The treatment of attention-deficit/hyperactivity disorder (ADHD) with increasing dosage of drug treatments could raise long-term cardiovascular risk, according to a new study. The findings, reported in a manuscript published Monday online and in the May 14 issue of the Journal of the American College of Cardiology, once again call into question the long-term safety of drugs used to treat the condition, including methylphenidate, atomoxetine, lisdexamfetamine, dexamfetamine, and modafinil. “In this study, ADHD treatment was found to be associated with increased risk of stroke, heart failure, and MACE [major adverse cardiac events],” said the authors of the paper, led by Anders Holt, MD, PhD, of Copenhagen University Hospital–Herlev and Gentofte, Hellerup, Denmark. “Especially, the incremental risk increases related to increasing dosage is noticeable because ADHD has been associated with cardiovascular risk irrespective of treatment. This could indicate that ADHD treatment use is individually associated with elevated cardiovascular risk.” Results of investigation The study found an elevated standardized 10-year absolute risk of stroke of 2.1% [95% confidence interval [CI]:1.8%-2.4%] vs 1.7% [95% CI:1.5%-1.9%], when comparing ≥1 defined daily dose (DDD) per day with prior users. The elevated standardized 10-year absolute risk of heart failure was 1.2% [95% CI:0.9%-1.4%] vs 0.7% [95% CI:0.6%-0.8%], and the composite outcome was 3.9% [95% CI:3.4%-4.3%] vs 3.0% [95% CI: 2.8 %-3.2%]. These results corresponded with risk ratios of 1.2 [95% CI:1.0-1.5], 1.7 [95% CI:1.3-2.2], and 1.3 [95% CI:1.1-1.5]. The nationwide cohort study also found no apparent associations for acute coronary syndrome (1.0% [95% CI: 0.8%-1.2%] vs 0.9% [95% CI:0.8%-1.0%]. “The discrepancies in concomitant psychopharmaceutical and NSAID [nonsteroid anti-inflammatory drug] treatment are noteworthy because these drugs have also been previously linked to cardiovascular disease,” said the paper’s authors. “This was emphasized by the analyses showing a higher absolute risk of heart failure and stroke in the subgroup of patients concomitantly treated with these drugs.” Growing body of evidence Commenting on the study, editorialists described the findings as, “adding to a growing body of evidence regarding the potential cardiovascular risks of psychostimulants.” Caleb Alexander, MD, MS, and Thomas J. Moore, from the Johns Hopkins Bloomberg School of Public Health in Baltimore, and Eric P. Brass, MD, PhD from the David Geffen School of Medicine, University of California-Los Angeles, added: “[These] risks must be appraised and balanced with the potential benefits of such treatments among some individuals.” Taking a deeper analysis into the study’s findings, the experts noted that among the higher-dose group, the adjusted 10-year risk of a serious cardiac event was 3.9%, compared with 3.0% for the prior-user group. This represented a 0.9% increase in absolute risk and a 1.3 relative risk—a finding that was supported by extensive sensitivity studies. “The modest 0.9% increase in absolute risk may be accounted for by several factors, including a study population (median age 31, 46% female, prior disease excluded) that was at low baseline risk,” the commentators said. “In addition, the authors did not capture a variety of cardiac outcomes (e.g., hypertension, atrial fibrillation, coronary angioplasty) of potential interest and thus may have underestimated the long-term cardiac risks of these products.” Confounding by indication Further points of contention highlighted include the study’s conclusion that noted ADHD had been reported to be associated with increased cardiovascular risk independent of medication. “There is a risk of confounding by indication; higher doses of psychostimulants may be a marker of more severe ADHD or of other conditions or factors that independently increase cardiovascular risk,” the commentators said. They also noted the extensive concomitant use of other psychiatric medications among the individuals examined. “The investigators acknowledge that they inferred a diagnosis of ADHD from the selected medications rather than diagnoses obtained directly from treating physicians,” they wrote. “Similarly, the use of nonsteroidal inflammatory drugs, a class potentially associated with increased cardiovascular events, was more prevalent in the high-dose psychostimulant group. In addition, the statistical analysis did not correct for multiplicity; therefore, the reported 95% CIs should be used cautiously when inferring statistical differences between groups.” Study setup Using nationwide registers, adult patients first-time initiated on ADHD treatment between 1998 and 2020 were identified. Exposure groups were prior users, <1 DDD per day, ≥1 DDD per day determined at start of follow-up, and 1 year after patients’ first claimed prescription. At the start of follow-up, individuals were correspondingly categorized as prior users (n=26,357; 42% female, median age: 30 years [interquartile range [IQR]: 23-41 years]). Baseline characteristics for individuals <1 DDD per day (n=31,211; 47% female, median age: 31 years [IQR: 24-41 years]) and ≥1 DDD per day (n=15,696; 47% female, median age: 33 years [IQR: 25–41 years]). Outcomes were acute coronary syndromes, stroke, heart failure, and a composite of these events. Sources: Holt A, Strange JE, Rasmussen PV, et al. Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. J Am Coll Cardiol. 2024;83:1870-1882. Alexander GC, Moore TJ, Brass EP. Long-Term Cardiovascular Risks of Psychostimulant Drugs for Treatment of Attention-Deficit/ Hyperactivity Disorder (ADHD). J Am Coll Cardiol. 2024;83:1883-1885. Image Credit: BillionPhotos.com – stock.adobe.com