Longitudinal Study Looks at Risk of Cardiovascular Disease With Long-Term ADHD Medication Use

Masha Impallaria, MD;Haley Schuster, MD;Mullen,Mark;Tampi,Rajesh;

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Recent decades have seen increased medication use for attention-deficit/hyperactivity disorder (ADHD), including both stimulants and nonstimulants. However, long-term effects of ADHD medications on the cardiovascular system are not fully understood.

There is limited evidence on whether long-term use is associated with an increased risk of cardiovascular disease (CVD), with most prior studies having an average follow-up time of no more than 2 years.

This study used the nationwide health registers in Sweden to assess the associations between the use of ADHD medications and CVD over the course of 14 years.¹

L. Zhang: Grants from Swedish Research Council for Health, Working Life, and Welfare

H. Larsson: European Union’s Horizon 2020 research and innovation program under grant agreement

To assess the association between long-term use of ADHD medication and the risk of CVD.

This was a population-based case-control study looking at all individuals in Sweden aged 6 to 64 years who either had an incident diagnosis of ADHD or had been prescribed ADHD medication between January 1, 2007 and December 31, 2020. Excluded from the study were patients with a previous CVD diagnosis, those who used ADHD medication for other indications, and those who had emigrated or died before the baseline.

In this study, the investigators defined baseline (cohort entry) as the date of incident ADHD diagnosis or ADHD medication dispensation, whichever event came earlier. Patient demographics including diagnosis, medication dispensation history, socioeconomic factors, and death information were obtained from multiple Swedish nationwide registries: the Swedish National Inpatient Register, the Swedish Prescribed Drug Register, the Longitudinal Integrated Database for Health Insurance and Labor Market Studies, and the National Cause of Death Register.

CVD diagnosis was defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and included ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease.

Each patient case—that is, a patient with ADHD who received a CVD diagnosis after initiation of ADHD medication—was matched with up to 5 controls who did not receive a CVD diagnosis. Patient cases and controls were matched based on age, sex, and calendar time to ensure similar lengths of follow-up. Each patient was followed for up to 14 years. The primary exposure was cumulative duration of ADHD medication use, and the primary outcome was incident CVD.

Study Strengths

1. This is a large study that included 278,027 individuals aged 6 to 64 years with ADHD.

2. The follow-up for this study was significantly longer than that of previous studies assessing long-term cardiovascular risk with ADHD medication use.

3. Data on ADHD medication prescriptions and CVD diagnoses were recorded prospectively, which mitigates the risk of recall bias.

4. Many confounding variables were accounted for, including age, sex, calendar time, country of birth, educational level, and psychiatric comorbidities.

5. Funders had no role in the study’s design, collection or interpretation of the data, or preparation or publication of the manuscript.

Study Limitations

1. Patients with CVD were identified based on diagnoses recorded in medical records, rather than assessment of symptomatology by investigators, which could lead to underreporting of CVD diagnoses.

2. As there was no way to ensure adherence with ADHD medications, it is possible that patients were misclassified due to discrepancies in adherence.

3. This study’s data cannot prove causality, as the study is observational.

4. Other time-varying confounders that were not accounted for, such as use of other psychotropic medications and lifestyle factors, could have impacted the risk for CVD.

5. Severity of ADHD is a potential confounding variable because patients with more severe ADHD symptoms tend to have more comorbidities and less healthy lifestyles, increasing the risk for CVD.

6. This is a Swedish study; it is possible that cultural differences regarding ADHD medication use may limit generalizability of the findings in the United States and in other countries.

Conditional logistic regression analyses were used to estimate odds ratios for the associations between cumulative durations of ADHD medication use and incident CVD. The crude odds ratios were adjusted for all matching variables, which included age, sex, and calendar time. The adjusted odds ratios (AORs) were additionally controlled for country of birth (Sweden vs another country), highest educational level, and diagnoses of somatic and psychiatric comorbidities before baseline.

The study’s treatment effect showed that longer use of ADHD medications was associated with increased CVD risk compared with nonuse (1 to ≤ 2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤ 3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤ 5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and > 5 years: AOR, 1.23 [95% CI, 1.12-1.36]).

Specifically, there was a significant association of long-term ADHD medication use with hypertension (AOR, 1.72 [95% CI, 1.51-1.97] for 3 to ≤ 5 years) and arterial disease (AOR, 1.65 [95% CI, 1.11-2.45] for 3 to ≤ 5 years). There were no statistically significant associations for arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease.

Throughout the study’s follow-up, each 1-year increase in the use of ADHD medications correlated with a 4% increased association of CVD (95% CI, 1.03-1.05) and an 8% increased association in the first 3 years (95% CI, 1.04-1.11). There was a rapid increase in association for the first 3 cumulative years, but the association stabilized thereafter.

The association between CVD and ADHD medications increased with higher average defined daily doses (DDDs; eg, 30 mg methylphenidate or 80 mg atomoxetine), with a statistically significant risk found only among individuals with a mean dose of at least 1.5 times the DDD. Researchers found a 4% increased risk for individuals receiving 1.5 to 2 times the DDD, whereas they found a 5% increased risk for individuals receiving more than 2 times the DDD.

Looking at specific classes of ADHD medications, atomoxetine’s association with CVD was significant only for the first year of use, with an AOR of 1.07 (95% CI, 1.01-1.13). For methylphenidate use vs no use, the AOR was 1.20 (95% CI, 1.10-1.31) for 3 to 5 or fewer years.

For greater than 5 years, the AOR was 1.19 (95% CI, 1.08-1.31). The data for lisdexamfetamine use vs no use showed an AOR of 1.23 (95% CI, 1.05-1.44) for 2 to 3 or fewer years. Across groups, researchers observed similar associations in females and males.

The results of this population-based case control study suggest that long-term ADHD medication use was associated with an increased risk of CVD, specifically hypertension and arterial diseases. The observed risk of CVD was greater when stimulant medications were used in comparison with nonstimulant medications to treat ADHD. There was also a significant association between the cumulative duration of ADHD medication use and increased risk of CVD.

Long-term use of ADHD medications is associated with CVD. It is important to weigh the risks and benefits of this treatment modality with every patient. It is also important to closely monitor patients for the signs and symptoms of CVD in those who are taking these medications.

This nested case-control study followed patients for 14 years and found that long-term ADHD medication use was associated with CVD, specifically hypertension and arterial diseases.

Dr Impallaria is a first-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Schuster is a third-year psychiatry resident at Creighton University. Dr Mullen is a fourth-year psychiatry resident at Creighton University. Dr Tampi is a professor and the chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine and a member of the Psychiatric Times editorial board.