Thyrotoxic Atrial Fibrillation

Malvinder S. Parmar, MD, FRCPC, FACP, Associate Professor; Assistant Professor

(VPT); Medical Director
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Abstract and Introduction

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Atrial Fibrillation and Hyperthyroidism

What Is the Incidence of Atrial Fibrillation in Thyrotoxicosis?
Atrial fibrillation is the most common cardiac complication of hyperthyroidism. It
occurs in up to 15% of hyperthyroid patients[1] compared with .4% in the general
population[2] and is more common in men and in patients with triiodothyronine (T 3)
toxicosis,[3] and its incidence increases with advancing age. Although it is rare in
patients under 40 years of age, 25% to 40% of hyperthyroid individuals over the age
of 60 experience atrial fibrillation, possibly reflecting an age-related reduction in
threshold for acquiring atrial fibrillation.[4] In addition, subclinical hyperthyroidism is
a risk factor that is associated with a 3-fold increase in risk of developing atrial
fibrillation,[5] and up to13% of patients with unexplained atrial fibrillation have
biochemical evidence of hyperthyroidism.[6]
What Is the Frequency of Hyperthyroidism in Patients Presenting With Atrial
Fibrillation?
In a large study[7] of patients with new-onset atrial fibrillation, less than 1% were
caused by overt hyperthyroidism. Therefore, although serum TSH is measured in all
patients with new-onset atrial fibrillation to rule out thyroid disease, this association is
uncommon in the absence of additional symptoms and signs of hyperthyroidism.[7]
Management
Rate control

The first step in the management of atrial fibrillation, despite the cause, is to control
the ventricular response.

Which Agent Should Be Used?

The choice of an agent for rate control depends on the coexisting medical conditions.
Beta-adrenergic blockers, calcium channel blockers, and digoxin are effective agents
that can be used for rate control.
Beta-Adrenergic Blockers

Beta-adrenergic blocking agents are effective in controlling the ventricular rate and
are the drugs of choice[8] in the absence of decompensated congestive heart failure.
These agents also help alleviate the beta-receptor-mediated symptoms, such as anxiety
and tremulousness. The patient requires cardiac and noninvasive arterial pressure
monitoring because of the potential risks of hypotension, worsening of heart failure,
or bradycardia. Higher-than-usual doses of these agents are often required because of
increased plasma clearance in hyperthyroidism.[9] The use of beta-blockers should be
carefully considered in patients with mild heart failure because of the risk of
exacerbation.
Which beta-blocker?

Of the beta-blockers, propranolol has the advantage of reducing the peripheral

conversion of T4 to T3; however, this effect is of minor therapeutic value, and other
cardioselective agents with longer half-lives are equally effective.[10] A short-acting
agent, such as esmolol,[11] can be tried under cardiac rhythm and invasive arterial
pressure monitoring in patients with associated heart failure to determine its
tolerability.
Calcium channel blockers

Oral calcium channel blockers, such as diltiazem or verapamil, can be useful for longterm control of ventricular rate12 in patients in whom beta-adrenergic blockade is
contraindicated, but these agents may also have negative inotropic effects. Intravenous
calcium channel blockers may be considered in which beta-blockers are
contraindicated but should be used cautiously, as these may cause severe
hypotension[13] and a further reduction in systemic vascular resistance that is already
low in patients with thyrotoxicosis.
Digoxin

Digoxin may be considered for rate control in patients with heart failure in whom
beta-blockers or calcium channel blockers may not be suitable. However,
hyperthyroid atrial fibrillation is typically resistant to digoxin that is caused in part by
an increase in the renal clearance and apparent volume of its distribution[14] as well

as increased sympathetic and reduced vagal tone. A larger-than-usual dose of digoxin

is required,[9] which increases the risk of its toxicity. Despite these limitations,
digoxin should still be considered in patients with heart failure and concomitant
thyrotoxic atrial fibrillation.
Could Amiodarone Be Used in Patients With Thyrotoxic Atrial Fibrillation?
Amiodarone is a lipid-soluble, iodine-rich antiarrhythmic drug with proven benefit in
the treatment of patients with symptomatic ventricular and atrial arrhythmias. It
inhibits the conversion of T4 to T3 in most tissues.[15] Because of its high iodine
content, it also inhibits thyroid hormone synthesis and secretion as well as reduced
binding of T3 to its nuclear receptors.[16] This inhibition of T3 production results in a
more rapid resolution of symptoms than classic blockers of T 4 synthesis and release.
Amiodarone may cause thyroid dysfunction in patients with preexisting thyroid
disease and destructive thyroiditis in patients with normal thyroid glands. The
combined incidence of hyper- and hypothyroidism in patients taking amiodarone is
14% to 18%, and because of its extraordinarily long half-life, either problem may
occur several months after stopping the drug. An antithyroid drug given
simultaneously blocks iodine organification and prevents iodide-induced exacerbation
of thyrotoxicosis.[17] Hence, the thyrotoxicosis-induced effect of amiodarone should
not preclude its use in thyrotoxic atrial fibrillation,[18] provided that it is given in
conjunction with antithyroid agents. However, amiodarone being an antiarrhythmic
agent may convert atrial fibrillation to sinus rhythm. In a patient who presented with
atrial fibrillation of unknown duration, early conversion of atrial fibrillation may not
be desirable because of its potential thromboembolic complications. Nevertheless,
occasionally we may have no other alternative and it should be used only if other
treatments fail.
What Is the Risk of Thromboembolism?
Studies examining the risk of embolism in thyrotoxic atrial fibrillation[19,20] are
limited but suggest that the rate of embolism in thyrotoxic atrial fibrillation exceeds
that for nonthyrotoxic atrial fibrillation not associated with rheumatic heart disease.
[20] Of note, the majority of clinically evident emboli in thyrotoxic atrial fibrillation
involve the central nervous system and occur early in the course of the disease;
[20] however, a retrospective analysis of 610 patients did not find a statistically
significant difference when patients with atrial fibrillation were compared with ageand sex-matched patients.[21]
The available studies have not unequivocally confirmed that thyrotoxic atrial
fibrillation is a more potent risk factor for stroke.[4] Several independent clinical and
echocardiographic predictors of increased risk of thromboembolism in patients with

nonrheumatic atrial fibrillation are age, history of heart failure, history of

hypertension or diabetes mellitus, previous thromboembolism, left atrial enlargement,
and global left ventricular dysfunction.[22,23] These validated risk factors should be
used to identify those patients who are at risk and are most likely to benefit from
anticoagulation.
Who Should Be Anticoagulated?
The decision to treat these patients with short- or long-term anticoagulation should be
made on an individual basis, taking into consideration age, associated heart disease,
and risks of such therapy. Two recent systematic reviews[24,25] about the efficacy of
long-term anticoagulation or antiplatelet therapy in patients with nonrheumatic atrial
fibrillation came to diametrically opposing conclusions, and another
review[26] recommends aspirin over anticoagulants in patients with nonvalvular atrial
fibrillation. However, the 7th American College of Chest Physicians (ACCP)
Conference[27] on antithrombotic therapy in atrial fibrillation recommends that
antithrombotic therapy should be chosen on the basis of the presence of validated
stroke risk factors, irrespective of the presence or absence of thyrotoxicosis.
In younger patients with thyrotoxic atrial fibrillation who do not have underlying heart
disease, hypertension, or independent risk factors for embolization, the risks of
anticoagulant therapy probably outweigh the benefits. Conversely, in older patients
who are known or suspected to have heart disease or in those with chronic atrial
fibrillation, anticoagulant therapy should be initiated. The recommended loading dose
of warfarin is similar to euthyroid patients, but a lower maintenance dose is required
because of accelerated clearance of vitamin K-dependent clotting factors.[9] If not
contraindicated, aspirin should be used in those not anticoagulated.
When Should Cardioversion Be Considered?
Attempts at cardioversion should not be made before restoration of the euthyroid state
because maintenance of sinus rhythm is unlikely as long as the patient remains
hyperthyroid.[28] Once the euthyroid state is achieved with treatment of
hyperthyroidism, spontaneous reversion to sinus rhythm occurs in nearly two thirds of
patients within 810 weeks, but only few revert spontaneously to sinus rhythm
beyond 3 months.[28] In addition to the duration of atrial fibrillation, factors that
influence spontaneous reversion to sinus rhythm are age, the presence of underlying
heart disease, and left atrial size. In the absence of spontaneous reversion to sinus
rhythm within this time period, electrical or pharmacologic cardioversion should be
attempted only after the patient has been rendered euthyroid and has been optimally
anticoagulated for at least 3 weeks, and the anticoagulation should be continued for at
least 4 weeks after successful cardioversion.[27]Antiarrhythmic agents of class I (IA

qunidine and procainamide; IC flecanide and propafenone) or class III (amiodarone,

dofetilide, or ibutilide) may be considered for pharmacologic cardioversion, and
continuous electrocardiographic monitoring for the first 4872 hours after initiating
therapy should be considered.
How Should Hyperthyroidism Be Controlled?
The prompt alleviation of thyrotoxicosis, the mainstay of the management of
thyrotoxic atrial fibrillation, is best accomplished in 2 steps: antithyroid drug therapy
followed by thyroid ablation with radioactive iodine. A thyroid specialist should be
involved in the definitive management of such patients. Ablation is indicated in these
patients because of the risk of recurrence, as is common among patients receiving
long-term antithyroid drug therapy. There should be noticeable clinical improvement
within 1014 days, and most patients will be biochemically euthyroid within 46
weeks of starting antithyroid drug therapy. Treatment should be initiated with an
antithyroid drug,[13] either methimazole or propylthiouracil, because drug therapy
results in more rapid reductions in serum T 4 and T3 concentrations than radioactive
iodine therapy. Propylthiouracil also inhibits the peripheral conversion of T 4 to T3.
Because these agents inhibit the synthesis of T 4 and T3, they deplete the stores of these
2 hormones, thereby forestalling the exacerbation of thyrotoxicosis that can result
from radiation thyroiditis after a therapeutic dose of radioactive iodine. The
antithyroid drug should be given for 48 weeks and then withdrawn 35 days before a
therapeutic dose of radioactive iodine is given. These agents may be reinstituted 1
week later to provide control until the therapeutic effect of radioactive iodine occurs.
Thyrotoxicosis can be alleviated even more rapidly by the administration of inorganic
iodine that abruptly inhibits[29] the secretion of T4 and T3. At least 1 dose of an
antithyroid agent should be given first to prevent new hormone stores from
incorporating iodide. Inorganic iodine therapy should be considered[13] and given for
35 days in patients in whom rapid control of the hyperthyroid state is important, such
as in patients with severe congestive heart failure or unstable angina.
What Is the Prognosis?
Hyperthyroidism is associated with an increase in cardiovascular and cerebrovascular
mortality, and in a large study, the standardized mortality ratio was 1.8:1 (95%
confidence interval 1.6-L2:1) in the year following radioablative therapy.[30] Atrial
premature beats are more frequent in thyrotoxic patients than matched controls before
and after treatment.[31] This suggests a continuing arrhythmic substrate despite
restoration of biochemical euthyroidism and the effects on myocardial electrical
remodeling, especially of the atria, by thyroid hormones.

The Case Revisited

In the emergency department, after initial assessment and securing an intravenous
line, we requested cardiac enzymes, an electrocardiogram, and a chest radiograph.
Under cardiac monitoring, we gave metoprolol 5 mg intravenously every 5 minutes
for 3 doses, followed by oral metoprolol 50 mg twice a day. We also started the patient
on intravenous heparin and initiated antithyroid drug therapy with propylthiouracil
200 mg 3 times a day and Lugol's iodine 10 drops 3 times a day after starting
propylthiouracil. We admitted the patient to the critical care unit. The patient reverted
to sinus rhythm after 72 hours of starting antithyroid therapy and was discharged
home the next day on antithyroid drug therapy, and oral anticoagulation therapy was
continued for 6 weeks and then discontinued, as the patient remained in sinus rhythm.
She elected to continue with antithyroid drug therapy.
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