Atrial fibrillation: medical management

Julián Pérez-Villacastín
MD PhD

Javier Pindado
MD
Arrhythmia Unit
Hospital Clínico San Carlos
Madrid, Spain

Atrial fibrillation (AF) is the most common sustained arrhythmia and carries a significant associated morbidity and mortality that increases with each decade of life.(1) The condition has adverse consequences related to a reduction in cardiac output and to atrial thrombus formation, which can lead to systemic embolisation.

Pharmacologic cardioversion to normal sinus rhythm
From a clinical point of view, patients with AF may be asymptomatic or exhibit symptoms such as palpitations, angina, heart failure or stroke. The choice of therapy is influenced by the presence of symptoms and by the duration and type of AF (paroxysmal, persistent or permanent).(2) The two main therapeutic alternatives are to restore and maintain normal sinus rhythm (NSR) or simply to allow AF to persist with adequate rate control. Although controlling symptoms associated with AF constitute the most compelling reason to pursue the restoration and maintenance of NSR, the choice between rhythm control and rate control depends not only on the physician’s indications but also on the patient’s preference.

The management of recent-onset AF depends on clinical tolerance. If severe hypotension, ischaemia, heart failure or pre-excited AF appears, urgent electrical cardioversion should be used (see Figure 1). When the patient remains in AF and is clinically stable, either direct current or pharmacologic cardioversion can be performed. Electrical cardioversion is usually preferred because of greater efficacy (75–90%) and a low risk of proarrhyrhmia.(3) If the pharmacologic cardioversion is chosen, flecainide, propafenone, intravenous ibutilide, dofetilide and amiodarone have been shown to convert 30–60% of patients.(2)

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There is evidence that the benefit from specific antiarrhythmic drugs varies with the duration of AF. Dofetilide, flecainide, ibutilide or propafenone can be recommended if ≤7 days duration;(2) dofetilide or Ibutilide, if AF is more prolonged. Amiodarone can be used in both settings, and in addition it is recommended whether the patient presents with heart failure, left ventricular dysfunction or severe LV hypertrophy.

Maintenance of normal sinus rhythm
Only 25% of patients who are successfully cardioverted maintain NSR for more than one year without chronic antiarrhythmic therapy.(4) Prophylactic antiarrhythmic drugs suppress the triggering of ectopic beats, reducing the likelihood of AF. This is more likely to occur in patients with AF for less than one year with no enlargement of the left atrium (≤4 cm) and a reversible cause of AF.(5,6) The 2006 ACC/AHA/ESC guidelines(2) concluded that before the initiation of antiarrhythmic therapy all precipitants must be correctly diagnosed and treated. Patients with paroxysmal AF often do not have structural heart disease or significant LA enlargement.(2) In these patients, chronic antiarrhythmic oral therapy with flecainide or propafenone is usually recommended.

Concurrent administration of an AV nodal blocker is indicated in patients who have demonstrated a moderate-to-rapid ventricular response to AF. There is increasing evidence that amiodarone is the most effective drug for maintenance of sinus rhythm.(7) However, due to its extracardiac toxicity, this drug is reserved for patients in whom IC class drugs fail, patients with heart failure or a reduced left ventricular ejection fraction. Sotalol appears to have equal efficacy to propafenone. Other drugs, such as dronedarone and tedisamil, are currently under evaluation (see Figure 2).

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Rate control in AF
For the majority of older patients with first-detected AF, rate control with chronic anticoagulation is the selected treatment. Beta-blockers (atenolol or metoprolol) and calcium-channel blockers (diltiazem or verapamil) are recommended for rate control at rest and at exercise. In contrast, digoxin is not effective during exercise, and is mainly used in patients with heart failure and in those who are not physically active.(2)

Rhythm control versus rate control
Based on the rationale that NSR should be better than AF, several studies compared pharmacologic rhythm and rate control strategies. Two show an almost significant trend toward a lower incidence of primary endpoint (mortality in AFFIRM and a composite endpoint in RACE) with rate control without differences in functional status or quality of life. Higher adverse effects related to medications have also been demonstrated with a rhythm control strategy.(6,8,9) These trials support the conclusion that rate control is the preferred initial approach in most patients. Rhythm control strategy must be considered by patient preference or in patients tolerating antiarrhythmic drugs and who have a good chance of remaining in sinus rhythm over an extended period of time, when adequate rate control is not possible or symptoms related to paroxysmal AF or recurrent AF persist despite adequate rate control. Some data support that in young patients or patients with heart failure the rhythm control strategy can be superior to the rate control strategy.(10)

Other studies have also revealed the limited efficacy of antiarrhythmic drugs, since a substantial percentage of patients in whom a rhythm control strategy is chosen, continue to have AF. In addition, most antiarrhythmic drugs have associated side-effects and other inconveniences that have a negative impact on quality of life. In one study recently published, only 60% of patients show no contraindications and good tolerability to chronic antiarrhythmic therapy during a one-year follow-up.(11) Furthermore, patients treated with class IA antiarrhythmic drugs showed significantly higher mortality. Amiodarone showed a neutral effect.

Antithrombotic agents
In addition to the optional antiarrhythmic treatment, anticoagulation to prevent systemic embolisation is a priority during cardioversion to sinus rhythm and in patients with chronic or paroxysmal AF. If AF onset is more than 48 hours before or of unknown duration, or there is associated mitral valve disease, or the patient has a prior history of a thromboembolic event, anticoagulant therapy should be given to prevent systemic embolisation for at least four weeks before cardioversion unless transoesophageal echocardiography demonstrates nonintracavitary thrombi.(12)
 
According to the results from several trials, embolic events occur with equal frequency regardless of whether a rate control or rhythm control strategy is pursued, and occur most often after warfarin has been stopped or when the international normalised ratio (INR) is subtherapeutic. Because factors that predispose to recurrent AF (advanced age, heart failure, hypertension, LA enlargement and LV dysfunction) are risk factors for thromboembolism, the risk of stroke may not be eliminated by correction of the rhythm disturbance. It is not known whether maintenance of sinus rhythm prevents thromboembolism, heart failure or death in patients with a history of AF.

The CHADS2 score is currently the best validated and one of the most clinically useful scores (see Table 1). It has been developed to estimate the risk of ischaemic stroke or peripheral embolisation. Reduction in ischaemic stroke with oral anticoagulation in patients with paroxysmal AF is similar to that in patients with chronic AF. Although conventional-dose warfarin reduces the risk of embolisation in AF, its use is not easy as frequent INR monitoring is required and there are dietary and medication interactions. For these reasons, a number of alternatives have been studied, including aspirin, low-dose warfarin plus aspirin, clopidogrel plus aspirin and ximelagatran. Warfarin has been superior to any alternative therapy in patients at high risk of stroke, while aspirin therapy is considered a reasonable option in patients at low thromboembolic risk. Ximelagatran is one of several investigational, orally administered direct thrombin inhibitors that inhibit the conversion of fibrinogen to fibrin by thrombin. It has consistent pharmacokinetics, which can eliminate the need for anticoagulation monitoring. Noninferiority of ximelagatran to warfarin was demonstrated in two large randomised trials of patients with AF. However, because of concerns about hepatotoxicity, the manufacturer removed ximelagatran from the market. Dabigatran, rivaroxaban and others are being studied and could become the replacement for current anticoagulants.

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Other drugs
Antiarrhythmic effects have also been reported by the use of ACE inhibitors, statins, aldosterone blockers and magnesium. These drugs may have beneficial effects in patients with AF and concomitant co-morbidities.

Summary
Medical treatment alleviates but does not cure atrial fibrillation. Currently available antiarrhythmic drugs are far from ideal agents. In fact, failure to demonstrate improved outcomes with rhythm control strategies can be due more to the inadequacies of these drugs than to a clinical equivalence between AF with rate control and NSR. Anticoagulants remain a key element in the treatment of patients with atrial fibrillation, to reduce the number of thromboembolic events.

References

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2. Fuster V, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation 2006;114:700-52.
3. Gallagher MM, et al. Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter. J Am Coll Cardiol 2001;38(5):1498-504.
4. Van Gelder IC, et al. Chronic atrial fibrillation: success of serial cardioversion therapy and safety of oral anticoagulation. Arch Intern Med 1996;156:2585-92.
5. Dittrich HC, et al. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989:63:193-7.
6. Lafuente-Lafuente C, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006;166(7):719-28.
7. Roy D, et al. Amiodarone to prevent recurrence of atrial fibrillation. NEJM 2000;342:913-20.
8. AFFIRM investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation: the atrial fibrillation follow-up investigation of rhythm management. NEJM 2002;347(23):1825-33.
9. Hagens VE, et al. Rate control versus rhythm control for patients with persistent atrial fibrillation with mild to moderate heart failure: results from the RAte Control versus Electrical cardioversion (RACE) study. Am Heart J. 2005;149(6):1106-11.
10. AFFIRM Investigators, (Curtis AB, facilitator of writing group). Clinical factors that influence response to treatment strategies in atrial fibrillation: the AFFIRM Study. Am Heart J 2005;149:645-9.
11. Humphries KH, et al, for the Canadian Registry of Atrial Fibrillation. Limitations to antiarrhythmic drug use in patients with atrial fibrillation. CMAJ 2004; 171:741-5.
12. Klein AL, Grimm RA, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. NEJM 2001;344(19):1411-20.