Download Attention Deficit Hyperactivity Disorder

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 3-8% of the schoolschool-age 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 Dopamine
Dopamine--beta
beta--hydroxylase gene
Š Possible association of noradrenergic genes
Š Most recently identified: Latrophilin 3 gene (LPHN3), may contribute
significantly
i ifi
tl
„ Association suggested between ADHD, parenting characteristics and
serotonergic genotypes
Swanson et al, 1998,
Sunohara
et al.and
J Am
Acad
Adolesc
2000;39:1537-1592.
Nikolas
M et al,G,Beh
Brain
Func
2010Psychiatry.
(6) 23
Giros B, et al. Nature. 1996;379:606-612.
Arcos--Burgos M, Jain M , et al Mol Psychiatry 2/16/10
Arcos
ADHD and Copy Number Variants
„ Comparison of genomegenome-wide 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, Zaharieva
Zaharieva,, I, et al Lancet published on line on 9/30/2010
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January 14-15, 2011 SCA Conference
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ADHD Treatments
1. Medications
2. Behavioral/Psychological Interventions
3. Educational Interventions
4. Alternative and Complementary Treatments
January 14-15, 2011 SCA Conference
ADHD Medications
Immediate-Release
Stimulants
Long-Acting
Formulated
Stimulants
Dexmethylphenidate HCl
Dexmethylphenidate HCl XR
Atomoxetine HCl
(FOCALIN)
(FOCALIN XR)
(STRATTERA)
Methylphenidate HCl
Methylphenidate HCl CD
Guanfacine XR
(RITALIN)
(METADATE CD)
(INTUNIV)
Mixed salts of a
single--entity
single
amphetamine product
(ADDERALL)
Methylphenidate HCl LA
Clonidine LA
(RITALIN LA)
(KAPVAY)
D-amphetamine
(DEXEDRINE)
Non-stimulant
Long-Acting
Prodrug
Stimulant
Lisdexamfetamine
di
dimesylate
l t
(VYVANSE)
Methylphenidate transdermal
system (DAYTANA)
Mixed salts of a singlesingle-entity
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 pro
pro--drug
„ Transcutaneous patch technology
„ Delayed disintegration via use off 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)
Plasma
a methylphenidate
Conce
entration (ng/ml)
MPH – IR 5 mg TID (n=27)
6
5
4
3
2
1
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
off--drug baseline
Š Changes in SYSSYS-BP and D
D--BP of 3.3 and1.5 mm Hg (P < 0.001)
Š HR increased (3.9 bpm
bpm,, P < 0.0001)
Š Short term data (previously discussed) did not suggest a change in
blood pressure with methylphenidate
„ No
N clear
l
d
dose-response relationship
dosel ti
hi and
d no tolerance
t l
tto 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):36
2004;24(1):36–
–41.
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January 14-15, 2011 SCA Conference
Mixed Amphetamine Salt XR: Mean (± SD) Heart
Rate during Extension Protocol
100
95
Heart Rate
Heart Rate (BPM)
90
85
80
75
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.
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MAS XR: Blood Pressures during Extension Protocol
140
Systolic BP
Blood Pressure (mm
mHg)
130
120
110
100
90
Diastolic BP
80
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.
January 14-15, 2011 SCA Conference
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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
Palpitation/tachycardia n=2
n 2
Š Palpitation/tachycardia,
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.
Spectr. 2005;10(12 Suppl 20):3520):35-43
13
Lisdexamfetamine CV Changes over Four Weeks
Stimulant Naive
Change
Mean
Final Visit
Prevlously Exposed
Change
Mean
Heart Rate 1.62
74
-4.6
69.5
Sys BP
5.38
102
-4.1
98.4
Diastolic
BP
1.00
57.6
.57
58.6
PR
Interval
0.46
133
1.0
132
QRS msec 1.54
82.6
0.57
84.1
Qtc msec
406
-0,57
407
5.15
Wigal SB, Lerner MA et al Postgraduate Medicine, 122(5) Sept 2010
January 14-15, 2011 SCA Conference
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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 stimulation of post
post--synaptic 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 Ventromedial
V t
di l PFC regulates
l t emotion
ti
„ New extended release forms, Guanfacine and Clonidine
Š GIR 75% in initial 45 mins Vs. GXR 85% in first 12 hours
Š Tmax
Tmax:: 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 post
post--operative CHD have
increased risk of Sudden Unexpected Death
„ Stimulants generally not recommended
Bass JL, et al. Pediatrics. 2004;114(3):805-816.
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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 children with an ICD
be allowed to receive stimulant medications for ADHD?
„ 1. Yes
„ 2. No
„ 3.
3 I defer
d f this
thi d
decision
i i tto others
th
on my cardiac
di
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
Serious CV AEs3
Pediatric
1.3 – 4.6
0.1
Adult
55
0.3
Pediatric
2.6 – 19.7
0.0
Adult
659
0.2
Pediatric
27
2.7
02
0.2
Adult
888
0.5
Pediatric
4.5
0.5
Adult
32.3
0.8
Sudden Death1
MI2
Stroke2
Hypertension2
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
Drug
Scripts
S
i t
(Millions)
Pediatric
Exposures
E
(Pt Yrs in
Thousands)
Deaths
Rate
P
Per
100K
Pt-Yr
9.9
816
2
0.2
69
6.9
583
4
07
0.7
3.3
276
4
1.5
Methylphenidate
Amphetamine/
Dextroamphetamine
Atomoxetine
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 66-year data for MTA (Swanson)
Š Minimal difference for heart rate and blood pressure
– Continuously using stimulants
– Stimulant naïve
– Local nonnon-ADHD 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 risk 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 treating patients with underlying
medical conditions
Š pre
pre--existing hypertension
Š heart failure
Š recent myocardial infarction, or ventricular arrhythmia
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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-therapeutic
uses o
or d
distribution
st but o to ot
others
esa
and
d tthe
ed
drugs
ugs sshould
ou 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
January 14-15, 2011 SCA Conference
Counselors
Prevalance of Attention Deficit/Hyperactivity Disorder
Symptoms in Patients With Congenital Heart Disease
Children with Congenital Heart Disease (n=64)
„ Age: 8
8--18 yrs (mean 13.4 ± 2.6 yrs)
Disorders of Subjects
•VSD (10)
•Coarc (14)
•AS (5)
•ASD (4)
•TOF (6)
•TGA (4)
•HLH ((5))
•Truncus (4)
•SV (7)
•MR (4)
•TAPVC (2)
•PS (3)
•Pul Atresia (3)
Cyanotic abnormalities: 31
Acyanotic abnormalities: 33
Severe CHD: 38
Mild to Moderate CHD: 26
ADHD Positive Comparison Group (n=75)
Ages 10-12 yrs old
ADHD Negative Comparison Group (n=41)
Ages 10-12 yrs old
Percentage with ADHD symp
ptoms
Prevalence of ADHD
10%
9%
8%
p = 0.05
9.3%
7%
6%
5%
5.0%
4%
3%
2%
1%
0%
CHD
Population
Hansen E. Batra AJ, et al.,
Presentation, AAP NCE 10/2008
January 14-15, 2011 SCA Conference
Cyanosis/Acyanosis
14
12
Acyanotic
Cyanotic
10
8
6
4
2
0
Hyperactiveimpulsive
Inattentive
Perce
entage with ADHD Syymptoms
Perce
entage with ADHD Syymptoms
Risk Factors for ADHD
Severity of Cardiac Disease
12
10
Mild-Moderate
Severe
8
6
4
2
0
Hyperactiveimpulsive
Inattentive
* No significance was found
Inattention
Ave
erage Parent SNAP-IV
V Rating
2.5
p < 0.001
2
1.5
1.4
1.2
1
0.5
0.5
0
ADHD Positive
January 14-15, 2011 SCA Conference
CHD
ADHD Negative
Average Parent SNAP-IV
V Rating
Hyperactivity/Impulsivity
2
1.8
p < 0.005
1.6
1.4
1.2
1
1.09
0.8
0.76
0.6
0.4
0.25
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:10.1161/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, short
short--QT syndrome,
y
or Brugada
g
syndrome
y
„ WPW or similar abnormal rhythm conditions.
„ Marfan syndrome
Vetter VL, Elia J, et al Circulation: 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 Circulation: 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
„ Wolff
Wolff--Parkinson
Parkinson--White anomaly or pattern (WPW)
„ Second
Second-- and thirdthird-degree atrioventricular block
„ Right BBB block, left BBB block, i-v conduction delay 0.12 s in
patients 12 y of age (0.10
(0 10 s in patients 8 y of age)
„ Prolonged QTc 0.46 s
„ Abnormal T waves with inversion V5, V6; bizarre TT-wave
morphology, findings suggesting ischemia or inflammation
„ Atrial
Atrial,, junctional,
junctional, or ventricular tachyarrhythmias
tachyarrhythmias,, including frequent
premature atrial contractions or premature ventricular contractions
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Stimulants are Option for Non-responsive ADHD
„ CHD that is not repaired or repaired but without current
hemodynamic or arrhythmic concerns
„ CHD considered
id d stable
t bl b
by th
the patient’s
ti t’ pediatric
di t i cardiologist
di l i t
„ 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 prepreparticipation comprehensive cardiac evaluation (EKG
and ECHO)?
„ 1. Yes
es
„ 2. No
„ 3. Undecided
„ 4. I defer this decision to my cardiac subspecialty team
39
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
„ Analysis
a ys s based on
o long
o g list
st o
of assu
assumptions
pt o s / pa
parameters
a ete s
(cost of cardiac studies, consultations, chance of
medication use, costs of meds, discontinuation rates
over time)
Denchev,, P,Kaltman J, MD; Michael Schoenbaum
Denchev
Schoenbaum,, 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 qualityquality-adjusted lifelife-year
„ Strategy 3 = $27 200 per qualityquality-adjusted lifelife-year
„ 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
per life for strategy
gy 3
Š $1.2 million p
„ 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-effective at or below
the target of $50 000/QALY relative to current practice
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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 cardiologist.
g
Because there is no compelling
p
g
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):579
2009;14(9):579--85 Reference No. CPS 20092009-02
43
Canadian Joint Statement – Should All ADHD
Patients See a Cardiologist?
„ “For
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 nonnon- ADHD
patient.”
„ "There
There is currently no evidence to support routine
consultation with a cardiologist before the start of ADHD
medication.”
Paediatr Child Health 2009;14(9):579
2009;14(9):579--85 Reference No. CPS 2009
2009--02
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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
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
45
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 person
person--years of observation
Š 73 youth died
Š 5 died because of cardiac causes
„ No cardiac death occurred during 42,612 personperson-years of
stimulant use
Winterstein A, Tobias Gerhard, T et al; PEDS Vol 120, # 6, 12/2007 e1494 - 1501
46
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