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Use of amiodarone for elderly patients.

Cardiac dysrhythmias are common in elderly people. One study on ambulatory monitoring detected supraventricular ectopics in 26%, ventricular ectopics in 17%, ventricular couplets in 11%, and ventricular tachycardia in 4% of healthy subjects aged between 60 and 85 years[1]. Another study has shown that 40% of elderly people with or without evidence of organic heart disease develop asymptomatic ventricular tachycardia on routine treadmill testing[2]. The prevalence of atrial fibrillation increases with age and is reported to be between 2% and 4% in those over 60 years of age[3]. The Framingham Study showed that the overall incidence of atrial fibrillation was 2% and that it increased sharply with age irrespective of the sex[4].

Not all cardiac dysrhythmias are dangerous and, therefore, antiarrhythmic treatment is not always necessary. However, treatment is obviously necessary in patients with symptomatic and/or life-threatening atrial and ventricular dysrhythmias. In addition, dysrhythmias are important risk factors for cardio-embolic stroke. Non-rheumatic chronic atrial fibrillation in particular is associated with a five-fold increase in the risk of embolic stroke[3]. Reverting such patients to sinus rhythm and maintaining them in sinus rhythm is therefore a desirable goal. Furthermore, elderly people are in general less likely to tolerate cardiac dysrhythmias, because of age-associated decline in cardiovascular function, and more likely than younger patients to need antiarrhythmic treatment.

There are several antiarrhythmic drugs available for clinical use, but because of adverse effects few are suitable for use in elderly patients. The most dangerous adverse effect is pro-arrhythmic potential which has been high-lighted by a number of studies over the past 10 years[5]. Recently, the Cardiac Arrhythmia Suppression Trial showed that the Class Ic drugs flecainide and encainide increased mortality by two and a half times compared with placebo in patients who were enrolled 6 days to 2 years after myocardial infarction and had six or more ventricular ectopics per hour, with no sustained ventricular tachycardia[6, 7].

Amiodarone is a Class III drug, which prolongs the action potentials of atrial and ventricular muscle, depresses atrio-ventricular nodal conduction and depresses sinus node function[8]. Following intravenous administration it decreases the heart rate, reduces myocardial contractility, decreases afterload and increases coronary blood flow. One of its major advantages is that on oral administration it does not usually produce significant deterioration of cardiac failure even in patients with severe left ventricular dysfunction[9].

Following the publication of the Cardiac Arrhythmia Suppression Trial[6], amiodarone has gained pre-eminence as an antiarrhythmic drug because of its efficacy and favourable haemodynamic effects. It has beep shown to be effective in both atrial and ventricular dysrhythmias and clear indications for its use have been established. It is a very effective drug for treatment of both chronic and paroxysmal atrial fibrillation. It has been shown to induce sinus rhythm in 53% to 97% of patients with long-standing atrial fibrillation, 30% to 46% of patients with paroxysmal atrial fibrillation, and 13% to 35% of patients with paroxysmal atrial flutter tachycardia[10]. It is also effective in controlling paroxysmal atrioventricular junctional supraventricular tachycardias which are refractory to other antiarrhythmic drugs[11]. Bradycardia-tachycardia syndrome is common in elderly people and amiodarone has been shown to be successful in controlling the tachyrhythmias associated with this condition[12]. Supraventricular dysrhythmias associated with pre-excitation syndromes also respond well[13]. The major indication for the use of amiodarone is in the treatment of life-threatening or symptomatic ventricular dysrhythmias. In 804 patients from 13 studies it has been shown to prevent recurrent, sustained ventricular tachycardia and/or ventricular fibrillation in 555 (69%), many of whom had not responded to other antiarrhythmic drugs[10]. In addition, amiodarone has been reported to reduce the incidence of sudden cardiac death to 5% to 15% in patients who were successfully resuscitated from a cardiac arrest[10]. This compares with a 30% to 40% two-year fatality in untreated patients.

Although amiodarone has been in wide clinical use, little is known about its use in elderly patients. An audit of its use in elderly patients was recently carried out in our department[14]. The most frequent indications were |resistant' atrial fibrillation (24%), malignant ventricular dysrhythmias (22%), and paroxysmal atrial fibrillation (20%) in 49 patients aged between 70 and 92 years (mean: 80 years). In one-third of patients, the use of amiodarone was considered questionable because they had sinus tachycardia, palpitations of unknown cause or undiagnosed dysrhythmias. In 14% of patients with |resistant' atrial fibrillation, amiodarone was commenced before they had received adequate treatment with digoxin. Although it is unwise to assume that the clinical practice is similar elsewhere on the basis of a local audit, informal enquiries with our colleagues have revealed that amiodarone does appear to be used excessively and inappropriately in elderly patients.

It is well recognized that amiodarone is associated with potentially dangerous adverse effects[15]. Most of these are dose-dependent and some appear to be more common in elderly patients. Dose-dependent symptomatic brady-cardia occurs more commonly in elderly subjects[15]. It also occurs in tachycardia-brady-cardia syndrome, and when amiodarone is concomitantly given with either beta-blockers or digoxin[15]. The bradycardia may be severe enough to necessitate temporary pacemaker insertion. Amiodarone does have pro-arrhythmic activity but it has been reported in less than 4% of patients which compares favourably, with 6-15% for Class I antiarrhythmic drugs[15].

Amiodarone inhibits peripheral conversion of [T.sub.4] to [T.sub.3] and causes an elevation in the levels of reverse [T.sub.3]. These changes in turn result in increased secretion of thyrotropin (TRH), and thyroid stimulating hormone (RSH). Clinical hyperthyroidism occurs in 1% to 5% of patients and may necessitate discontinuation of treatment[15]. Hypothyroidism occurs in 1% to 20% of patients, and it is more frequent in elderly patients[15, 16]. Thyroxine replacement and dose reduction may be necessary.

Pulmonary toxicity occurs in 1% to 10% of patients within 1 to 3 months of initiation of treatment, often in those on high doses, but can also occur in those on low doses[15]. Total cumulative dose may be important. Exertional dyspnoea (93%), dry cough (39%), and low-grade fever are the most frequent symptoms. The important clinical features include bilateral pulmonary crackles (40%), diminished breath sounds and diffuse bilateral interstitial changes or patchy alveolar infiltrates in chest radiographs[15]. Amiodarone should be withdrawn in patients with suspected pulmonary toxicity, and improvement usually occurs within a few weeks. In one study, nine out of 39 patients with pulmonary toxicity died and the remainder recovered on withdrawal of the drug[17].

Tremors, peripheral neuropathy, photo-sensitivity, slate-grey pigmentation of the skin, and elevation of serum liver enzyme levels are all dose-dependent adverse effects[15]. Corneal microdeposits occur in almost all patients, but do not affect vision[15].

In our audit, 11 of 49 patients (24%) were noted to have adverse effects, which included peripheral neuropathy (4), pneumonitis/fibrosis (3), hypothyroidism (2), thyrotoxicosis (1) and hepatic dysfunction (1). Forty-five of our patients (91%) were on 200 mg/day and two each were on 400 mg/day and 100 mg/day, respectively. Interestingly, nearly a quarter of our patients experienced potentially dangerous adverse effects in spite of the fact that the majority of them were on the recommended maintenance dose of 200 mg/day.

Obviously, there is a need for measures aimed at reducing the relatively high incidence of serious adverse effects in elderly patients. There is little information about the pharmacokinetics of amiodarone in elderly people. Pharmacokinetic studies in younger subjects have revealed that it has a large volume of distribution and long elimination half-life ranging between 26 and 107 (mean 52.6) days[10]. Both amiodarone and its major metabolite desethylamiodarone are excreted via the biliary tract with negligible renal elimination[10]. The value of serum amiodarone and desethylamiodarone levels in predicting the occurrence of adverse effects is uncertain. However, there is some evidence that the incidence of adverse effects is lower when the serum amiodarobe levels are below 1.5 mg/1 and higher when they are above 2.5 mg/1 during long-term therapy[18]. As it is also known that most of the adverse effects are dose-dependent, use of lowest possible maintenance doses can be expected to reduce the incidence of adverse effects. Before commencing amiodarone it is useful to check the baseline thyroid function, obtain a chest radiograph and assess lung function. Repetition of these investigations at regular intervals may help in early recognition and assessment of severity of the adverse effects.

In addition to causing the adverse effects, amiodarone is known to interact with a number of drugs and some of these interactions can be dangerous. It decreases renal elimination of digoxin and enhances the activity of warfarin and phenytoin, probably by inhibiting hepatic microsomal enzymes[10]. Doses of these drugs should be reduced if they need to be administered concomitantly with amiodarone. Serious dysrhythmias may occur if amiodarone is used with Class I antiarrhythmic drugs and the suppressive effect of beta-blockers and calcium antagonists on the sinus and atrioventricular nodes may be enhanced[10]. These drug combinations should probably be avoided.

Amiodarone is undoubtedly a very useful antiarrhythmic drug, particularly in the treatment of malignant ventricular dysrhythmias. However, it can cause a number of serious adverse effects and potentially dangerous drug interactions. There is little information either about its pharmacokinetics or clinical use in the elderly. Our audit of elderly patients detected a high incidence of adverse effects, and also revealed its use for questionable indications in one-third of the patients studied. There appears to be, therefore, a need for a change in the current practice of prescribing amiodarone for elderly patients. By prescribing the lowest possible maintenance doses, probably 100 mg/ day, or extending the dosing interval to every other or every third day (as is the practice of some of our colleagues), the dose-dependent adverse effects may be prevented. Most importantly, a clear-cut indication for the use of amiodarone should be established before it is prescribed.


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Author:Shetty, H.G.M.; Woodhouse, K.W.
Publication:Age and Ageing
Date:Jul 1, 1992
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