Version May 2024
INTRODUCTION — Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder, affecting approximately 5 to 15 percent of all school-aged children. Stimulant drugs and other pharmacologic agents are commonly used for treatment of ADHD.
Reports of sudden unexpected deaths among patients taking stimulant drugs for ADHD led to concerns regarding the safety of ADHD medications. These findings were not confirmed in subsequent large cohort studies. Nevertheless, the question of whether ADHD medication increases the risk of adverse cardiovascular (CV) events continues to be debated, and uncertainties remain as to what pretreatment evaluation is necessary (if any) prior to starting stimulant medications to identify patients who may be at increased risk for arrhythmia and sudden cardiac death (SCD).
The risk of serious CV events, including SCD, in patients receiving ADHD medications and the pretreatment cardiac evaluation for such patients will be reviewed here. Other related topics include:
●(See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications".)
●(See "Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in children".)
PHYSIOLOGIC EFFECTS OF ADHD MEDICATIONS
Stimulant medications — Stimulant drugs (eg, methylphenidate, dexmethylphenidate, dextroamphetamine, dextroamphetamine-amphetamine) have known effects on heart rate (HR) and blood pressure (BP). However, these effects are generally modest and, in most cases, they are not clinically significant.
In studies evaluating stimulant medications, the reported changes in HR and BP were [1-7]:
●HR increases ranged from 3 to 10 beats per minute
●Systolic BP increases ranged from 3 to 8 mmHg
●Diastolic BP increases ranged from 2 to 6 mmHg
The pharmacology of these agents is discussed in greater detail separately. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulants'.)
Nonstimulants — Nonstimulant medications used to treat ADHD include selective norepinephrine reuptake inhibitors (eg, atomoxetine, viloxazine) and alpha-2 adrenergic agonists (eg, guanfacine, clonidine). (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents".)
●Atomoxetine – In a comprehensive review of a clinical trial database that included >8000 patients treated with atomoxetine, most pediatric patients experienced modest increases in heart rate and blood pressure and 8 to 12 percent experienced more pronounced changes (≥20 beats per minute, ≥15 to 20 mmHg) [8]. Thus, the prescribing information for atomoxetine includes a warning that the drug "generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to its noradrenergic effects" [9]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)
●Alpha-2 adrenergic agonists – Alpha-2 adrenergic agonists (eg, guanfacine, clonidine) have known cardiovascular side effects which can include bradycardia and hypotension. Clinically significant HR and BP changes are uncommon when these drugs are used at the typical doses for ADHD treatment. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Alpha-2-adrenergic agonists'.)
RISK OF ADVERSE CARDIOVASCULAR EVENTS — In the late 2000s, reports of unexpected deaths among children receiving stimulant therapy led to concerns that these medications may increase the risk of adverse cardiovascular (CV) events, including sudden cardiac death (SCD) [10-12]. However, large cohort studies have not shown an increased risk of serious CV adverse events in individuals treated with stimulant therapy compared with the general population, as discussed in the following section [13-17].
General population — Based on the available evidence, there does not appear to be an increased risk for adverse CV events associated with ADHD drugs in the general population.
In a meta-analysis of 19 studies (14 cohort studies, 3 nested case-control studies, and 2 before-after studies) including >3.9 million patients (children and adolescents accounted for approximately 75 percent of the study populations) from various regions in the world (United States, South Korea, Canada, Denmark, Spain, and Hong Kong), the following findings were noted [17]:
●No apparent association between ADHD medications and CV events – In the main analysis, the study did not detect an association between ADHD medication use and the overall risk of any adverse CV event (relative risk [RR] 1.22, 95% CI 0.88-1.68) [17]. In an analysis limited to only studies evaluating stimulant medications, there was also no apparent association (1.24, 95% CI 0.84-1.83).
In subgroup analyses of studies involving different age groups, there was no apparent association between ADHD medications and CV events in any subpopulation:
•Children and adolescents – RR 1.18, 95% CI 0.91-1.53
•Young and middle-aged adults – RR 1.04, 95% CI 0.43-2.48
•Older adults – RR 1.59, 95% CI 0.62-4.05
●Specific types of CV events
•SCD and tachyarrhythmias – It is unclear whether ADHD medication use is associated with increased risk of SCD. If there is an effect, the absolute risk is very small. In an analysis of nine studies that reported rates of SCD, cardiac arrest, or tachyarrhythmia, the pooled risk was slightly higher among individuals using ADHD medications, but the finding was not statistically significant (RR 1.60, 95% CI 0.94-2.72) [17]. The studies in this analysis involved both pediatric (four studies) and adult (five studies) populations.
The absolute risk of SCD in these studies was exceedingly low. For example, in the largest study in the meta-analysis which included >1,200,000 children and young adults (ages 2 to 24 years), the overall rate of SCD was 1.3 per 100,000 patients per year (1.6 per 100,000 patient-years among individuals with current or prior ADHD medication use versus 1.1 per 100,000 person-years among non-users) [13].
•Myocardial infarction (MI) – In an analysis of eight studies reporting rates of MI, there was no apparent association between ADHD medications and MI (RR 1.06, 95% CI 0.68-1.65) [17]. Most of studies in this analysis (six of eight) involved adult populations.
•Stroke – In an analysis of 10 studies reporting rates of stroke, there was no apparent association between ADHD medications and cerebrovascular diseases (RR 0.91, 95% CI 72-1.15) [17]. The studies in this analysis involved both pediatric (four studies) and adult (six studies) populations.
●Patients with prior CV disease – In a meta-analysis of seven studies involving patients with prior CV disease history, there was no apparent association between ADHD medications and risk of adverse CV events (RR 1.31, 95% CI 0.80-2.16) [17]. However, the studies in the meta-analysis largely used diagnostic codes from medical billing to identify patients with prior CV history, and the definition was very broad. As discussed below, children with serious cardiac conditions (eg, complex congenital heart disease [CHD], cardiomyopathy) were not well represented in these studies. (See 'Children with cardiac disease' below.)
Children with cardiac disease — No studies to date have demonstrated that ADHD medications increase the risk of SCD in children with congenital or acquired heart disease. However, few studies have adequately evaluated the safety of stimulant drugs in this population. For example, there are few studies on the use of ADHD medications specifically in children with complex CHD, among whom ADHD is a common comorbidity [18,19].
There are no specific cardiac diagnoses in which ADHD medications are absolutely contraindicated. However, caution should be used when prescribing ADHD medications in children with underlying conditions in which the known physiologic effects of stimulant medications (ie, modest increase in heart rate and blood pressure) might be poorly tolerated. This includes [20]:
●Children with poorly controlled hypertension (see "Nonemergent treatment of hypertension in children and adolescents")
●Children with arrhythmia syndromes (eg, long QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome) [21] (see "Congenital long QT syndrome: Diagnosis" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation" and "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis")
●Children with symptomatic cardiomyopathy (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy) (see "Definition and classification of the cardiomyopathies" and "Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis")
●Children with aortic root disease (eg, Marfan syndrome) (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")
In these conditions, decisions regarding initiation of pharmacotherapy for ADHD are individualized and should be made in collaboration with the family/caregivers and the child's cardiologist. If ADHD medication is used in such patients, close monitoring is advised. (See 'Monitoring' below.)
PRETREATMENT CLINICAL EVALUATION — Prior to initiating medication for ADHD in children and adolescents, we suggest performing a clinical evaluation aimed at identifying underlying cardiac disease that may predispose the child to sudden cardiac death (SCD) or other serious cardiovascular events. This generally includes the following:
●Comprehensive medical history with particular attention to warning signs for cardiac disease (eg, unexplained syncope, chest pain or dyspnea with exercise) (see "Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in children", section on 'Warning signs')
●Family history, including whether any family members have experienced SCD or life-threatening cardiac arrhythmias
●Physical examination, including:
•Measurement of blood pressure and heart rate
•Cardiac auscultation to detect the presence of a heart murmur, or irregular or rapid heart rhythm (see "Approach to the infant or child with a cardiac murmur")
•Physical findings associated with Marfan syndrome (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")
If the history and examination do not suggest cardiac disease, the available evidence suggests that ADHD pharmacotherapy can be safely initiated without any additional evaluation [22,23]. (See 'No role for routine ECG screening' below.)
If there are concerns for cardiac disease based upon the clinical evaluation, additional evaluation may be warranted under the direction of a pediatric cardiologist. This is discussed in greater detail separately. (See "Suspected heart disease in infants and children: Criteria for referral".)
For children with suspected or known cardiac disease, decisions regarding initiation of pharmacotherapy for ADHD are individualized and should be made in collaboration with the family/caregivers and the child's cardiologist. Based upon the available evidence, there are no specific cardiac diagnoses in which ADHD medications are absolutely contraindicated. However, when prescribing these medications in children with serious cardiac disease, it is prudent to consider the known physiologic effects of stimulant medications (ie, modest increase in heart rate and blood pressure). If ADHD medications are used in patients with serious cardiac disease, close monitoring is advised. (See 'Children with cardiac disease' above and 'Monitoring' below.)
Our approach is generally consistent with the recommendations of the American Academy of Pediatrics and the American Heart Association [23]. This approach is also endorsed by several other professional organizations, including the American Academy of Child and Adolescent Psychiatry, the American College of Cardiology, Children and Adults with Attention-Deficit/Hyperactivity Disorder, the National Institute for Children's Health Quality, and the Society for Developmental and Behavioral Pediatrics.
However, it is important to note that based upon the available evidence, it remains uncertain if there truly is an association between stimulant use and SCD. If there is an effect, the absolute risk is very small. What is clear, however, is that limiting or delaying a child's access to effective treatment for ADHD could have serious implications (such as increased risk of adolescent substance use disorder, academic failure, and accidents) in patients who are not effectively treated. These relative risks should be discussed with families/caregivers. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Prognosis'.)
MONITORING — During treatment with ADHD stimulant therapy, the patient should be assessed for any new symptoms (eg, fainting or dizziness, chest pain or shortness of breath with exercise, unexplained change in exercise tolerance, or palpitations). Evaluation should include measurement of heart rate and blood pressure to ascertain whether there have been any significant changes compared with pretreatment values, especially if the blood pressure reaches either prehypertension or hypertension levels. (See "Definition and diagnosis of hypertension in children and adolescents".)
In patients with concerning symptoms or findings, consultation with a pediatric cardiologist is advised. (See "Suspected heart disease in infants and children: Criteria for referral".)
NO ROLE FOR ROUTINE ECG SCREENING — An electrocardiogram (ECG) is not required before initiating ADHD medication. This is because:
●The incidences of arrhythmia and sudden cardiac death (SCD) do not appear to be significantly increased in children receiving ADHD medications. (See 'Risk of adverse cardiovascular events' above.)
●ECG has a poor sensitivity and specificity for identifying individuals at risk for SCD [24]. False positives are common and false negatives can also occur. This issue is discussed separately. (See "Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in children", section on 'Screening at routine health care visits'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Attention deficit hyperactivity disorder".)
SUMMARY AND RECOMMENDATIONS
●Physiologic effects of ADHD medications – Medications that are used to treat attention deficit hyperactivity disorder (ADHD) include stimulants, selective norepinephrine reuptake inhibitors (SNRIs), and alpha-2 adrenergic agonists. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents".)
These drugs have known effects on heart rate (HR) and blood pressure (BP):
•Stimulant medications – In studies evaluating stimulant medications (eg, methylphenidate, dexmethylphenidate, dextroamphetamine, dextroamphetamine-amphetamine), the reported changes in HR and BP were (see 'Stimulant medications' above):
-HR increases ranged from 3 to 10 beats per minute (bpm)
-Systolic BP increases ranged from 3 to 8 mmHg
-Diastolic BP increases ranged from 2 to 6 mmHg
•SNRIs – In studies evaluating atomoxetine, most patients experienced modest increases in HR and BP and approximately 10 percent experienced more pronounced changes (HR increase of ≥20 bpm, BP increase of ≥15 to 20 mmHg). (See 'Nonstimulants' above and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)
•Alpha-2 adrenergic agonists – Alpha-2 adrenergic agonists (eg, guanfacine, clonidine) can cause bradycardia and, less commonly, hypotension. (See 'Nonstimulants' above and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Alpha-2-adrenergic agonists'.)
●Risk of serious cardiovascular (CV) events – Following several reports of unexpected deaths in children receiving stimulant therapy, concerns arose about the risk of experiencing adverse CV events, particularly sudden cardiac death (SCD), when receiving ADHD medications. However, large cohort studies have not shown an increased risk of serious CV events in individuals treated with ADHD therapy (stimulant or nonstimulant) compared with the general population. (See 'Risk of adverse cardiovascular events' above.)
●Pretreatment evaluation – Prior to initiating medication for ADHD in children and adolescents, we suggest performing a clinical evaluation aimed at identifying underlying cardiac disease that may predispose the child to SCD or other serious cardiovascular events. This generally includes (see 'Pretreatment clinical evaluation' above):
•Comprehensive medical history
•Family history
•Physical examination, including measurement of BP and HR, cardiac auscultation to identify heart murmurs or abnormal heart rhythm, and assessment for findings of Marfan syndrome
If the history and examination do not suggest cardiac disease, ADHD pharmacotherapy can be initiated without any additional evaluation. A screening ECG is not required. (See 'No role for routine ECG screening' above.)
●Monitoring – Children who are prescribed ADHD medications should be routinely evaluated for any changes in HR or BP, as well as CV symptoms during treatment. (See 'Monitoring' above.)
●Use of ADHD medications in children with cardiac disease – No studies to date have demonstrated that ADHD medications increase the risk of SCD in children with congenital or acquired heart disease. However, few studies have adequately evaluated the safety of these drugs in this population. (See 'Children with cardiac disease' above.)
There are no specific cardiac diagnoses in which ADHD medications are absolutely contraindicated. However, decisions regarding initiation of ADHD medication in patients with underlying cardiac disease are individualized and should be made in collaboration with the family/caregivers and the child's cardiologist. If ADHD medications are used in such patients, close monitoring is advised. (See 'Monitoring' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
