ADHD medications and cardiovasc effects

 A recent large retrospective case-control study found that long-term exposure to ADHD medications was associated with an increased risk of hypertension and arterial disease (see ADHD meds inc CVD risk JAMAPsych2024 in dropbox, or doi:10.1001/jamapsychiatry.2023.4294)

 

Details:

-- 278,027 individuals aged 6 to 64 years old with an diagnosis of incident ADHD were identified and 10,388 also had cardiovascular disease (CVD), from 2007 and 2021

    -- data on ADHD and CVD diagnoses were obtained from the Swedish National Inpatient Register and data on ADHD medications dispensed were from the Swedish Prescribed Drug Register

    -- cases selected included individuals with ADHD and an incident CVD diagnosis (ischemic heart disease, cerebrovascular disease, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease)

    -- these 10,388 individuals with ADHD and CVD were matched with 51,672 controls without CVD (they were matched based on age, sex, and calendar time), all with the same duration of follow-up of up to 14 years (median follow-up time 4.1 years)

-- median age 45, 41% female, 92% born in Sweden, 70% had primary or secondary education

-- psychiatric comorbidities: anxiety disorders 34%, autism spectrum disorders 8%, bipolar 8%, depression 32%, eating disorders 4%,  personality disorders 14%, schizophrenia 5%, substance use disorders 32%

-- comorbidities: obesity 7%, sleep disorders 6%, type II diabetes 3%

 

-- Primary outcome: incident CVD diagnoses (as per above), and assessment of the association between CVD diagnoses and cumulative duration of ADHD medications

 

Results:

-- meds prescribed: 84% on methylphenidate, the rest largely on atomoxetine (non-stimulating med) and lisdexamfetamine (a prodrug converted into d-amphetamine and renally excreted)

    -- adderall, by comparison, is a combo of amphetamine plus dextroamphetamine and is widely used in the US

-- incidence of CVD: 7.34 per 1000 person-years

-- most common types of CVD:

    -- hypertension 41% (no definition of blood pressure cutoff for this diagnosis)

    -- arrhythmias 13% (not further defined in paper or supplement)

-- cumulative duration of ADHD medication use, comparing their risk of CVD versus the risk in those not taking ADHD medications:

    -- 0-1 year: adjusted odds ratio 0.99 (0.93-1.06), not statistically significant

    -- 1-2 years: aOR 9% increased risk, 1.09 (1.01-1.18)

    -- 2-3 years: 15% increased risk, aOR 1.15 (1.05-1.25)

    -- 3-5 years: 27% increased risk, aOR 1.27 (1.17-1.39)

    -- >5 years: 49% increased risk, aOR 1.49 (0.96-2.32), very close to being statistically significant

 

 

-- summary evaluation: across the 14 year follow-up, each one year increase in ADHD medicines was associated with a 4% increased risk of CVD, aOR 1.04 (1.03-1.05)

    -- this increase was more profound in the first three years of cumulative use: 8% increased, aOR 1.08 (1.04-1.11), then become more stable for the remaining follow-up years (see graph above)

 

-- specific cardiovascular associations with the meds (the following were the only findings that reached statistical significance):
    --hypertension:

        -- 1-2 years of meds: 34% increase, aOR 1.34 ( 1.18-1.52)

        -- 2-3 years of meds: 30% increase, aOR 1.30 (1.12-1.50)

        -- 3-5 years of meds: 72% increase, aOR 1.72 (1.51-1.97)

        -- >5 years: 80% increase, aOR 1.80 (1.55-2.08)

    -- arterial disease (also not defined specifically in the article):

        -- 0-1 year of meds: 42% increase, aOR 1.42 (1.04-1.93)

        -- 1-2 years of meds: 63% increase, aOR 1.63 ( 1.15-2.32)

        -- 2-3 years of meds: 72% increase, aOR 1.72 (1.17-2.53)

        -- 3-5 years of meds: 65% increase, aOR 1.65 (1.11-2.45)

 

    -- average DDD (defined daily dose), a measure of the average amount of the meds taken each day. For example, 1 DDD for methylphenidate=30mg; 1 DDD for atomoxetine=80mg.

        -- aOR for 1.0-1.5 DDD 1.01 (0.99-1.03), not significant

        -- aOR for 1.5-2.0 DDD 1.04 (1.02-1.05), statistically significant

        -- aOR for >2.0 DDD 1.05 (1.03-1.06), statistically significant

        -- ie, the cardiovasc events increased with higher average DDDs, becoming statistically significant with a mean dose of at least 1.5 times the average DDD

 

-- Breakdown of cardiovasc risk by medications (only statistically significant risks below):

    -- methylphenidate:

        -- 1-2 years: 8% increase, adjusted OR 1.08 (1.00-1.16)

        -- 2-3 years: 10% increase, aOR 1.10 (1.01-1.20)

        -- 3-5 years: 20% increase, aOR 1.20 (1.10-1.31)

        -- >5 years: 19% increase, aOR 1.19 (1.08-1.31)

    -- atomoxetine:

       -- 0-1 year: 7% increase, aOR 1.07 (1.01-1.13)

    --lisdexamphetamine:

        -- 0-1 year: 13% increase, adjusted OR 1.13 (1.05-1.21)

        -- 2-3 years: 23% increase, aOR 1.23 (1.05-1.44)

 

-- similar associations for males and females, as well as in those <25yo and those >25yo

-- increasing cardiovasc risk as the length of time on the meds increased:  those on meds >5yrs had the most events; those on meds 3-5 years somewhat less; and those taking meds 0 to 1 year the least

-- adding cardiovascular deaths to the primary outcome had similar results

-- propensity scoring to equalize the subgroups statistically resulted in similar results (the above “adjusted” HR or OR was adjusted only for age, sex, and calendar time)

 

Commentary:

-- prior longitudinal observational studies have had mixed results for the association between ADHD medications and cardiovascular effects, though they had short follow-up times overall (mostly <2 years)

-- studies have found that both stimulant and non-stimulant ADHD medications are associated with increased cardiovascular risk

    -- a metanalysis/systematic review found that both stimulants and the non-stimulant atomoxetine are associated with increased blood pressure: https://www.sciencedirect.com/science/article/pii/S2215036618302694?via%3Dihub

    -- one issue with the ADHD studies is that it seems that ADHD by itself is associated with a 2-fold risk of incident cardiovascular disease, independent of taking meds for ADHD: https://onlinelibrary.wiley.com/doi/10.1002/wps.21020 , though these increases tracked largely with the psych comorbidities associated with ADHD (and about 80% of those with ADHD have depression and other mood disorders, substance use disorders, anxiety, personality disorders, and/or bipolar disease; all of these psych issues themselves are associated with increased morbidity/mortality by themselves)

    -- this study was designed with these concerns in mind, finding:

        -- an increase in cardiovasc events as both with the length of ADHD med consumption and with the average daily dose taken

        -- the association with increased cardiovascular outcomes was found for both children as well as adults, and for males and females

        -- the increased cardiovascular outcomes were limited to hypertension and arterial disease, and was largely limited to stimulant medications. atomoxetine had limited increase, and was statistically confined to those in the first year of use; however, it is important to realize that only a small number of people were on atomoxetine (only 271 people took it for 1 to 2 years and under 150 people took it for longer, limiting the statistical power to associate the atomoxetine with adverse cardiovasc effects)

        -- the increased risk found in the study was most significant in the first three years; the increased risk then stabilized and persisted throughout the 14 year follow-up.

-- to put this pharmacologic approach in perspective:

    -- there is evident benefit from some non-pharmacologic interventions, sometimes without meds and sometimes as an adjunct to the meds, such as cognitive behavioral therapy for adults, or behavioral  therapies in children delivered consistently by parents and teachers to teach children how to control their symptoms

    -- several studies and a recent meta-analysis found that omega-3 polyunsaturated fatty acids as well as regular exercise have been associated with significant improvement in inattention, hyperactivity, and total ADHD symptoms: see https://pubmed.ncbi.nlm.nih.gov/35305344/  for studies on exercise, and https://www.sciencedirect.com/science/article/pii/S0735109720357417?via%3Dihub for a systematic review of exercise and omega-3 fatty acids

 

Limitations:

-- this study took place in Sweden, limiting the generalizability to other areas with different populations (Sweden is 83% white European or Scandinavian), different stressors, different parenting, different diet and levels of  exercise, different diagnostic thresholds to defining ADHD, etc

-- the vast majority of people were on methylphenidate, limiting the statistical power to evaluate the other medications. In particular, the only non-stimulating medication assessed, atomoxetine, was used by a small number of individuals; this was also true for use of lisdexamphetamine (this article did not give explicit numbers of patients on these medications, but 84% were on methylphenidate). Therefore the results of the study may not be generalizable to non-methylphenidate medications.

    -- Other research studies have suggested increased blood pressure and heart rate with all of the meds in this study (methylphenidate, lisdexamfetamine and atomoxetine); this observation narrows the legitimacy of the definition of stimulating versus non-stimulating medications, though atomoxetine takes much longer to have clear effects and lasts longer in the body

-- there were no definitions of what constituted arterial disease, what the level of blood pressure was qualifying as hypertension (or how blood pressure was checked) or what arrhythmias were found, either in the report or the supplemental materials

-- in terms of the outcomes that they did measure, it is clear that hypertension is a major risk factor for atherosclerotic risk as well as the myriad of other effects on the kidneys, brain (including cognition), vision, erectile function, etc;  many of these hypertension effects result in long-term multi-organ dysfunction and morbidity/mortality

-- also, in terms of arrhythmias, it seems the only ones measured were those that were clinically evident and detected in a healthcare setting. This may result in a major undercounting of the arrhythmias that might be associated with these medications. And a small number of serious arrhythmias may not be large enough to reach statistical significance within this sample. So, it is hard to conclude that arrhythmias are not a significant problem, as was found in this study. For example, it has been shown there is about a 6 bpm increase with stimulants (amphetamines increase catecholamine sensitivity in the brain and also act peripherally; catecholamines play a role in development of severe and potentially fatal cardiac arrhythmias). It is also possible that some of these patients on ADHD medications may be receiving beta blockers or other medications that could attenuate the association with arrhythmias (no data in this study on any other meds taken, and very few comorbidities were assessed)

-- even the definition of CVD was limited to those who entered the medical system and having documentation of CVD as an issue. Many people have undiagnosed CVD, so this would also limit the generalizability of the study’s results to the overall population at risk

--this was an observational study and there may well be confounding variables (e.g. other medications, or lifestyle and other medical factors that could affect both ADHD medication use and the development of cardiovascular events) that were not assessed (and, per above, many of those that were assessed were not well categorized), limiting our ability to attribute causality, and only to be able to assess a potential association.

    -- for a review of many of the known cardiovascular risk factors, see https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html

 

So, despite the limitations of this study, it seems quite likely that methylphenidate is associated with potentially serious cardiac effects in a dose-dependent fashion. And the long-term effects of increases in hypertension and the perhaps shorter-term effects on arrhythmias might well be associated with significant adverse consequences. It also seems that non-stimulants such as atomoxetine may also confer these adverse effects, which leads to several actionable conclusions:

-- there are viable alternatives to meds for ADHD, including behavioral and psychotherapeutic interventions, and perhaps exercise and omega-3 fatty acids. And these should be an important part of ADHD therapy and may even avoid the need for medications

-- when meds are needed, the lowest dose and shortest interval are likely better (I have several patients who take these meds only quite intermittently)

-- it makes sense to periodically try to decrease med dosing to attain the lowest effective dose

-- it would be useful to have an actual randomized controlled study assessing several medications for ADHD vs nonpharmacologic approaches vs the combination of the two (hopefully leading to lower med doses) to assess cardiovasc and other outcomes (and since ADHD seems to have its own association with adverse cardiovasc effects, there should also be a non-ADHD control group as well)

-- and all of this has become more urgent as more kids and adults are identified with ADHD, and the adults may have already been on meds as kids, conferring a major increase in cumulative med doses.

    --and adults typically require higher doses

 

geoff

-----------------------------------

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@bidmc.harvard.edu

  

to get access to all of the blogs:

 

 go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

  -- click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

  -- or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them

 

if you would like to see the articles in this blog, please email me. 

 

please feel free to circulate this to others. also, if you send me their emails (gmodest@bidmc.harvard.edu), i can add them to the list