Download Clinical Implications of Abnormal Thyroid Function in Heart

JACC: Heart Failure
Ó 2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Clinical Implications of
Abnormal Thyroid Function
in Heart Failure*
Steven Goldman, MD,y Stephen Thomson, MD,z
Madeline McCarren, PHD, MPHx
Tucson, Arizona; and Hines, Illinois
We read with interest the excellent report by Mitchell et al. (1)
in this issue of JACC: Heart Failure. In brief, the investigators
conducted a subset analysis of the SCD-HeFT (Sudden
Cardiac Death in Heart Failure) trial that was originally
published in 2005. They looked at the subset of patients with
evidence of thyroid hormone dysfunction at the beginning of
the trial and those who developed evidence of thyroid
hormone dysfunction during the trial. The investigators
found that evidence of abnormal thyroid function in patients
with heart failure portends a poor prognosis and is associated
with increased mortality. The study is based on clinical trial
data, with a protocol for follow-up measures that should
minimize bias. Various subgroup analyses were conducted
that, if sufficiently powered, raise the question of whether the
thyroid abnormalities have a causal relationship to mortality.
See page 48
For instance, patients treated for hypothyroidism were found
to have risk that was apparently not significantly different
from those untreated. Furthermore, the increased mortality
risk was reported to be similar for hyperthyroidism and
hypothyroidism. Might the thyroid test abnormalities be
only a marker for an underlying condition that is the actual
causal factor for increased mortality? Unfortunately, the
investigators present only p values, not confidence intervals,
which would have assisted with interpretation as to whether
there was a nonsignificant trend and its direction.
An important aspect of this report is that treatment
with an implantable cardioverter-defibrillator (ICD) was not
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not
necessarily represent the views of JACC: Heart Failure or the American College of
Cardiology.
From the yDepartment of Cardiology, Southern Arizona VA Medical Center,
University of Arizona, Tucson, Arizona; zDepartment of Endocrinology, Southern
Arizona VA Medical Center, University of Arizona, Tucson, Arizona; and the
xPharmacy Benefits Management Services, Department of Veterans Affairs, Hines,
Illinois. The authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
Vol. 1, No. 1, 2013
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2012.11.004
associated with more benefit in patients with abnormal
thyroid function data. If ventricular arrhythmias are the main
reason that thyroid abnormalities are associated with increased
mortality, then ICD use has the potential to decrease mortality
associated with thyroid abnormalities. Because ICD use did
not improve mortality in those with thyroid abnormalities over
those without thyroid abnormalities, ventricular arrhythmias
may not be the main mechanism for thyroid abnormality–
associated increased mortality. However, further benefit may
not have been detected, because the analysis of the thyroid
abnormality subgroup within the ICD subgroup may not have
had enough power to exclude benefit.
The issue of whether we should aggressively treat low
triiodothyronine or mild thyroid abnormalities in patients
with heart failure has not been settled. As pointed out by
Mitchell et al. (1), the associations among abnormal thyroid
function, hypothyroidism, and increased mortality in heart
failure have been known for years. Although only thyroidstimulating hormone (TSH) was measured in this study,
as noted, low triiodothyronine is common in patients with
heart failure. Through the years, investigators have tried to
treat patients with heart failure using supplemental thyroid
hormone replacement, with disappointing results. Although
one can achieve beneficial therapeutic effects in the short
term, longer treatment results in manifestation of the
systemic effects of thyroid hormone (2,3). This has led us
and other investigators to develop thyroid hormone
analogues to treat heart failure. Unfortunately, in the only
randomized multicenter trial of the use of a thyroid hormone
analogue, we showed that although left ventricular function
improved, the side effects were such that the analogue was
poorly tolerated (4).
Clinicians should still look for and treat classic thyroid
disease in patients with heart failure. Furthermore, many
clinicians favor treatment of subclinical thyroid disease,
especially in “severe” subclinical disease (5). The present
findings of increased risk for mortality and a high prevalence of thyroid abnormalities with the use of amiodarone
can be combined with other findings of increased adverse
outcomes associated with thyroid abnormalities to influence the diagnosis and treatment of thyroid disease. They
are also consistent with the current emphasis on case
finding with TSH and free thyroxine (FT4) for the diagnosis of thyroid disease rather than universal screening.
Clinicians should continue to measure TSH and FT4 in
patients with symptoms compatible with thyroid disease,
such as fatigue, weight changes, tachycardia, bradycardia,
and fluid retention, symptoms often found in those with
heart failure. They should also be measured in patients at
increased risk for thyroid abnormalities, including those
using amiodarone, and in those with illnesses that may not
tolerate thyroid abnormalities, including those with heart
failure.
These findings also support strict maintenance of normal
TSH as a goal of therapy for classic thyroid disease, because
TSH values outside the reference range may confer risk for
JACC: Heart Failure Vol. 1, No. 1, 2013
February 2013:56–7
several poor outcomes, including mortality. Thus, for those
with classic hyperthyroidism, TSH <0.1 mU/l and elevated
FT4, and for those with classic hypothyroidism, TSH
>10 mU/l and decreased FT4, should have normal TSH as
the treatment goal.
Treatment of patients with subclinical thyroid disease,
typically defined as an abnormal TSH level and concurrent
FT4 in the normal range, is controversial. The controversy
stems from the lack of randomized controlled trial data
showing efficacy for the treatment of subclinical thyroid
disease. However, many clinicians treat “severe” subclinical
thyroid disease. For example, patients with normal FT4 and
TSH >10 mU/l and symptoms compatible with hypothyroidism often are considered to have “severe” subclinical
hypothyroidism and are treated. Patients with TSH higher
than the upper limit of normal, typically >5 but <10 mU/l,
have “mild” subclinical hypothyroidism and are less likely to
be treated. Likewise, those with TSH <0.1 mU/l and
normal FT4 (“severe” subclinical hyperthyroidism) are more
likely to be treated than those with “mild” subclinical
hyperthyroidism, with TSH >0.1 mU/l but less than the
lower limit of normal, often 0.4 mU/l. Those in favor of
treating patients with subclinical thyroid disease despite the
lack of randomized controlled trial data cite the association
of untreated disease with an increase in serious outcomes,
the low cost of therapy, the ability to monitor TSH to guide
therapy, and a low likelihood of serious side effects of therapy. Thus, many clinicians will diagnose and treat subclinical
thyroid disease, including patients with heart failure. Others
will note the present post hoc analysis, consider it hypothesis
generating rather than demonstrating causality, and wait to
Goldman et al.
Editorial Comment
57
treat “mild” subclinical thyroid disease until randomized
controlled trials demonstrate efficacy.
Treatment of subclinical thyroid disease in those taking
amiodarone deserves special consideration. Because amiodarone can block the effects of thyroid hormone, some
patients develop mild increases in TSH, usually <10 mU/l,
and mild increases in FT4. These increases may compensate
for the blocking effects of amiodarone and may be required
to maintain normal tissue activity of thyroid hormone. Thus,
most clinicians will not treat mild elevations in TSH or FT4
in patients taking amiodarone.
Reprint requests and correspondence: Dr. Steven Goldman,
Tucson VA Hospital, Cardiology 111C, Cardiology Division, S.
Sixth Avenue, 111C, Tucson, Arizona 85723-0001. E-mail:
[email protected].
REFERENCES
1. Mitchell JE, Helkamp AS, Mark DB, et al. Thyroid function in heart
failure and impact on mortality. J Am Coll Cardiol HF 2013;1:48–55.
2. Moruzzi P, Doria E, Agostoni PG, Capacchione V, Sganzerla P.
Usefulness of L-thyroxine to improve cardiac and exercise performance
in idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73:374–8.
3. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V.
Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology 1996;87:509–15.
4. Goldman S, McCarren M, Morkin E, et al. DITPA, a thyroid hormone
analog to treat heart failure: phase II trial VA Cooperative Study.
Circulation 2009;119:3093–100.
5. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379:
1142–54.
Key Words: amiodarone
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heart failure
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ICD
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thyroid disease.