I have several posts on this blog about prescribing ADHD
medications with a goal of minimizing adverse psychiatric and medical side
effects. Like all medical treatments,
close follow-up and monitoring is required to assure efficacy while reducing
the risk of adverse effects. To a
trained physician it does not take much effort other than being rigorous in
examinations and discussions with patients. In the area of ADHD, there is the
frequent assumption that patients are young, healthy, and can probably tolerate
medications better than older populations. With the increasing diagnosis of
adult ADHD, all the comorbidities need to be carefully addressed and a
recommendation of no treatment also needs to be considered.
Who have I advised against treatment? Older adults with
obvious cardiovascular problems that are inadequately treated or controlled who
may or may not have ADHD. I do not
really care if you are 60 years old and I think you really have ADHD, I am not
going to start treatment if your blood pressure is not in good control or if
you have other unstable conditions like angina, congestive heart failure,
cardiomyopathy, or arrhythmias.
The commonest reason for not treating people was
hypertension, measured by me in the office.
In some cases, there was an abnormal ECG showing a previously unknown
arrhythmia. It can be difficult to tell a patient that you will not treat them
because of a medical condition – but that is just the way it is. Even if treatment is started – blood pressure
monitoring needs to occur at every visit.
In some cases, I recommend that the patient purchase a home blood
pressure monitor and send me the results.
Referring the patient to their primary care physician or cardiologist is
useful to let that physician know that their patient wants stimulant treatment
and provide feedback on what your assessment of their cardiac status was. It is common for physicians prescribing
adequate does of antihypertensives to not know that their patient is still
hypertensive. It is always clear that the decision to prescribe stimulants is
made by me and does not depend on the opinion of another physician.
White coat hypertension (WCH) is not an exception. WCH is the idea that people get hypertensive
related to the stress of being in physician’s office. Conventional wisdom was that resolved when
the patient left the office and therefore this was a being condition. The
problem with that assessment is that it depends on knowing that the blood pressure
did normalize away from the office. That
lead to a more modern definition that required ambulatory blood pressure
measurements away from the office and subsequent more detailed definitions. As
an example, the European Society of Hypertension recommends the following: subjects with office systolic/diastolic blood
pressure readings of ≥140/90 mm Hg and a 24-hour blood pressure <130/80 mm
Hg.
In the most recent review, the authors do an excellent job
pointing out some of the flaws in the early research that led to no significant
differences between subjects with WCH and controls. The control subjects often had cardiovascular
disease or were treated with antihypertensives.
They also make the distinction between white coat effect (WCE)
and white coat hypertension (WCH). WCE is defined as “an alerting
reaction working through reflex activation of the sympathetic nervous
system.” A standard research technique
to assess stress effects on blood pressure is to ask subjects to do mental
arithmetic and it generally leads to a blood pressure effect like what the
authors describe in this paper of 20 mm systolic or 10 mm diastolic. The authors provide guidance on
differentiating the various combinations of white coat hypertension and
hypertension as well as providing guidance for future research. In the office for the purpose of prescribing
stimulants the key question is whether there is a white coat effect, white coat
hypertension, and whether it occurs in the context of treated or untreated
hypertension. Short of ambulatory blood pressure measurements other sources can
provide some additional guidance. Access
to the electronic health record can show long term trends. If indicated - I would not hesitate to suggest
that the patient consult with their primary care physicians or hypertension
specialist for ambulatory BP measurement.
Studies have shown that patients who continue to exhibit a
reactive blood pressure problem at home have similar cardiovascular risks to
hypertensive individuals. On the flip
side, I have assessed many distressed patients in inpatient settings who were normotensive. Based on this experience, I do not dismiss
elevated blood pressure readings in the office especially if I am going to
prescribe a medication that may elevate blood pressure.
That brings me to the paper that led me to write this post
(1). This is a nested case control study
of registry data in Sweden that looked at 10,388 cases of ADHD and 51,672
matched controls (aged 6-64 years old).
Exclusion criteria included pre-existing cardiovascular disease,
previous use of ADHD medication, and emigration or death before baseline
(defined as day of first ADHD medication or diagnosis – whichever came first). This study design basically looks at the
defined illness (in this case ADHD) and then matches the selected cases to
controls from the same cohort – in this case up to 5 controls without known
cardiovascular disease. The exposure in
this case was ADHD medications including study period, including methylphenidate,
amphetamine] dexamphetamine lisdexamfetamine, atomoxetine, and guanfacine. The last two medications are nonstimulants
and guanfacine has also been used as an antihypertensive medication. The cardiovascular outcomes included:
Ischemic heart disease, cerebrovascular disease, hypertension, heart failure,
arrhythmias, thromboembolic disease, and arterial disease. The statistics of interest were adjusted odds
rations comparing cases to controls. The
authors also did a brief literature review in both the introduction and
discussion sections of the existing literature in this area and what can be
described as mixed results.
Their main finding was that only two cardiovascular conditions
– arterial disease and hypertension were significantly associated with
stimulant medication use but not with atomoxetine or lisdexamfetamine use. Risk also increased at a level of 1.5 DDD
(defined daily doses) of stimulant medication.
Those specific doses except for guanfacine can be found at this
link.
The authors do a good job of interpreting the limitations of
their data including the possibilities of under detection of the true rate of cardiovascular
disease at baseline, the possibility of mediation nonadherence and underestimating
the effects of medication exposure, and confounding by severity could be an
issue through the effect for more severe ADHD on lifestyle factors important in
the genesis of cardiovascular disease (CVD). Finally, since the study
eliminated subjects with existing CVD – stimulant exposure was not measured at
all in that population. The authors advise very cautious treatment and monitoring
of those individuals.
All things considered, this was a good approach to studying the
effects of ADHD medication exposure and the development of cardiovascular disease
on a significant sample. It was a convenience
sample from a pre-existing registry. The
authors point out that some treatment groups were very small and advocated for
a similar study with a larger N. Just
looking at the trends in their tables, there is clearly significant
cardiovascular disease in both the test and control subjects. The odds ratios for medication exposure were
low when they were significant. Few
medical variables were controlled for (obesity, Type 2 diabetes mellitus, dyslipidemia,
and sleep disorders) and of those 3 out of 4 are more common in patient with
ADHD (3). More subtle forms of effects
from ADHD like whether there are affective changes (typically irritability and anger) leading to hypertension or a
white coat effect are unknown currently.
That leads me back to the need for close monitoring for
cardiovascular risk factors and conditions before any medication is considered.
The group with pre-existing cardiovascular disease is at highest risk and they
have not been studied. My speculation is that even using a large health plan
database those numbers (patients with cardiovascular disease started on ADHD
medication) will be small. Any real
world clinical scenario where this is being considered should be approached as
cautiously as possible and monitored the same way.
George Dawson, MD, DFAPA
Photo Credit: Sgt. 1st Class Shane Klestinski, Public domain, via Wikimedia Commons. For full details click on the photo to see Wikimedia Commons page. I chose this photo because several adults that I diagnosed with ADHD told me that they had adapted to work in warehouse management and logistics - in many cases that involved driving fork lifts.
References:
1: Zhang L, Li L, Andell P, Garcia-Argibay M,
Quinn PD, D'Onofrio BM, Brikell I, Kuja-Halkola R, Lichtenstein P, Johnell K,
Larsson H, Chang Z. Attention-Deficit/Hyperactivity Disorder Medications and
Long-Term Risk of Cardiovascular Diseases. JAMA Psychiatry. 2024 Feb
1;81(2):178-187. doi: 10.1001/jamapsychiatry.2023.4294. PMID: 37991787; PMCID:
PMC10851097.
2: Franklin SS, Thijs
L, Hansen TW, O'Brien E, Staessen JA. White-coat hypertension: new insights
from recent studies. Hypertension. 2013 Dec;62(6):982-7. doi:
10.1161/HYPERTENSIONAHA.113.01275. Epub 2013 Sep 16. PMID: 24041952.
3: Chen Q, Hartman
CA, Haavik J, Harro J, Klungsøyr K, Hegvik TA, Wanders R, Ottosen C, Dalsgaard
S, Faraone SV, Larsson H. Common psychiatric and metabolic comorbidity of adult
attention-deficit/hyperactivity disorder: A population-based cross-sectional study.
PLoS One. 2018 Sep 26;13(9):e0204516. doi: 10.1371/journal.pone.0204516. PMID:
30256837; PMCID: PMC6157884.
4: Fuemmeler BF, Østbye T, Yang C, McClernon FJ, Kollins SH. Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study. Int J Obes (Lond). 2011 Jun;35(6):852-62. doi: 10.1038/ijo.2010.214. Epub 2010 Oct 26. PMID: 20975727; PMCID: PMC3391591.
