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Therapeutic goals of treating atrial fibrillation

The goals of treating atrial fibrillation are prevention of thromboembolism and control of rate and rhythm. Prevention is usually achieved with antithrombotic agents, particularly in elderly subjects who are most at risk of ischaemic stroke

Jaap W Deckers
Associate Professor of Medicine

Yves van Belle

Department of Cardiology
Cardiovascular Research School
Erasmus University Rotterdam
The Netherlands

The normal heart rhythm, designated sinus rhythm, is the result of coordinated action from specialised cells in the atria and the ventricles of the heart. Regular electric activity in the atrial sinus node triggers this process and thus determines the rate at which the heart beats. The electric activity of the atria reaches the ventricles following a short pause of the depolarisation wave in the atrioventricular node. This conduction delay allows the ventricles to fill with blood. The signal is subsequently conducted through the ventricles such that the muscular contraction of the ventricles takes place in a
coordinated manner.

Atrial fibrillation is characterised by uncoordinated electric activity in the atria with consequent deterioration of atrial function. This rhythm abnormality is the most common
sustained cardiac arrhythmia. Because of the altered mechanics of the atria, impaired blood flow occurs and stasis of the blood may result in clots. This thrombotic material can then migrate from the atria into the arterial system  (embolisation), often with dire clinical sequelae. Atrial fibrillation also has negative consequences on cardiac efficiency and function. Since the normal atrial contraction (“kick”) is lacking, there is incomplete filling of the cardiac ventricles prior
to contraction. In addition, the atrioventricular node is stimulated in a haphazard manner, leading to irregular and usually fast ventricular activity. Both factors may lead to further deterioration of cardiac function and thus trigger the clinical condition of heart failure.

The incidence and prevalence of atrial fibrillation both increase sharply with age. The lifetime risk of developing the arrhythmia has been estimated to be as high as 25%. The prevalence of atrial fibrillation is at least 10% in elderly men and women over the age of 80. The rhythm abnormality is not only the most common arrhythmia in clinical practice, but also accounts for about a third of all hospitalisations for rhythm abnormalities. Atrial fibrillation results in substantial imortality and morbidity from stroke and heart failure, and is associated with significant cost. The mortality rate of patients with atrial fibrillation is about twice as high as that of comparable
subjects with normal sinus rhythm.

The clinical management of atrial fibrillation has been described in considerable detail in recent guidelines of American and European professional societies as well as in a clinical review update, and the interested reader is referred
to these excellent documents for additional information.[1,2]

In a considerable number of patients, no specific cause can be found for the arrhythmia. Some morbid conditions increase the likelihood that atrial fibrillation may develop: these include the
presence of hypertension, obesity, heart failure, coronary artery disease and other diseases of the heart, including valve abnormalities, specifically disease of the mitral valve such as that resulting from rheumatic heart disease or endocarditis
(Table 1).

The increase of the rhythm abnormality with age is also indicative of a degenerative component in the disease process, such as fibrosis of the cardiac conductance system and loss of atrial muscle mass. Atrial fibrillation may also occur as a
result of concomitant hyperthyroidism, infection and fever, diverse metabolic disorders as well as in postoperative settings. In such circumstances, sinus rhythm usually re-establishes quickly when the external trigger is removed.

When atrial fibrillation occurs in attacks, it is called paroxysmal when the episodes of rhythm abnormality are shorter than one week. Persistent atrial fibrillation is defined when the arrhythmia does not disappear spontaneously, and the term permanent atrial fibrillation is employed when the arrhythmia persists and when attempts to convert the irregular rhythm to sinus rhythm using pharmacological or electrical means are
unsuccessful. In such instances, the presence of atrial fibrillation is accepted, and therapeutic measures are aimed at preventing long-term complications.

Clinical evaluation and diagnosis
Physical examination findings of irregular pulse and heart rate are suggestive of the presence of atrial fibrillation. Further examination may also show evidence of associated co-morbid conditions, such as fever, hypertension, valvular heart disease or heart failure.

Establishment of a final diagnosis of atrial fibrillation is relatively simple and can be made by standard 12-lead electrocardiography. The presence of irregular fibrillatory waves in combination with irregular ventricular response (QRS complex) are pathognomic. Even in asymptomatic subjects, the diagnosis is usually straightforward. Echocardiography is the technique of choice to investigate possible causes for the rhythm abnormality, to determine its consequences on cardiac function and to plan therapeutic measures. The most relevant echocardiographic parameters are those reflecting left ventricular and valvular function, the presence (or absence)
of other structural cardiac abnormalities and the dimension of the left atrium. With increasing dilation of the left atrium, the chances of obtaining long-term sinus rhythm through any therapeutic means are decreased.

Therapeutic goals
Prevention of thromboembolic complications Prevention of thromboembolism and associated clinical sequelae is a major therapeutic objective. To this end, administration of antithrombotic agents is almost invariably necessary, usually by subcutaneous or intravenous administration of heparin in inpatient settings, and using oral anticoagulants (vitamin K antagonists) in ambulant patients. The recommended target of anticoagulation is an international normalised ratio (INR) of between 2 and 3. Since the risk of the most feared complication, ischaemic stroke, is particularly high in subjects over the age of 75, elderly subjects are the main target for antithrombotic treatment, even more so in the presence of structural heart disease, hypertension, diabetes and previous stroke or TIA (Table 2).

Long-term anticoagulation is usually recommended in all patients with recurrent or persistent atrial fibrillation, with the exception of the (sub)group of patients characterised by young age (<65 years) without previous stroke and without cardiac abnormalities. In such subjects, aspirin may be an alternative treatment option. In a recent meta-analysis, aspirin proved to be better than placebo (or no drug) in preventing stroke, vascular death or myocardial infarction. The efficacy of aspirin may be derived partly from the drug’s general effects on platelet aggregation preventing the development of new atherosclerotic complications. Aspirin is less effective than oral anticoagulants in patients with previous thromboembolic complications.

Rhythm restoration and control
Normalisation of rhythm is often possible when atrial fibrillation has developed acutely. Under such circumstances, pharmacological or electrical cardioversion is appropriate and often successful. Because thrombus formation is usually not an issue when the arrhythmia has just commenced, anticoagulant therapy is not mandatory when rhythm restoration takes place within two days following its onset. Still, even then, many cardiologists prefer to perform oesophageal echocardiographic examination prior to attempted cardioversion to exclude the presence of a small thrombus.

Direct-current electronic cardioversion is recommended when atrial fibrillation is accompanied by a rapid ventricular response not reactive to pharmacological measures, or when the arrhythmia is accompanied by myocardial ischaemia or angina, severe hypotension or heart failure. Using monophasic cardioversion, it is customary to start with energy levels of at least 100 J, although some prefer 200 J. If unsuccessful,
energy levels should be increased by 100 J until the maximum level of 400 J has been reached. Pretreatment with  beta-blockers or antiarrhythmic drugs may increase the success rate of electronic cardioversion.

Some trials have compared outcomes of rhythm versus rate-control strategies in patients with atrial fibrillation. A trend towards slightly lower mortality in the rate-control strategy has
been observed. It is therefore reasonable to conclude that rate control is a sensible approach in elderly subjects without major symptoms.

Drugs and (invasive) ablative procedures are both effective for rate and rhythm control. Betablockers are effective for control of ventricular response, in particular in states of elevated
adrenergic tone such as in postoperative atrial fibrillation. The calcium antagonists verapamil and diltiazem are also commonly used. However, all of these drugs should be used with considerable caution in patients with cardiac abnormalities because they may decrease cardiac function or exert other unwanted effects on the heart. Digoxin is still popular in atrial fibrillation. This drug can be used in combination with beta-blockers, and such combination therapy is employed in many patients with permanent atrial fibrillation. Because digoxin increases vagal tonus, atrioventricular conduction is delayed, and this in turn decreases the heart rate. There is
usually no role for digoxin in subjects with paroxysmal atrial fibrillation because it has no effect on recurrence.

Antiarrhythmic drugs may be useful to restore sinus rhythm. Different drugs can be used, including amiodarone, propafenone, ibutilide and dofetilide, flecainide and disopyramide.

These drugs can also be prescribed in paroxysmal atrial fibrillation.

Amiodarone is an alternative agent for heart rate control when other, more conventional measures are ineffective. However, the drug has serious side-effects and its long-term employment for this indication is better left to cardiac specialists. Amiodarone is effective in controlling rate in subjects with atrial fibrillation and heart failure. Ablation procedures for atrial fibrillation have become more popular recently, but are technically difficult and require considerable experience. Such procedures are not without risk. At this moment, favourable long-term data are available for paroxysmal atrial fibrillation (freedom of atrial fibrillation in 80–90%). For persistent and permanent atrial fibrillation, ablative procedures appear to be somewhat less successful
(success rate in the order of 30%). Another strategy, usually only applied in severely symptomatic, therapy-resistant patients, consists of His bundle ablation in combination with permanent pacemaker implantation.