Clinical Updates of Interest to Providers
CARDIOVASCULAR MONITORING OF CHILDREN AND ADOLESCENTS WITH
HEART DISEASE RECEIVING STIMULANT DRUGS
Background
In 1999, an AHA scientific statement regarding children and adolescents receiving
psychotropic drugs included no specific cardiovascular monitoring recommendations. Since
then, a constellation of circumstances have come together necessitating a second look at this
complicated issue. These circumstances include an increased awareness of the presence of
ADHD in the general population and in children with preexisting cardiac conditions; public
concerns about the side effects and toxicities of medications, especially psychotropic
medications in children; and regulatory factors and warnings issued by the US Food and Drug
Administration (FDA) and by the pharmaceutical industry in response to the FDA. This
prompted the most recent AHA statement, which can be read in its entirety at http://circ.
ahajournals.org/. On April 22, the AAP issued a commentary on the AHA statement. This is an
abbreviated review of the AHA statement which includes the essential recommendations
relevant to pediatricians. A few background facts:
• There are probably between 2.5 – 4.4 million U.S. children with ADHD (2003 data);
• ADHD is more prevalent in children with heart disease than in the general population;
• In early 2005, Health Canada, (the Canadian FDA equivalent), suspended the sale of
Adderall XR based on U.S. postmarketing reports of sudden deaths in pediatric patients, with
a preponderance having cardiac defects (it was subsequently reinstated);
• In August, 2005, the FDA added a warning to the Adderall labeling regarding potential
adverse effect in children with preexisting structural cardiac defects;
• There are no systematically collected data to indicate that “structural heart disease”
broadly should be a reason to avoid these medications. Likewise, there are no data which
identify the actual risks of stimulant medication in children with congenital heart disease;
• On February 21, 2007, the FDA issued a press release titled “FDA Directs ADHD Drug
Manufacturers to Notify Patients About Cardiovascular Adverse Events and Psychiatric
Adverse Events;
• The general cardiovascular side effects of stimulant drugs include an average increase in
heart rate of 1 to 2 bpm and an increase in systolic and diastolic blood pressures of 3 to 4 mm
Hg. No study has demonstrated a significant change in the QT or QTc intervals;
• The current warning in drug monographs states that these medications generally should
not be used in children with “serious structural cardiac abnormalities, cardiomyopathy, heart
rhythm abnormalities, or other serious cardiac problems that may place them at increased
vulnerability to the sympathomimetic effects of a stimulant drug.”
• The entities that are most important to exclude are hypertrophic cardiomyopathy (HCM),
other myopathies, long QT syndrome (LQTS), short-QTS, arrhythmogenic right ventricular
cardiomyopathy, WPW, Marfan Syndrome, Brugada Syndrome and congenital coronary artery
anomalies.
Recommendations
These patient medication guidelines have been developed for 15 medications, including all of
the stimulant medications used for ADHD such as amphetamines, methylphenidates, and
atomoxetine.
A. In new patients, after a diagnosis of ADHD has been made but before therapy with a
stimulant or other medication is initiated, a thorough evaluation should be performed: The
AHA recommendations are:
1. A complete personal history including questions regarding fainting or dizziness
(particularly with exercise), seizures, chest pain or shortness of breath with exercise (not
related to asthma), palpitations or skipped heart beats, high blood pressure, heart murmur
other than innocent, and current medications (prescribed, over the counter and dietary
supplements.
2. A complete family history including questions regarding young (<35 years) family
members with sudden or unexplained death, sudden death during exercise, cardiac
arrhythmias, HCM, other cardiomyopathies, LQTS or short-QTS, Brugada syndrome, WPW, and
events requiring resuscitation in young family members.
3. A thorough physical examination including blood pressure, heart rate and rhythm,
physical features of Marfan Syndrome and presence of abnormal cardiac murmurs (innocent
murmurs excluded).
4. A baseline ECG ‘is reasonable to obtain’. It is classified as a 2A indication. It is
acknowledged that an ECG will not identify all cardiac conditions. ECGs should be read by a
pediatric cardiologist or other physician with expertise in reading pediatric electrocardiograms.
Abnormalities in any of the above components should trigger cardiac consultation before
initiation of therapy.
B. Once medication is started, if the initial ECG was obtained before the child was 12 years of
age, a repeat ECG may be useful after the child is >12 years of age. A repeat ECG should also
be obtained whenever there is a significant (as listed above) change in family history,
personal history or physical examination.
C. Recommendations for continuing assessment of patients already on ADHD medications:
1. For children already taking methylphenidate, amphetamine, or other stimulant agents, it is
reasonable to obtain a history, review the physical examination, and order an ECG if these
were not previously done.
2. Personal history, family history and physical examination should be repeated at each
follow-up visit.
3. Blood pressure and heart rate and rhythm should be evaluated during routine follow-up
within 1 – 3 months of beginning medication and at follow-up visits every 6 – 12 months.
4. Any new cardiac symptoms should prompt referral for cardiac evaluation.
D. There are no clinical studies or data indicating that children with most types of congenital
heart disease are at significant risk for SCD while on these medications. It is reasonable to
consider the use of stimulant medication in patients with congenital heart disease that is not
repaired or repaired but without current hemodynamic or arrhythmic concerns or congenital
heart disease that is considered to be stable by the patient’s pediatric cardiologist.
MIGRAINE HEADACHE IN CONGENITAL HEART DISEASE
The prevalence of migraine headaches (MH) is 12% in the general population and increases to
about 40% in patients with patent foramen ovale. A recently published study (Am J Cardiol;
Feb., 2008) evaluated the prevalence of MH in adult patients with congenital heart disease
(CHD). Of 395 patients (mean age = 45.2±14yrs) from the UCLA Adult Congenital Heart
Disease Center, the prevalence of MH was 45% compared to 11% (similar to the ‘normal’
population) in a sex and age-matched group with acquired heart disease (p <0.001). MH
patients with CHD were stratified by type of shunt. Although the prevalence was much higher
than the control population for all 3 groups, there was no significant difference in the
prevalence of MH among the groups with right-to-left shunt (52%), left-to-right shunt (44%)
and no intracardiac shunt (40%). The higher than expected incidence of MH in the group
without shunts is difficult to explain based on current concepts of MH etiology in PFO (R → L
shunt of microemboli and/or neuromediators). Of the 179 patients with MH, 143 (80%) had
migraines with aura and 36 (20%) had migraines without aura versus 36% and 64%
observed in the controls (which matches the distribution of MH and aura in the general
population)(p<0.001). Of 44 patients with shunts (L → R or R → L) who had surgery and who
recalled having MH before surgical correction, 18 (41%) reported complete resolution of their
migraines, and 29 (66%) reported a significant improvement (including resolution). This is
similar to the data from 6 published trials that evaluated the effect of percutaneous
transcatheter PFO closure in 215 patients with cryptogenic stroke and MH where 79%
reported either complete resolution or significant improvement in their symptoms. Although
there was a trend toward greater benefit after surgery in patients with R → L shunt, it did not
approach clinical significance. (The effect of surgical repair in patients without shunts was not
evaluated in this study). Therefore, the effect of shunt closure appears to be similar in
patients with PFO compared to adults with CHD adults and right-to-left shunt. In conclusion,
the prevalence of MH in all groups of adults with CHD is 3 to 4 times more than a sex-matched
control population, with increasing prevalence of MH in patients with no shunt, left-to-right,
and right-to-left shunt. The higher than expected frequency of MH in patients with CHD
without an intracardiac shunt (mostly patients with aortic abnormalities) suggests additional
mechanisms to explain the association with MH.
PEDIATRIX CARDIOLOGY ASSOCIATES AFFILIATES WITH NIH MARFAN
SYNDROME ATENOLOL vs LOSARTAN STUDY
Marfan Syndrome (MFS) is an autosomal dominant disorder of connective tissue that affects
the eyes, skeleton, skin, heart and blood vessels. It affects 1 in 5-10,000 individuals; there
are more than 200,000 Americans with MFS. It is caused by defects in the fibrillin-1 gene
located on chromosome 15. The cardiovascular sequelae of MFS include mitral valve prolapse
with or without insufficiency, dysrrhthmias, aortic valve insufficiency, and aortic root dilation
and possible aneurysm. The latter may lead to a catastrophic cardiac event. Current
treatment considerations to prevent or forestall the severe aortic complications include beta-
blockade, and/or ACE inhibitor therapy. Composite aortic root replacement is indicated if
sequential imaging studies demonstrate a root diameter approaching 45-50 cm in an adult.
A recent study (Science; 312: 117-121) utilizing a mouse model of MFS demonstrated that the
aortic manifestations of MFS seem due to excessive signaling of the transforming growth
factor β (TGF- β) family of cytokines. The study demonstrated that aortic aneurysms in the
mouse model could be stopped and reversed by using neutralizing antibody to TGF- β, or the
angiotensin II type 1 receptor blocking agent losartan (Cozaar).
PCANM has become a participating center in the NIH study intended to compare the effects of
beta-blockers (specifically atenolol) and angiotensin II receptor blockade (specifically losartan)
on aortic growth characteristics and aortic regurgitation in patients with MFS who are
between the ages of 6 months and 25 years and who have an enlarged aortic root (Z-score >
3.0). Exclusion criteria are available on request. There are funds available for medical studies,
lodging and travel. If you are interested in participating, contact Bradley Raisher, MD at 505-
848-3700 or 800-613-2179 for additional information.
CARDIOVASCULAR MONITORING OF CHILDREN AND ADOLESCENTS WITH
HEART DISEASE RECEIVING STIMULANT DRUGS
Background
In 1999, an AHA scientific statement regarding children and adolescents receiving
psychotropic drugs included no specific cardiovascular monitoring recommendations. Since
then, a constellation of circumstances have come together necessitating a second look at this
complicated issue. These circumstances include an increased awareness of the presence of
ADHD in the general population and in children with preexisting cardiac conditions; public
concerns about the side effects and toxicities of medications, especially psychotropic
medications in children; and regulatory factors and warnings issued by the US Food and Drug
Administration (FDA) and by the pharmaceutical industry in response to the FDA. This
prompted the most recent AHA statement, which can be read in its entirety at http://circ.
ahajournals.org/. On April 22, the AAP issued a commentary on the AHA statement. This is an
abbreviated review of the AHA statement which includes the essential recommendations
relevant to pediatricians. A few background facts:
• There are probably between 2.5 – 4.4 million U.S. children with ADHD (2003 data);
• ADHD is more prevalent in children with heart disease than in the general population;
• In early 2005, Health Canada, (the Canadian FDA equivalent), suspended the sale of
Adderall XR based on U.S. postmarketing reports of sudden deaths in pediatric patients, with
a preponderance having cardiac defects (it was subsequently reinstated);
• In August, 2005, the FDA added a warning to the Adderall labeling regarding potential
adverse effect in children with preexisting structural cardiac defects;
• There are no systematically collected data to indicate that “structural heart disease”
broadly should be a reason to avoid these medications. Likewise, there are no data which
identify the actual risks of stimulant medication in children with congenital heart disease;
• On February 21, 2007, the FDA issued a press release titled “FDA Directs ADHD Drug
Manufacturers to Notify Patients About Cardiovascular Adverse Events and Psychiatric
Adverse Events;
• The general cardiovascular side effects of stimulant drugs include an average increase in
heart rate of 1 to 2 bpm and an increase in systolic and diastolic blood pressures of 3 to 4 mm
Hg. No study has demonstrated a significant change in the QT or QTc intervals;
• The current warning in drug monographs states that these medications generally should
not be used in children with “serious structural cardiac abnormalities, cardiomyopathy, heart
rhythm abnormalities, or other serious cardiac problems that may place them at increased
vulnerability to the sympathomimetic effects of a stimulant drug.”
• The entities that are most important to exclude are hypertrophic cardiomyopathy (HCM),
other myopathies, long QT syndrome (LQTS), short-QTS, arrhythmogenic right ventricular
cardiomyopathy, WPW, Marfan Syndrome, Brugada Syndrome and congenital coronary artery
anomalies.
Recommendations
These patient medication guidelines have been developed for 15 medications, including all of
the stimulant medications used for ADHD such as amphetamines, methylphenidates, and
atomoxetine.
A. In new patients, after a diagnosis of ADHD has been made but before therapy with a
stimulant or other medication is initiated, a thorough evaluation should be performed: The
AHA recommendations are:
1. A complete personal history including questions regarding fainting or dizziness
(particularly with exercise), seizures, chest pain or shortness of breath with exercise (not
related to asthma), palpitations or skipped heart beats, high blood pressure, heart murmur
other than innocent, and current medications (prescribed, over the counter and dietary
supplements.
2. A complete family history including questions regarding young (<35 years) family
members with sudden or unexplained death, sudden death during exercise, cardiac
arrhythmias, HCM, other cardiomyopathies, LQTS or short-QTS, Brugada syndrome, WPW, and
events requiring resuscitation in young family members.
3. A thorough physical examination including blood pressure, heart rate and rhythm,
physical features of Marfan Syndrome and presence of abnormal cardiac murmurs (innocent
murmurs excluded).
4. A baseline ECG ‘is reasonable to obtain’. It is classified as a 2A indication. It is
acknowledged that an ECG will not identify all cardiac conditions. ECGs should be read by a
pediatric cardiologist or other physician with expertise in reading pediatric electrocardiograms.
Abnormalities in any of the above components should trigger cardiac consultation before
initiation of therapy.
B. Once medication is started, if the initial ECG was obtained before the child was 12 years of
age, a repeat ECG may be useful after the child is >12 years of age. A repeat ECG should also
be obtained whenever there is a significant (as listed above) change in family history,
personal history or physical examination.
C. Recommendations for continuing assessment of patients already on ADHD medications:
1. For children already taking methylphenidate, amphetamine, or other stimulant agents, it is
reasonable to obtain a history, review the physical examination, and order an ECG if these
were not previously done.
2. Personal history, family history and physical examination should be repeated at each
follow-up visit.
3. Blood pressure and heart rate and rhythm should be evaluated during routine follow-up
within 1 – 3 months of beginning medication and at follow-up visits every 6 – 12 months.
4. Any new cardiac symptoms should prompt referral for cardiac evaluation.
D. There are no clinical studies or data indicating that children with most types of congenital
heart disease are at significant risk for SCD while on these medications. It is reasonable to
consider the use of stimulant medication in patients with congenital heart disease that is not
repaired or repaired but without current hemodynamic or arrhythmic concerns or congenital
heart disease that is considered to be stable by the patient’s pediatric cardiologist.
MIGRAINE HEADACHE IN CONGENITAL HEART DISEASE
The prevalence of migraine headaches (MH) is 12% in the general population and increases to
about 40% in patients with patent foramen ovale. A recently published study (Am J Cardiol;
Feb., 2008) evaluated the prevalence of MH in adult patients with congenital heart disease
(CHD). Of 395 patients (mean age = 45.2±14yrs) from the UCLA Adult Congenital Heart
Disease Center, the prevalence of MH was 45% compared to 11% (similar to the ‘normal’
population) in a sex and age-matched group with acquired heart disease (p <0.001). MH
patients with CHD were stratified by type of shunt. Although the prevalence was much higher
than the control population for all 3 groups, there was no significant difference in the
prevalence of MH among the groups with right-to-left shunt (52%), left-to-right shunt (44%)
and no intracardiac shunt (40%). The higher than expected incidence of MH in the group
without shunts is difficult to explain based on current concepts of MH etiology in PFO (R → L
shunt of microemboli and/or neuromediators). Of the 179 patients with MH, 143 (80%) had
migraines with aura and 36 (20%) had migraines without aura versus 36% and 64%
observed in the controls (which matches the distribution of MH and aura in the general
population)(p<0.001). Of 44 patients with shunts (L → R or R → L) who had surgery and who
recalled having MH before surgical correction, 18 (41%) reported complete resolution of their
migraines, and 29 (66%) reported a significant improvement (including resolution). This is
similar to the data from 6 published trials that evaluated the effect of percutaneous
transcatheter PFO closure in 215 patients with cryptogenic stroke and MH where 79%
reported either complete resolution or significant improvement in their symptoms. Although
there was a trend toward greater benefit after surgery in patients with R → L shunt, it did not
approach clinical significance. (The effect of surgical repair in patients without shunts was not
evaluated in this study). Therefore, the effect of shunt closure appears to be similar in
patients with PFO compared to adults with CHD adults and right-to-left shunt. In conclusion,
the prevalence of MH in all groups of adults with CHD is 3 to 4 times more than a sex-matched
control population, with increasing prevalence of MH in patients with no shunt, left-to-right,
and right-to-left shunt. The higher than expected frequency of MH in patients with CHD
without an intracardiac shunt (mostly patients with aortic abnormalities) suggests additional
mechanisms to explain the association with MH.
PEDIATRIX CARDIOLOGY ASSOCIATES AFFILIATES WITH NIH MARFAN
SYNDROME ATENOLOL vs LOSARTAN STUDY
Marfan Syndrome (MFS) is an autosomal dominant disorder of connective tissue that affects
the eyes, skeleton, skin, heart and blood vessels. It affects 1 in 5-10,000 individuals; there
are more than 200,000 Americans with MFS. It is caused by defects in the fibrillin-1 gene
located on chromosome 15. The cardiovascular sequelae of MFS include mitral valve prolapse
with or without insufficiency, dysrrhthmias, aortic valve insufficiency, and aortic root dilation
and possible aneurysm. The latter may lead to a catastrophic cardiac event. Current
treatment considerations to prevent or forestall the severe aortic complications include beta-
blockade, and/or ACE inhibitor therapy. Composite aortic root replacement is indicated if
sequential imaging studies demonstrate a root diameter approaching 45-50 cm in an adult.
A recent study (Science; 312: 117-121) utilizing a mouse model of MFS demonstrated that the
aortic manifestations of MFS seem due to excessive signaling of the transforming growth
factor β (TGF- β) family of cytokines. The study demonstrated that aortic aneurysms in the
mouse model could be stopped and reversed by using neutralizing antibody to TGF- β, or the
angiotensin II type 1 receptor blocking agent losartan (Cozaar).
PCANM has become a participating center in the NIH study intended to compare the effects of
beta-blockers (specifically atenolol) and angiotensin II receptor blockade (specifically losartan)
on aortic growth characteristics and aortic regurgitation in patients with MFS who are
between the ages of 6 months and 25 years and who have an enlarged aortic root (Z-score >
3.0). Exclusion criteria are available on request. There are funds available for medical studies,
lodging and travel. If you are interested in participating, contact Bradley Raisher, MD at 505-
848-3700 or 800-613-2179 for additional information.
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| PEDIATRIX CARDIOLOGY ASSOCIATES OF NEW MEXICO |