Diagnoses of Cardiovascular Disease or Substance Addiction/Abuse in US Adults Treated for ADHD with Stimulants or Atomoxetine: Is Use Consistent with Product Labeling?
Diagnoses of Cardiovascular Disease or Substance Addiction/ Abuse in US Adults Treated for ADHD with Stimulants or Atomoxetine: Is Use Consistent with Product Labeling?
Kathleen A. Fairman 0 1
Lindsay E. Davis 0 1
Alyssa M. Peckham 0 1
David A. Sclar 0 1
0 Department of Pharmacy Practice, College of Pharmacy, Midwestern University-Glendale , 19555 N. 59th Avenue, Glendale, AZ 85308 , USA
1 & Kathleen A. Fairman
Background Among US adults, utilization of pharmacotherapy for attention-deficit hyperactivity disorder (ADHD) has increased more than ninefold since 1995-1996. Potential contraindications to ADHD pharmacotherapy include serious cardiovascular disease (CVD) and, for stimulants, addictions and bipolar disorder (BPD). Objective To assess the prevalence of potential contraindications among adults treated with ADHD pharmacotherapy. Methods A retrospective cohort analysis was performed using the Truven Health MarketScan database. Subjects filled C 1 prescription for atomoxetine or C 1 stimulant in 2014-2015, were aged 18-64 years, commercially insured throughout observation, and diagnosed with ADHD on two or more medical claims. Diagnoses and medical procedures were measured in the 12 months prior to pharmacotherapy initiation. Metrics included serious CVD (cardiomegaly, cardiomyopathy, cerebrovascular occlusion, congestive heart failure, myocardial infarction, pacemaker, or valvular
disorder) and any CVD (serious CVD, other atherosclerotic
CVD, arrhythmia, congenital heart anomaly, or
hypertensive heart disease). Rates of substance addiction or abuse
were measured in a range to address nonspecific diagnostic
Results Only 2.0% of treated adults (n = 91,588) had one
or more diagnosis indicating serious CVD. CVD
prevalence increased monotonically with age. Of patients aged
55–64 years (n = 5,237), 7.2% had serious CVD; 15.9%
had any CVD; and 1.9% had been hospitalized with one or
more CVD. Of patients treated with stimulants
(n = 87,167), 11.3–18.5% were diagnosed with addiction/
abuse and 4.1% with BPD.
Conclusions CVD prevalence is generally low among
adults using ADHD medication but increases with age.
Although difficult to estimate precisely, the rate of
addiction/abuse among stimulant-treated patients appears
unexpectedly high. Further research should assess
cardiovascular events and other potential harms associated
with contraindicated use in high-risk adults.
This study of potential contraindications to
pharmacotherapy for attention-deficit hyperactivity
disorder (ADHD) in commercially insured US adults
found that, measured in the 12 months prior to
initiation of treatment with stimulants or
atomoxetine in 2014–2015, prevalence rates of
serious cardiovascular disease were 7.2% among
those aged 55–64 years and 3.6% among those aged
Of adults initiating treatment with stimulants,
11.3–18.5% had been diagnosed in the past year with
substance addiction or potential abuse.
In light of rapid growth in diagnosis and
pharmacologic treatment for ADHD in recent years,
a study of adverse drug events among adults at
highest risk—those who are older and/or have a
potential contraindication to pharmacotherapy—is
In the past two decades, prevalence rates of diagnosis and
pharmacologic treatment for attention-deficit hyperactivity
disorder (ADHD) have increased exponentially among
United States (US) adults [
]. One study of National
Ambulatory Medical Care Survey (NAMCS) data found
that per 1,000 office-based physician visits made by US
adults aged C 20 years, rates of ADHD diagnosis and
pharmacologic treatment increased by 52.6 and 35.2%,
respectively, from 2008–2009 to 2012–2013 . Moreover,
from 1995–1996 to 2007–2008, the population-adjusted
rate of physician visits at which ADHD pharmacotherapy
was prescribed to adults increased fivefold; and by
2012–2013, a more than ninefold increase had occurred,
from 1.9 to 11.4 visits per 1000 US adults [
2, 5, 6
It has been suggested that these changes are
attributable to expansion of the diagnostic criteria for
ADHD in the Diagnostic and Statistical Manual of Mental
Disorders (DSM)-5 in 2013 [
], as well as the launch of
new medications and formulations (e.g., chewables,
sustained-release tablets, patches, and new molecular entities)
in recent years [
5, 8, 9
]. Along with these expansions, two
factors complicate the management of pharmacotherapy
for the rapidly growing population of US adults diagnosed
First, ADHD medications increase diastolic blood
pressure (BP), systolic BP, and heart rate by amounts that
are generally considered modest but potentially clinically
significant in patients with pre-existing cardiovascular
disease (CVD) or CVD risk factors [
]. For this reason,
stimulants, which are the most common and
guidelinerecommended medications to treat ADHD [
6, 11, 12
US Food and Drug Administration (FDA) labeled warnings
for serious cardiovascular events, including sudden death,
stroke, and myocardial infarction (MI) [
product labels state that stimulants ‘‘generally should not
be used’’ in patients with ‘‘serious structural cardiac
abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems that may
place them at increased vulnerability to the
sympathomimetic effects of a stimulant drug’’; and that ‘‘caution is
indicated’’ in treating patients with pre-existing
]. Atomoxetine, a non-stimulant therapeutic
option in the treatment of ADHD, carries a similar warning
. Because older age increases the risk of CVD [
increased pharmacovigilance for cardiovascular risk factors
and events is appropriate as the population of adults treated
with ADHD pharmacotherapy expands and ages [
Second, prescription stimulant medications are the
subject of a growing degree of public health concern about
addiction and related adverse medical events [
From 2005 to 2011, the number of US emergency
department (ED) visits attributable to non-medical use of
stimulant pharmaceuticals by young adults (aged 18–34 years)
more than tripled, from 5,605 to 22,949 . Additionally,
for all age groups combined, more than 31,000 ED visits
were made because of ADHD medications in 2010 in the
]. Because these increases have taken place
primarily among adults, rather than among children and
adolescents, the US Drug Abuse Warning Network
(DAWN) has identified ‘‘a need for increased attention
toward … diversion and misuse among adults … as
treatment for ADHD among adults becomes more widespread’’
]. FDA product labels for stimulants indicate that they
should ‘‘be given cautiously to patients with a history of
drug dependence or alcoholism’’ [
In theory, the publication of evidence and of
evidencebased guidelines, such as those currently available for adult
ADHD, should be reflected in the pharmacotherapies
prescribed for the disorder in real-world practice. However,
prescribing behaviors do not consistently respond to the
available base of evidence. For example, there was no
discernible decline in prescribing of pharmacotherapy for
pediatric ADHD after the FDA issued a warning in 2006
about cardiac and psychiatric risks of stimulants [
Additionally, previous work has documented potentially
contraindicated prescribing of a variety of medication
classes, for example, antidepressants, statins, and serotonin
receptor agonists [
]. Thus, it is important to examine
the rate of potentially contraindicated prescribing
systematically, particularly when the patient population treated
with a given class of medication changes over time, as it
has in ADHD.
Current evidence about potential contraindications in the
prescribing of ADHD medications to adults is limited. One
analysis of adults with a new diagnosis of ADHD in 2006
or 2007 examined the likelihood of ADHD
pharmacotherapy use as a function of baseline cardiovascular risk
]. Another assessed the risk of serious cardiovascular
events, controlling for baseline cardiovascular risk, in
patients treated from 1986 to 2005 [
]. The time periods
studied in both these analyses preceded promulgation of
the DSM-5 [
7, 30, 31
]. Additional studies of cardiovascular
events associated with pharmacotherapy for adult ADHD
have either excluded patients with high-risk conditions
from the sample or used a propensity-matched cohort
design, thereby making it difficult to determine the
percentage of stimulant- or atomoxetine-treated patients who
are potentially at increased risk of adverse events [
The present study addressed this gap in available
information by profiling the relevant clinical histories of
cohorts of adult patients filling prescriptions for either
stimulants or atomoxetine to treat ADHD in 2014–2015.
Specifically, the study examined rates of (1) CVD and
CVD risk factors, which are potential contraindications for
both stimulants and atomoxetine; and (2) substance
addiction or abuse, bipolar disorder, and glaucoma, which
are potential contraindications for stimulants [
2.1 Study Design and Data
The study was a retrospective cohort analysis of patients
identified using the Truven MarketScan Commercial
Claims and Encounters database, which includes claims for
all healthcare services (medical care and prescription
medications) delivered to approximately 50 million
commercially insured enrollees each year. The MarketScan
database, which has been used in more than 1400 published
studies of US healthcare, is fully compliant with Health
Insurance Portability and Accountability Act (HIPAA)
]. Data are obtained by Truven Health from
employers and health insurance plans, cleaned for quality
and accuracy, and de-identified using encrypted case
numbers for research purposes. The database includes the
Truven Health Red Book table, available to licensed
users, which matches national drug code numbers to
medication product information, including generic name.
The study was deemed exempt from Institutional Review
Board (IRB) review by the Midwestern University IRB
2.2 Study Sample
The sample was drawn from claims for all filled
prescriptions and medical services with dates of service from 1
January 2013, through 31 December 2015. All patients
aged 18–64 years, as measured on the first enrollment date
in each calendar year, who met the criteria listed below
were included in the sample (Fig. 1):
Filled C 1 prescription for an ADHD medication
(amphetamines, atomoxetine, dexmethylphenidate or
methylphenidate), identified using generic product
name, in either 2014 or 2015. Use of lisdexamfetamine
did not qualify patients for the sample because it has a
labeled indication for binge-eating disorder [
obesity-related condition that is associated with CVD
risk factors including diabetes, hypertension, and
Were continuously enrolled for healthcare benefits
for C 12 months prior to the first ADHD medication
claim date (index date), creating a sample of new users
(i.e., after a C 12-month ‘‘washout’’ period). To allow
for C 12 months of eligibility prior to the index
medication claim, the earliest index date was 1 January
Had two or more medical claims with a diagnosis of
ADHD (International Classification of Diseases
[ICD]9 code of 314.xx or ICD-10 code of F90.xx) at any
time. This sampling step excluded patients who used
the medications either off-label or for other
FDAlabeled uses, such as narcolepsy or obesity [
application of a ‘‘two or more’’ claim rule for ADHD
diagnosis was used to exclude patients whose claims
reflect ‘‘rule-out’’ diagnoses or coding errors, a
technique that is common in claims database analyses
One or more claim with an ADHD diagnosis either
preceded the index date or followed it by no more than
90 days. The 90-day standard was used to link
medication therapy to diagnosis, while allowing for minor
variations in practice patterns (e.g., empirical treatment
followed by diagnosis) or billing practices.
2.3 Measurement of Potential Contraindications and Co-morbidities
Medical diagnoses and procedures were measured and
calculated as prevalence rates (i.e., percentages: total
number diagnosed divided by total number of patients)
during the 12-month time period preceding the index date.
Unique Enrollees, All Years
>1 Claim for S mulant Medica on or
Atomoxe ne in 2014 or 2015
Con nuously Enrolled for >12 Months
Prior to First Medica on Claim
Any ADHD Diagnosis
>2 Medical Claims with ADHD
ADHD Diagnosis Precedes or Is <90
Days A er Medica on Start
Diagnoses were measured in any of the first four diagnosis
fields reported on ambulatory claims (outpatient hospital
department, ED, and physician office), and in these four
fields plus the primary diagnosis field and diagnosis-related
group (DRG) codes on inpatient hospital claims.
Additionally, detoxification services (identified by revenue
codes, place of service codes, and Health Care Common
Procedural Coding System codes) were used to identify
addiction/abuse; and revascularization (i.e., percutaneous
transluminal angioplasty, stenting, balloon angioplasty, and
coronary artery bypass grafting) was measured using
procedure codes for all treatment settings and DRG codes for
Potential contraindications were measured in three
categories: CVD, addiction/abuse, and other (bipolar disorder
and glaucoma). Within the CVD category, a measure of
serious CVD—intended to represent the FDA’s warning
language for ‘‘serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, CAD
or other serious cardiac problems’’—was defined as
cardiomegaly, cardiomyopathy, cerebrovascular occlusion,
congestive heart failure, myocardial infarction, pacemaker,
or valvular disorder [
]. CVD was defined as serious
CVD, other atherosclerotic CVD, arrhythmia, congenital
heart anomaly, or hypertensive heart disease. Although not
included in the summary measure of CVD, prevalence rates
of diabetes, hyperlipidemia, and hypertension were
reported because these are risk factors for CVD events
]. Diagnosis codes are shown in Online Appendix A,
and procedure codes are shown in Online Appendix B.
Sensitivity analyses were performed to address one area
of ambiguity in diagnostic coding on medical claims.
Specifically, the a priori definition of abuse/addiction
included diagnoses of V58.69 (ICD-9, ‘‘long-term (current)
use of other medications’’) and Z79.891 (ICD-10,
‘‘longterm (current) use of opiate analgesic’’) [
approach was used for several reasons: (1) Previous
research has documented variations in diagnostic coding
specificity in administrative data, particularly for
conditions that are stigmatized and/or difficult to diagnose
]; (2) The ICD-9 code description for long-term
medication use specifically refers to methadone, opiate
analgesics, and ‘‘other high-risk medications’’ ; and,
(3) Of all inpatient claims for the study sample that
included a nonspecific code, 97% also were coded for a
specific diagnosis of abuse or addiction.
Nonetheless, because the ICD-9 code for long-term
medication use was indeterminate as to specific drug, a set
of post hoc sensitivity analyses limited the addiction/abuse
prevalence indicator to patients with either (1) a specific
diagnosis of abuse/addiction during the 12-month
pretreatment time frame or (2) a code for long-term
medication/opiate use and a procedure code indicating a
laboratory test for a specific controlled substance at any time
prior to treatment initiation. This choice was made because
a post hoc exploratory analysis showed that 36% of
outpatient claims with the nonspecific code lacked a substance
abuse diagnosis; and, of those, 25% were laboratory claims
for specific controlled substance tests. Codes for drug
screens that were not specific as to substance were not
included in this measure. The codes and substances
captured in this assessment are shown in online Appendix C.
To assess the relationship between potential
contraindications and aging, the percentages of patients with
each diagnosis were calculated not only overall, but also by
age group. To determine whether risk from potential
contraindications increases ordinally (i.e., monotonically) with
age, between-group differences were tested using the
Mantel–Haenszel (linear-by-linear association) test for
]. To produce nationally representative estimates,
all results were weighted for the sample-to-population ratio
across strata formed on sex, age group, region, and
policyholder status (i.e., enrollee vs. dependent), using a method
and strata population sizes provided by Truven Health. The
total sample size after weighting was held to the original
(pre-weighting) cohort size by applying a constant to all
strata weights. All calculations were performed using SPSS
v24.0 (IBM Corporation, Armonk, NY, USA) at an a priori
alpha (critical P value) of 0.05.
Among all adult patients in the sample who were treated
for ADHD with stimulants or atomoxetine in 2014–2015
(n = 91,588), most individual CVD diagnoses were rare
(B 0.5% prevalence), and almost no patients had a history
of pacemaker implantation or revascularization (Table 1).
Within the sample overall, 2.0% had a diagnostic history
potentially indicating serious CVD (cardiomegaly,
cardiomyopathy, cerebrovascular occlusion, congestive heart
failure, myocardial infarction, pacemaker, or valvular
disorder); 1.6% had ASCVD (angina, cerebral occlusion, MI,
peripheral arterial disease, transient ischemic attack (TIA),
revascularization, or other ASCVD); and 5.5% had some
form of CVD (serious CVD, other atherosclerotic CVD,
arrhythmia, congenital heart anomaly, or hypertensive
heart disease). Only 0.6% of patients treated with any
ADHD medication, and 1.3% of patients treated with
atomoxetine, were hospitalized with a diagnosis of any CVD
condition in the 12 months prior to the start of
Like the individual CVD diagnoses, co-morbidities were
relatively uncommon in the sample overall (Table 1). For
example, hyperlipidemia and hypertension were each
diagnosed in 11.5% of patients, and diabetes in 3.1%.
Chronic kidney disease of at least moderate severity
(Stages 3 or higher) was rare (0.1% of the sample).
A history of addiction/abuse as defined in the a priori
analysis plan was much more common - 18.8% of the
sample overall, 18.5% of patients treated with stimulants
(n = 87,167), and 23.9% of patients treated with
atomoxetine (n = 7051; Table 1). However, measurement of
addiction/abuse prevalence was sensitive to the inclusion
of nonspecific codes for long-term medication use. In the
post hoc sensitivity analysis with the modified (stricter)
definition of addiction/abuse, prevalence rates were 11.7%
for the sample overall, 11.3% for stimulant-treated patients,
and 17.1% for patients treated with atomoxetine. Of
patients treated with stimulants, 4.1% were diagnosed with
bipolar disorder and 0.6% with glaucoma.
Despite the generally low rate of potential
contraindications and co-morbidities in the sample overall, the
prevalence of all CVD diagnoses and risk factors increased
monotonically with age, as expected (Table 2). Of patients
aged 45–54 years (n = 12,801), 8.7% had any CVD; 3.6%
had serious CVD; and 1.0% were hospitalized with a
diagnosis of CVD in the 12 months prior to the start of
ADHD pharmacotherapy. These rates were nearly doubled
in patients aged 55–64 years (n = 5237): 15.9% had any
CVD; 7.2% had serious CVD; and 1.9% were hospitalized
with a diagnosis of CVD in the 12 months prior to the start
of ADHD pharmacotherapy (all P\0.001).
Rates of glaucoma and hypertension were also
considerably elevated in older patients (Table 2). Specifically,
among those aged 55–64 years compared with patients in
the youngest age group (aged 18–24 years, n = 30,499)
the rate of glaucoma was multiplied 18-fold (3.6 vs. 0.2%,
respectively); and the rate of hypertension was
multiplied[20-fold (40.1 vs. 2.0%, respectively). Rates of
diabetes and hyperlipidemia were similarly elevated:
diabetes[14-fold and hyperlipidemia[20-fold (all
In an analysis of commercially insured adults treated with
pharmacotherapy for ADHD in 2014-2015, we found
prevalence rates of CVD and CVD risk factors that were
generally low overall but markedly elevated with advancing
age, particularly among patients aged 55–64 years. In that
age group, 15.9% were diagnosed with CVD and 7.2% with
serious CVD; and 40% had diagnosed hypertension.
Additionally, we found a high rate of pre-existing addiction/abuse
in the sample overall. Among adults treated with stimulants,
11.3–18.5% were diagnosed with some form of addiction or
potential abuse in the 12 months prior to the start of ADHD
pharmacotherapy. To the knowledge of these authors, these
ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular
aBecause subcohorts are not mutually exclusive, sum of the subcohort counts exceeds total sample size
bASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic
18–24 years 25–34 years 35–44 years 45–54 years 55–64 years
ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular
*P\0.001, linear-by-linear association test
aSum of cell counts exceeds sample size by 1 because of the application of sample weights
bASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic
findings represent the first ‘‘real-world’’ assessment of
potentially contraindicated prescribing of atomoxetine and
stimulants for adults since expansion of the diagnostic
criteria for ADHD in the DSM-5.
Prevalence rates for CVD and CVD risk factors
observed in the present study are generally similar to those
observed in research conducted in earlier time periods,
despite some methodological differences. In a retrospective
analysis of health records for commercially insured and
Medicaid-enrolled adults (aged 25–64 years, time period
1986–2007), Habel et al. found prevalence rates of 14.8%
for hypertension, 18.7% for hyperlipidemia, 1.2% for
stroke/TIA, and 0.2% for MI, measured in the 12 months
prior to the start of ADHD pharmacotherapy [
]. In the
subset of patients aged 25–64 in the present analysis, we
found prevalence rates of 16.2% for hypertension, 16.3%
for hyperlipidemia, 0.8% for cerebral occlusion, 0.3% for
TIA, and 0.1% for MI.
Similarly, Gerhard et al. used a claims database to study
adults (aged 21–64 years) with a new diagnosis of ADHD
in 2006–2007, followed through March 2008 [
]. In that
study’s subcohort of patients treated with stimulants or
atomoxetine, 8.8% had either any cardiovascular condition
or diagnosed hypertension in the 12 months prior to initial
diagnosis, with prevalence rates increasing monotonically
from 2.7% among those aged 21–29 years to 22.0% among
those aged 46–64 years (percentages calculated from
counts shown in study report).
A notable difference between our results and those of
Habel et al. is the markedly higher rate of diagnosed
substance addiction or abuse observed in the present study
sample: 11.7–18.8% compared with 5.2% observed by
Habel et al. for ‘‘alcohol/substance abuse’’ in 1986–2007
]. It is possible that methodological differences, such as
the use of health records by Habel et al. and claims data in
the present study, contribute to the observed increase in the
addiction/abuse prevalence rate. However, given the
marked increase in use and abuse of controlled prescription
medications that has been noted by US public health
organizations in recent years [
21, 23, 24
], it appears more
likely that the results of the present study are a
manifestation of the public health crisis associated with increases
in the prevalence of prescription medication abuse in the
]. In one study of U.S. college students who were
asked to self-report use of stimulants in the previous year,
5.4% in 2003 and 9.3% in 2013 reported non-medical use,
whereas 1.9% in 2003 and 4.7% in 2013 reported medical
]. It is also possible that patients with pre-existing
addictions were erroneously diagnosed with ADHD,
because substance abuse disorders complicate the process
of differential diagnosis in patients presenting with
symptoms of ADHD, such as restlessness, inattention, or
Present study findings suggest that prescribers were
aware that a history of addiction places adults at risk when
treated with stimulants [
], as addiction was more
prevalent among atomoxetine-treated patients
(17.1–23.9%) than among those treated with stimulants
(11.3–18.5%). However, it is somewhat puzzling that CVD
was also more prevalent among atomoxetine- than
stimulant-treated patients (8.2 vs. 5.4%, respectively), because
product labels for both atomoxetine and stimulants have
similar warnings for cardiovascular events.
In considering the policy implications of these findings,
it is appropriate to take into account the concerns
underlying the FDA’s Drug Safety and Risk Management
Advisory Committee 2006 recommendation that a
‘‘blackbox’’ warning for cardiovascular effects be added to
stimulant product labels, although the FDA did not adopt
the recommendation. As described by a committee advisor
in an editorial published later that year, one factor
considered by the committee was the ‘‘rapid increase in
exposure’’ associated with expanding prevalence of ADHD
diagnosis and stimulant use in adults [
]. Because this
expansion would result in ‘‘the administration of potent
sympathomimetic agents to millions of Americans,’’ the
editorialist noted, the committee ‘‘sought to emphasize
more selective and restricted use, while increasing
awareness of potential hazards’’ [
]. In the decade that has
passed since that editorial was written, exposure to ADHD
pharmacotherapy has rapidly increased among US adults,
making the Committee’s concerns even more cogent today.
However, previous studies of the cardiovascular safety
of pharmacotherapy for adult ADHD either controlled for
baseline CVD or excluded patients with CVD from the
]. Although these methodological features
are standard techniques used to control for pre-existing
disease in a population-wide assessment of adverse drug
effects, the present study results may suggest the need for a
more targeted approach: assess hazards in those
subpopulations most at risk. Specifically, among adult patients
treated for ADHD with stimulants or atomoxetine, future
research should assess the prevalence of (1) cardiovascular
events in those who are aged 55 years or older or have a
pre-existing CVD, perhaps with special emphasis on those
with both risk factors; and (2) sequelae of addiction/abuse
(e.g., hospitalization for adverse drug reactions or
mortality) in those with pre-existing histories of substance use
Several limitations of the present study should be noted.
First, the study did not assess the effects of long-term
medication exposure occurring prior to the start of the
study, for example, use throughout childhood in a patient
who is now an adult. Similarly, diagnoses of
contraindications could have been made either prior to the 12-month
measurement time frame used in the present study, or for
services paid out-of-pocket by patients and therefore not
recorded in insurance claims. Thus, the calculated
prevalence rates may be underestimated.
Second, the study was limited to commercially insured
enrollees aged 18–64 years; its results may not be
applicable to those enrolled in Medicaid or Medicare.
Study results also may not be applicable to patients treated
with lisdexamfetamine, especially those with co-morbid
binge-eating disorder, or to patients using the study
medications off-label or for a labeled use other than ADHD.
Third, errors and omissions may occur in coding of
diagnoses or procedures; however, there is no reason to
believe that these disproportionately affected particular age
groups. Similarly, a number of different classification
symptoms could reasonably have been used to define
serious CVD, and any clinical classification system based
on claims data may be imperfect. However, findings of the
present study were consistent with those of previous studies
of CVD and related co-morbidities in adults treated with
pharmacotherapy for ADHD [
Fourth, claims data generally do not indicate severity of
illness, although proxy measures (e.g., a hospital stay for
CVD) and certain diagnoses (e.g., a diagnosis of congestive
heart failure) do provide some indication of level of risk.
Most notably, it is not possible from the present study to
determine the severity of ADHD, or the benefit-versus-risk
ratio of treating ADHD with pharmacotherapy for any
Fifth, diagnoses representing addiction/abuse in the
present study were not specific as to particular substance,
partly because of limitations of diagnostic coding, and
partly because patients with addictions to one substance
may be predisposed to abuse of others (i.e., the
phenomenon known as ‘‘addiction transfer’’) [
Additionally, because of uncertainty in diagnostic coding in
claims data, particularly for conditions that are either
stigmatized or difficult to diagnose, we reported rates of
addiction/abuse in a range that reflects a sensitivity analysis
around nonspecific codes for long-term medication/opiate
use. Because diagnostic coding is generally more complete
in inpatient than outpatient settings , and because 97%
of inpatient claims with the nonspecific code also had a
specific diagnosis code for addiction/abuse, we believe that
the true rate of addiction is probably closer to the upper end
than the lower end of our estimate. However, there is no
‘‘gold standard’’ method to identify non-medical use of
abusable drugs in automated claims data [
research should investigate this issue in an attempt to
produce a more precise estimate of addiction/abuse
prevalence among adults using stimulants for ADHD.
In a commercially insured sample of US adults treated with
stimulants or atomoxetine for ADHD, prevalence of
preexisting serious CVD was 3.6% among those aged
45–54 years and 7.2% among those aged 55–64 years.
Among adults treated with stimulants, 11.3–18.5% were
diagnosed with abuse or addiction in the 12 months prior to
the start of ADHD pharmacotherapy. Future research
should assess possible harms associated with potentially
contraindicated uses of ADHD pharmacotherapy by adults,
particularly in those at highest baseline risk of adverse drug
Compliance with Ethical Standards
Funding This work was funded by Midwestern University with no
external support or funding.
Conflicts of interest KAF, LED, AMP, and DAS have no financial
or other conflicts of interest in the subject of this manuscript.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits any noncommercial use, distribution, and reproduction in any
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author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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