Long-term risk of cardiovascular side-effects following attention-deficit hyperactivity disorder treatment with sympathomimetic amines
Authors: Holt A , Strange J E , Rasmussen P V , Nouhravesh N , Nielsen S K , Sindet C , Fosboel E L , Koeber L , Torp-Pedersen C , Gislason G , Mcgettigan P , Schou M , Lamberts M 
Published: November 2023

Abstract

Background
In recent years, patients diagnosed with attention-deficit/hyperactivity disorder (ADHD) has risen markedly, and treatment with sympathomimetic amines has proven effective in mitigating symptoms. However, due to sympathomimetic amines’ amplifying effect on heart rate and blood pressure, long-term cardiovascular drug-safety should be scrutinized.

Purpose
We investigated long-term risk of heart failure, acute coronary syndrome, and stroke associated with long-term sympathomimetic amine treatment.

Methods
Using nationwide Danish registers, we identified all patients &gt;18 years of age initiated on sympathomimetic amines (methylphenidate, atomoxetine, lisdexamphetamine, or dexamphetamine) during 1998–2020. Follow-up began one year after patients’ first claimed prescription for patients without known history of heart failure, acute coronary syndrome, or stroke. Exposure was defined according to claimed prescriptions of sympathomimetic amines within 180 days prior to follow-up start and categorized as "discontinued", "low dosage", or "high dosage". Outcomes were heart failure, acute coronary syndrome, stroke, and a composite of all outcomes. We reported standardized 10-year absolute risk (AR) with 95% confidence intervals (CI) and risk ratios (RR) from fitted multivariable cause-specific Cox models with competing risk of death, comparing patients according to their exposure. Similar analyses were conducted at landmarks 1, 2, 3, 4, and 5 years after initial follow-up start where only patients still in treatment at the previous landmark were eligible.

Results
At follow-up start, 27,724 (36%) patients (42% female, median age: 29 [interquartile range (IQR) 23–41]) had discontinued treatment, 37,772 (49%) patients (47% female, median age: 31 [IQR 24–40]) were categorized as low dosage, and 11,924 (15%) patients (45% female, median age: 30 [IQR 23–41]) as high dosage. Comparing high dosage with discontinuation, there was a significant association with elevated 10-year absolute risk of heart failure (RR 1.7 [95% CI 1.2–2.2], numbers needed to harm [NNH]: 188), stroke (RR 1.3 [95% CI 1.0–1.6], NNH: 190), and the composite outcome (RR 1.4 [95% CI 1.1–1.6], NNH: 93), but not with acute coronary syndrome (RR 1.2 [95% CI 0.8–1.5]) (Figure 1). Comparing high dosage with low dosage, RRs of 1.4 (95% CI 1.0–1.9), 1.0 (95% CI 0.7–1.3), 1.2 (95% CI 1.0–1.5), and 1.2 (95% CI 1.1–1.4) were correspondingly found for the association with 10-year absolute risk of heart failure, acute coronary syndrome, stroke, and the composite outcome (Figure 1). Comparing low dosage with discontinuation, no significant associations were found (Figure 1). Landmark analyses yielded comparable results (Figure 2).

Conclusion
Effective and well-indicated treatment for ADHD is key; but a possible association with elevated cardiovascular risk in a young patient group should emphasize the need for risk factor mitigation and shared decision making based on available evidence.Figure 1Figure 2