0 1 2 3 4 5 6 7 8 9 10 11 12

Time (h)

Oral Osmotic Methylphenidate: Heart Rate and Hypertension

„ 1 year safety data in children Š Compared to off -drug baseline Š Changes in SYSSYS--BPBP and DD--BPBP of 3.3 and1.5 mm Hg (P < 0.001) Š HR increased (3.9 bpmbpm,, P < 0.0001) Š Short term data (previously discussed) did not suggest a change in blood pressure with methylphenidate

„ NlNo clear doseose--responseresponse reltilationshi p and no t tlolerance to pressor effects

„ Inverse relationship between baseline vital signs and positive change in vital signs at end point Wilens T, Biederman J, Lerner M. J Clin Psychopharmacol. Psychopharmacol. 2004;24(1):362004;24(1):36––41.41. 10

January 14-15, 2011 SCA Conference Mixed Amphetamine Salt XR: Mean (± SD) Heart Rate during Extension Protocol 100

95 Heart Rate 90

85

80

75 Heart Rate (BPM) 70

65

60 B Wk 1 Wk 2 Wk 6 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 30 E (LOCF)

n=455 n=454 n=453 n=455 n=455 n=422 n=400 n=353 n=245 n=170 n=455 B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8.

Silva RR et al. Clin Pediatr 2010 Sep;49(9):840-51. Data on file, Shire US Inc., 2005. 11

MAS XR: Blood Pressures during Extension Protocol

140 Systolic BP 130

120 Hg) m 110

100 Diastolic BP 90

80 Blood Pressure (m Blood Pressure

70

60 B Wk 1 Wk 2 Wk 6 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 30 E (LOCF)

n=455 n=454 n=453 n=455 n=455 n=422 n=400 n=353 n=245 n=170 n=455

B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8. Adderall XR is contraindicated in patients with symptomatic cardiovascular disease and moderate to severe hypertension. Adderall XR generally should not be used in those with structural cardiac abnormalities. Data on file, Shire US Inc., 2005. 12

January 14-15, 2011 SCA Conference Use of MAS XR for Up to Two Years in Adults „ Daily doses of mixed amphetamine salts XR from titrated from 20 – 60 mg per day

„ Most subjects with a significant V/S abnormality had it at only one visits.

„ Seven subjects (of 223 otherwise well adult subjects) discontinued due to a cardiovascular adverse event Š Hypertension, n=5 Š Palpitation/tachycardia, nn2=2 Š None of these events was reported as serious

„ Several subjects with borderline elevated baseline values exhibited shifts to abnormal values during MAS XR therapy Weisler R , Biederman J et al . CNS Spectr. 2005;10(12 Suppl 20):35- 20):35-4343

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Lisdexamfetamine CV Changes over Four Weeks

Stimulant Naive Prevlously Exposed

Change Mean Change Mean Final Visit Heart Rate 1.62 74 -4.6 69.5 Sys BP 5.38 102 -4.1 98.4 Diastolic 1.00 57.6 .57 58.6 BP PR 0.46 133 1.0 132 Interval QRS msec 1.54 82.6 0.57 84.1 Qtc msec 5.15 406 -0,57 407

Wigal SB, Lerner MA et al Postgraduate Medicine, 122(5) Sept 2010 14

January 14-15, 2011 SCA Conference Transmission of Neuronal Signal is Modulated by the a2A Receptor

NE presynaptic terminal Excitatory signal

Reuptake transporter

Postsynaptic neuron NE a2A receptor

Ion channel

Wang M, et al. Cell. 2007;129:397-410.

Guanfacine and Clonidine Extended Release Agents are Approved for ADHD

„ Alpha 2 Adrenergic Receptor Agonists

„ Action: Direct stimulationstimulation of postpost--synapticsynaptic sites which support improved working memory and function in the prefrontal cortex Š Dorsal PFC inhibits distractibility Š Right Inferior PFC projections involve behavior inhibition Š VVtentromedi dilal PFC regul at es emoti on

„ New extended release forms, Guanfacine and Clonidine Š GIR 75% in initial 45 mins Vs. GXR 85% in first 12 hours Š TmaxTmax:: Shift from 3 hour to 6 hours

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January 14-15, 2011 SCA Conference ADHD and Congenital Heart Disease

„ Clinical trials typically screen for serious heart disease and exclude these children from studies

„ Screening of blood pressure and heart rate for safety (EKGs) common

„ Children with many postpost--operativeoperative CHD have increased risk of Sudden Unexpected Death

„ Stimulants generally not recommended

Bass JL, et al. Pediatrics. 2004;114(3):805-816. 17

Audience Participation : ADHD and SCD Question 1

„ Should patients with LQTs on beta blockers be allowed to receive stimulant medications for ADHD?

„ 1. Yes

„ 2. No

„ 3. Undecided

„ 4. I defer this decision to my cardiac subspecialty team

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January 14-15, 2011 SCA Conference Audience Participation : ADHD and SCD Question 2 (for pediatric cardiologists)

„ Should hemodynamically stable chchildrenildren with an ICD be allowed to receive stimulant medications for ADHD?

„ 1. Yes

„ 2. No

„ 3Idf3. I defer thidthis dec iiision to o thers on my car diac subspecialty team

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Background on the ADHD Controversies

1. Charatan, Fred. BMJ Journal. Volume 332 p380. February 18, 2006. 2. Vetter VL, Elia J, Erickson C, et al. Circulation 2008; 117:2407-2423.

January 14-15, 2011 SCA Conference Baseline Cardiovascular Risks

Rate/100,000 OROS MPH Patient –Yr– Yr Serious CV AEs3

Pediatric 1.3 ––4.64.6 0.1 Sudden Death1 Adult 55 0.3

Pediatric 2.6 – 19.7 0.0 MI2 Adult 659 0.2

Pediatric 272.7 020.2 Stroke2 Adult 888 0.5

Pediatric 4.5 0.5 Hypertension2 Adult 32.3 0.8 1Liberthson RR. N Eng J Med. 1996;334:1039-1044; 2American Heart Association, Heart Disease and Stroke Stats 2006; 3McNeil FDA Pediatric Advisory Panel Testimony. March 22, 2006. 21

Estimated 1-year (2005) Reporting Rates for Pediatric Sudden Death Children <17 Years of Age

Pediatric Rate SitScripts Exposures Per Drug Deaths (Millions) (Pt Yrs in 100K Thousands) Pt-Yr

Methylphenidate 9.9 816 2 0.2

Amphetamine/ 696.9 583 4 070.7 Dextroamphetamine

Atomoxetine 3.3 276 4 1.5

Gelperin K. FDA Pediatric Advisory Panel Testimony. March 22, 2006.

January 14-15, 2011 SCA Conference FDA Findings: Cardiac Risks for ADHD Class Medications „ Presentation of 6-6-yearyear data for MTA (Swanson) Š Minimal difference for heart rate and blood pressure – Continuously using stimulants – Stimulant naïve – Local nonnon--ADHDADHD classroom controls

„ Added risk for rare cardiac events difficult to ascertain Š No recommendation for universal screening (EKG / ECHO) Š Similar to challenge of identifying risk to children who participate in vigorous exercise (also not recommended for routine screening)

„ Consideration of cardiac ririsksk warnings for atomoxetine

„ Management of patients with congenital/structural heart disease will often require consultation with pediatric cardiologists FDA Pediatric Advisory Panel Testimony. March 22, 2006. 23

Cardiac Issues and Stimulant Medication Warnings

„ Stimulants should generally not be used in children, adolescents and adults with: Š Serious structural cardiac abnormalities Š Cardiomyopathy Š Serious heart rhythm abnormalities Š Symptomatic cardiovascular disease

„ Use with caution in treatitreatingng patients with underlying medical conditions Š prepre--existingexisting hypertension Š heart failure Š recent myocardial infarction, or ventricular arrhythmia 24

January 14-15, 2011 SCA Conference Stimulant Class Cardiac Warnings

„ Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems

„ Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses in ADHD

„ Physicians should take a careful patient history, including family history, and physical exam, to assess the presence of cardiac disease

„ Patients who report symptoms of cardiac disease such as exertional chest pain and unexplained syncope should be promptly evaluated

„ Use with caution in patients whose underlying medical condition might be affected by increases in blood pressure or heart rate 25

Amphetamine Black Box Warning: Important Safety Information

„ Amphetamines have a high potential for abuse

„ Administration of amphetamines for long periods of time may lead to drug dependence

„ Particular attention should be paid to the possibility of subjects obtaining amphetamines for nonnon--therapeutictherapeutic uses or di stri buti on to oth er s an d th e dr ugs sh oul d be prescribed sparingly

„ Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events

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January 14-15, 2011 SCA Conference ADHD in Children with Congenital Heart Disease

„ ADHD symptoms may be more prevalent in children with CHD concerns Š Abnormal attention scores in 45% with children with CHD Š Abnormal hyperactivity scores in 39% of children with heart disease (parents and teacher ratings)

„ Increased risk with specific congenital cardiac issues Š > 2/3 with hypoplastic left heart syndrome Š 50% of children with TAPVR Š Cardiac issues associated with 22q11microdeletion caused ADHD 35% to 55% of children

Vetter VL, Elia J, Erickson C, et al. Circulation 2008; 117:2407-2423. 27

Methods

SNAP-IV Questionnaires

Parents Counselors

January 14-15, 2011 SCA Conference Prevalance of Attention Deficit/Hyperactivity Disorder Symptoms in Patients With Congenital Heart Disease Children with Congenital Heart Disease (n=64) „ Age: 88--1818 yrs (mean 13.4 ±2.6 yrs)

Disorders of Subjects Cyanotic abnormalities: 31 •VSD (10) •Coarc (14) Acyanotic abnormalities: 33 •AS (5) Severe CHD: 38 •ASD (4) Mild to Moderate CHD: 26 •TOF (6) •TGA (4) •HLH (()5) •Truncus (4) •SV (7) ADHD Positive Comparison Group (n=75) •MR (4) Ages 10-12 yrs old •TAPVC (2) •PS (3) ADHD Negative Comparison Group (n=41) •Pul Atresia (3) Ages 10-12 yrs old

Prevalence of ADHD

10% p = 0.05 9%

toms 9.3% p 8% 7% 6% 5% 5.0% 4% 3% age with ADHD sym age with 2% 1% Percent 0% CHD Population Hansen E. Batra AJ, et al., Presentation, AAP NCE 10/2008

January 14-15, 2011 SCA Conference Risk Factors for ADHD

Cyanosis/Acyanosis Severity of Cardiac Disease 14 12

mptoms 12 mptoms y 10 y Mild-Moderate 10 Acyanotic Cyanotic 8 Severe 8 6 6 4 4

2 2 ntage with ADHD S ntage with ntage with ADHD S ntage with e 0 e 0 Hyperactive- Inattentive Hyperactive- Inattentive Perc impulsive Perc impulsive

* No significance was found

Inattention 2.5 p < 0.001 2 Rating V

1.5 1.4 1.2 1

0.5 rage Parent SNAP-I 0.5 e Av 0 ADHD Positive CHD ADHD Negative

January 14-15, 2011 SCA Conference Hyperactivity/Impulsivity

2 1.8 p < 0.005

Rating 1.6 V 1.4 1.2 1 1.09 0.8 0.76 0.6

rage Parent SNAP-I 0.4 0.25 Ave 0.2 0 ADHD Positive CHD ADHD Negative

The Patient History Prior to Stimulant Use

„ History of fainting or dizziness (particularly with exercise)

„ Seizures

„ Rheumatic fever

„ Shortness of breath or noticeable change in exercise tolerance

„ Chest pain, palpitations, increased heart rate, or extra or skipped heart beats

„ History of high BP, significant heart murmur or disease Vetter VL, Elia J, et al DOI:10.DOI:10.1161/CIRCULATIONAHA.107.1894731161/CIRCULATIONAHA.107.189473 Warren AE, Hamilton RM Can J Cardiol Vol 25 No 11 November 2009

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January 14-15, 2011 SCA Conference Family History Prior to Stimulant Use

„ Sudden or unexplained death in young

„ SCD or “heart attack” or need for CPR if <35 years of age or during exercise or syncope requiring resuscitation

„ Cardiac arrhythmias, HCM or other cardiomyopathy

„ LQTS, shortshort--QTQT syndrome, or Brugada syndrome

„ WPW or similar abnormal rhythm conditions.

„ Marfan syndrome

Vetter VL, Elia J, et al CirculaCirculatition:on: DOI:10.1161 AHA.107.189473 35

Physical Examination Findings Mandating Referral

„ Abnormal heart murmur

„ Other cardiovascular abnormalities, hypertension or irregular or rapid heart rhythm

„ Physical findings suggestive of Marfan syndrome

Vetter VL, Elia J, et al CirculaCirculatition:on: DOI:10.1161 AHA.107.189473

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January 14-15, 2011 SCA Conference Significant ECG Abnormalities Needing Referral

„ Left or right ventricular hypertrophy

„ Left axis deviation or right axis deviation, especially 8 y of age

„ Right atrial enlargement and right axis deviation

„ Right ventricular conduction delay and right axis deviation

„ WolffWolff--ParkinsonParkinson--WhiteWhite anomaly or pattern (WPW)

„ SecondSecond-- and thirdthird--degreedegree atrioventricular block

„ Right BBB block, left BBB block, ii--vv conduction delay 0.12 s in patients 12 y of age (0 . 10 s in patients 8 y of age)

„ Prolonged QTc 0.46 s

„ Abnormal T waves with inversion V5, V6; bizarre TT--wavewave morphology, findings suggesting ischemia or inflammation

„ AtrialAtrial,, junctional,junctional, or ventricular tachyarrhythmiastachyarrhythmias,, including frequent premature atrial contractions or prematurprematuree ventricular contractions 37

Stimulants are Option for Non-responsive ADHD

„ CHD that is not repaired or repaired but without current hemodynamic or arrhythmic concerns

„ CHD cons idere d s tblbtable by the pa tit’tient’s pe ditidiatric car dilitdiologist

„ Use stimulants with caution after other treatments Š Heart condition associated with SCD Š History of an arrhythmia requiring CPR or resuscitation cardioversion or defibrillation Š History of an arrhythmia associated with death or SCD or previous aborted SCD Š Clinically significant arrhythmia not treated or controlled Š QTc on ECG 0.46 seconds. Š Heart rate or BP > 2 S.D. for age

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January 14-15, 2011 SCA Conference Audience Participation : ADHD and SCD Question 3

„ Should competitive athletes with ADHD who receive stimulant medications be encouraged to receive a prepre-- participation comprehensive cardiac evaluation (EKG and ECHO)?

„ 1. Yes

„ 2. No

„ 3. Undecided

„ 4. I defer this decision to my cardiac subspecialty team

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Alternative Screening Strategies for Cardiac Abnormalities in Children with ADHD

Denchev, P,Kaltman J, MD; Michael Schoenbaum, et al; CIRCULATION 109.901256

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January 14-15, 2011 SCA Conference ADHD and Universal ECGs: Expected Incremental Cost-effectiveness (vs. Current Practice)

„ Study models heart disease screening at 7 and ADHD treatment from age 7 to 17

„ Paper assumes that stimulants for ADHD increase the risk of SCD in children with HD by 10% over the baseline SCD rate

„ Anal ysi s based o n l on g li st of assum pti on s / par am eter s (cost of cardiac studies, consultations, chance of medication use, costs of meds, discontinuation rates over time)

DenchevDenchev,, P,Kaltman J, MD; Michael SchoenbaumSchoenbaum,, et al; CIRCULATION 109.901256 41

Conclusions - Adding ECG screening Hx and PE as a PreRx Screening Has Borderline Cost-effectiveness for Preventing SCD „ Strategy 2 = $39 300 per quality-quality-adjustedadjusted life-life-yearyear

„ Strategy 3 = $27 200 per quality-quality-adjustedadjusted life-life-yearyear

„ Both strategies would avert 13 SCDs per 400 000 children seeking stimulants for ADHD

„ Cost per saved life: Š $1.6 million per life for strategy 2 Š $1.2 million ppgyer life for strategy 3

„ There is substantial uncertainty surrounding several of the assumptions

„ When this uncertainty is taken into account, adding ECG to H&P has a 55% probability of being costcost--effectiveeffective at or below the target of $50 000/QALY relative to current practice 42

January 14-15, 2011 SCA Conference Pediatric Cardiac Risk Assessment Before the Use of Stimulant Medications „ A joint position statement Š Canadian Paediatric Society Š Canadian Cardiovascular Society Š Canadian Academy of Child and Adolescent Psychiatry

„ “For patients with known CHD or arrhythmias, certain disorders are known to be associated with an increased risk of sudden death. Such patients should already be under the care of a cardiologgpgist. Because there is no compelling evidence that ADHD medications raise the risk of sudden death even further, initiation of ADHD medication should be primarily at the recommendation of an ADHD specialist, although discussion of treatment choices with the responsible cardiologist is appropriate.” Paediatr Child Health 2009;14(9):5792009;14(9):579--8585 Reference No. CPS 2009-2009-0202 43

Canadian Joint Statement – Should All ADHD Patients See a Cardiologist?

„ “For patients with newly identified risk factors for coexistent cardiac disease, as per the proposed checklist, consultation with a heart specialist should be sought, regardless of whether ADHD medication will be prescribed. This would also be true in the non-non-ADHD patient.”

„ "There is currently no evidence to support routine consultation with a cardiologist before the start of ADHD medication.”

Paediatr Child Health 2009;14(9):5792009;14(9):579--8585 Reference No. CPS 20092009--0202

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January 14-15, 2011 SCA Conference Cardiac Deaths / Events linked to ADHD in Florida

„ Retrospective cohort study (July 1994 -June 2004) of Florida Medicaid claims data cross -linked to Vital Statistics Death Registry data

„ Data on all youth 3 to 20 years old who were newly diagnosed with ADHD Š 55 383 patients with new ADHD – 32 807 of these with claims for stimulants – 22 576 without claim

„ Preexisting heart disease = presence of any inpatient or outpatient claim within 6 months before first ADHD diagnosis or first stimulant claim Winterstein A, Tobias Gerhard, T et al; PEDS Vol 120, # 6, 12/2007 e1494 -1501

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Cardiac Deaths / Events linked to ADHD in Florida

„ Stimulants associated with increased ED and office visits for cardiac symptoms

„ Rates of cardiac hospitalizations and fatalities were small and similar to national background

„ 124,932 personperson--yearsyears of observation Š 73 youth died Š 5 died because of cardiac causes

„ No cardiac death occurred during 42,612 person-person-yearsyears of stimulant use Winterstein A, Tobias Gerhard, T et al; PEDS Vol 120, # 6, 12/2007 e1494 -1501

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January 14-15, 2011 SCA Conference Summary:

„ ADHD is a common neurobehavioral disorder of childhood

„ Cardiovascular parameters are impacted by ADHD treatments

„ Many children with CHD have symptoms of ADHD

„ Screening of children with ADHD for cardiac concerns is recommended, universal use of ECGs prior to the initiation of ADHD medication is controversial

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January 14-15, 2011 SCA Conference