Radioiodine ablation of the thyroid to prevent recurrence of amiodarone-induced thyrotoxicosis in patients with resistant tachyarrhythmias

Abstract

Amiodarone-induced thyrotoxicosis (AIT) is a common complication of amiodarone therapy. Although permanent withdrawal of amiodarone is recommended due notably to the risk of worsening of tachyarrhythmias, some patients may require the reintroduction of amiodarone several months after normalizing their thyroid function. We, retrospectively, assessed the effects of ¹³¹I therapy to prevent recurrence of AIT in euthyroid patients requiring reintroduction of amiodarone.

Subjects and methods

Amiodarone was required in 10 cases of recurrent symptomatic paroxysmal atrial fibrillation (AF) and in 5 cases of ventricular tachycardia (VT) (M=12, F=3, mean age: 63±14 years). The underlying heart disease was dilated cardiomyopathy (n=4), ischaemic heart disease (n=4), hypertensive heart disease (n=2), arrhythmogenic right ventricular dysplasia (n=2) and valvulopathy (n=1). Two patients had idiopathic paroxysmal AF.

Results

A mean ¹³¹I dose of 579±183 MBq was administered 34±37 months after the episode of AIT. Amiodarone was reintroduced in 14 of 15 patients after a mean interval of 103±261 d. Fourteen patients developed definite hypothyroidism necessitating l-thyroxine but we observed no late recurrence of AIT. After a mean follow-up of 22±16 months, tachyarrhythmias were controlled in 12 of 14 patients.

Conclusion

¹³¹I therapy appears to be an effective and safe approach to prevent the recurrence of AIT in a patient requiring the reintroduction of amiodarone for tachyarrhythmias.

Amiodarone is a major antiarrhythmic drug used for short-term inpatient and outpatient management. However, its long-term use is limited due to its important side effects on the thyroid, pulmonary, neurological and hepatic function. The incidence of amiodarone-induced thyrotoxicosis (AIT) is estimated between 2 and 20% and is dependent on the dietary iodine content [1,,2]. AIT is generally subdivided into two types: Type 1, in which the iodine load triggers autonomous thyroid hormone production and Type 2, in which thyroid hormone release may be linked to destructive thyroiditis [3,,4]. In the majority of the patients, with mildly impaired thyroid function and/or stable rhythm, amiodarone can safely be withdrawn, resulting in the spontaneous regression of AIT in many cases [5]. When thyrotoxicosis persists, specific treatment with prednisone, potassium perchlorate or carbimazole may be required. Depending on the intensity of the thyroid impairment and on the severity of the arrhythmias, a new antiarrhythmic strategy such as class I antiarrhythmic drugs, beta-blockers, radiofrequency ablation or implantable defibrillator may be proposed. In other patients, amiodarone withdrawal is unacceptable in the absence of other therapeutic alternatives to control life-threatening arrhythmias. Near total thyroidectomy is then a definitive and sometimes preferred option [6], although recent data indicate that continuing amiodarone does not seem to have any adverse influence on the response to the treatment of AIT [7].

At a later stage, after full recovery of the thyroid function, the reintroduction of amiodarone can offer a valuable solution to control worsening arrhythmias despite the use of the above therapeutic options. However, a former episode of AIT, despite lack of specific studies published in the literature, is a traditional contraindication to amiodarone treatment because of the risk of recurrence. An attractive alternative could be to treat preventively selected patients who would benefit from amiodarone re-introduction with 131 radioiodine (¹³¹I), a substance commonly used in adults with overactive thyroids. The aim of this study is to describe the overall results of this novel approach which may be considered in patients in whom the withdrawal period from amiodarone had been long enough to allow significant iodine uptake.

Methods

Study population

We reviewed the medical records of 15 patients (12 men and 3 women, mean age 63±14 years) who received ¹³¹I to prevent the recurrence of AIT. All patients were recruited between 1996 and 2001 at the University Hospital of Amiens (n=8, patients 1–8) and at the Jean Godinot Institute in Reims (n=7, patients 9–15). The episode of AIT was confirmed in all cases by the presence of decreased levels of serum thyrotropin (TSH) with an increase in free T₃ levels. The range of normal values was obtained for each laboratory. ¹³¹I therapy was recommended to patients if all the following criteria were fulfilled.

• Former well-documented episode of AIT with normalized thyroid function.

• ¹³¹I uptake rate > 10%.

• Recurrence of symptomatic atrial or ventricular tachyarrhythmia.

• Failure of radiofrequency ablation, persistent difficulties with ventricular tachycardia (VT) management despite the use of an internal defibrillator or patient refusal/ineligibility for these techniques.

• Previous antiarrhythmic efficacy of amiodarone.

During follow-up, patients were considered controlled if there was no recurrence of their arrhythmia as assessed by the absence of new clinical events and normal Holter monitoring. For each patient, we obtained these data after contacting their referring cardiologist.

¹³¹I administration

Depending on the size of the thyroid and the iodine uptake, a standard dose of ¹³¹I was administered orally [between 370 and 740 MBq (10–20 mCi)].

Presentation of data

All variables are expressed as mean ± standard deviation.

Results

Initial presentation and outcome

Amiodarone treatment was initially prescribed for atrial fibrillation (AF) (n=10) or VT (n=5) in patients with dilated cardiomyopathy (n=4), ischaemic heart disease (n=4), hypertensive heart disease (n=2), arrhythmogenic right ventricular dysplasia (n=2) or valvulopathy (n=1). Two patients had idiopathic paroxysmal AF. AIT occurred after 26±14 months of effective treatment with amiodarone. Eight patients with isolated biochemical evidence of AIT were detected during systematic TSH screening, 6 patients had mild clinical features of thyrotoxicosis and 1 patient was diagnosed following the worsening of ventricular arrhythmias. ¹³¹I uptake was uniformly absent in 14 of 15 patients and 1 patient had heterogeneous thyroid nodules. Ultrasound evaluation was performed in 14 cases and showed 1 nodular thyroid. Antithyroid peroxidase and TSH receptor antibodies were absent in the 6 patients in whom they were measured. These retrospective data support the diagnosis of Type 1 AIT in only 1 patient.

Amiodarone withdrawal was possible in all patients and the only case of worsening ventricular arrhythmias was controlled with nadolol. AIT resolved spontaneously in 4 patients but 5 patients received prednisone, 3 patients received carbimazole and 1 patient received the combination of both. The management of the initial episode of AIT is unknown for 2 patients.

Indications for ¹³¹I treatment and amiodarone reintroduction

Recurrent VT occurred in 5 patients (syncope n=1, pulmonary oedema n=2, low cardiac output n=2) and multiple episodes of symptomatic paroxysmal AF in 10 patients (daily episodes n=6, weekly episodes n=4) despite medical treatment (Table 1). Electrical cardioversion was performed in 7 patients and unsuccessful radiofrequency ablation in 3 patients. A pacemaker was inserted in 5 patients and an implantable defibrillator in 2 patients. Mean left ventricular ejection fraction was 47±10%.

The indications for ¹³¹I and reintroduction of amiodarone are listed in Table 1. Of the 10 cases with recurrent AF, 8 cases occurred before the era of ablation of foci in the pulmonary veins. ¹³¹I and reintroduction of amiodarone were preferred to ablation of the His bundle in order to try to maintain sinus rhythm and to avoid pacemaker implantation. Two patients were treated after the development of pulmonary vein ablation but 1 patient refused this technique and the approach failed in the other. For patients with VT, ¹³¹I and reintroduction of amiodarone were proposed in 2 cases because of foreseeable mapping difficulties during radiofrequency ablation (multiple morphologies of non-sustained or sustained VTs). In one case, radiofrequency ablation failed due to intolerance of the induced VTs. In another case, the patient experienced a high number of internal defibrillator discharges and in the last one, the left ventricular ejection fraction was considered too low for implantation of an implantable defibrillator.

¹³¹I treatments

All patients were euthyroid prior to ¹³¹I treatment which was carried out with a mean dose of 579±183 MBq 34±37 months (5–147 months) after the episode of AIT. An early, mild and transient hyperthyroidism developed in 2 patients after ¹³¹I treatment. Patient 1, in whom the initial episode of AIT had occurred 13 months after the initiation of amiodarone, showed an increase in free T₃ levels to a maximum of 8.55 pmol/l (3.1<N>6.5) with a concomitant TSH decrease to 0.03 μui/ml (0.15<N>5) after the 12th day. Normalization of the thyroid function and control of the arrhythmia were obtained simultaneously 3 weeks after the reintroduction of amiodarone. Patient 4 experienced transient hyperthyroidism at the end of the first month and amiodarone was reintroduced because of poorly tolerated persistent AF despite cardioversion and the prescription of class I antiarrhythmic drugs or beta-blockers. Sinus rhythm was restored by electrical cardioversion 1 month later and the outcome was uneventful.

Amiodarone reintroduction

Amiodarone was reintroduced in all but one patient: patient 10 developed permanent AF and became asymptomatic, refusing to take amiodarone again or to undergo electrical cardioversion. Amiodarone (200–400 mg/d) was started with a mean period of 107±261 d following ¹³¹I treatment in most patients (n=12). It is to be noted that patient 8, presenting with arrhythmogenic right ventricular dysplasia and syncopal VT despite beta-blockade underwent simultaneous ¹³¹I therapy and a defibrillator implantation. Unexpectedly, no recurrence of VT was observed during the first month following ¹³¹I therapy whereas, previously, the patient had VT episodes every week. Thus, amiodarone was not immediately reintroduced. It became useful only 3 years later, when 4 appropriate shocks were delivered by his defibrillator in a single week.

Evolution of thyroid function following ¹³¹I treatment

Follow-up of 22±16 months required 14 of 15 patients (93%) developing hypothyroidism and requiring treatment with l-thyroxine. Only 1 patient remained euthyroid. No recurrence of AIT was observed (Table 2).

Cardiac outcome following ¹³¹I treatment and amiodarone reintroduction

Control of tachyarrhythmias was achieved in 12 of 14 patients (86%) after the reintroduction of amiodarone (4 of the 5 patients with VT and 8 of the 9 patients with episodes of AF). Persistent AF was converted by external (patients 5 and 7) or internal (patient 6) electrical cardioversion. In one other case, sinus rhythm was restored by the combination of flecainide and amiodarone.

The arrhythmias were not controlled by amiodarone in 2 patients: patient 13 improved but had episodes of VT treated by his internal defibrillator and patient 14 developed permanent AF.

It is to be noted that patient 10 refused the reintroduction of amiodarone after developing asymptomatic permanent AF. Amiodarone was not withdrawn from any patient. Death from low cardiac output unrelated to the recurrence of cardiac arrhythmias occurred in 2 patients (patients 3 and 11).

Discussion

In our series of patients with prior AIT, defined by the presence of both biological and clinical signs, and recurrent tachyarrythmias, ¹³¹I treatment allowed the reintroduction of amiodarone and, ultimately, control of the tachyarrythmias in 12 of 14 patients. Early, transient hyperthyroidism (2 cases) and definite hypothyroidism in most cases were the major disadvantages of this approach which nevertheless appeared to be a valuable solution in this selected population.

Recurrence of AIT

In case of AIT, amiodarone withdrawal is recommended [3,,7] whenever possible and the antiarrhythmic strategy has to be redefined. Another possibility is to continue amiodarone which, in a recent retrospective study of patients with biochemical Type 1 or 2 AIT, did not seem adversely to influence the response to thionamide [6]. In this report, serum free T4 was similar after 12 weeks of carbimazole when amiodarone was stopped and when it was continued.

When amiodarone has been stopped, recurrence of tachyarrhythmias can be observed long after the initial episode of AIT has resolved and, in this situation, the reintroduction of amiodarone may be the most attractive option, especially if it was initially effective. Nevertheless, amiodarone reintroduction is traditionally contraindicated. The foremost argument against this is the potential risk of life-threatening arrhythmias in patients with a severe underlying rhythm disorder. Few options are available to prevent repeat AIT. The first possibility, reported in patients with severe acute AIT, is thyroidectomy [5]. We believe that such an indication should be only reserved for cases requiring urgent amiodarone treatment. The second option is to reintroduce amiodarone under very close medical and biological monitoring as proposed in one study [8]. The recurrence rate of AIT was only 10% after 25±19 months of follow-up and in this eventuality, thyroidectomy was performed. However, as no prevention of repeat AIT was proposed, an increase in the incidence of AIT has to be expected with time [9]. In the last possibility, described here, reintroduction of amiodarone should be performed, when possible, only 1 month after the treatment to allow ¹³¹I re-uptake. With this approach, recurrences of AIT are not expected as radioiodine ablation of the thyroid has been performed.

Potential risks of ¹³¹I treatment

Permanent hypothyroidism is the main complication of ¹³¹I therapy [10]. It occurs in the majority of patients, sometimes many years after treatment. A recent study conducted in patients with hyperthyroidism found that the incidence of hypothyroidism was 61% 1 year after radioiodine [11]. In our series of patients, we observed a higher rate (93%) of hypothroidism. However, when trying to prevent the recurrence of AIT, hypothyroidism should be viewed as a goal rather than a complication.

Another less frequent complication of ¹³¹I treatment is early transient hyperthyroidism, which might be a direct consequence of the radiation or linked to an immunological mechanism [11]. Although we only observed 2 cases within the first month of treatment in our series, with no clinical consequences, patients must be followed closely during that time. Three large studies suggest that the overall risk of cancer is not related to the dose of ¹³¹I or to the time after exposure [12–14]. Although a small increase in the relative individual risk for certain types of cancer has been reported, these observations are still controversial [10].

Potential indications for preventive ¹³¹I treatment

In view of the potential risk/benefit ratio and because long-term therapy with amiodarone may have other side effects than thyroid dysfunction, we believe that the preventive use of ¹³¹I treatment has to be strictly reserved for patients who meet all the following criteria:

1. Prior documented episode of AIT.

2. Highly symptomatic atrial or life-threatening ventricular tachyarrhythmias.

3. Previous efficacy of amiodarone on the index arrhythmia.

4. Resistance to all other antiarrhythmic strategies.

For AF patients, this method could be considered in case of pulmonary vein ablation failure, in the absence of clear ablation indication (age) or because of patient refusal. It could be preferred over His bundle ablation with the aim of maintaining sinus rhythm and avoiding pacemaker implantation. For VT patients, this approach could be useful in case of a high number of implanted defibrillator discharges or in case of difficulties in achieving radiofrequency ablation (unmappable VTs).

In summary, the prevention of recurrent AIT by ¹³¹I treatment, after normalizing the iodine uptake, appears to be an effective and safe solution in patients in whom amiodarone can temporarily be discontinued. We observed tachyarrhythmia control in most cases (87%), with no late recurrence of AIT in patients in whom amiodarone was previously effective. Following the results of this preliminary series, a comparison with control groups in whom amiodarone is either continued combined with thionamide [7] or reintroduced without preventive treatment after withdrawal [8], seems not only ethical but necessary.

References