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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... Drugs - Real World Outcomes (2018) 5:69–79 https://doi.org/10.1007/s40801-017-0129-2 ORIGINAL RESEARCH ARTICLE Diagnoses of Cardiovascular Disease or Substance Addiction/ Abuse in US Adults Treated for ADHD with Stimulants or Atomoxetine: Is Use Consistent with Product Labeling? 1 1 1 1 • • • Kathleen A. Fairman Lindsay E. Davis Alyssa M. Peckham David A. Sclar Published online: 5 January 2018 The Author(s) 2018. This article is an open access publication Abstract disorder) and any CVD (serious CVD, other atherosclerotic Background Among US adults, utilization of pharma- CVD, arrhythmia, congenital heart anomaly, or hyperten- cotherapy for attention-deficit hyperactivity disorder sive heart disease). Rates of substance addiction or abuse (ADHD) has increased more than ninefold since were measured in a range to address nonspecific diagnostic 1995–1996. Potential contraindications to ADHD phar- coding. macotherapy include serious cardiovascular disease (CVD) Results Only 2.0% of treated adults (n = 91,588) had one and, for stimulants, addictions and bipolar disorder (BPD). or more diagnosis indicating serious CVD. CVD preva- Objective To assess the prevalence of potential con- lence increased monotonically with age. Of patients aged traindications among adults treated with ADHD 55–64 years (n = 5,237), 7.2% had serious CVD; 15.9% pharmacotherapy. had any CVD; and 1.9% had been hospitalized with one or Methods A retrospective cohort analysis was performed more CVD. Of patients treated with stimulants using the Truven Health MarketScan database. Subjects (n = 87,167), 11.3–18.5% were diagnosed with addiction/ filled C 1 prescription for atomoxetine or C 1 stimulant in abuse and 4.1% with BPD. 2014–2015, were aged 18–64 years, commercially insured Conclusions CVD prevalence is generally low among throughout observation, and diagnosed with ADHD on two adults using ADHD medication but increases with age. or more medical claims. Diagnoses and medical procedures Although difficult to estimate precisely, the rate of addic- were measured in the 12 months prior to pharmacotherapy tion/abuse among stimulant-treated patients appears unex- initiation. Metrics included serious CVD (cardiomegaly, pectedly high. Further research should assess cardiomyopathy, cerebrovascular occlusion, congestive cardiovascular events and other potential harms associated heart failure, myocardial infarction, pacemaker, or valvular with contraindicated use in high-risk adults. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40801-017-0129-2) contains supple- mentary material, which is available to authorized users. & Kathleen A. Fairman kfairm@midwestern.edu Department of Pharmacy Practice, College of Pharmacy, Midwestern University-Glendale, 19555 N. 59th Avenue, Glendale, AZ 85308, USA 70 K. A. Fairman et al. First, ADHD medications increase diastolic blood pressure (BP), systolic BP, and heart rate by amounts that Key Points are generally considered modest but potentially clinically significant in patients with pre-existing cardiovascular This study of potential contraindications to disease (CVD) or CVD risk factors [10]. For this reason, pharmacotherapy for attention-deficit hyperactivity stimulants, which are the most common and guideline- disorder (ADHD) in commercially insured US adults recommended medications to treat ADHD [6, 11, 12], carry found that, measured in the 12 months prior to US Food and Drug Administration (FDA) labeled warnings initiation of treatment with stimulants or for serious cardiovascular events, including sudden death, atomoxetine in 2014–2015, prevalence rates of stroke, and myocardial infarction (MI) [13]. Specifically, serious cardiovascular disease were 7.2% among product labels state that stimulants ‘‘generally should not those aged 55–64 years and 3.6% among those aged be used’’ in patients with ‘‘serious structural cardiac 45–54 years. abnormalities, cardiomyopathy, serious heart rhythm Of adults initiating treatment with stimulants, abnormalities, or other serious cardiac problems that may 11.3–18.5% had been diagnosed in the past year with place them at increased vulnerability to the sympath- substance addiction or potential abuse. omimetic effects of a stimulant drug’’; and that ‘‘caution is indicated’’ in treating patients with pre-existing hyperten- In light of rapid growth in diagnosis and pharmacologic treatment for ADHD in recent years, sion [14–17]. Atomoxetine, a non-stimulant therapeutic option in the treatment of ADHD, carries a similar warning a study of adverse drug events among adults at [18]. Because older age increases the risk of CVD [19], highest risk—those who are older and/or have a increased pharmacovigilance for cardiovascular risk factors potential contraindication to pharmacotherapy—is and events is appropriate as the population of adults treated needed. with ADHD pharmacotherapy expands and ages [20]. Second, prescription stimulant medications are the subject of a growing degree of public health concern about addiction and related adverse medical events [21, 22]. From 2005 to 2011, the number of US emergency depart- 1 Introduction ment (ED) visits attributable to non-medical use of stim- ulant pharmaceuticals by young adults (aged 18–34 years) In the past two decades, prevalence rates of diagnosis and more than tripled, from 5,605 to 22,949 [23]. Additionally, pharmacologic treatment for attention-deficit hyperactivity for all age groups combined, more than 31,000 ED visits disorder (ADHD) have increased exponentially among were made because of ADHD medications in 2010 in the United States (US) adults [1–6]. One study of National US [24]. Because these increases have taken place pri- Ambulatory Medical Care Survey (NAMCS) data found marily among adults, rather than among children and that per 1,000 office-based physician visits made by US adolescents, the US Drug Abuse Warning Network adults aged C 20 years, rates of ADHD diagnosis and (DAWN) has identified ‘‘a need for increased attention pharmacologic treatment increased by 52.6 and 35.2%, toward … diversion and misuse among adults … as treat- respectively, from 2008–2009 to 2012–2013 [6]. Moreover, ment for ADHD among adults becomes more widespread’’ from 1995–1996 to 2007–2008, the population-adjusted [24]. FDA product labels for stimulants indicate that they rate of physician visits at which ADHD pharmacotherapy should ‘‘be given cautiously to patients with a history of was prescribed to adults increased fivefold; and by drug dependence or alcoholism’’ [14–17]. 2012–2013, a more than ninefold increase had occurred, In theory, the publication of evidence and of evidence- from 1.9 to 11.4 visits per 1000 US adults [2, 5, 6]. based guidelines, such as those currently available for adult It has been suggested that these changes are ADHD, should be reflected in the pharmacotherapies pre- attributable to expansion of the diagnostic criteria for scribed for the disorder in real-world practice. However, ADHD in the Diagnostic and Statistical Manual of Mental prescribing behaviors do not consistently respond to the Disorders (DSM)-5 in 2013 [7], as well as the launch of available base of evidence. For example, there was no new medications and formulations (e.g., chewables, sus- discernible decline in prescribing of pharmacotherapy for tained-release tablets, patches, and new molecular entities) pediatric ADHD after the FDA issued a warning in 2006 in recent years [5, 8, 9]. Along with these expansions, two about cardiac and psychiatric risks of stimulants [25]. factors complicate the management of pharmacotherapy Additionally, previous work has documented potentially for the rapidly growing population of US adults diagnosed contraindicated prescribing of a variety of medication with ADHD. classes, for example, antidepressants, statins, and serotonin Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 71 receptor agonists [26–29]. Thus, it is important to examine Board (IRB) review by the Midwestern University IRB the rate of potentially contraindicated prescribing system- committee. atically, particularly when the patient population treated with a given class of medication changes over time, as it 2.2 Study Sample has in ADHD. Current evidence about potential contraindications in the The sample was drawn from claims for all filled prescrip- prescribing of ADHD medications to adults is limited. One tions and medical services with dates of service from 1 analysis of adults with a new diagnosis of ADHD in 2006 January 2013, through 31 December 2015. All patients or 2007 examined the likelihood of ADHD pharma- aged 18–64 years, as measured on the first enrollment date cotherapy use as a function of baseline cardiovascular risk in each calendar year, who met the criteria listed below [30]. Another assessed the risk of serious cardiovascular were included in the sample (Fig. 1): events, controlling for baseline cardiovascular risk, in • Filled C 1 prescription for an ADHD medication (am- patients treated from 1986 to 2005 [31]. The time periods phetamines, atomoxetine, dexmethylphenidate or studied in both these analyses preceded promulgation of methylphenidate), identified using generic product the DSM-5 [7, 30, 31]. Additional studies of cardiovascular name, in either 2014 or 2015. Use of lisdexamfetamine events associated with pharmacotherapy for adult ADHD did not qualify patients for the sample because it has a have either excluded patients with high-risk conditions labeled indication for binge-eating disorder [35], an from the sample or used a propensity-matched cohort obesity-related condition that is associated with CVD design, thereby making it difficult to determine the per- risk factors including diabetes, hypertension, and centage of stimulant- or atomoxetine-treated patients who dyslipidemias [36, 37]. are potentially at increased risk of adverse events [32, 33]. • Were continuously enrolled for healthcare benefits The present study addressed this gap in available for C 12 months prior to the first ADHD medication information by profiling the relevant clinical histories of claim date (index date), creating a sample of new users cohorts of adult patients filling prescriptions for either (i.e., after a C 12-month ‘‘washout’’ period). To allow stimulants or atomoxetine to treat ADHD in 2014–2015. for C 12 months of eligibility prior to the index med- Specifically, the study examined rates of (1) CVD and ication claim, the earliest index date was 1 January CVD risk factors, which are potential contraindications for both stimulants and atomoxetine; and (2) substance • Had two or more medical claims with a diagnosis of addiction or abuse, bipolar disorder, and glaucoma, which ADHD (International Classification of Diseases [ICD]- are potential contraindications for stimulants [14–18]. 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 FDA- 2 Methods labeled uses, such as narcolepsy or obesity [38]. The application of a ‘‘two or more’’ claim rule for ADHD 2.1 Study Design and Data diagnosis was used to exclude patients whose claims reflect ‘‘rule-out’’ diagnoses or coding errors, a tech- The study was a retrospective cohort analysis of patients nique that is common in claims database analyses identified using the Truven MarketScan Commercial [39–41]. Claims and Encounters database, which includes claims for • One or more claim with an ADHD diagnosis either all healthcare services (medical care and prescription preceded the index date or followed it by no more than medications) delivered to approximately 50 million com- 90 days. The 90-day standard was used to link med- mercially insured enrollees each year. The MarketScan ication therapy to diagnosis, while allowing for minor database, which has been used in more than 1400 published variations in practice patterns (e.g., empirical treatment studies of US healthcare, is fully compliant with Health followed by diagnosis) or billing practices. Insurance Portability and Accountability Act (HIPAA) standards [34]. Data are obtained by Truven Health from employers and health insurance plans, cleaned for quality 2.3 Measurement of Potential Contraindications and accuracy, and de-identified using encrypted case and Co-morbidities numbers for research purposes. The database includes the Truven Health Red Book table, available to licensed Medical diagnoses and procedures were measured and calculated as prevalence rates (i.e., percentages: total users, which matches national drug code numbers to medication product information, including generic name. number diagnosed divided by total number of patients) The study was deemed exempt from Institutional Review during the 12-month time period preceding the index date. 72 K. A. Fairman et al. Fig. 1 Sample selection flowchart. Amphetamines Unique Enrollees, All Years (amphetamine salt combination, Aged 18-64 Years N=48,566,626 amphetamine sulfate, N=33,100,487 Aged 18-64 Years dextroamphetamine sulfate, N=35,121,673 Aged 18-64 Years hydroxyamphetamine, N=21,457,986 methamphetamine), >1 Claim for Smulant Medicaon or dexmethylphenidate, or Atomoxene in 2014 or 2015 methylphenidate. ADHD N=391,437 attention-deficit hyperactivity disorder Connuously Enrolled for >12 Months Prior to First Medicaon Claim N=167,665 Any ADHD Diagnosis N=115,723 >2 Medical Claims with ADHD Diagnosis N=97,633 ADHD Diagnosis Precedes or Is <90 Days Aer Medicaon Start N=91,588 Diagnoses were measured in any of the first four diagnosis reported because these are risk factors for CVD events fields reported on ambulatory claims (outpatient hospital [42]. Diagnosis codes are shown in Online Appendix A, department, ED, and physician office), and in these four and procedure codes are shown in Online Appendix B. fields plus the primary diagnosis field and diagnosis-related Sensitivity analyses were performed to address one area group (DRG) codes on inpatient hospital claims. Addi- of ambiguity in diagnostic coding on medical claims. tionally, detoxification services (identified by revenue Specifically, the a priori definition of abuse/addiction codes, place of service codes, and Health Care Common included diagnoses of V58.69 (ICD-9, ‘‘long-term (current) Procedural Coding System codes) were used to identify use of other medications’’) and Z79.891 (ICD-10, ‘‘long- addiction/abuse; and revascularization (i.e., percutaneous term (current) use of opiate analgesic’’) [43, 44]. This transluminal angioplasty, stenting, balloon angioplasty, and approach was used for several reasons: (1) Previous coronary artery bypass grafting) was measured using pro- research has documented variations in diagnostic coding cedure codes for all treatment settings and DRG codes for specificity in administrative data, particularly for condi- inpatient admissions. tions that are stigmatized and/or difficult to diagnose Potential contraindications were measured in three cat- [45–47]; (2) The ICD-9 code description for long-term egories: CVD, addiction/abuse, and other (bipolar disorder medication use specifically refers to methadone, opiate and glaucoma). Within the CVD category, a measure of analgesics, and ‘‘other high-risk medications’’ [48]; and, serious CVD—intended to represent the FDA’s warning (3) Of all inpatient claims for the study sample that language for ‘‘serious structural cardiac abnormalities, included a nonspecific code, 97% also were coded for a cardiomyopathy, serious heart rhythm abnormalities, CAD specific diagnosis of abuse or addiction. or other serious cardiac problems’’—was defined as car- Nonetheless, because the ICD-9 code for long-term diomegaly, cardiomyopathy, cerebrovascular occlusion, medication use was indeterminate as to specific drug, a set congestive heart failure, myocardial infarction, pacemaker, of post hoc sensitivity analyses limited the addiction/abuse or valvular disorder [14–18]. CVD was defined as serious prevalence indicator to patients with either (1) a specific CVD, other atherosclerotic CVD, arrhythmia, congenital diagnosis of abuse/addiction during the 12-month pre- heart anomaly, or hypertensive heart disease. Although not treatment time frame or (2) a code for long-term medica- included in the summary measure of CVD, prevalence rates tion/opiate use and a procedure code indicating a labora- of diabetes, hyperlipidemia, and hypertension were tory test for a specific controlled substance at any time Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 73 prior to treatment initiation. This choice was made because Chronic kidney disease of at least moderate severity a post hoc exploratory analysis showed that 36% of out- (Stages 3 or higher) was rare (0.1% of the sample). patient claims with the nonspecific code lacked a substance A history of addiction/abuse as defined in the a priori abuse diagnosis; and, of those, 25% were laboratory claims analysis plan was much more common - 18.8% of the for specific controlled substance tests. Codes for drug sample overall, 18.5% of patients treated with stimulants screens that were not specific as to substance were not (n = 87,167), and 23.9% of patients treated with atomox- included in this measure. The codes and substances cap- etine (n = 7051; Table 1). However, measurement of tured in this assessment are shown in online Appendix C. addiction/abuse prevalence was sensitive to the inclusion To assess the relationship between potential con- of nonspecific codes for long-term medication use. In the traindications and aging, the percentages of patients with post hoc sensitivity analysis with the modified (stricter) each diagnosis were calculated not only overall, but also by definition of addiction/abuse, prevalence rates were 11.7% age group. To determine whether risk from potential con- for the sample overall, 11.3% for stimulant-treated patients, traindications increases ordinally (i.e., monotonically) with and 17.1% for patients treated with atomoxetine. Of age, between-group differences were tested using the patients treated with stimulants, 4.1% were diagnosed with Mantel–Haenszel (linear-by-linear association) test for bipolar disorder and 0.6% with glaucoma. trend [49]. To produce nationally representative estimates, Despite the generally low rate of potential contraindi- all results were weighted for the sample-to-population ratio cations and co-morbidities in the sample overall, the across strata formed on sex, age group, region, and policy- prevalence of all CVD diagnoses and risk factors increased holder status (i.e., enrollee vs. dependent), using a method monotonically with age, as expected (Table 2). Of patients and strata population sizes provided by Truven Health. The aged 45–54 years (n = 12,801), 8.7% had any CVD; 3.6% total sample size after weighting was held to the original had serious CVD; and 1.0% were hospitalized with a (pre-weighting) cohort size by applying a constant to all diagnosis of CVD in the 12 months prior to the start of strata weights. All calculations were performed using SPSS ADHD pharmacotherapy. These rates were nearly doubled v24.0 (IBM Corporation, Armonk, NY, USA) at an a priori in patients aged 55–64 years (n = 5237): 15.9% had any alpha (critical P value) of 0.05. 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). 3 Results Rates of glaucoma and hypertension were also consid- erably elevated in older patients (Table 2). Specifically, Among all adult patients in the sample who were treated among those aged 55–64 years compared with patients in for ADHD with stimulants or atomoxetine in 2014–2015 the youngest age group (aged 18–24 years, n = 30,499) (n = 91,588), most individual CVD diagnoses were rare the rate of glaucoma was multiplied 18-fold (3.6 vs. 0.2%, (B 0.5% prevalence), and almost no patients had a history respectively); and the rate of hypertension was multi- of pacemaker implantation or revascularization (Table 1). plied[20-fold (40.1 vs. 2.0%, respectively). Rates of Within the sample overall, 2.0% had a diagnostic history diabetes and hyperlipidemia were similarly elevated: dia- potentially indicating serious CVD (cardiomegaly, car- betes[14-fold and hyperlipidemia[20-fold (all diomyopathy, cerebrovascular occlusion, congestive heart P\0.001). failure, myocardial infarction, pacemaker, or valvular dis- order); 1.6% had ASCVD (angina, cerebral occlusion, MI, peripheral arterial disease, transient ischemic attack (TIA), 4 Discussion revascularization, or other ASCVD); and 5.5% had some form of CVD (serious CVD, other atherosclerotic CVD, In an analysis of commercially insured adults treated with arrhythmia, congenital heart anomaly, or hypertensive pharmacotherapy for ADHD in 2014-2015, we found heart disease). Only 0.6% of patients treated with any prevalence rates of CVD and CVD risk factors that were ADHD medication, and 1.3% of patients treated with ato- generally low overall but markedly elevated with advancing moxetine, were hospitalized with a diagnosis of any CVD age, particularly among patients aged 55–64 years. In that condition in the 12 months prior to the start of age group, 15.9% were diagnosed with CVD and 7.2% with pharmacotherapy. serious CVD; and 40% had diagnosed hypertension. Addi- Like the individual CVD diagnoses, co-morbidities were tionally, we found a high rate of pre-existing addiction/abuse relatively uncommon in the sample overall (Table 1). For in the sample overall. Among adults treated with stimulants, example, hyperlipidemia and hypertension were each 11.3–18.5% were diagnosed with some form of addiction or diagnosed in 11.5% of patients, and diabetes in 3.1%. potential abuse in the 12 months prior to the start of ADHD pharmacotherapy. To the knowledge of these authors, these 74 K. A. Fairman et al. Table 1 Demographic characteristics and 12-month pre-treatment diagnoses, patients aged 18–64 years treated for ADHD with stimulants or atomoxetine in 2014–2015 Stimulants Atomoxetine Whole sample N 87,167 7051 91,588 Age (years) Mean (median) 33 (31) 34 (32) 33 (31) Age group (%) 18–24 33.3 33.0 33.3 25–34 26.0 22.5 25.8 35–44 21.2 21.6 21.2 45–54 13.9 16.3 14.0 55–64 5.6 6.6 5.7 Female (%) 51.3 48.0 51.1 Cardiovascular disease (%) Angina 0.2 0.3 0.2 Arrhythmia/tachycardia 3.0 5.0 3.1 Cardiomegaly 0.3 0.4 0.3 Cardiomyopathy 0.1 0.3 0.2 b,c Cerebral occlusion 0.5 0.6 0.6 Congenital heart anomaly 0.3 0.4 0.3 Congestive heart failure 0.1 0.3 0.1 Hypertensive heart disease 0.3 0.4 0.3 b,c Myocardial infarction 0.1 0.1 0.1 Peripheral arterial disease 0.2 0.2 0.2 Transient ischemic attack 0.2 0.3 0.2 Valvular disorder 1.0 1.4 1.0 Cardiac procedures (%) Pacemaker (facility claims) 0.0 0.1 0.0 Revascularization (facility claims) 0.0 0.1 0.0 Cardiovascular summary measures (%) Any CVD 5.4 8.2 5.5 Inpatient stay associated with CVD 0.6 1.3 0.6 Serious CVD 1.9 2.8 2.0 Any ASCVD 1.6 2.1 1.6 Other potential contraindications (%) Addiction/abuse or long-term medication/opiate use 18.5 23.9 18.8 Addiction/abuse or long-term medication/opiate use with testing for abusable substances 11.3 17.1 11.7 Bipolar disorder 4.1 7.8 4.3 Glaucoma 0.6 0.6 0.6 Co-morbidities (%) Diabetes 3.1 3.9 3.1 Moderate-to-severe CKD 0.1 0.2 0.1 Hyperlipidemia 11.3 14.8 11.5 Hypertension 11.3 14.5 11.5 Seizure disorder 0.7 1.2 0.7 ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular disease Because subcohorts are not mutually exclusive, sum of the subcohort counts exceeds total sample size ASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic heart disease Serious CVD Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 75 Table 2 Demographic characteristics and 12-month pre-treatment diagnoses, patients aged 18–64 years treated for ADHD with stimulants or atomoxetine, by age group 18–24 years 25–34 years 35–44 years 45–54 years 55–64 years N 30,499 23,633 19,419 12,801 5,237 Female (%)* 45.1 47.8 56.4 60.5 58.7 Cardiovascular disease b, Angina * 0.0 0.0 0.1 0.5 0.8 Arrhythmia/tachycardia* 2.4 2.8 3.2 3.7 6.0 c, Cardiomegaly * 0.1 0.1 0.3 0.6 1.0 c, Cardiomyopathy * 0.1 0.1 0.2 0.2 0.6 b,c, Cerebral occlusion * 0.2 0.3 0.6 1.1 2.6 Congenital heart anomaly 0.3 0.3 0.2 0.3 0.3 c, Congestive heart failure * 0.0 0.1 0.2 0.3 0.7 Hypertensive heart disease* 0.0 0.1 0.4 0.5 1.4 b,c, Myocardial infarction * 0.0 0.0 0.1 0.3 0.6 b, Peripheral arterial disease * 0.0 0.1 0.1 0.5 1.0 b, Transient ischemic attack * 0.0 0.1 0.2 0.5 0.6 c, Valvular disorder * 0.5 0.6 1.2 1.6 3.3 Cardiovascular summary measures* Any CVD 3.3 4.2 5.9 8.7 15.9 Inpatient stay associated with CVD 0.4 0.6 0.6 1.0 1.9 Serious CVD 0.8 1.1 2.3 3.6 7.2 Any ASCVD 0.4 0.6 1.4 3.7 8.3 Cardiac procedures* Pacemaker 0.0 0.0 0.1 0.1 0.1 Revascularization 0.0 0.0 0.1 0.1 0.2 Potential contraindications* Addiction/abuse or long-term medication/opiate use 16.9 18.1 20.0 21.3 23.2 Addiction/abuse or long-term medication/opiate use with testing for 11.0 11.9 12.3 11.7 11.7 abusable substances Bipolar disorder 3.6 4.1 4.5 5.2 5.7 Glaucoma 0.2 0.3 0.5 1.2 3.6 Co-morbidities Diabetes* 0.9 1.5 3.7 7.0 12.2 Moderate-to-severe CKD* 0.0 0.0 0.1 0.3 0.9 Hyperlipidemia* 2.0 6.1 15.2 26.7 40.9 Hypertension* 2.0 6.7 15.2 25.6 40.1 Seizure disorder 0.7 0.8 0.6 0.6 0.8 ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular disease *P\0.001, linear-by-linear association test Sum of cell counts exceeds sample size by 1 because of the application of sample weights ASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic heart disease Serious CVD findings represent the first ‘‘real-world’’ assessment of Prevalence rates for CVD and CVD risk factors potentially contraindicated prescribing of atomoxetine and observed in the present study are generally similar to those stimulants for adults since expansion of the diagnostic cri- observed in research conducted in earlier time periods, teria for ADHD in the DSM-5. despite some methodological differences. In a retrospective 76 K. A. Fairman et al. analysis of health records for commercially insured and product labels for both atomoxetine and stimulants have Medicaid-enrolled adults (aged 25–64 years, time period similar warnings for cardiovascular events. 1986–2007), Habel et al. found prevalence rates of 14.8% In considering the policy implications of these findings, for hypertension, 18.7% for hyperlipidemia, 1.2% for it is appropriate to take into account the concerns under- stroke/TIA, and 0.2% for MI, measured in the 12 months lying the FDA’s Drug Safety and Risk Management prior to the start of ADHD pharmacotherapy [31]. In the Advisory Committee 2006 recommendation that a ‘‘black- subset of patients aged 25–64 in the present analysis, we box’’ warning for cardiovascular effects be added to found prevalence rates of 16.2% for hypertension, 16.3% stimulant product labels, although the FDA did not adopt for hyperlipidemia, 0.8% for cerebral occlusion, 0.3% for the recommendation. As described by a committee advisor TIA, and 0.1% for MI. in an editorial published later that year, one factor con- Similarly, Gerhard et al. used a claims database to study sidered by the committee was the ‘‘rapid increase in adults (aged 21–64 years) with a new diagnosis of ADHD exposure’’ associated with expanding prevalence of ADHD in 2006–2007, followed through March 2008 [30]. In that diagnosis and stimulant use in adults [54]. Because this study’s subcohort of patients treated with stimulants or expansion would result in ‘‘the administration of potent atomoxetine, 8.8% had either any cardiovascular condition sympathomimetic agents to millions of Americans,’’ the or diagnosed hypertension in the 12 months prior to initial editorialist noted, the committee ‘‘sought to emphasize diagnosis, with prevalence rates increasing monotonically more selective and restricted use, while increasing aware- from 2.7% among those aged 21–29 years to 22.0% among ness of potential hazards’’ [54]. In the decade that has those aged 46–64 years (percentages calculated from passed since that editorial was written, exposure to ADHD counts shown in study report). pharmacotherapy has rapidly increased among US adults, A notable difference between our results and those of making the Committee’s concerns even more cogent today. Habel et al. is the markedly higher rate of diagnosed sub- However, previous studies of the cardiovascular safety stance addiction or abuse observed in the present study of pharmacotherapy for adult ADHD either controlled for sample: 11.7–18.8% compared with 5.2% observed by baseline CVD or excluded patients with CVD from the Habel et al. for ‘‘alcohol/substance abuse’’ in 1986–2007 sample [31–33]. Although these methodological features [31]. It is possible that methodological differences, such as are standard techniques used to control for pre-existing the use of health records by Habel et al. and claims data in disease in a population-wide assessment of adverse drug the present study, contribute to the observed increase in the effects, the present study results may suggest the need for a addiction/abuse prevalence rate. However, given the more targeted approach: assess hazards in those subpopu- marked increase in use and abuse of controlled prescription lations most at risk. Specifically, among adult patients treated for ADHD with stimulants or atomoxetine, future medications that has been noted by US public health organizations in recent years [21, 23, 24], it appears more research should assess the prevalence of (1) cardiovascular likely that the results of the present study are a manifes- events in those who are aged 55 years or older or have a tation of the public health crisis associated with increases pre-existing CVD, perhaps with special emphasis on those in the prevalence of prescription medication abuse in the with both risk factors; and (2) sequelae of addiction/abuse US [50]. In one study of U.S. college students who were (e.g., hospitalization for adverse drug reactions or mortal- asked to self-report use of stimulants in the previous year, ity) in those with pre-existing histories of substance use 5.4% in 2003 and 9.3% in 2013 reported non-medical use, disorder. whereas 1.9% in 2003 and 4.7% in 2013 reported medical use [51]. It is also possible that patients with pre-existing 4.1 Limitations addictions were erroneously diagnosed with ADHD, because substance abuse disorders complicate the process Several limitations of the present study should be noted. of differential diagnosis in patients presenting with symp- First, the study did not assess the effects of long-term toms of ADHD, such as restlessness, inattention, or medication exposure occurring prior to the start of the impulsivity [52]. study, for example, use throughout childhood in a patient Present study findings suggest that prescribers were who is now an adult. Similarly, diagnoses of contraindi- aware that a history of addiction places adults at risk when cations could have been made either prior to the 12-month treated with stimulants [53], as addiction was more measurement time frame used in the present study, or for prevalent among atomoxetine-treated patients services paid out-of-pocket by patients and therefore not (17.1–23.9%) than among those treated with stimulants recorded in insurance claims. Thus, the calculated preva- (11.3–18.5%). However, it is somewhat puzzling that CVD lence rates may be underestimated. was also more prevalent among atomoxetine- than stimu- Second, the study was limited to commercially insured lant-treated patients (8.2 vs. 5.4%, respectively), because enrollees aged 18–64 years; its results may not be Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 77 applicable to those enrolled in Medicaid or Medicare. Among adults treated with stimulants, 11.3–18.5% were Study results also may not be applicable to patients treated diagnosed with abuse or addiction in the 12 months prior to with lisdexamfetamine, especially those with co-morbid the start of ADHD pharmacotherapy. Future research binge-eating disorder, or to patients using the study med- should assess possible harms associated with potentially ications off-label or for a labeled use other than ADHD. contraindicated uses of ADHD pharmacotherapy by adults, Third, errors and omissions may occur in coding of particularly in those at highest baseline risk of adverse drug diagnoses or procedures; however, there is no reason to events. believe that these disproportionately affected particular age Compliance with Ethical Standards groups. Similarly, a number of different classification symptoms could reasonably have been used to define Funding This work was funded by Midwestern University with no serious CVD, and any clinical classification system based external support or funding. on claims data may be imperfect. However, findings of the Conflicts of interest KAF, LED, AMP, and DAS have no financial present study were consistent with those of previous studies or other conflicts of interest in the subject of this manuscript. of CVD and related co-morbidities in adults treated with pharmacotherapy for ADHD [30, 31]. Open Access This article is distributed under the terms of the Fourth, claims data generally do not indicate severity of Creative Commons Attribution-NonCommercial 4.0 International illness, although proxy measures (e.g., a hospital stay for License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits any noncommercial use, distribution, and reproduction in any CVD) and certain diagnoses (e.g., a diagnosis of congestive medium, provided you give appropriate credit to the original heart failure) do provide some indication of level of risk. author(s) and the source, provide a link to the Creative Commons Most notably, it is not possible from the present study to license, and indicate if changes were made. determine the severity of ADHD, or the benefit-versus-risk ratio of treating ADHD with pharmacotherapy for any individual patient. Fifth, diagnoses representing addiction/abuse in the References present study were not specific as to particular substance, 1. 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Diagnoses of Cardiovascular Disease or Substance Addiction/Abuse in US Adults Treated for ADHD with Stimulants or Atomoxetine: Is Use Consistent with Product Labeling?

Fairman, Kathleen A.; Davis, Lindsay E.; Peckham, Alyssa M.; Sclar, David A.
Drugs - Real World Outcomes , Volume 5 (1) – Jan 5, 2018
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2199-1154
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10.1007/s40801-017-0129-2
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Drugs - Real World Outcomes (2018) 5:69–79 https://doi.org/10.1007/s40801-017-0129-2 ORIGINAL RESEARCH ARTICLE Diagnoses of Cardiovascular Disease or Substance Addiction/ Abuse in US Adults Treated for ADHD with Stimulants or Atomoxetine: Is Use Consistent with Product Labeling? 1 1 1 1 • • • Kathleen A. Fairman Lindsay E. Davis Alyssa M. Peckham David A. Sclar Published online: 5 January 2018 The Author(s) 2018. This article is an open access publication Abstract disorder) and any CVD (serious CVD, other atherosclerotic Background Among US adults, utilization of pharma- CVD, arrhythmia, congenital heart anomaly, or hyperten- cotherapy for attention-deficit hyperactivity disorder sive heart disease). Rates of substance addiction or abuse (ADHD) has increased more than ninefold since were measured in a range to address nonspecific diagnostic 1995–1996. Potential contraindications to ADHD phar- coding. macotherapy include serious cardiovascular disease (CVD) Results Only 2.0% of treated adults (n = 91,588) had one and, for stimulants, addictions and bipolar disorder (BPD). or more diagnosis indicating serious CVD. CVD preva- Objective To assess the prevalence of potential con- lence increased monotonically with age. Of patients aged traindications among adults treated with ADHD 55–64 years (n = 5,237), 7.2% had serious CVD; 15.9% pharmacotherapy. had any CVD; and 1.9% had been hospitalized with one or Methods A retrospective cohort analysis was performed more CVD. Of patients treated with stimulants using the Truven Health MarketScan database. Subjects (n = 87,167), 11.3–18.5% were diagnosed with addiction/ filled C 1 prescription for atomoxetine or C 1 stimulant in abuse and 4.1% with BPD. 2014–2015, were aged 18–64 years, commercially insured Conclusions CVD prevalence is generally low among throughout observation, and diagnosed with ADHD on two adults using ADHD medication but increases with age. or more medical claims. Diagnoses and medical procedures Although difficult to estimate precisely, the rate of addic- were measured in the 12 months prior to pharmacotherapy tion/abuse among stimulant-treated patients appears unex- initiation. Metrics included serious CVD (cardiomegaly, pectedly high. Further research should assess cardiomyopathy, cerebrovascular occlusion, congestive cardiovascular events and other potential harms associated heart failure, myocardial infarction, pacemaker, or valvular with contraindicated use in high-risk adults. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40801-017-0129-2) contains supple- mentary material, which is available to authorized users. & Kathleen A. Fairman kfairm@midwestern.edu Department of Pharmacy Practice, College of Pharmacy, Midwestern University-Glendale, 19555 N. 59th Avenue, Glendale, AZ 85308, USA 70 K. A. Fairman et al. First, ADHD medications increase diastolic blood pressure (BP), systolic BP, and heart rate by amounts that Key Points are generally considered modest but potentially clinically significant in patients with pre-existing cardiovascular This study of potential contraindications to disease (CVD) or CVD risk factors [10]. For this reason, pharmacotherapy for attention-deficit hyperactivity stimulants, which are the most common and guideline- disorder (ADHD) in commercially insured US adults recommended medications to treat ADHD [6, 11, 12], carry found that, measured in the 12 months prior to US Food and Drug Administration (FDA) labeled warnings initiation of treatment with stimulants or for serious cardiovascular events, including sudden death, atomoxetine in 2014–2015, prevalence rates of stroke, and myocardial infarction (MI) [13]. Specifically, serious cardiovascular disease were 7.2% among product labels state that stimulants ‘‘generally should not those aged 55–64 years and 3.6% among those aged be used’’ in patients with ‘‘serious structural cardiac 45–54 years. abnormalities, cardiomyopathy, serious heart rhythm Of adults initiating treatment with stimulants, abnormalities, or other serious cardiac problems that may 11.3–18.5% had been diagnosed in the past year with place them at increased vulnerability to the sympath- substance addiction or potential abuse. omimetic effects of a stimulant drug’’; and that ‘‘caution is indicated’’ in treating patients with pre-existing hyperten- In light of rapid growth in diagnosis and pharmacologic treatment for ADHD in recent years, sion [14–17]. Atomoxetine, a non-stimulant therapeutic option in the treatment of ADHD, carries a similar warning a study of adverse drug events among adults at [18]. Because older age increases the risk of CVD [19], highest risk—those who are older and/or have a increased pharmacovigilance for cardiovascular risk factors potential contraindication to pharmacotherapy—is and events is appropriate as the population of adults treated needed. with ADHD pharmacotherapy expands and ages [20]. Second, prescription stimulant medications are the subject of a growing degree of public health concern about addiction and related adverse medical events [21, 22]. From 2005 to 2011, the number of US emergency depart- 1 Introduction ment (ED) visits attributable to non-medical use of stim- ulant pharmaceuticals by young adults (aged 18–34 years) In the past two decades, prevalence rates of diagnosis and more than tripled, from 5,605 to 22,949 [23]. Additionally, pharmacologic treatment for attention-deficit hyperactivity for all age groups combined, more than 31,000 ED visits disorder (ADHD) have increased exponentially among were made because of ADHD medications in 2010 in the United States (US) adults [1–6]. One study of National US [24]. Because these increases have taken place pri- Ambulatory Medical Care Survey (NAMCS) data found marily among adults, rather than among children and that per 1,000 office-based physician visits made by US adolescents, the US Drug Abuse Warning Network adults aged C 20 years, rates of ADHD diagnosis and (DAWN) has identified ‘‘a need for increased attention pharmacologic treatment increased by 52.6 and 35.2%, toward … diversion and misuse among adults … as treat- respectively, from 2008–2009 to 2012–2013 [6]. Moreover, ment for ADHD among adults becomes more widespread’’ from 1995–1996 to 2007–2008, the population-adjusted [24]. FDA product labels for stimulants indicate that they rate of physician visits at which ADHD pharmacotherapy should ‘‘be given cautiously to patients with a history of was prescribed to adults increased fivefold; and by drug dependence or alcoholism’’ [14–17]. 2012–2013, a more than ninefold increase had occurred, In theory, the publication of evidence and of evidence- from 1.9 to 11.4 visits per 1000 US adults [2, 5, 6]. based guidelines, such as those currently available for adult It has been suggested that these changes are ADHD, should be reflected in the pharmacotherapies pre- attributable to expansion of the diagnostic criteria for scribed for the disorder in real-world practice. However, ADHD in the Diagnostic and Statistical Manual of Mental prescribing behaviors do not consistently respond to the Disorders (DSM)-5 in 2013 [7], as well as the launch of available base of evidence. For example, there was no new medications and formulations (e.g., chewables, sus- discernible decline in prescribing of pharmacotherapy for tained-release tablets, patches, and new molecular entities) pediatric ADHD after the FDA issued a warning in 2006 in recent years [5, 8, 9]. Along with these expansions, two about cardiac and psychiatric risks of stimulants [25]. factors complicate the management of pharmacotherapy Additionally, previous work has documented potentially for the rapidly growing population of US adults diagnosed contraindicated prescribing of a variety of medication with ADHD. classes, for example, antidepressants, statins, and serotonin Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 71 receptor agonists [26–29]. Thus, it is important to examine Board (IRB) review by the Midwestern University IRB the rate of potentially contraindicated prescribing system- committee. atically, particularly when the patient population treated with a given class of medication changes over time, as it 2.2 Study Sample has in ADHD. Current evidence about potential contraindications in the The sample was drawn from claims for all filled prescrip- prescribing of ADHD medications to adults is limited. One tions and medical services with dates of service from 1 analysis of adults with a new diagnosis of ADHD in 2006 January 2013, through 31 December 2015. All patients or 2007 examined the likelihood of ADHD pharma- aged 18–64 years, as measured on the first enrollment date cotherapy use as a function of baseline cardiovascular risk in each calendar year, who met the criteria listed below [30]. Another assessed the risk of serious cardiovascular were included in the sample (Fig. 1): events, controlling for baseline cardiovascular risk, in • Filled C 1 prescription for an ADHD medication (am- patients treated from 1986 to 2005 [31]. The time periods phetamines, atomoxetine, dexmethylphenidate or studied in both these analyses preceded promulgation of methylphenidate), identified using generic product the DSM-5 [7, 30, 31]. Additional studies of cardiovascular name, in either 2014 or 2015. Use of lisdexamfetamine events associated with pharmacotherapy for adult ADHD did not qualify patients for the sample because it has a have either excluded patients with high-risk conditions labeled indication for binge-eating disorder [35], an from the sample or used a propensity-matched cohort obesity-related condition that is associated with CVD design, thereby making it difficult to determine the per- risk factors including diabetes, hypertension, and centage of stimulant- or atomoxetine-treated patients who dyslipidemias [36, 37]. are potentially at increased risk of adverse events [32, 33]. • Were continuously enrolled for healthcare benefits The present study addressed this gap in available for C 12 months prior to the first ADHD medication information by profiling the relevant clinical histories of claim date (index date), creating a sample of new users cohorts of adult patients filling prescriptions for either (i.e., after a C 12-month ‘‘washout’’ period). To allow stimulants or atomoxetine to treat ADHD in 2014–2015. for C 12 months of eligibility prior to the index med- Specifically, the study examined rates of (1) CVD and ication claim, the earliest index date was 1 January CVD risk factors, which are potential contraindications for both stimulants and atomoxetine; and (2) substance • Had two or more medical claims with a diagnosis of addiction or abuse, bipolar disorder, and glaucoma, which ADHD (International Classification of Diseases [ICD]- are potential contraindications for stimulants [14–18]. 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 FDA- 2 Methods labeled uses, such as narcolepsy or obesity [38]. The application of a ‘‘two or more’’ claim rule for ADHD 2.1 Study Design and Data diagnosis was used to exclude patients whose claims reflect ‘‘rule-out’’ diagnoses or coding errors, a tech- The study was a retrospective cohort analysis of patients nique that is common in claims database analyses identified using the Truven MarketScan Commercial [39–41]. Claims and Encounters database, which includes claims for • One or more claim with an ADHD diagnosis either all healthcare services (medical care and prescription preceded the index date or followed it by no more than medications) delivered to approximately 50 million com- 90 days. The 90-day standard was used to link med- mercially insured enrollees each year. The MarketScan ication therapy to diagnosis, while allowing for minor database, which has been used in more than 1400 published variations in practice patterns (e.g., empirical treatment studies of US healthcare, is fully compliant with Health followed by diagnosis) or billing practices. Insurance Portability and Accountability Act (HIPAA) standards [34]. Data are obtained by Truven Health from employers and health insurance plans, cleaned for quality 2.3 Measurement of Potential Contraindications and accuracy, and de-identified using encrypted case and Co-morbidities numbers for research purposes. The database includes the Truven Health Red Book table, available to licensed Medical diagnoses and procedures were measured and calculated as prevalence rates (i.e., percentages: total users, which matches national drug code numbers to medication product information, including generic name. number diagnosed divided by total number of patients) The study was deemed exempt from Institutional Review during the 12-month time period preceding the index date. 72 K. A. Fairman et al. Fig. 1 Sample selection flowchart. Amphetamines Unique Enrollees, All Years (amphetamine salt combination, Aged 18-64 Years N=48,566,626 amphetamine sulfate, N=33,100,487 Aged 18-64 Years dextroamphetamine sulfate, N=35,121,673 Aged 18-64 Years hydroxyamphetamine, N=21,457,986 methamphetamine), >1 Claim for Smulant Medicaon or dexmethylphenidate, or Atomoxene in 2014 or 2015 methylphenidate. ADHD N=391,437 attention-deficit hyperactivity disorder Connuously Enrolled for >12 Months Prior to First Medicaon Claim N=167,665 Any ADHD Diagnosis N=115,723 >2 Medical Claims with ADHD Diagnosis N=97,633 ADHD Diagnosis Precedes or Is <90 Days Aer Medicaon Start N=91,588 Diagnoses were measured in any of the first four diagnosis reported because these are risk factors for CVD events fields reported on ambulatory claims (outpatient hospital [42]. Diagnosis codes are shown in Online Appendix A, department, ED, and physician office), and in these four and procedure codes are shown in Online Appendix B. fields plus the primary diagnosis field and diagnosis-related Sensitivity analyses were performed to address one area group (DRG) codes on inpatient hospital claims. Addi- of ambiguity in diagnostic coding on medical claims. tionally, detoxification services (identified by revenue Specifically, the a priori definition of abuse/addiction codes, place of service codes, and Health Care Common included diagnoses of V58.69 (ICD-9, ‘‘long-term (current) Procedural Coding System codes) were used to identify use of other medications’’) and Z79.891 (ICD-10, ‘‘long- addiction/abuse; and revascularization (i.e., percutaneous term (current) use of opiate analgesic’’) [43, 44]. This transluminal angioplasty, stenting, balloon angioplasty, and approach was used for several reasons: (1) Previous coronary artery bypass grafting) was measured using pro- research has documented variations in diagnostic coding cedure codes for all treatment settings and DRG codes for specificity in administrative data, particularly for condi- inpatient admissions. tions that are stigmatized and/or difficult to diagnose Potential contraindications were measured in three cat- [45–47]; (2) The ICD-9 code description for long-term egories: CVD, addiction/abuse, and other (bipolar disorder medication use specifically refers to methadone, opiate and glaucoma). Within the CVD category, a measure of analgesics, and ‘‘other high-risk medications’’ [48]; and, serious CVD—intended to represent the FDA’s warning (3) Of all inpatient claims for the study sample that language for ‘‘serious structural cardiac abnormalities, included a nonspecific code, 97% also were coded for a cardiomyopathy, serious heart rhythm abnormalities, CAD specific diagnosis of abuse or addiction. or other serious cardiac problems’’—was defined as car- Nonetheless, because the ICD-9 code for long-term diomegaly, cardiomyopathy, cerebrovascular occlusion, medication use was indeterminate as to specific drug, a set congestive heart failure, myocardial infarction, pacemaker, of post hoc sensitivity analyses limited the addiction/abuse or valvular disorder [14–18]. CVD was defined as serious prevalence indicator to patients with either (1) a specific CVD, other atherosclerotic CVD, arrhythmia, congenital diagnosis of abuse/addiction during the 12-month pre- heart anomaly, or hypertensive heart disease. Although not treatment time frame or (2) a code for long-term medica- included in the summary measure of CVD, prevalence rates tion/opiate use and a procedure code indicating a labora- of diabetes, hyperlipidemia, and hypertension were tory test for a specific controlled substance at any time Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 73 prior to treatment initiation. This choice was made because Chronic kidney disease of at least moderate severity a post hoc exploratory analysis showed that 36% of out- (Stages 3 or higher) was rare (0.1% of the sample). patient claims with the nonspecific code lacked a substance A history of addiction/abuse as defined in the a priori abuse diagnosis; and, of those, 25% were laboratory claims analysis plan was much more common - 18.8% of the for specific controlled substance tests. Codes for drug sample overall, 18.5% of patients treated with stimulants screens that were not specific as to substance were not (n = 87,167), and 23.9% of patients treated with atomox- included in this measure. The codes and substances cap- etine (n = 7051; Table 1). However, measurement of tured in this assessment are shown in online Appendix C. addiction/abuse prevalence was sensitive to the inclusion To assess the relationship between potential con- of nonspecific codes for long-term medication use. In the traindications and aging, the percentages of patients with post hoc sensitivity analysis with the modified (stricter) each diagnosis were calculated not only overall, but also by definition of addiction/abuse, prevalence rates were 11.7% age group. To determine whether risk from potential con- for the sample overall, 11.3% for stimulant-treated patients, traindications increases ordinally (i.e., monotonically) with and 17.1% for patients treated with atomoxetine. Of age, between-group differences were tested using the patients treated with stimulants, 4.1% were diagnosed with Mantel–Haenszel (linear-by-linear association) test for bipolar disorder and 0.6% with glaucoma. trend [49]. To produce nationally representative estimates, Despite the generally low rate of potential contraindi- all results were weighted for the sample-to-population ratio cations and co-morbidities in the sample overall, the across strata formed on sex, age group, region, and policy- prevalence of all CVD diagnoses and risk factors increased holder status (i.e., enrollee vs. dependent), using a method monotonically with age, as expected (Table 2). Of patients and strata population sizes provided by Truven Health. The aged 45–54 years (n = 12,801), 8.7% had any CVD; 3.6% total sample size after weighting was held to the original had serious CVD; and 1.0% were hospitalized with a (pre-weighting) cohort size by applying a constant to all diagnosis of CVD in the 12 months prior to the start of strata weights. All calculations were performed using SPSS ADHD pharmacotherapy. These rates were nearly doubled v24.0 (IBM Corporation, Armonk, NY, USA) at an a priori in patients aged 55–64 years (n = 5237): 15.9% had any alpha (critical P value) of 0.05. 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). 3 Results Rates of glaucoma and hypertension were also consid- erably elevated in older patients (Table 2). Specifically, Among all adult patients in the sample who were treated among those aged 55–64 years compared with patients in for ADHD with stimulants or atomoxetine in 2014–2015 the youngest age group (aged 18–24 years, n = 30,499) (n = 91,588), most individual CVD diagnoses were rare the rate of glaucoma was multiplied 18-fold (3.6 vs. 0.2%, (B 0.5% prevalence), and almost no patients had a history respectively); and the rate of hypertension was multi- of pacemaker implantation or revascularization (Table 1). plied[20-fold (40.1 vs. 2.0%, respectively). Rates of Within the sample overall, 2.0% had a diagnostic history diabetes and hyperlipidemia were similarly elevated: dia- potentially indicating serious CVD (cardiomegaly, car- betes[14-fold and hyperlipidemia[20-fold (all diomyopathy, cerebrovascular occlusion, congestive heart P\0.001). failure, myocardial infarction, pacemaker, or valvular dis- order); 1.6% had ASCVD (angina, cerebral occlusion, MI, peripheral arterial disease, transient ischemic attack (TIA), 4 Discussion revascularization, or other ASCVD); and 5.5% had some form of CVD (serious CVD, other atherosclerotic CVD, In an analysis of commercially insured adults treated with arrhythmia, congenital heart anomaly, or hypertensive pharmacotherapy for ADHD in 2014-2015, we found heart disease). Only 0.6% of patients treated with any prevalence rates of CVD and CVD risk factors that were ADHD medication, and 1.3% of patients treated with ato- generally low overall but markedly elevated with advancing moxetine, were hospitalized with a diagnosis of any CVD age, particularly among patients aged 55–64 years. In that condition in the 12 months prior to the start of age group, 15.9% were diagnosed with CVD and 7.2% with pharmacotherapy. serious CVD; and 40% had diagnosed hypertension. Addi- Like the individual CVD diagnoses, co-morbidities were tionally, we found a high rate of pre-existing addiction/abuse relatively uncommon in the sample overall (Table 1). For in the sample overall. Among adults treated with stimulants, example, hyperlipidemia and hypertension were each 11.3–18.5% were diagnosed with some form of addiction or diagnosed in 11.5% of patients, and diabetes in 3.1%. potential abuse in the 12 months prior to the start of ADHD pharmacotherapy. To the knowledge of these authors, these 74 K. A. Fairman et al. Table 1 Demographic characteristics and 12-month pre-treatment diagnoses, patients aged 18–64 years treated for ADHD with stimulants or atomoxetine in 2014–2015 Stimulants Atomoxetine Whole sample N 87,167 7051 91,588 Age (years) Mean (median) 33 (31) 34 (32) 33 (31) Age group (%) 18–24 33.3 33.0 33.3 25–34 26.0 22.5 25.8 35–44 21.2 21.6 21.2 45–54 13.9 16.3 14.0 55–64 5.6 6.6 5.7 Female (%) 51.3 48.0 51.1 Cardiovascular disease (%) Angina 0.2 0.3 0.2 Arrhythmia/tachycardia 3.0 5.0 3.1 Cardiomegaly 0.3 0.4 0.3 Cardiomyopathy 0.1 0.3 0.2 b,c Cerebral occlusion 0.5 0.6 0.6 Congenital heart anomaly 0.3 0.4 0.3 Congestive heart failure 0.1 0.3 0.1 Hypertensive heart disease 0.3 0.4 0.3 b,c Myocardial infarction 0.1 0.1 0.1 Peripheral arterial disease 0.2 0.2 0.2 Transient ischemic attack 0.2 0.3 0.2 Valvular disorder 1.0 1.4 1.0 Cardiac procedures (%) Pacemaker (facility claims) 0.0 0.1 0.0 Revascularization (facility claims) 0.0 0.1 0.0 Cardiovascular summary measures (%) Any CVD 5.4 8.2 5.5 Inpatient stay associated with CVD 0.6 1.3 0.6 Serious CVD 1.9 2.8 2.0 Any ASCVD 1.6 2.1 1.6 Other potential contraindications (%) Addiction/abuse or long-term medication/opiate use 18.5 23.9 18.8 Addiction/abuse or long-term medication/opiate use with testing for abusable substances 11.3 17.1 11.7 Bipolar disorder 4.1 7.8 4.3 Glaucoma 0.6 0.6 0.6 Co-morbidities (%) Diabetes 3.1 3.9 3.1 Moderate-to-severe CKD 0.1 0.2 0.1 Hyperlipidemia 11.3 14.8 11.5 Hypertension 11.3 14.5 11.5 Seizure disorder 0.7 1.2 0.7 ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular disease Because subcohorts are not mutually exclusive, sum of the subcohort counts exceeds total sample size ASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic heart disease Serious CVD Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 75 Table 2 Demographic characteristics and 12-month pre-treatment diagnoses, patients aged 18–64 years treated for ADHD with stimulants or atomoxetine, by age group 18–24 years 25–34 years 35–44 years 45–54 years 55–64 years N 30,499 23,633 19,419 12,801 5,237 Female (%)* 45.1 47.8 56.4 60.5 58.7 Cardiovascular disease b, Angina * 0.0 0.0 0.1 0.5 0.8 Arrhythmia/tachycardia* 2.4 2.8 3.2 3.7 6.0 c, Cardiomegaly * 0.1 0.1 0.3 0.6 1.0 c, Cardiomyopathy * 0.1 0.1 0.2 0.2 0.6 b,c, Cerebral occlusion * 0.2 0.3 0.6 1.1 2.6 Congenital heart anomaly 0.3 0.3 0.2 0.3 0.3 c, Congestive heart failure * 0.0 0.1 0.2 0.3 0.7 Hypertensive heart disease* 0.0 0.1 0.4 0.5 1.4 b,c, Myocardial infarction * 0.0 0.0 0.1 0.3 0.6 b, Peripheral arterial disease * 0.0 0.1 0.1 0.5 1.0 b, Transient ischemic attack * 0.0 0.1 0.2 0.5 0.6 c, Valvular disorder * 0.5 0.6 1.2 1.6 3.3 Cardiovascular summary measures* Any CVD 3.3 4.2 5.9 8.7 15.9 Inpatient stay associated with CVD 0.4 0.6 0.6 1.0 1.9 Serious CVD 0.8 1.1 2.3 3.6 7.2 Any ASCVD 0.4 0.6 1.4 3.7 8.3 Cardiac procedures* Pacemaker 0.0 0.0 0.1 0.1 0.1 Revascularization 0.0 0.0 0.1 0.1 0.2 Potential contraindications* Addiction/abuse or long-term medication/opiate use 16.9 18.1 20.0 21.3 23.2 Addiction/abuse or long-term medication/opiate use with testing for 11.0 11.9 12.3 11.7 11.7 abusable substances Bipolar disorder 3.6 4.1 4.5 5.2 5.7 Glaucoma 0.2 0.3 0.5 1.2 3.6 Co-morbidities Diabetes* 0.9 1.5 3.7 7.0 12.2 Moderate-to-severe CKD* 0.0 0.0 0.1 0.3 0.9 Hyperlipidemia* 2.0 6.1 15.2 26.7 40.9 Hypertension* 2.0 6.7 15.2 25.6 40.1 Seizure disorder 0.7 0.8 0.6 0.6 0.8 ADHD attention-deficit hyperactivity disorder, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular disease *P\0.001, linear-by-linear association test Sum of cell counts exceeds sample size by 1 because of the application of sample weights ASCVD. In addition to the specific diagnoses shown, the ASCVD summary measure includes diagnosis codes for atherosclerosis or ischemic heart disease Serious CVD findings represent the first ‘‘real-world’’ assessment of Prevalence rates for CVD and CVD risk factors potentially contraindicated prescribing of atomoxetine and observed in the present study are generally similar to those stimulants for adults since expansion of the diagnostic cri- observed in research conducted in earlier time periods, teria for ADHD in the DSM-5. despite some methodological differences. In a retrospective 76 K. A. Fairman et al. analysis of health records for commercially insured and product labels for both atomoxetine and stimulants have Medicaid-enrolled adults (aged 25–64 years, time period similar warnings for cardiovascular events. 1986–2007), Habel et al. found prevalence rates of 14.8% In considering the policy implications of these findings, for hypertension, 18.7% for hyperlipidemia, 1.2% for it is appropriate to take into account the concerns under- stroke/TIA, and 0.2% for MI, measured in the 12 months lying the FDA’s Drug Safety and Risk Management prior to the start of ADHD pharmacotherapy [31]. In the Advisory Committee 2006 recommendation that a ‘‘black- subset of patients aged 25–64 in the present analysis, we box’’ warning for cardiovascular effects be added to found prevalence rates of 16.2% for hypertension, 16.3% stimulant product labels, although the FDA did not adopt for hyperlipidemia, 0.8% for cerebral occlusion, 0.3% for the recommendation. As described by a committee advisor TIA, and 0.1% for MI. in an editorial published later that year, one factor con- Similarly, Gerhard et al. used a claims database to study sidered by the committee was the ‘‘rapid increase in adults (aged 21–64 years) with a new diagnosis of ADHD exposure’’ associated with expanding prevalence of ADHD in 2006–2007, followed through March 2008 [30]. In that diagnosis and stimulant use in adults [54]. Because this study’s subcohort of patients treated with stimulants or expansion would result in ‘‘the administration of potent atomoxetine, 8.8% had either any cardiovascular condition sympathomimetic agents to millions of Americans,’’ the or diagnosed hypertension in the 12 months prior to initial editorialist noted, the committee ‘‘sought to emphasize diagnosis, with prevalence rates increasing monotonically more selective and restricted use, while increasing aware- from 2.7% among those aged 21–29 years to 22.0% among ness of potential hazards’’ [54]. In the decade that has those aged 46–64 years (percentages calculated from passed since that editorial was written, exposure to ADHD counts shown in study report). pharmacotherapy has rapidly increased among US adults, A notable difference between our results and those of making the Committee’s concerns even more cogent today. Habel et al. is the markedly higher rate of diagnosed sub- However, previous studies of the cardiovascular safety stance addiction or abuse observed in the present study of pharmacotherapy for adult ADHD either controlled for sample: 11.7–18.8% compared with 5.2% observed by baseline CVD or excluded patients with CVD from the Habel et al. for ‘‘alcohol/substance abuse’’ in 1986–2007 sample [31–33]. Although these methodological features [31]. It is possible that methodological differences, such as are standard techniques used to control for pre-existing the use of health records by Habel et al. and claims data in disease in a population-wide assessment of adverse drug the present study, contribute to the observed increase in the effects, the present study results may suggest the need for a addiction/abuse prevalence rate. However, given the more targeted approach: assess hazards in those subpopu- marked increase in use and abuse of controlled prescription lations most at risk. Specifically, among adult patients treated for ADHD with stimulants or atomoxetine, future medications that has been noted by US public health organizations in recent years [21, 23, 24], it appears more research should assess the prevalence of (1) cardiovascular likely that the results of the present study are a manifes- events in those who are aged 55 years or older or have a tation of the public health crisis associated with increases pre-existing CVD, perhaps with special emphasis on those in the prevalence of prescription medication abuse in the with both risk factors; and (2) sequelae of addiction/abuse US [50]. In one study of U.S. college students who were (e.g., hospitalization for adverse drug reactions or mortal- asked to self-report use of stimulants in the previous year, ity) in those with pre-existing histories of substance use 5.4% in 2003 and 9.3% in 2013 reported non-medical use, disorder. whereas 1.9% in 2003 and 4.7% in 2013 reported medical use [51]. It is also possible that patients with pre-existing 4.1 Limitations addictions were erroneously diagnosed with ADHD, because substance abuse disorders complicate the process Several limitations of the present study should be noted. of differential diagnosis in patients presenting with symp- First, the study did not assess the effects of long-term toms of ADHD, such as restlessness, inattention, or medication exposure occurring prior to the start of the impulsivity [52]. study, for example, use throughout childhood in a patient Present study findings suggest that prescribers were who is now an adult. Similarly, diagnoses of contraindi- aware that a history of addiction places adults at risk when cations could have been made either prior to the 12-month treated with stimulants [53], as addiction was more measurement time frame used in the present study, or for prevalent among atomoxetine-treated patients services paid out-of-pocket by patients and therefore not (17.1–23.9%) than among those treated with stimulants recorded in insurance claims. Thus, the calculated preva- (11.3–18.5%). However, it is somewhat puzzling that CVD lence rates may be underestimated. was also more prevalent among atomoxetine- than stimu- Second, the study was limited to commercially insured lant-treated patients (8.2 vs. 5.4%, respectively), because enrollees aged 18–64 years; its results may not be Cardiovascular Risk Factors and Addiction/Abuse in Adults Treated for ADHD 77 applicable to those enrolled in Medicaid or Medicare. Among adults treated with stimulants, 11.3–18.5% were Study results also may not be applicable to patients treated diagnosed with abuse or addiction in the 12 months prior to with lisdexamfetamine, especially those with co-morbid the start of ADHD pharmacotherapy. Future research binge-eating disorder, or to patients using the study med- should assess possible harms associated with potentially ications off-label or for a labeled use other than ADHD. contraindicated uses of ADHD pharmacotherapy by adults, Third, errors and omissions may occur in coding of particularly in those at highest baseline risk of adverse drug diagnoses or procedures; however, there is no reason to events. believe that these disproportionately affected particular age Compliance with Ethical Standards groups. Similarly, a number of different classification symptoms could reasonably have been used to define Funding This work was funded by Midwestern University with no serious CVD, and any clinical classification system based external support or funding. on claims data may be imperfect. However, findings of the Conflicts of interest KAF, LED, AMP, and DAS have no financial present study were consistent with those of previous studies or other conflicts of interest in the subject of this manuscript. of CVD and related co-morbidities in adults treated with pharmacotherapy for ADHD [30, 31]. Open Access This article is distributed under the terms of the Fourth, claims data generally do not indicate severity of Creative Commons Attribution-NonCommercial 4.0 International illness, although proxy measures (e.g., a hospital stay for License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits any noncommercial use, distribution, and reproduction in any CVD) and certain diagnoses (e.g., a diagnosis of congestive medium, provided you give appropriate credit to the original heart failure) do provide some indication of level of risk. author(s) and the source, provide a link to the Creative Commons Most notably, it is not possible from the present study to license, and indicate if changes were made. determine the severity of ADHD, or the benefit-versus-risk ratio of treating ADHD with pharmacotherapy for any individual patient. Fifth, diagnoses representing addiction/abuse in the References present study were not specific as to particular substance, 1. 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Drugs - Real World Outcomes – Pubmed Central

Published: Jan 5, 2018

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