Education And Debate


BMJ 1995; 311 doi: (Published 16 December 1995) Cite this as: BMJ 1995;311:1631
  1. Gregory Y H Lip,
  2. Robert D S Watson,
  3. Shyam P Singh

    One of the most important principles of using antiarrhythmic drugs for controlling any arrhythmia is to treat only patients who are symptomatic, have malignant arrhythmias (such as ventricular fibrillation), or are haemodynamically compromised (for example, with hypotension or heart failure). If a patient has only mild and infrequent symptoms, treatment with antiarrhythmic drugs should be avoided. This strategy is justified by evidence of substantial morbidity associated with such treatment and worsened long term prognosis, particularly if class I agents are used. Many antiarrhythmic drugs also depress cardiac function and may precipitate heart failure, and most can aggravate or cause an arrhythmia (arrhythmogenesis or proarrhythmic effect).

    Vaughan-Williams classification of antiarrhythmic drugs

    • Class I--Membrane-stabilising agents (fast sodium channel blockers) Class Ia--Blockssodium channel and delays repolarisation, increasing duration of action potential (for example, quinidine, disopyramide, procainamide)

      Class Ib--Blocks sodium channel and accelerates repolarisation, decreasing duration of action potential (for example, lignocaine, phenytoin)

      Class Ic--Blocks sodium channel, with little effect on repolarisation (for example, flecainide, propafenone)

    • Class II--£ Adrenoceptor blockers

      For example, atenolol, metoprolol

    • Class III--Drugs increasing duration of action potential

      For example, amiodarone, bretylium, sotalol (also has class II activity)

    • Class IV--Calcium channel blockers

      For example, verapamil, diltiazem

    Antiarrhythmic drugs can be used for rate control of chronic atrial fibrillation, cardioversionof atrial fibrillation to sinus rhythm, maintenance of sinus rhythm after cardioversion, and control of symptoms (including as a prophylaxis in paroxysmal atrial fibrillation). Antithrombotic prophylaxis with warfarin or aspirin should also be given. Prescribing habits for atrial fibrillation,however, vary greatly, perhaps reflecting uncertainty about what the best drug is and a lack of scientific evidence from controlled trials.

    An approach to drug management of atrial fibrillation Paroxysmal atrial fibrillation

    • Consider drugs for prevention of paroxysms and maintenance of sinus rhythm

    • Consider treatment with antithrombotic drugs Chronic atrial fibrillation

    • What is the objective of management? Consider cardioversion to sinus rhythm or heartrate control

      Cardioversion: Is the patient taking anticoagulants? Have antiarrhythmic drugs to maintain sinus rhythm after cardioversion been considered? Heart rate control: Has the appropriate drug been chosen? Has treatment with antithrombotic drugs been considered?


    Digoxin toxicity

    Is common in elderly people May occur with renal impairment May occur with electrolyte abnormalities (for example, after use of diuretics resulting in hypokalaemia)

    May result from interaction with other drugs (for example, quinidine, amiodarone) Should be anticipated through monitoring of drug treatments

    Digoxin remains the most commonly prescribed antiarrhythmic drug in patients with atrial fibrillation. It is useful in controlling the resting ventricular rate in atrial fibrillation. It has limited value, however, in patients with an accessory pathway (and may even accelerate the ventricular response). In addition, digoxin poorly controls the ventricular response in exercise and in conditions of high sympathetic drive. In such conditions, adequate rate control requires the concomitant use of a £ blocker or calcium antagonist with actions at the atrioventricular node, such as verapamil or diltiazem.


    The leaf of the foxglove (Digitalis purpurea) contains digoxin.

    Digoxin is commonly prescribed in paroxysmal atrial fibrillation both to suppress the arrhythmia and to control the initial heart rate if any such paroxysms occur. But, although it remains an effective treatment for chronic atrial fibrillation, it may be detrimental in paroxysmal atrial fibrillation.


    Ward observation chart showing apex-radial pulse deficit in patient with atrial fibrillation who had been given digoxin.

    Clinical evidence has shown that paroxysms of atrial fibrillation occur more frequently and for appreciably longer in patients receiving digoxin. Furthermore, the initial heart rate in such patients is poorly controlled. The mechanism behind this poor control is unclear. Digoxin increases vagal tone, moderating the speed of atrioventricular conduction, and also reduces the atrial refractory period. This latter property may paradoxically render the atrium more susceptible to fibrillation and may reduce or even prevent the chance of reversion to sinus rhythm.

    Conditions for resistance of atrial fibrillation to digoxin

    Patient is not taking tablets

    Accessory pathway is present (for example, the Wolff-Parkinson-White syndrome)


    Poor left ventricular function

    Respiratory disease (including cor pulmonale and lung cancer) Metabolic and electrolyte abnormalities, hypoxia

    Drug treatment in patients with paroxysmal atrial fibrillation

    Avoid digoxin

    If no contraindications try sotalol

    Alternatively, try propafenone or other class I drug (but not if cardiac impairment is present)

    If poor left ventricular function is present use amiodarone as first choice

    Verapamil and diltiazem

    Another commonly prescribed drug, verapamil, increases atrioventricular block and the effectiverefractory period of the atrioventricular node. This results in control of the ventricular rate insustained atrial fibrillation and may lead to much improved exercise capacity. Verapamil is therefore useful in controlling the ventricular response in atrial fibrillation, both at rest and with exercise. Diltiazem acts in a similar way to verapamil and is a popular alternative in North America.

    Drawbacks of verapamil

    • Verapamil (a class IV drug) is associated with a much lower rate of conversion to sinus rhythm than drugs in class III (for example,amiodarone, sotalol) or class I (for example, flecainide, propafenone)

    • It is ineffective in controlling paroxysmal atrial fibrillation

    • Giving verapamil to patients with underlying Wolff-Parkinson-White syndrome may lead to serious adverse effects, including ventricular fibrillation and severe haemodynamic impairment. This is due to poor control of very fast ventricular rates in response to electrical impulses passing down the accessory pathway, as the atrioventricular node is blocked by verapamil

    Class I antiarrhythmic drugs

    Class I antiarrhythmic drugs remain popular for atrial fibrillation, especially in North America. Many class I agents, however, have adverse side effects, including proarrhythmic properties, associated with prolongation of the QT interval and torsades des pointes (a polymorphic ventricular tachycardia). Many of these drugs should therefore be started in hospital under medical supervision.


    It is important, however, to distinguish between atrial fibrillation and flutter, as the use of a class I agent in patients with atrial flutter may accelerate the ventricular response with a 1:1 atrioventricular conduction. This may be due partly to the slowing in atrial rate and the anticholinergic effects (especially with disopyramide and quinidine), which result in an increase in atrioventricular conduction. Therefore if class I agents are given in atrial flutter then digoxin, £ blockers, or verapamil should be given alongside to avoid the potential for the accelerated atrioventricular conduction.

    Torsades des pointes

    Polymorphic ventricular tachycardia, where QRS complexes in the electrocardiogram seem to “twist”--that is, changes in QRS axis occur repeatedly

    Diagnosis from an electrocardiogram is made by a rapid QRS rate (200-250 beats/min) with the amplitude of the QRS complexes frequently changing in a sinusoidal fashion

    It may be self limiting but repetitive, leading to recurrent syncope; occasionally it may progress to ventricular fibrillation and sudden death Care is needed as this arrhythmia is often induced or worsened by antiarrhythmic agents (especially class I and III)--particularly if the QT interval is prolonged and there are electrolyte disturbances--or by drugs that further prolong theQT interval (phenothiazines, tricyclic antidepressants, some antihistamines)

    Class Ia

    Quinidine is used often, especially in North America, for maintaining sinus rhythm after cardioversion or for reducing the frequency of paroxysmal atrial fibrillation. This strategy is supported by a meta-analysis of six controlled trials that showed that patients treated with quinidine were less likely to have a recurrence of atrial fibrillation. Importantly, however, this analysis also showed an excess of mortality for the treated group. Quinidine also interacts with digoxin and is associated with serious side effects, such as polymorphic ventricular tachycardia, quinidine syncope, blood dyscrasias, and cinchonism.


    Efficacy of quinidine in maintaining sinus rhythm after cardioversion

    Disopyramide may also prevent recurrences of atrial fibrillation, but its effects are inconsistent. It is also poorly tolerated, particularly in elderly people and those with glaucoma and prostatism, primarily because of its profound anticholinergic properties. Procainamide also shares some electrophysiological properties with quinidine and disopyramide, but no placebo controlled studies of this drug have been carried out.


    Quinidine v sotalol in maintenance of sinus rhythm after direct current conversion of atrial fibrillation.

    Class Ic

    By contrast, class Ic antiarrhythmic drugs, such as flecainide and propafenone, have been well investigated. They have potent effects on conduction within cardiac cell membranes and lengthen the PR interval and QRS complex in the electrocardiogram. Flecainide has been shown to be effective in preventing recurrences of atrial fibrillation in up to 60% of patients but does not limit the ventricular response. Adverse effects with flecainide have been reported in up to 74% of patients, but these effects were mostly tolerable. Nevertheless, doubts about the safety of flecainide have been raised by the cardiac arrhythmia suppression trial, in which patients (with previous myocardial infarction) given flecainide for ventricular arrhythmias had a worsened prognosis (with about athreefold increase in mortality).

    Although limited information exists, the safety record in patients with atrial arrhythmias may be more favourable. Flecainide may be used with caution in patients with atrial fibrillation without evidence of ischaemic heart disease or ventricular dysfunction, especially to control paroxysmal atrial fibrillation, achieve pharmacological cardioversion, or to control atrial fibrillation associated with the Wolff-Parkinson-White syndrome. Current recommendations in the British National Formulary are that treatment with these drugs should be started in hospital under supervision.

    Propafenone may also be effective in paroxysmal atrial fibrillation. This is particularly pertinent in view of its inherent rate limiting (class II) properties, permitting potentially greater ventricular rate control. In paroxysmal atrial fibrillation flecainide may be more effective than propafenone in converting patients to sinus rhythm (90% v 55% conversion rate respectively). Propafenone and sotalol (which also has class III activity), however, are equally effective in maintaining sinus rhythm in patients with recurrent atrial fibrillation.


    Flecainide v placebo in prevention of symptomatic recurrences of paroxysmal atrial fibrillation.

    Class III antiarrhythmic drugs

    Sotalol, another commonly prescribed drug, combines the antiarrhythmic effects of drugs in bothclass II (blockade) and class III (prolongation of repolarisation). This second property is thought to be mainly due to the dextro (D) isomer of the sotalol compound. Little evidence exists, however, for the efficacy of sotalol specifically in paroxysmal atrial fibrillation. Sotalol seems effective in controlling the ventricular response in atrial fibrillation, thus permitting rate control, without the need for other drugs, such as digoxin. As sotalol has £ blocker activity, it may also be useful in patients with concomitant ischaemic heart disease and hypertension.

    Useful drug options in various clinical situations

    Atrial fibrillation in hypertensive patient Calcium antagonist (for example, verapamil, diltiazem)

    Atrial fibrillation and thyroid disease

    Non-specific £ blocker (for example propranolol)

    Atrial fibrillation and ischaemic heart disease

    £ Blocker if possible (otherwise diltiazem,verapamil)

    Heart failure and poor cardiac function

    Digoxin or possibly amiodarone

    Atrial fibrillation and hypertrophic cardiomyopathy

    £ Blockers or calcium antagonists

    Amiodarone is a very effective drug for treating atrial fibrillation, but its use has to be moderated because of its common side effects, although serious side effects do not often occur with maintenance doses of 200 mg or less. Side effects of amiodarone include photosensitivity and skin rashes, hepatic dysfunction or hepatitis, pulmonary fibrosis, neuromyopathy, and thyroid disorders These side effects are more common with higher doses of amiodarone and with prolonged treatment, although some may be reversible on withdrawal of the drug. Nevertheless, amiodarone is particularlyuseful in atrial fibrillation for treating patients refractory to other measures, and low doses of 200 mg/day (often much less than doses needed for controlling ventricular arrhythmias, which require 400 mg/day or more) may be effective with little risk of side effects.


    Success of amiodarone in maintaining sinus rhythm in patients with atrial fibrillation with respect to underlying aetiology.

    Amiodarone has also been shown to be highly effective in converting atrial fibrillation to sinus rhythm and to be capable of maintaining sinus rhythm long term. It also seems more effective than either verapamil or quinidine and is highly effective in controlling symptoms, possibly by moderating the ventricular response even if an attack occurs. Amiodarone may have a particular role in patients with arrhythmias and severe impairment of left ventricular function. It can be used both orally and intravenously, although if given intravenously it may act quite rapidly, more rapidly than if given orally (when it has a slow onset due to its long half life). The use of a rapid loading regimen of intravenous amiodarone to suppress paroxysmal atrial fibrillation is, however, seldom indicated. Care should also be taken with amiodarone as it can substantially increase the plasma concentrations of digoxin, thus leading to potential toxicity. It also commonly leads to overanticoagulation in patients taking warfarin, perhaps by a hepatic interaction.

    A stepped care approach to drugs for rate control in chronic atrial fibrillation

    • Try digoxin first

    • If unsuccessful add or substitute verapamil, diltiazem, or £ blocker

    • If still unsuccessful consider adding or substituting propafenone, flecainide, or amiodarone

    • Referral to specialist may be indicated in difficult cases

    View Abstract

    Sign in

    Log in through your institution

    Free trial

    Register for a free trial to to receive unlimited access to all content on for 14 days.
    Sign up for a free trial