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TITLE: Assessment and Treatment of Thyroid Function in
Heart Failure Clinics - Incidence of Abnormal Thyroid
Function and Impact on Heart Failure Decompensation.
AUTHOR NAMES:
Daniel M Shafran* BSc (Hon) 1
Debra L Isaac MD FRCPC 1,2
AUTHOR AFFILIATIONS:
1 Faculty of Medicine, University of Calgary |1403 29th Street NW Calgary, AB
2 Director, Cardiac Transplant, Foothills Medical Center; Clinical Professor, Faculty of Medicine,
University of Calgary |1403 29th Street NW Calgary, AB
…
CORRESPONDING AUTHOR EMAIL ADDRESS: [email protected]
ABSTRACT
BACKGROUND Abnormal thyroid function (TF) is associated with cardiac dysfunction and may
result in decompensation in patients with pre-existing heart failure (HF). International HF
guidelines recommend routine assessment and treatment of TF. It is unclear to what extent TF
is monitored in Canadian clinics, what the incidence of abnormal TF is in HF patients, and how
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TF abnormalities impact outcomes. METHODS Retrospective review was performed for all
patients managed at 3 hospital-based HF clinics in Calgary from November 2010 to January
2011. RESULTS Charts of 773 patients were reviewed. Of these, 719 (93.0%) patients had
some documentation of TFTs; 592 (76.6%) had TFTs in the previous 12 months, and 54 (7.0%)
had no record of TFTs. 21.3% (165) of patients had documented abnormal TF. Of 658 patients
with normal TFTs (treated or not), 30.2% (199) decompensated compared to 41.0% (25) with
abnormal TFTs (P=0.1109). Decompensation rates in patients with normal TFTs versus patients
whose TFTs were abnormal or never measured were 30.2% (199) and 47.8% (55) respectively
(P=0.0003). CONCLUSIONS TF abnormalities are common in Calgary HF Clinic patients. The
rate of HF decompensation is significantly lower in patients with normal TFTs than in those with
unmeasured or abnormal TFTs. Further investigation is required to further evaluate the role of
assessment and treatment of TF in reducing HF decompensation.
KEYWORDS: thyroid, heart failure, decompensation, cardiac function
MANUSCRIPT TEXT
BACKGROUND
Heart failure (HF) is a common problem that affects as many as 2% of the population in the
western world, and carries an incidence of 5-10 people per 1000 each year.1 Recently, the
prevalence of HF was shown to be 0.7% in persons aged 45 to 54 years and 8.4% in patients
aged 75 and older.2 HF currently affects approximately 400,000 Canadians; with an aging
population and improved survival from acute coronary syndromes, both the incidence and
prevalence of HF is expected to rise, with some estimates suggesting it will nearly double by the
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year
2030.3
Additionally, HF imparts a significant economic burden upon the healthcare system.
In British Columbia alone, the cost of managing HF exceeds 90 million dollars annually. 3 Much
of this cost is due to hospitalization. In Canada in 2005/06, there were 54,333 hospitalizations
due to HF.4 As 23.6% of patients who survive primary admission are readmitted within one
year,5 many of these hospitalizations were readmissions.
Multidisciplinary cardiac function clinics are dedicated to improving outcomes in patients with HF
via the use of recent therapies, practice guidelines, patient education, and careful follow-up. A
key element of these clinics is prevention and early intervention of potential precipitants of
decompensation. Incidents of decompensation of HF can be reduced not only through the
proper utilization of evidence-based therapies but also through early follow-up after discharge.6
However, despite these therapies and interventions, acute decompensation can occur for many
reasons. Among these are potentially correctable precipitants, including the presence of thyroid
dysfunction.
The thyroid gland’s influence on the cardiovascular system is well documented. 7 By influencing
heart rate, contractility, and systemic vascular resistance (SVR), the thyroid has a profound
effect on the heart. Consequently, both hyper- and hypothyroidism may adversely impact the
course of HF.
Adding to the potential impact of thyroid dysfunction on HF is the influence of subclinical hyperand hypothyroidism. In these conditions, patients are generally asymptomatic and have normal
levels of T3 and T4 despite abnormally decreased or increased levels of TSH. These subclinical
conditions have significant effects: subclinical hyperthyroidism is associated with an increased
resting heart rate, atrial arrhythmias, and increased left ventricular mass.13 Subclinical
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hypothyroidism (scHypo) has been shown to exert all the same effects of overt hypothyroidism
on the cardiovascular system, albeit to a lesser degree; the reason for this is still unknown.14
Screening for and treatment of thyroid disease may reduce hospital admissions and episodes of
acute decompensation in patients with HF. Indeed, a prospective study recently showed
increased hospitalizations and poorer prognosis in HF patients who developed scHypo.15
Additionally, one recent observational study showed hyperthyroidism is present in nearly 10% of
patients presenting with new-onset atrial fibrillation to the emergency department.16 This
presents another avenue through which the diagnosis and treatment of thyroid disease may
reduce the burden on the healthcare system. Furthermore, it has been shown that even a mildly
altered thyroid status is associated with increased mortality in cardiac patients. 17
Due to the profound effects the thyroid exerts on the heart, The Canadian Cardiovascular
Society, Heart Failure Society of America, and the European Society of Cardiology have all
included in their guidelines the recommendation to assess thyroid function in HF patients. 18,19,20
In a recent trial, however, only 36% of HF patients had thyroid function tests (TFTs) performed
while awaiting implantation of a left ventricular assist device (LVAD).21 Furthermore, only 40% of
HF patients in an American HF clinic had TFTs appropriately assessed, defined as TFT
measurements every 6 months for patients receiving amiodarone, and every 12 months for
patients not receiving amiodarone.22 In this study, we aimed to determine to what extent TFTs
are monitored in Canadian multidisciplinary cardiac function clinics, the incidence of abnormal
thyroid function in HF patients, and how thyroid function abnormalities impact outcomes.
METHODS
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A retrospective chart review of all patients enlisted at the cardiac function clinics at three sites in
Calgary was performed. All data was collected between November 16, 2010 and January 28,
2011. It was recorded whether TFTs were performed within the previous 12 months, earlier than
12 months prior, or if there was an absence of any record of TFTs. For those patients with a
record of TFTs, his/her most recent TFTs were recorded. One of five diagnoses was assigned:
euthyroid, hypothyroid, hyperthyroid, subclinical hypothyroid, or subclinical hyperthyroid. A
euthyroid designation was assigned to patients in whom TSH was within the normal range.
Distinguishing between subclinical or overt hypo- or hyperthyroidism proved more difficult, as
T3/T4 was rarely measured. In these cases, a designation of a subclinical diagnosis was given
to patients with abnormal TSH values and no reported history or symptoms of overt thyroid
disease. In patients with a history of atrial arrhythmia, a diagnosis of overt or subclinical thyroid
dysfunction was dependent on whether the treating clinician felt the arrhythmia was secondary
to thyroid dysfunction (in which case it would be overt) or due to another cause (subclinical).
Whether or not patients were receiving treatment for thyroid disease was noted. Patients
receiving thyroid-altering medication – despite no record of TFTs – were considered to have
thyroid dysfunction, with the presumption that either TFTs were performed prior to the creation
of Alberta’s online lab result database, in a province outside of Alberta, or a clinical diagnosis
was the impetus for initiating therapy. Additionally, the occurrence of any episodes of acute
decompensation in the past 12 months – as defined by non-scheduled hospitalization for a
cardiac-related cause, emergency department visit for a cardiac-related cause, intravenous
diuretics during a clinic appointment, or a doubling of the dose of oral diuretics – were
documented. Any history of amiodarone use was recorded.
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All data was input into spreadsheet software for analysis. Simple counts and division determined
the number and proportion of patients belonging to different categories by diagnosis, time of
most recent TFT, amiodarone use, etc. Data was stratified by clinic site. Patients with thyroid
dysfunction were defined as adequately controlled if they were on thyroid medication and their
latest TFTs were within normal range; inadequately controlled patients were on thyroid
medication and had TFTs outside of normal limits. Fisher’s exact test was used to determine
significance between rates of binary outcomes.
RESULTS
The study included 773 HF patients from three cardiac function clinics. 719 (93.0%) patients
had previous records of TFTs. 592 (76.6%) patients had TFTs performed in the previous 12
months. 127 (16.4%) had their most recent TFTs performed greater than 12 months prior
(Figure 1).
There was, however, variability in the frequency of TFT testing between sites. At Hospital A,
TFT testing in the previous 12 months had occurred in only 69.4% (347 of 500) of patients;
Hospital B tested TFTs in 84.4% (130 of 154) of patients, while Hospital C tested 96.6% (115 of
119) of patients’ TFTs over the same time period. Accordingly, the proportion of patients tested
for thyroid dysfunction greater than 12 months earlier ranged from a high of 22.2% (111) at
Hospital A to a low of 1.7% (2) at Hospital C (Figure 2).
Of the 719 patients with recorded TFTs, 165 (22.9%) had thyroid dysfunction. 7 (4.2%) had
hyperthyroidism, 111 (67.3%) had hypothyroidism, 6 (3.6%) were subclinically hyperthyroid, and
41 (24.8%) were subclinically hypothyroid (Figure 3).
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Among the 165 patients with thyroid dysfunction, adequate control was achieved in 104
(63.0%). 31 (18.8%) were receiving thyroid-altering medication yet were inadequately controlled,
and 30 (18.2%) were not receiving any treatment for their thyroid disease. 8 (4.8%) patients
were receiving thyroid medication despite no record of TFTs.
Approximately one-third (254, or 32.9%) of all patients suffered an acute episode of
decompensation (hospital admission or ED visit for a cardiac-related reason, intravenous
diuretics or doubling of regular diuretic dose) in the preceding 12 months. Of those patients, 211
(83.1%) had TFTs performed in the previous year, 13 (5.1%) had their most recent TFTs
performed greater than 12 months earlier, and 30 (11.8%) patients had no history of TFTs.
As with the frequency of TFT testing, there was also variability between sites in terms of
episodes of decompensation. Hospital A saw a significantly lower proportion (29.0%) of patients
decompensate in the previous year than Hospital C (42.9%) (P<0.005).
608 (78.7%) of all patients did not have any evidence of thyroid disease, of which 192 (31.6%)
decompensated in the past 12 months. In patients with thyroid disease, regardless of presence
or adequacy of treatment, 62 (37.6%) decompensated over the same period of time. This
difference was not statistically significant (P=0.1611).
In those whose thyroid disease was adequately controlled, 37 (35.6%) decompensated. In
those whose thyroid disease was inadequately controlled, 11 (35.5%) decompensated.
Altogether, 48 (35.6%) patients receiving treatment for thyroid disease – whether they were
adequately controlled or not – decompensated. Of those receiving no treatment for their thyroid
disease, 14 (46.7%) decompensated in the previous 12 months. However, the difference
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between number of episodes of acute decompensation between patients receiving and not
receiving treatment was not statistically significant (P=0.2993). The proportion of patients who
suffered an episode of acute decompensation with normal TFTs, either naturally or with
treatment, versus patients whose TFTs were abnormal were 199 (30.2%) and 25 (41.0%)
respectively (P=0.1109).
Almost 1 in 5 patients (141, 18.2%) had a history of use of amiodarone, with 118 (15.3%)
currently taking it. 3 patients (2.1%) who had never taken amiodarone had no record of a thyroid
workup. However, 13 patients (11.0%) currently taking amiodarone had not had TFTs measured
in the previous year. 122 (86.5%) patients with a history of use of amiodarone had TFTs
performed in the previous 12 months while 470 (74.4%) patients with no history of amiodarone
had their TFTs measured in the past year, significantly less than in those with a history of
amiodarone use (P<0.005).
Among patients with a history of amiodarone use, 42.6% (60 of 141) had thyroid dysfunction,
which was significantly more than the 16.6% (105 of 632) of patients who had never used the
drug (P<0.0001).
DISCUSSION
Dedicated cardiac function clinics measured TFTs in 93.0% of all patients, a much higher rate
than the 36% reported in patients awaiting LVAD implantation 21 and 40% in an American heart
failure clinic.22 However, only 76.6% of patients had thyroid workups performed in the previous
year, and at one site, that number dipped as low as 69.4%. What is promising, however, is that
real improvement in the frequency of TFT testing is possible, as one site tested 96.6% of their
patients in the previous 12 months. It is therefore not unreasonable to suggest that annual TFT
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testing in HF patients could approach 100%, especially in patients followed by dedicated cardiac
function clinics.
Contrary to what we expected, the clinic with the best record of TFT testing (96.6% in the
previous year) suffered from the highest proportion of patients experiencing episodes of acute
decompensation (42.9%). The clinic with the worst record of TFT testing (69.4% in the previous
year) had a decompensation rate of 32.9%. Clearly, there exist a multitude of reasons why a HF
patient may decompensate, though the significant difference in rate of decompensation between
the two sites is cause for concern. Since all sites achieved the same levels of adequate control
of thyroid dysfunction, the answer likely lies somewhere beyond the thyroid’s influence. Part of
this result may be artifact, in that patients with increased surveillance allowed for more frequent
diuretic adjustment or hospitalizations. Further investigation into the cause of these
decompensations is warranted.
The overall results from thyroid treatment are more encouraging. 46.7% of patients receiving no
treatment for thyroid disease decompensated, compared to 35.6% of patients receiving thyroid
treatment. While the finding that the reduction of episodes of decompensation with treatment is
not statistically significant, it is a trend that warrants further investigation and a larger sample
size to better assess its validity. Interestingly, there was negligible difference in the rate of
decompensation in patients whose thyroid disease was adequately (35.6%) or inadequately
(35.5%) controlled. This may indicate that even partial correction of thyroid dysfunction imparts
some benefit, and is consistent with others’ findings that decreases in thyroid hormone are
proportional to severity of heart disease.23
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A third (32.9%) of all patients suffered an episode of acute decompensation in the preceding 12
months. The rate of decompensation was higher in patients with thyroid disease (37.6%) than in
euthyroid patients (31.6%), though this difference was not statistically significant. However,
patients with normal TFTs - either naturally or after treatment - decompensated at a significantly
lower rate than patients with abnormal or unmeasured TFTs (30.2% vs. 47.8%, P=0.0003). This
discrepancy cannot be attributed strictly to thyroid dysfunction - unmeasured TFTs may be due
to patients who routinely miss appointments or are noncompliant with their medication,
physicians who are unaware of or choose not to follow guidelines, or other factors. This result
emphasizes the importance of ensuring that adequate testing and appropriate treatment for
thyroid dysfunction and other comorbidities is properly performed.
92.1% of all thyroid disease in the study was either overt or subclinical hypothyroidism. This
finding seems to indicate that both overt and subclinical hypothyroidism are much more
common conditions in heart failure patients than is hyperthyroidism. This may be due to the fact
that a lack of T3 and T4 has more immediate effects on cardiac function, such as increasing both
afterload and diastolic pressure and decreasing cardiac output by up to 50%.7 Conversely, the
effects of hyperthyroidism, such as ventricular hypertrophy, require an extended course of
excess thyroid hormone in order to manifest themselves.7 In light of evidence that increased
levels of TSH are associated with more hospital admissions in patients with HF, 15 these findings
further stress the importance of regular performance of TFTs in HF patients, and illustrate the
prevalence of hypothyroidism in this population. In addition, the prevalence of hypothyroidism in
these patients is cause for one to at least consider the utility of making thyroid replacement
therapy more widespread in HF patients. Trials to this effect are already underway. 24
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The prevalence of thyroid disease in this patient population was notably higher than estimates
for the general population. While one study on the prevalence of thyroid disease found 11.7% of
people in the general public to have thyroid dysfunction 25, 22.9% of HF patients in this study are
either currently receiving treatment for pre-existing thyroid disease or had an abnormal result on
their most recent TFT. This finding is likely due to two main factors: first, the age of HF patients
is generally much higher than that of the general population and the prevalence of thyroid
disease increases with age.25 The lack of demographic data collected here is a significant
limitation of this study. Second, the common use of amiodarone in these patients is also likely to
have contributed to the high rate of thyroid dysfunction.
18.2% of patients had a history of use of amiodarone, and 15.3% of patients were currently
taking the drug. Amiodarone is known to cause thyroid dysfunction, thought to be the result of
the effect of its iodine-containing moiety. 26 Accordingly, 42.6% of patients with a history of use
of amiodarone had thyroid dysfunction, compared to only 16.6% of patients who had never used
the drug. It is therefore important that thyroid-safe alternatives to amiodarone be developed,
especially for use in patients with HF. In the meantime, patients with a history of amiodarone
administration were monitored more carefully for thyroid dysfunction than amiodarone-naïve
patients: 86.5% of patients with a history of amiodarone use had their TFTs measured in the
past year compared to 74.4% of patients with no amiodarone history.
In conclusion, dedicated cardiac function clinics performed TFTs in approximately three-quarters
of patients in the past year, well outperforming the rate of HF patients at other centers.
However, there was significant variability between sites, and it is not an unreasonable goal for
cardiac function clinics to measure annual TFTs in every patient. Subclinical and overt
hypothyroidism was profoundly more prevalent than either form of hyperthyroidism, and thyroid
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dysfunction of all types was twice as prevalent in HF patients as in the general population.
Further investigation with larger sample sizes is necessary to show whether the trends observed
here are significant: the first suggesting that patients with thyroid disease decompensated more
often than euthyroid patients and the second suggesting that patients with adequately or
inadequately controlled thyroid disease decompensated less often than those without treatment.
However, these trends, in addition to the prevalence of hypothyroidism in HF patients, lend
further credence to the possibility that thyroid hormone supplementation may be beneficial in HF
patients. Further investigation is required to determine whether the burden of HF patients on the
healthcare system can be diminished via increased thyroid function testing and treatment.
ACKNOWLEDGMENTS
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
SUPPORTING INFORMATION
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FIGURES AND FIGURE CAPTIONS
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Figure 1: Frequency of timing of most recent assessment of TFTs of 773 HF patients followed
by three cardiac function clinics (A, B, and C).
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Figure 2: Percentage of timing of TFTs of 773 patients performed at three cardiac function
clinics.
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Figure 3: Frequency of various thyroid dysfunction diagnoses amongst HF patients with thyroid
dysfunction.
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