Thyroid function tests before prescribing anti-dementia drugs: a retrospective observational study
Clinical Interventions in Aging
Thyroid function tests before prescribing anti-dementia drugs: a retrospective observational study
Yasuyuki Okumura 0 1
0 Department of Psychiatry and Behavioral science, Tokyo Metropolitan Institute of Medical science , Tokyo , Japan
1 r esearch Department, Institute for health economics and Policy, Association for h ealth economics research and social Insurance and Welfare , Tokyo , Japan
8 1 0 2 - l u J - 2 1 n o 5 0 2 . 7 . 8 6 . 1 5 y b / m o c . s s e r PowerdbyTCPDF(ww.tcpdf.org) Purpose: Treatable causes of cognitive dysfunction, such as hypothyroidism, should be excluded by physicians before prescribing anti-dementia drugs. Many clinical guidelines for dementia recommend a thyroid function test (TFT) as one of the standard screening tests for cognitive dysfunction. This study aimed to investigate the national implementation rate of TFTs during the 365 days before the initiation of anti-dementia drugs. Patients and methods: In this retrospective observational study, using Japan's nationwide claim database, we enrolled $65-year-old patients who were newly prescribed anti-dementia drugs between April 2015 and March 2016. The outcome of this study was the implementation of TFTs in the 365 days prior to the index date. We used demographic data, including age, sex, comorbidities, home-based/institutional care, and provider type, as covariates. Results: We identified 262,279 patients newly prescribed anti-dementia drugs; of these, only 32.6% underwent TFTs before the initiation of anti-dementia drug treatment. Patients treated in dementia care centers were twice as likely to undergo TFTs as those treated in clinics (57% vs 26%; adjusted risk ratio: 2.17; 95% confidence interval: 2.01-2.33). Conclusion: In Japan, patients with dementia often do not undergo TFTs before being prescribed anti-dementia drugs, particularly in a primary care setting. This suggests that the practice of screening treatable cognitive dysfunction should be audited.
cognitive dysfunction; drug treatment; guideline adherence; hypothyroidism
open access to scientific and medical research
The prevalence of dementia has increased globally. Japan has the highest dementia
prevalence among the Organization for Economic Co-operation and Development
countries, with 22.3 persons with dementia per 100,000 individuals in the population,
as compared to the 17.1 persons in the UK and 11.6 persons in the USA.1 This is
because the proportion of individuals aged $65 years relative to the population was
much higher in Japan (27.3%) than in the UK (17.9%) and in the USA (15.2%).1
Physicians are currently prescribing anti-dementia drugs more frequently. However,
before initiating such drug treatment, physicians should exclude other, treatable causes
of cognitive dysfunction, such as hypothyroidism.2
Previous reports have indicated that the prevalence of treatable causes of cognitive
dysfunction was 0%–30% among patients with dementia.3–5 In most cases of
reversible dementia, even adequate treatment cannot result in full recovery from cognitive
dysfunction; however, appropriate treatment is considered to contribute to the partial
reversal of the condition or preventing symptom progression.3 Thus, there is a consensus
Clinical Interventions in Aging 2018:13 1219–1223 1219
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that physicians should identify patients with cognitive
dysfunction due to treatable causes at the initial assessment for
Hypothyroidism is a common treatable cause of cognitive
dysfunction and can be treated by thyroid hormone
replacement therapy. Therefore, many clinical practice guidelines
for dementia recommend a thyroid function test (TFT) as one
8 of the standard screening tests during the initial assessment
-102 of dementia.6–8 Hypothyroidism could be underdiagnosed
-Ju in elderly people since the symptoms of hypothyroidism,
1n2 such as fatigue and cognitive dysfunction, are mostly
nono50 specific in elderly people and are often attributed to the aging
..72 process.9 In a previous study, a retrospective chart review
.168 of patients with cognitive dysfunction in geriatric clinics
yb5 revealed that 2.6% of the patients newly diagnosed with
/om dementia have hypothyroidism.10
.scs Although only two studies have investigated the
adherre ence to the clinical practice guideline for dementia in a few
.vdoepww l.syoeun has been made to assess the nationwide adherence to the
memory clinics and secondary health care sectors, no attempt
:s an guideline recommending TFT prior to initial assessment of
tthp rseo dementia.11,12
Therefore, the present study aimed to examine the
national implementation rate of TFTs before newly
prescribing anti-dementia drugs and to assess the association between
provider adherence and patient characteristics.
Materials and methods
A retrospective observational study was conducted using
the nationwide claims database of Japan, called the National
Database of Health Insurance Claim Information and
Specified Medical Checkups (NDB). The NDB includes all claims
issued electronically from .98% of medical institutions in
Japan and covers 98% of all patients who have received
medical services under Japan’s health insurance system.
The NDB comprises clinical and procedural information,
such as sex, age, patient identification number, institution
identification number, diagnostic codes based on the
International Statistical Classification of Diseases, 10th Revision
(ICD-10), date of laboratory tests, test codes, date of
prescription, and drug codes.13,14
Our study design was reviewed and approved by the
institutional review board at the Institute for Health Economics
and Policy. Informed consent was not required for the present
study, because the database had data that were completely
anonymized of patients’ personal information.
Japan has 34 million inhabitants who are $65 years old and
provides universal health insurance coverage to the entire
population through employee- and community-based
insurance associations.15,16 In Japan, patients are free to choose
clinics and hospitals; thus, patients with cognitive
dysfunction can not only consult primary care physicians but also
specialists, without referral.15 Primary care physicians are not
necessarily required to refer patients with cognitive
dysfunction to specialists for evaluation and can initiate anti-dementia
drug treatment by themselves.
In this study, we enrolled patients aged $65 years who were
newly prescribed anti-dementia drugs between April 2015
and March 2016. The first day of prescription was designated
as the index date. These “newly prescribed” patients were
defined as those who had not been prescribed anti-dementia
drugs for 365 days before the index date. To confirm new
users of anti-dementia drugs and receipts of TFTs, we
identified those who were enrolled in the database at least
365 days before the index date and excluded those who had
a claim reimbursed by bundled payment plans, in which
the status of prescription and laboratory testing were not
recorded within 365 days before the index date. To focus on
patients in whom anti-dementia drugs were initiated shortly
after diagnosis of dementia, we excluded patients with a
definitive diagnosis of dementia (ICD-10 codes F00–03
and G30–G31) in the period between 365 days and 31 days
prior to the index date.
The outcome of the present study was the implementation
of TFTs (tests for thyroid-stimulating hormone as well as
for free thyroxine) within 365 days before the index date.
The medical practice codes for TFTs were 160031710 and
Demographic data, such as age, sex, comorbidities,
homebased/institutional care, and provider type, were used as
covariates. The provider type was classified into three
categories: 1) clinics, 2) hospitals, and 3) dementia centers
certified by municipalities, based on the placement of
specialists. Furthermore, we used the Charlson Comorbidity Index
(0, 1 or 2, 3 or more) for evaluating comorbidities, using the
patients’ ICD-10 diagnostic codes.17
tion for TFTs. Then, we used a Poisson generalized
estimating equation model with the consideration of the correlated
data structure (patients clustered within medical facilities)
to analyze the association between the implementation of
TFTs and each covariate. All covariates were simultaneously
entered into the model. Risk ratios (RRs) and their 95%
confidence intervals (CIs) were computed by the exponential
of the regression coefficient.18 Covariate-adjusted incidence
proportions were also estimated from the model.19 To obtain
crude RRs, we fitted Poisson generalized estimating equation
models stratified by each covariate. All data were analyzed
using R version 3.4.1 (R Foundation for Statistical
Computing, Vienna, Austria).
We identified 262,279 patients who were newly prescribed
anti-dementia drugs in 34,492 medical facilities (Table 1).
First, we calculated the incidence proportion of
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450 with a median of 3 (interquartile range: 1–7). Our study
population predominantly comprised women and outpatients,
and 54% of the patients were treated in clinics, whereas 5.6%
of the patients were treated in dementia centers. TFTs were
performed for 32.6% (95% CI: 32.5–32.8) of the enrolled
patients before their first prescription.
associations between the implementation of TFTs and
covariates. Patients treated in hospitals were 1.5 times more likely
to undergo TFTs than those treated in clinics (38% vs 26%;
aRR: 1.47, 95% CI: 1.41–1.53). Patients treated in
dementia care centers were twice as likely to undergo TFTs as
those treated in clinics (57% vs 26%; aRR: 2.17, 95% CI:
2.01–2.33). Patients aged $85 years were 25% less likely
to undergo TFTs than patients aged 65–69 years (28% vs
39%; aRR: 0.74; 95% CI: 0.72–0.77). Older patients were
less likely to undergo TFTs.
To the best of our knowledge, this is the first study to evaluate
the nationwide implementation rate of TFTs for the initial
assessment of dementia. In Japan, .60% of patients with
dementia did not undergo TFTs during the 365-day period
before being prescribed anti-dementia drugs.
The difference between the implementation rates for
the patients treated in clinics and dementia centers could
be attributed to the expertise of physicians in dementia
centers, since they are better acquainted with the diagnosis
of dementia than the majority of primary care physicians
who examine elderly patients in clinics.20 A previous
study reported that the accuracy of dementia diagnosis by
primary care physicians was not as good as that by geriatric
experts.21 Furthermore, the lack of implementation of TFTs
by physicians in clinics could be related to some reasons other
than inadequate knowledge. Prior research has suggested that
lack of resources and organizational constraints, such as an
insufficient number of staff members, were barriers to the
implementation of clinical guidelines among primary care
physicians.22,23 Further research is warranted to elucidate the
reason for the low implementation rate of TFTs in the primary
.vdoepww l.syoeun rceacreomsemtteinngd.edInteasdtsdistuiocnh, atshebriaminpliemmaegnitnagtiorenmraaitnesoufnoctlheearr
:s an and calls for further investigations.
ttph rsoe In the present study, older patients were less likely
from ropF to undergo TFTs. This may be because physicians often
edd assume that cognitive dysfunction should be caused by
lona primary dementia, such as Alzheimer’s disease, given that
odw the prevalence of primary dementia increases with age.24
ing Another possible explanation is that physicians generally tend
gnA to prioritize avoiding potential harm caused by unnecessary
isn tests and treatments in elderly patients and therefore refrain
iteno from requiring laboratory tests for elderly individuals more
trve than they would for younger patients.
lIna Hypothyroidism is more likely to occur in the elderly
iilcn than in the young and is often less symptomatic in these
C individuals.9 As the study of the Framingham cohort reported
that 4.4% of the unselected population of elderly subjects
(.60 years) had thyroid deficiency, elderly patients with
cognitive dysfunction are more likely to have thyroid
dysfunction than the general elderly population, given that cognitive
dysfunction is one of the symptoms in hypothyroidism.9,25,26
Appropriate thyroid hormone replacement can reverse the
symptoms of hypothyroidism; not only cognitive
dysfunction, but also other symptoms, such as fatigue and muscle
weakness, for which anti-dementia drugs are not indicated.
In contrast, untreated hypothyroidism can progress to severe
state called myxedema. It is impossible to differentiate
hypothyroidism without laboratory tests due to its nonspecific
symptoms. In addition, TFTs can be performed
concurrently with basic blood tests, such as complete blood counts,
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without causing any additional discomfort to patients.
Therefore, thyroid function should be assessed for patients with
dementia even if they do not present the typical symptoms
of hypothyroidism, in accordance with the clinical practice
guidelines for dementia.2,6,7
This study has several limitations. First, our study
population was selected only from patients with dementia
who were treated with anti-dementia drugs. This population
might be more likely to undergo the screening tests for the
dementia work-up than those who have not been prescribed
anti-dementia drugs. Second, because of our study design,
we could not assess the implementation of TFTs .1 year
before the diagnosis of dementia. It is possible that
cognitive function was followed for more than 1 year in some
patients, without a diagnosis of dementia after the dementia
work-up, which could have led to an underestimation of the
implementation rate. Third, we excluded those who had a
claim reimbursed by a bundled payment plan, because of
the insufficient information of the prescription and
laboratory tests. Accordingly, the generalizability of this study
Patients with dementia often do not undergo TFTs before
being prescribed anti-dementia drugs, particularly in a
primary care setting in Japan. The practice of screening
treatable cognitive dysfunction at the time of presentation
should be audited.
This study was supported by grants from the Japan
Agency for Medical Research and Development (No
16dk0207024h0001). The sponsors of this study had no role
in the design and conduct of the study; collection,
management, analysis, or interpretation of the data; preparation,
review, or approval of the manuscript; or the decision to
submit the manuscript for publication. We would like to
express our appreciation to Editage for providing editorial
During the past 3 years, YO received personal fees from
Janssen Pharmaceuticals, Inc., the Medical Technology
Association, and Cando Inc. He has also received research
grants from the Japan Agency for Medical Research and
Development; Ministry of Health, Labor, and Welfare;
Japan Society for the Promotion of Science; Institute for
Health Economics and Policy; and Mental Health and Morita
Therapy. The authors report no other conflicts of interest in
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