Long-Term ADHD Medication Use Linked to Potential Risk of Cardiovascular Diseases

Long-term exposure to ADHD medication is linked to an increased risk of cardiovascular diseases, particularly hypertension and arterial disease, according to a new study.¹

Randomized clinical trials (RCTs) may have demonstrated ADHD medications effectiveness, but some studies raise concerns about the drug’s cardiovascular safety. Meta-analyses found ADHD medications can slightly increase heart rate and blood pressure. Investigators of a 2015 study wrote how randomized clinical trials typically evaluate short-term effects as the average treatment duration sits at 75 days^.2 Therefore, the increase in blood pressure and heart race ADHD medication causes could potentially lead to cardiovascular disease over time.

Little is known about the effects of using ADHD medication long-term. Yet, studies observed a rising trend in long-term use of ADHD medication—about half of individuals use ADHD medication for over 5 years.³ There is also inadequate information on the cardiovascular risk varies on factors such as type of cardiovascular disease, type of ADHD medication, age, and sex.⁴

Led by Le Zhang, PhD, of the department of medical epidemiology and biostatistics at Karolinska Institute in Stockholm, Sweden, the case-control study assessed the association between long-term use of ADHD medication up to 14 years and the risk of cardiovascular diseases in a Sweden population.¹ The team also examined if the associations differed between ADHD medication type, cardiovascular disease type, sex, and age. The study examined all ADHD medications approved in Sweden during the study period, including stimulants (methylphenidate, amphetamine, dexamphetamine, and lisdexamfetamine) and nonstimulants (atomoxetine and guanfacine).

“The study by Zang… should remind us that clinical decision-making is often based on tricky trade-offs that should be considered at the individual patient level, rather than straightforward one-size-fits-all recommendations,” wrote Samuele Cortese, MD, PhD, and Cristiano Fava, MD, PhD, in an editorial review.5

The investigators drew data from a Swedish nationwide database and collected diagnoses from a National Inpatient Register.1 The database included inpatient diagnoses since 1973 and outpatient diagnoses since 2001. Then, the team received information on prescribed medications from Swedish Prescribed Drug Register. The sample included 278,027 participants aged 6 – 64 years old who received either an ADHD diagnosis or ADHD medication between January 1, 2007 – December 31, 2020. The team excluded participants if they took ADHD medication for conditions other than ADHD and individuals who emigrated, died, or had a history of cardiovascular disease before baseline.

At the follow-up, the team identified who had an incident diagnosis of any cardiovascular disease, such as ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other types of heart disease. The cases in the study were individuals with ADHD who develop cardiovascular diseases during the study, and the controls are the individuals with ADHD who do not develop cardiovascular diseases. The investigators matched the cases and controls by age, sex, and calendar time.

After matching and excluding individuals, the study included 10,388 cases (median age at baseline: 34.6 years old) with over half (59.2%) of the sample being male (n = 6154). Meanwhile, the 51,672 matched controls had a median age at baseline of 34.6 years old and 59.2% were male (n = 30,601).

The median follow-up in both cases and controls was 4.1 (1.9 – 6.8) years. After the follow-up, 3363 of the controls received a cardiovascular diagnosis. The common diagnoses were hypertension (40.5%, n = 4210) and arrhythmias (12.6%, n = 1310).

About the same percentage of participants in cases and controls used ADHD medication during the follow-up (83.9% and 83.5%, respectively). Though, long-term use of ADHD medicine was associated with an increased risk of cardiovascular disease, more than nonuse. The adjusted odds ratio for 0 to < 1 year was 0.99 (95; CI, 0.93 – 1.06); for 1 to < 2 years it was 1.09 (95% CI, 1.01-1.18); for 2 to ≤3 years it was 1.15 (95% CI, 1.05-1.25) for 3 to ≤5 years it was 1.27 (95% CI, 1.17-1.39); and for >5 years it was 1.23 (95% CI, 1.12-1.36).

Moreover, each 1-year increase in the use of ADHD medication was associated with a 4% increased risk of cardiovascular disease (adjusted odds ratio [AOR], 1.04; 95% CI, 1.03 – 1.05), and the risk for medication increase for the first 3 years was 9% (adjusted odds ratio [AOR], 1.08 (95% CI, 1.04 – 1.11).

The findings suggest long-term use of ADHD medication is associated with an increased risk of hypertension (adjusted odds ratio [AOR], 1.72; 95% CI, 1.51-1.97) for 3 to ≤5 years and (adjusted odds ratio [AOR], 1.80; 95% CI 1.55-2.08) for >5 years, as well as arterial disease (adjusted odds ratio [AOR], 1.65; 95% CI, 1.11 – 2.45) for 3 to ≤5 years; (adjusted odds ratio [AOR], 1.49; 95% CI 0.96 – 2.32) for >5 years.

The investigators did not observe statistically significant increased risk for arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease.

Both long-term use of methylphenidate and lisdexamfetamine was associated with an increased risk for cardiovascular disease. As for atomoxetine, it only had a significant increased risk for only the first year of use.

“These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions on long-term ADHD medication use,” investigators wrote. “Clinicians should be vigilant in monitoring patients, particularly among those receiving higher doses, and consistently assess signs and symptoms of [cardiovascular disease] throughout the course of treatment.”

References

1. ^{Zhang L, Li L, Andell P, et al. Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases [published online ahead of print, 2023 Nov 22]. JAMA Psychiatry. 2023;10.1001/jamapsychiatry.2023.4294. doi:10.1001/jamapsychiatry.2023.4294}
2. ^{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. doi:10.1002/14651858.CD009885.pub2}
3. ^{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. doi:10.1177/ 00048674221114782}
4. ^{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 NetwOpen. 2022;5(11):e2243597. doi:10.1001/jamanetworkopen.2022.43597}
5. ^{Cortese S, Fava C. Long-Term Cardiovascular Effects of Medications for Attention-Deficit/Hyperactivity Disorder-Balancing Benefits and Risks of Treatment [published online ahead of print, 2023 Nov 22]. JAMA Psychiatry. 2023;10.1001/jamapsychiatry.2023.4126. doi:10.1001/jamapsychiatry.2023.4126}