ADHD Stimulant Medication and the Risk of Sudden Cardiac Death Lerner 10 50 am... · 2014-11-18 · January 14-15, 2011 SCA Conference ADHD Stimulant Medication and the Risk of Sudden

January 14-15, 2011 SCA Conference

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 Attention Deficit Hyperactivity Disorder

Neurobehavioral disorder marked by one or more of the following:Neurobehavioral disorder marked by one or more of the following:Inattention (poor focus / distractibility)Inattention (poor focus / distractibility)Hyperactivity (excessive motor activity)Hyperactivity (excessive motor activity)Impulsivity (no “brakes”)Impulsivity (no “brakes”)

Prevalence ratesPrevalence rates33--8% of the school8% of the school--age populationage populationClinically presents more often in boys than in girls (3:1)Clinically presents more often in boys than in girls (3:1)Clinically presents more often in boys than in girls (3:1)Clinically presents more often in boys than in girls (3:1)Three quarters of children retain ADHD symptoms in Three quarters of children retain ADHD symptoms in adolescence, and up to one half as adultsadolescence, 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.


Molecular Genetics of ADHD Molecular Genetics of ADHD

Specific genes associated with ADHDSpecific genes associated with ADHDDopamine receptor D4 gene (DRD4) on Dopamine receptor D4 gene (DRD4) on chromosome 11chromosome 11chromosome 11chromosome 11

Dopamine transporter gene (DAT1) on Dopamine transporter gene (DAT1) on chromosome 5chromosome 5

D2 dopamine receptor geneD2 dopamine receptor gene

DopamineDopamine--betabeta--hydroxylasehydroxylase genegene

Possible association of noradrenergic genesPossible association of noradrenergic genes

Most recently identified: Most recently identified: LatrophilinLatrophilin 3 gene (LPHN3), may contribute 3 gene (LPHN3), may contribute i ifi tli ifi tl

Sunohara G, et al. J Am Acad Adolesc Psychiatry. 2000;39:1537-1592.Giros B, et al. Nature. 1996;379:606-612.

significantlysignificantly

Association suggested between ADHD, parenting characteristics and Association suggested between ADHD, parenting characteristics and serotonergicserotonergic genotypesgenotypes

Swanson et al, 1998, Swanson et al, 1998,

Nikolas M et al, Nikolas M et al, BehBeh and Brain and Brain FuncFunc 2010 (6) 232010 (6) 23

ArcosArcos--Burgos M, Jain M , et al Mol Psychiatry 2/16/10Burgos M, Jain M , et al Mol Psychiatry 2/16/10

ADHD and Copy Number VariantsADHD and Copy Number VariantsComparison of genomeComparison of genome--wide analysis in children with ADHD (366) wide analysis in children with ADHD (366) and controls (1047)and controls (1047)

CNVs were found twice as often in children with ADHDCNVs were found twice as often in children with ADHDCNVs were found twice as often in children with ADHDCNVs were found twice as often in children with ADHD

Rate 5X higher in individuals with ADHD and MRRate 5X higher in individuals with ADHD and MR

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

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

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

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

4


5

ADHD TreatmentsADHD Treatments

1. Medications1. Medications

2. Behavioral/Psychological Interventions2. Behavioral/Psychological Interventions

3. Educational Interventions3. Educational Interventions

4. Alternative and Complementary Treatments4. Alternative and Complementary Treatments


ADHD MedicationsADHD Medications

Immediate-Release Stimulants

Long-Acting FormulatedStimulants Non-stimulant

Long-ActingProdrug

StimulantDexmethylphenidateDexmethylphenidate HClHCl DexmethylphenidateDexmethylphenidate HClHCl XRXR AtomoxetineAtomoxetine HClHCl LisdexamfetamineLisdexamfetamine

di l tdi l t(FOCALIN)(FOCALIN) (FOCALIN XR)(FOCALIN XR) (STRATTERA)(STRATTERA) dimesylatedimesylate(VYVANSE)(VYVANSE)

Methylphenidate Methylphenidate HClHCl

(RITALIN)(RITALIN)

Methylphenidate Methylphenidate HClHCl CDCD

(METADATE CD)(METADATE CD)

GuanfacineGuanfacine XRXR

(INTUNIV)(INTUNIV)Mixed salts of a Mixed salts of a singlesingle--entity entity amphetamine product amphetamine product (ADDERALL)(ADDERALL)

Methylphenidate Methylphenidate HClHCl LALA

(RITALIN LA)(RITALIN LA)

ClonidineClonidine LALA

(KAPVAY)(KAPVAY)

DD--amphetamineamphetamine

(DEXEDRINE)(DEXEDRINE)

Methylphenidate Methylphenidate transdermaltransdermalsystem (DAYTANA)system (DAYTANA)

Mixed salts of a singleMixed salts of a single--entity entity amphetamine product XRamphetamine product XR

(ADDERALL XR)(ADDERALL XR)OROS methylphenidate OROS methylphenidate HClHCl

(CONCERTA)(CONCERTA)

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

Oral osmotic systemOral osmotic systemOral osmotic systemOral osmotic system

Timed beadsTimed beads

Use of proUse of pro--drugdrug

TranscutaneousTranscutaneous patch technologypatch technology

ffDelayed disintegration via use of Delayed disintegration via use of incipientsincipients

8


Plasma Profiles Following MPH -IR tid and OROS MPH

ADHDADHD

OROS MPH 18mg (n=27)MPH – IR 5 mg TID (n=27)

2

3

4

5

6

a m

ethy

lphe

nida

teen

trat

ion

(ng/

ml)

MPH – IR 5 mg TID (n=27)

0

1

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

Plas

ma

Con

ce

Time (h)

Oral Osmotic Methylphenidate: Heart Rate and Hypertension Oral Osmotic Methylphenidate: Heart Rate and Hypertension

1 year safety data 1 year safety data in childrenin children

Compared to offCompared to off--drug baselinedrug baselineCompared to offCompared to off drug baselinedrug baseline

Changes in SYSChanges in SYS--BP and DBP and D--BP of 3.3 and1.5 mm Hg (P < 0.001)BP of 3.3 and1.5 mm Hg (P < 0.001)

HR increased (3.9 HR increased (3.9 bpmbpm, P < 0.0001) , P < 0.0001)

Short term data (previously discussed) did not suggest a change in Short term data (previously discussed) did not suggest a change in blood pressure with methylphenidateblood pressure with methylphenidate

N l dN l d l ti hi d t l tl ti hi d t l t

10

No clear doseNo clear dose--response relationship and no tolerance to response relationship and no tolerance to pressorpressoreffects effects

Inverse relationship between baseline vital signs and positive change Inverse relationship between baseline vital signs and positive change in vital signs at end in vital signs at end pointpoint

WilensWilens T, T, BiedermanBiederman J, Lerner M. J, Lerner M. J J ClinClin PsychopharmacolPsychopharmacol.. 2004;24(1):362004;24(1):36––41.41.


Mixed Amphetamine Salt XR: Mean (± SD) Heart Rate during Extension ProtocolMixed Amphetamine Salt XR: Mean (± SD) Heart Rate during Extension Protocol

Heart RateHeart Rate90

95

100

70

75

80

85

Hea

rt R

ate

(BPM

)

11

B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8.

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

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

60

65

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

MAS XR: Blood Pressures during Extension ProtocolMAS XR: Blood Pressures during Extension Protocol

Systolic BPSystolic BP

120

130

140

mH

g)

Diastolic BPDiastolic BP

70

80

90

100

110

Blo

od P

ress

ure

(mm

12

B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8.

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

Data on file, Shire US Inc., 2005.

Adderall XR is contraindicated in patients with symptomatic cardiovascular disease and moderate to severe hypertension.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.Adderall XR generally should not be used in those with structural cardiac abnormalities.

Adderall XR is contraindicated in patients with symptomatic cardiovascular disease and moderate to severe hypertension.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.Adderall XR generally should not be used in those with structural cardiac abnormalities.

60

70

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


Use of MAS XR for Up to Two Years in Adults Use of MAS XR for Up to Two Years in Adults Daily doses of mixed amphetamine salts XR from Daily doses of mixed amphetamine salts XR from titrated from 20 titrated from 20 –– 60 mg per day60 mg per day

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

Seven subjects (of 223 otherwise well adult subjects) Seven subjects (of 223 otherwise well adult subjects) discontinued due to a cardiovascular adverse event discontinued due to a cardiovascular adverse event

Hypertension, n=5Hypertension, n=5

Palpitation/tachycardia n=2Palpitation/tachycardia n=2Palpitation/tachycardia, n 2 Palpitation/tachycardia, n 2

None of these events was reported as seriousNone of these events was reported as serious

Several subjects with borderline elevated baseline values Several subjects with borderline elevated baseline values exhibited shifts to abnormal values during MAS XR therapyexhibited shifts to abnormal values during MAS XR therapy

WeislerWeisler R , R , BiedermanBiederman J et al . CNS J et al . CNS SpectrSpectr. 2005;10(12 . 2005;10(12 SupplSuppl 20):3520):35--4343

13

Lisdexamfetamine CV Changes over Four WeeksLisdexamfetamine CV Changes over Four Weeks

Change Mean Change Mean

Prevlously ExposedStimulant Naive

Change Mean Final Visit

Change Mean

Heart Rate 1.62 74 -4.6 69.5Sys BP 5.38 102 -4.1 98.4DiastolicBP

1.00 57.6 .57 58.6

PR Interval

0.46 133 1.0 132IntervalQRS msec 1.54 82.6 0.57 84.1Qtc msec 5.15 406 -0,57 407

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


Excitatory signalNE presynaptic terminal

Transmission of Neuronal Signal is Modulated by the a2A ReceptorTransmission of Neuronal Signal is Modulated by the a2A Receptor

a2A receptor

NE

Ion channel

Reuptake transporter

Postsynaptic neuron

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

Guanfacine and Clonidine Extended Release Agents are Approved for ADHDGuanfacine and Clonidine Extended Release Agents are Approved for ADHD

Alpha 2 Adrenergic Receptor AgonistsAlpha 2 Adrenergic Receptor Agonists

Action: Direct stimulation of postAction: Direct stimulation of post--synaptic sites which synaptic sites which support improved working memory and function in the support improved working memory and function in the prefrontal cortexprefrontal cortex

Dorsal PFC inhibits distractibilityDorsal PFC inhibits distractibility

Right Inferior PFC projections involve behavior inhibitionRight Inferior PFC projections involve behavior inhibition

V t di lV t di l PFC l t tiPFC l t tiVentromedialVentromedial PFC regulates emotionPFC regulates emotion

New extended release forms, New extended release forms, GuanfacineGuanfacine and and ClonidineClonidineGIR 75% in initial 45 GIR 75% in initial 45 minsmins Vs. GXR 85% in first 12 hoursVs. GXR 85% in first 12 hours

TmaxTmax: Shift from 3 hour to 6 hours: Shift from 3 hour to 6 hours

16


ADHD and Congenital Heart DiseaseADHD and Congenital Heart Disease

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

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

Children with many postChildren with many post--operative CHD have operative CHD have increased risk of Sudden Unexpected Deathincreased risk of Sudden Unexpected Death

17

increased risk of Sudden Unexpected Deathincreased risk of Sudden Unexpected Death

Stimulants generally not recommended Stimulants generally not recommended

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

Audience Participation : ADHD and SCDQuestion 1Audience Participation : ADHD and SCDQuestion 1

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

1. Yes1. Yes

2. No2. No

3. Undecided3. Undecided

4. I defer this decision to my cardiac subspecialty team4. I defer this decision to my cardiac subspecialty team

18


Audience Participation : ADHD and SCDQuestion 2 (for pediatric cardiologists)Audience Participation : ADHD and SCDQuestion 2 (for pediatric cardiologists)

Should Should hemodynamicallyhemodynamically stable children with an ICD stable children with an ICD be allowed to receive stimulant medications for ADHD?be allowed to receive stimulant medications for ADHD?be allowed to receive stimulant medications for ADHD?be allowed to receive stimulant medications for ADHD?

1. Yes1. Yes

2. No2. No

3 I d f thi d i i t th di3 I d f thi d i i t th di3. I defer this decision to others on my cardiac 3. I defer this decision to others on my cardiac subspecialty teamsubspecialty team

19

Background on the ADHD ControversiesBackground 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.


Baseline Cardiovascular Risks Baseline Cardiovascular Risks

Rate/100,000Rate/100,000

Patient Patient –– YrYr

OROS MPHOROS MPH

Serious CV AEsSerious CV AEs33

Sudden DeathSudden Death11PediatricPediatric

AdultAdult

1.3 1.3 –– 4.64.6

5555

0.10.1

0.30.3

MIMI22PediatricPediatric

AdultAdult

2.6 2.6 –– 19.719.7

659659

0.00.0

0.20.2

PediatricPediatric 2 72 7 0 20 2

21

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.

StrokeStroke22PediatricPediatric

AdultAdult

2.72.7

888888

0.20.2

0.50.5

HypertensionHypertension22PediatricPediatric

AdultAdult

4.54.5

32.332.3

0.50.5

0.80.8

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

S i tPediatric

ERatePDrug Scripts

(Millions)Exposures(Pt Yrs in

Thousands)Deaths Per

100KPt-Yr

Methylphenidate 9.9 816 2 0.2

Amphetamine/6 9 583 4 0 7

Dextroamphetamine6.9 583 4 0.7

Atomoxetine 3.3 276 4 1.5

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


FDA Findings: Cardiac Risks for ADHD Class MedicationsFDA Findings: Cardiac Risks for ADHD Class MedicationsPresentation of 6Presentation of 6--year data for year data for MTA (Swanson)MTA (Swanson)

Minimal difference for heart rate and blood pressure Minimal difference for heart rate and blood pressure –– Continuously using stimulantsContinuously using stimulants–– Stimulant naïve Stimulant naïve –– Local nonLocal non--ADHD classroom controlsADHD classroom controls

Added risk for rare cardiac events difficult to ascertain Added risk for rare cardiac events difficult to ascertain No recommendation for universal screening (EKG / ECHO)No recommendation for universal screening (EKG / ECHO)

Similar to challenge of identifying risk to children who participate in Similar to challenge of identifying risk to children who participate in vigorous exercise (also not recommended for routine screening)vigorous exercise (also not recommended for routine screening)

23

Consideration of cardiac risk warnings for Consideration of cardiac risk warnings for atomoxetineatomoxetine

Management of patients with congenital/structural heart Management of patients with congenital/structural heart disease will often require consultation with pediatric disease will often require consultation with pediatric cardiologistscardiologists

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

Cardiac Issues and Stimulant Medication WarningsCardiac Issues and Stimulant Medication Warnings

Stimulants should generally not be used in children, Stimulants should generally not be used in children, adolescents and adultsadolescents and adults with:with:adolescents and adults adolescents and adults with:with:

Serious structural cardiac abnormalitiesSerious structural cardiac abnormalities

CardiomyopathyCardiomyopathy

Serious heart rhythm abnormalitiesSerious heart rhythm abnormalities

Symptomatic cardiovascular diseaseSymptomatic cardiovascular disease

24

Use Use with caution in treating patients with underlying with caution in treating patients with underlying medical conditions medical conditions

prepre--existing hypertensionexisting hypertension

heart failureheart failure

recent recent myocardial infarction, or ventricular myocardial infarction, or ventricular arrhythmiaarrhythmia


Stimulant Class Cardiac WarningsStimulant Class Cardiac WarningsSudden death has been reported in association with CNS Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heartwith structural cardiac abnormalities or other serious heartwith structural cardiac abnormalities or other serious heart with structural cardiac abnormalities or other serious heart problems problems

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

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

Patients who report symptoms of cardiac disease such as Patients who report symptoms of cardiac disease such as exertionalexertional chest pain and unexplained syncope should be promptly chest pain and unexplained syncope should be promptly evaluatedevaluated

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

25

Amphetamine Black Box Warning: Important Safety InformationAmphetamine Black Box Warning: Important Safety Information

Amphetamines have a high potential for abuseAmphetamines have a high potential for abuseAmphetamines have a high potential for abuseAmphetamines have a high potential for abuse

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

Particular attention should be paid to the possibility of Particular attention should be paid to the possibility of subjects obtaining amphetamines for nonsubjects obtaining amphetamines for non--therapeutic therapeutic uses or distribution to others and the drugs should be uses or distribution to others and the drugs should be uses o d st but o to ot e s a d t e d ugs s ou d beuses o d st but o to ot e s a d t e d ugs s ou d beprescribed sparinglyprescribed sparingly

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

26


ADHD in Children with Congenital Heart DiseaseADHD in Children with Congenital Heart Disease

ADHD symptoms may be more prevalent in children ADHD symptoms may be more prevalent in children with CHD concernswith CHD concernswith CHD concernswith CHD concerns

Abnormal attention scores in 45% with children with CHDAbnormal attention scores in 45% with children with CHD

Abnormal hyperactivity scores in 39% of children with Abnormal hyperactivity scores in 39% of children with heart disease (parents and teacher ratings) heart disease (parents and teacher ratings)

Increased risk with specific congenital cardiac issuesIncreased risk with specific congenital cardiac issues> 2/3 with> 2/3 with hypoplastichypoplastic left heart syndromeleft heart syndrome> 2/3 with > 2/3 with hypoplastichypoplastic left heart syndrome left heart syndrome

50% of children with TAPVR50% of children with TAPVR

Cardiac issues associated with 22q11microdeletion Cardiac issues associated with 22q11microdeletion caused ADHD 35% to 55% of childrencaused ADHD 35% to 55% of children

27

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

MethodsMethods

CounselorsParents

SNAP-IV Questionnaires


Prevalance of Attention Deficit/Hyperactivity Disorder Symptoms in Patients With Congenital Heart Disease Prevalance of Attention Deficit/Hyperactivity Disorder Symptoms in Patients With Congenital Heart Disease

Children with Congenital Heart Disease (n=64)Children with Congenital Heart Disease (n=64)Age: 8Age: 8--18 yrs (mean 13.4 18 yrs (mean 13.4 ±± 2.6 yrs)2.6 yrs)

Disorders of Subjects•VSD (10)•Coarc (14)•AS (5)•ASD (4)•TOF (6)•TGA (4)•HLH (5)

Cyanotic abnormalities: 31Acyanotic abnormalities: 33Severe CHD: 38Mild to Moderate CHD: 26

( )•Truncus (4)•SV (7)•MR (4)•TAPVC (2)•PS (3)•Pul Atresia (3)

ADHD Positive Comparison Group (n=75)Ages 10-12 yrs old

ADHD Negative Comparison Group (n=41)Ages 10-12 yrs old

Prevalence of ADHDPrevalence of ADHD

9.3%8%9%

10%

ptom

s p = 0.05

5.0%

3%4%5%6%7%8%

age

with

AD

HD

sym

p

0%1%2%

CHD Population

Per

cent

Hansen E. Batra AJ, et al., Presentation, AAP NCE 10/2008


12

14

ympt

oms

Risk Factors for ADHDRisk Factors for ADHD

10

12

ympt

oms Severity of Cardiac DiseaseCyanosis/Acyanosis

2

4

6

8

10 AcyanoticCyanotic

enta

ge w

ith A

DH

D S

y

2

4

6

8

10Mild-ModerateSevere

enta

ge w

ith A

DH

D S

y

0Hyperactive-

impulsiveInattentiveP

erce 0

Hyperactive-impulsive

InattentivePer

ce

* No significance was found

2

2.5InattentionInattention

p < 0.001

V R

atin

g

1.41.2

0.50.5

1

1.5

erag

e P

aren

t SN

AP

-IV

0ADHD Positive CHD ADHD Negative

Ave


1.61.8

2

Hyperactivity/ImpulsivityHyperactivity/ImpulsivityV

Rat

ing

p < 0.005

1.09

0.76

0.40.60.8

11.21.4

rage

Par

ent S

NA

P-IV

0.250

0.20.4

ADHD Positive CHD ADHD Negative

Ave

The Patient History Prior to Stimulant UseThe Patient History Prior to Stimulant Use

History of fainting or dizziness (particularly with exercise)History of fainting or dizziness (particularly with exercise)

SeizuresSeizures

Rheumatic feverRheumatic fever

Shortness of breath or noticeable change in exercise Shortness of breath or noticeable change in exercise tolerancetolerance

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

History of high BP, significant heart murmur or diseaseHistory of high BP, significant heart murmur or diseaseVetter VL, Vetter VL, EliaElia J, et al DOI:10.1161/CIRCULATIONAHA.107.189473J, et al DOI:10.1161/CIRCULATIONAHA.107.189473

Warren AE, Hamilton RM Can J Warren AE, Hamilton RM Can J CardiolCardiol VolVol 25 No 11 November 200925 No 11 November 2009

34


Family History Prior to Stimulant UseFamily History Prior to Stimulant Use

Sudden or unexplained death in youngSudden or unexplained death in youngSudden or unexplained death in youngSudden or unexplained death in young

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

Cardiac arrhythmias, HCM or other Cardiac arrhythmias, HCM or other cardiomyopathycardiomyopathy

LQTS, shortLQTS, short--QT syndrome, or QT syndrome, or BrugadaBrugada syndromesyndromeyy gg yy

WPW or similar abnormal rhythm conditions.WPW or similar abnormal rhythm conditions.

MarfanMarfan syndromesyndrome

Vetter VL, Vetter VL, EliaElia J, et al Circulation: DOI:10.1161 AHA.107.189473J, et al Circulation: DOI:10.1161 AHA.107.189473 35

Physical Examination Findings Mandating Referral Physical Examination Findings Mandating Referral

Abnormal heart murmurAbnormal heart murmurAbnormal heart murmurAbnormal heart murmur

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

Physical findings suggestive of Physical findings suggestive of MarfanMarfan syndromesyndrome

Vetter VL, Vetter VL, EliaElia J, et al Circulation: DOI:10.1161 AHA.107.189473J, et al Circulation: DOI:10.1161 AHA.107.189473

36


Significant ECG Abnormalities Needing Referral Significant ECG Abnormalities Needing Referral Left or right ventricular hypertrophyLeft or right ventricular hypertrophy

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

RightRight atrialatrial enlargement and right axis deviationenlargement and right axis deviationRight Right atrialatrial enlargement and right axis deviationenlargement and right axis deviation

Right ventricular conduction delay and right axis deviationRight ventricular conduction delay and right axis deviation

WolffWolff--ParkinsonParkinson--White anomaly or pattern (WPW)White anomaly or pattern (WPW)

SecondSecond-- and thirdand third--degree degree atrioventricularatrioventricular blockblock

Right BBB block, left BBB block, Right BBB block, left BBB block, ii--v conduction delay 0.12 s in v conduction delay 0.12 s in patients 12 y of age (0 10 s in patients 8 y of age)patients 12 y of age (0 10 s in patients 8 y of age)patients 12 y of age (0.10 s in patients 8 y of age)patients 12 y of age (0.10 s in patients 8 y of age)

Prolonged Prolonged QTcQTc 0.46 s0.46 s

Abnormal T waves with inversion V5, V6; bizarre TAbnormal T waves with inversion V5, V6; bizarre T--wave wave morphology, findings suggesting ischemia or inflammationmorphology, findings suggesting ischemia or inflammation

AtrialAtrial, , junctionaljunctional, or ventricular , or ventricular tachyarrhythmiastachyarrhythmias, including frequent , including frequent premature premature atrialatrial contractions or premature ventricular contractionscontractions or premature ventricular contractions

37

Stimulants are Option for Non-responsive ADHDStimulants are Option for Non-responsive ADHD

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

CHD id d t bl b th ti t’ di t i di l i tCHD id d t bl b th ti t’ di t i di l i tCHD considered stable by the patient’s pediatric cardiologistCHD considered stable by the patient’s pediatric cardiologist

Use stimulants with caution after other treatmentsUse stimulants with caution after other treatments

Heart condition associated with SCD Heart condition associated with SCD

History of an arrhythmia requiring CPR or resuscitation History of an arrhythmia requiring CPR or resuscitation cardioversioncardioversion or defibrillationor defibrillation

History of an arrhythmia associated with death or SCD orHistory of an arrhythmia associated with death or SCD orHistory of an arrhythmia associated with death or SCD or History of an arrhythmia associated with death or SCD or previous aborted SCDprevious aborted SCD

Clinically significant arrhythmia not treated or controlledClinically significant arrhythmia not treated or controlled

QTcQTc on ECG 0.46 seconds.on ECG 0.46 seconds.

Heart rate or BP > 2 S.D. for ageHeart rate or BP > 2 S.D. for age38


Audience Participation : ADHD and SCDQuestion 3Audience Participation : ADHD and SCDQuestion 3

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

1. Yes1. Yeseses

2. No2. No

3. Undecided3. Undecided

4. I defer this decision to my cardiac subspecialty team4. I defer this decision to my cardiac subspecialty team39

Alternative Screening Strategies for Cardiac Abnormalities in Children with ADHDAlternative Screening Strategies for Cardiac Abnormalities in Children with ADHD

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


ADHD and Universal ECGs: Expected Incremental Cost-effectiveness (vs. Current Practice) ADHD and Universal ECGs: Expected Incremental Cost-effectiveness (vs. Current Practice)

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

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

Analysis based on long list of assumptions / parameters Analysis based on long list of assumptions / parameters a ys s based o o g st o assu pt o s / pa a ete sa ys s based o o g st o assu pt o s / pa a ete s(cost of cardiac studies, consultations, chance of (cost of cardiac studies, consultations, chance of medication use, costs of meds, discontinuation rates medication use, costs of meds, discontinuation rates over time)over time)

DenchevDenchev, , P,KaltmanP,Kaltman J, MD; Michael J, MD; Michael SchoenbaumSchoenbaum, et al; CIRCULATION 109.901256, et al; CIRCULATION 109.90125641

Conclusions - Adding ECG screening Hx and PE as a PreRx Screening Has Borderline Cost-effectiveness for Preventing SCD

Conclusions - Adding ECG screening Hx and PE as a PreRx Screening Has Borderline Cost-effectiveness for Preventing SCD

Strategy 2 = $39 300 per qualityStrategy 2 = $39 300 per quality--adjusted lifeadjusted life--year year

Strategy 3 = $27 200 per qualityStrategy 3 = $27 200 per quality--adjusted lifeadjusted life--yearyear

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

Cost per saved life: Cost per saved life:

$1.6 million per life for strategy 2 $1.6 million per life for strategy 2

$1.2 million per life for strategy 3$1.2 million per life for strategy 3p gyp gy

There is substantial uncertainty surrounding several of the There is substantial uncertainty surrounding several of the assumptionsassumptions

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

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Pediatric Cardiac Risk Assessment Before the Use of Stimulant Medications Pediatric Cardiac Risk Assessment Before the Use of Stimulant Medications

A joint position statement A joint position statement Canadian Canadian PaediatricPaediatric SocietySociety

Canadian Cardiovascular SocietyCanadian Cardiovascular Society

Canadian Academy of Child and Adolescent PsychiatryCanadian Academy of Child and Adolescent Psychiatry

“For patients with known CHD or arrhythmias, certain “For patients with known CHD or arrhythmias, certain disorders are known to be associated with an increased risk disorders are known to be associated with an increased risk of sudden death. Such patients should already be under the of sudden death. Such patients should already be under the care of a cardiologist. Because there is no compelling care of a cardiologist. Because there is no compelling g p gg p gevidence that ADHD medications raise the risk of sudden evidence that ADHD medications raise the risk of sudden death even further, initiation of ADHD medication should be death even further, initiation of ADHD medication should be primarily at the recommendation of an ADHD specialist, primarily at the recommendation of an ADHD specialist, although discussion of treatment choices with the although discussion of treatment choices with the responsible cardiologist is appropriate.”responsible cardiologist is appropriate.”

PaediatrPaediatr Child Health 2009;14(9):579Child Health 2009;14(9):579--85 Reference No. CPS 200985 Reference No. CPS 2009--020243

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

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

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

PaediatrPaediatr Child Health 2009;14(9):579Child Health 2009;14(9):579--85 Reference No. CPS 200985 Reference No. CPS 2009--0202

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Cardiac Deaths / Events linked to ADHD in FloridaCardiac Deaths / Events linked to ADHD in Florida

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

Data on all youth 3 to 20 years old who were newly Data on all youth 3 to 20 years old who were newly diagnosed with ADHDdiagnosed with ADHD

55 383 patients with new ADHD55 383 patients with new ADHD–– 32 807 of these with claims for stimulants 32 807 of these with claims for stimulants –– 22 576 without claim22 576 without claim

Preexisting heart disease = presence of any inpatient or Preexisting heart disease = presence of any inpatient or outpatient claim within 6 months before first ADHD diagnosis outpatient claim within 6 months before first ADHD diagnosis or first stimulant claimor first stimulant claim

WintersteinWinterstein A, Tobias Gerhard, T et al; PEDS A, Tobias Gerhard, T et al; PEDS VolVol 120, # 6, 12/2007 e1494 120, # 6, 12/2007 e1494 -- 1501150145

Cardiac Deaths / Events linked to ADHD in FloridaCardiac Deaths / Events linked to ADHD in FloridaStimulants associated with increased ED and office visits for Stimulants associated with increased ED and office visits for cardiac symptomscardiac symptoms

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

124,932 person124,932 person--years of observation years of observation 73 youth died73 youth died

5 died because of cardiac causes5 died because of cardiac causes

No cardiac death occurred during 42,612 personNo cardiac death occurred during 42,612 person--years of years of stimulant usestimulant use

WintersteinWinterstein A, Tobias Gerhard, T et al; PEDS A, Tobias Gerhard, T et al; PEDS VolVol 120, # 6, 12/2007 e1494 120, # 6, 12/2007 e1494 -- 15011501

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Summary: Summary:

ADHD is a common neurobehavioral disorder ofADHD is a common neurobehavioral disorder ofADHD is a common neurobehavioral disorder of ADHD is a common neurobehavioral disorder of childhoodchildhood

Cardiovascular parameters are impacted by ADHD Cardiovascular parameters are impacted by ADHD treatmentstreatments

Many children with CHD have symptoms of ADHDMany children with CHD have symptoms of ADHD

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

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ADHD Stimulant Medication and the Risk of Sudden Cardiac Death Lerner 10 50 am... · 2014-11-18 · January 14-15, 2011 SCA Conference ADHD Stimulant Medication and the Risk of Sudden