Thyrotoxic Atrial Fibrillation

Abstract and Introduction

Abstract

Atrial fibrillation is the most common cardiac complication of hyperthyroidism and occurs in 15% of patients with hyperthyroidism. It is associated with a higher risk of thromboembolism that often involves the central nervous system. Oral anticoagulation is important in the majority of these patients to prevent thromboembolic complications. These patients require adjustment in the dose of various rate-controlling agents because of increased clearance associated with hyperthyroidism and a decrease in warfarin dosage because of increased clearance of vitamin K-dependent clotting factors. The management of thyrotoxic atrial fibrillation is summarized in this clinical review.

Introduction

A 52-year-old woman presents with symptoms of palpitations and mild shortness of breath. She is noted to be in atrial fibrillation with a rapid ventricular response of 157 beats per minute. She gives a 1-year history of increasing fatigue, intermittent palpitations, hot flashes, and weight loss of 15 lb in the past 6 months. She denies chest pain. Examination revealed an apprehensive woman with mild proptosis and diffuse thyroid enlargement. Lungs are clear. Heart sounds are irregular and rapid. Thyroid function studies performed last week at the doctor's office show a suppressed thyroid-stimulating hormone (TSH) level of .01 with elevated free thyroxine (T₄) of 60 pmol/L (normal, 9–23 pmol/L).

How Should This Patient Be Managed in the Emergency Department?

Management of the patient in the emergency department with thyrotoxic atrial fibrillation depends on the presence or absence of associated cardiac symptoms. A conservative management with antithyroid agents is appropriate for patients without associated cardiac complications, such as angina or heart failure. However, if the patient is symptomatic with angina or heart failure, then in addition to control of rapid heart rate, therapy to inhibit thyroid hormone release and synthesis should be initiated at the same time. The goal of therapy in the emergency department is the control of ventricular rate and relief of associated cardiac symptoms. Beta-adrenergic blocking agents may be particularly helpful because of the hypersympathetic state associated with hyperthyroidism. A cardiologist and a thyroid specialist should be involved early on in the management of such patients.

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 (T₃) 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 long-term 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 T₄ 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 age- and 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 8–10 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 48–72 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 10–14 days, and most patients will be biochemically euthyroid within 4–6 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 T₄ and T₃ concentrations than radioactive iodine therapy. Propylthiouracil also inhibits the peripheral conversion of T₄ to T₃. Because these agents inhibit the synthesis of T₄ 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 4–8 weeks and then withdrawn 3–5 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 3–5 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.