ADHD Medications and Long-Term Cardiovascular Risk

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CASE VIGNETTE

“Kelly” is an 11-year-old Caucasian female with recently diagnosed attention-deficit/hyperactivity disorder (ADHD). She presented with primarily inattentive symptoms and minimal issues with hyperactivity and impulsivity. She also has a history of seasonal allergies and mild asthma. She had a positive response to treatment with methylphenidate, which she continues to take. At an outpatient visit, her mother asks about potential risks of long-term treatment with ADHD medication. As her psychiatrist, how would you respond?

There is ongoing concern regarding the cardiovascular safety of medications for ADHD.¹ Meta-analyses of randomized controlled trials (RCTs) have found increased pulse and blood pressure associated with both stimulant and non-stimulant ADHD medications.^1-3 Given the shorter-term nature of RCTs, whether these changes lead to clinically significant long-term risk of cardiovascular disease (CVD) remains unknown.

Previous longitudinal observational studies have yielded mixed findings,^4,5 and a meta-analysis of observational studies did not find an association.⁶ However, most of these studies had a follow-up of <2 years. Given that ADHD symptoms may persist into adulthood⁷ and the trend for long-term use of ADHD medications,⁸ long-term risks of these medications represent an important area of study.

The Current Study

Zhang and colleagues⁹ assessed the association between cumulative ADHD medication use (up to 14 years) and CVD risk using nationwide health registers in Sweden. Diagnoses were obtained from the National Inpatient Register. Medication information was retrieved from the Swedish Prescribed Drug Register. Socioeconomic factors were obtained from the Longitudinal Integrated Database for health Insurance and Labour Market studies. Death information was retrieved from the Swedish Cause of Death Register.

The investigators conducted a nested case-control study on all individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD (ICD-10) or ADHD medication dispensation (after at least 18 months without any such medication dispensation) between 2007 and 2020. Exclusion criteria were ADHD medication prescriptions for indications other than ADHD, individuals who emigrated or died, or individuals with a history of CVD before study baseline.

Cohort members were followed until the date of CVD diagnosis, death, migration, or the end of 2020 (whichever came first). Incident diagnosis of CVD included ischemic heart disease, cerebrovascular disease, hypertension, heart failure, arrhythmia, thromboembolic disease, arterial disease, and other heart disease. For each case, up to 5 controls without CVD were randomly selected and matched based on age, sex, and calendar time. Controls were alive, living in Sweden, and free of CVD at the time when their matched case received a diagnosis of CVD.

The primary exposure was cumulative duration of ADHD medication use, based on free text in prescription records. The last 3 months before the index date of CVD were excluded to reduce reverse causation. The authors conducted conditional logistic regression analyses to estimate odds ratios (ORs) for the association between cumulative ADHD medication duration and incident CVD. Analyses were adjusted for age, sex, calendar time, country of birth, education, and somatic and psychiatric comorbidity.

Duration of ADHD medication use was assessed using both continuous and categorical measures. The risk of CVD was also estimated for each 1-year increase in use of ADHD medication across different dosage groups categorized by the average defined daily dose (DDD). Subgroup analyses examined the association between ADHD medication use and specific CVDs, as well as the most commonly prescribed medications (methylphenidate, lisdexamfetamine, and atomoxetine).

The study cohort consisted of 278,027 individuals with ADHD. The incidence rate of CVD was 7.3 per 1000 person-years. The analyses included 10,388 cases and 51,672 matched controls (median age 35 years; 59% male). The median follow-up was 4.1 years. The most common types of CVD in cases were hypertension (41%) and arrhythmias (13%). Cases had high rates of somatic and psychiatric comorbidities and less education compared with controls.

Longer cumulative duration of ADHD medication use was associated with increased CVD risk compared with non-use in a dose-response fashion (>5 years: aOR=1.23, 95% CI 1.12-1.36). Throughout follow-up, each 1-year increase in the use of ADHD medication was associated with a 4% increased risk of CVD (aOR=1.04, 95% CI 1.03-1.05).

A similar pattern of findings was observed when considering 1) males and females, and 2) children/adolescents and adults, separately. Dosage analysis found that CVD risk associated with each 1 year of ADHD medication use increased with higher-average DDDs and was statistically significant for individuals with a mean dose of at least 1.5 DDD.

Regarding specific CVDs, long-term use of ADHD medication was associated with increased risk of hypertension (>5 years: aOR=1.80, 95% CI 1.55-2.08) and arterial disease (>5 years: aOR=1.49, 95% CI 0.96-2.32). Regarding specific medications, methylphenidate (>5 years: aOR=1.19, 95% CI 1.08-1.31), and lisdexamfetamine (>3 years: aOR=1.17, 95% CI 10.98-1.40) were associated with increased CVD risk. Atomoxetine use was significant only for the first year of use (aOR=1.07, 95% CI 1.01-1.13).

Study Conclusions

The investigators concluded that long-term ADHD medication use was associated with increased risk of incident CVD, and this risk increased in a dose-response manner. Findings were consistent regardless of age or sex. The primary drivers of this association were increased risk of hypertension and arterial disease.

Study strengths include the longer duration of follow-up than previous studies and consideration of specific causes of CVD. Another study strength was the use of prospective data collection, so results were not affected by recall bias.

Study limitations include potential lack of ascertainment of cases of CVD that did not require medical care, which would tend to underestimate associations. Exposure misclassification may have occurred if patients did not take medications as prescribed. Finally, the observational nature of the study design did not permit causal inferences.

The Bottom Line

Findings suggest that long-term use of ADHD medication is associated with an increase in CVD risk, especially hypertension and arterial disease, and with a higher risk for stimulant medications. Clinicians should vigilantly monitor patients, especially those taking higher doses, for signs and symptoms of CVD.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Storebø OJ, Ramstad E, Krogh HB, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015;2015(11):CD009885.

2. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738.

3. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23(6):534-541.

4. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-1904.

5. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.

6. Zhang L, Yao H, Li L, et al. Risk of cardiovascular diseases associated with medications used in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. JAMA Netw Open. 2022;5(11):e2243597.

7. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med. 2006;36(2):159-165.

8. Bruno C, Havard A, Gillies MB, et al. Patterns of attention deficit hyperactivity disorder medicine use in the era of new non-stimulant medicines: a population-based study among Australian children and adults (2013-2020). Aust N Z J Psychiatry. 2023;57(5):675-685.

9. Zhang L, Li L, Andell P, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry. 2024;81(2):178-187.