Atrial fibrillation: part one

In order to most effectively treat people with atrial fibrillation (AF), clinicians need to understand key issues, including the indications, and evidence for rhythm control versus ventricular rate control and how to reduce the risk of ischaemic stroke. This review aims to outline the current challenges posed by AF in older adults and to provide a practical guide to the current evidence regarding its management.

The prevalence of AF in the developed world is estimated at 1.5-2% of the general population.  Prevalence increases with age and it is more common in males. Average age of patients with the condition is steadily increasing and mean age is now between 75 and 85 years.¹ Prevalence from age 50 years on doubles every 10 years.² The ATRIA study found the prevalence was 0.1%, in females below 55 years of age, while in those above 85 years old, it was 9.1%; for males, figures were 0.2% and 11.0%, respectively.³

In addition to intrinsic cardiac causes such as valve disease and congestive heart failure, risk factors for cardiovascular disease also predispose to AF. Risk factors from the Framingham heart study are shown in box 1.⁴

AF is by no means a benign condition. It is associated with significant morbidity and mortality, including a fivefold increase in stroke and a threefold increase in cardiac failure.¹ Hospitalisation of patients with AF is also common. Follow up data from two large trials has shown it to be an independent predictor for mortality.^{5, 6} It therefore carries a significant social and economic burden. Potential complications of AF are outlined as follows:

Stroke

Incidence of stroke attributable to AF rises from 1.5% in people aged 50-59 years, to 23.5% in people 80-89 years of age.⁷ In addition, mortality from AF-related strokes is almost double that of strokes unrelated to AF, and functional deficits after AF-related strokes are more likely to be severe.⁸ There is a wealth of recent evidence showing the benefits of anticoagulation over antiplatelets or placebo in preventing stroke, as discussed later in this review. Elderly patients seem to have increased benefit compared to their younger counterparts. Despite this, many physicians remain reticent to recommend warfarin or oral anticoagulants in older patients.⁹ Risk of falls and previous bleeding are disproportionate barriers to their prescription.

Peripheral thromboembolism

One study showed a 4.0-fold increased risk of thromboembolic events in the aorta and the renal, mesenteric, pelvic, and extremity arteries in men with a hospital diagnosis of AF, and a 5.7-fold increased risk in women.¹⁰

Heart failure

AF may reduce cardiac output by 10-20% and can therefore precipitate failure in an already compromised ventricle. Other complications include tachycardia induced cardiomyopathy and critical cardiac ischaemia. These may result from a persistently elevated ventricular rate.⁷ In addition to the above, AF can reduce exercise tolerance, lead to impaired cognition and have a negative impact on quality of life. One study found that those with AF reported significantly poorer quality of life than healthy controls, the general population and other people with coronary heart disease.¹¹

Considering the associated morbidity and mortality, AF should be prevented if possible. This said, recent trials investigating upstream therapy have failed to show any convincing benefit with angiotensin receptor blockers or polyunsaturated fatty acids.¹² Measures to prevent or treat associated diseases may be useful in preventing their evolution to AF. The disease most often associated with AF is hypertension, followed by heart failure and coronary disease.  Weight loss and optimal treatment of associated conditions may help reduce development of AF.¹³

Given the prevalence of AF in older adults, its potential to lead to significant morbidity if untreated and the fact that there are readily available, effective treatments, early diagnosis is imperative. Epidemiological studies support the assumption that even short episodes of asymptomatic AF convey an increased risk of stroke.¹⁴ The SAFE randomised controlled trial showed that active screening for atrial fibrillation detects additional cases over current practice.

The detection rate of new cases of AF was 1.63% a year in the intervention practices and 1.04% in control practices. Systematic and opportunistic screening detected similar numbers of new cases (1.62% versus 1.64%).¹⁵ The European Society of Cardiology (ESC) now recommends opportunistic screening of all patients aged 65 and over (by pulse palpation followed by an ECG) to detect AF prior to first stroke.  All healthcare professionals should be vigilant in actively looking for, and appropriately treating AF in patients in both primary and secondary care settings. It is not a benign condition and prompt recognition and management can significantly reduce morbidity and mortality.

The main goals in the management of AF are as follows:^1,16

• To identify and treat any underlying structural heart disease, or predisposing factors
• To prevent stroke and thromboembolism
• To prevent tachycardia-induced cardiomyopathy
• To relieve symptoms
• To reduce AF associated hospital admission
• To improve functional capacity and quality of life.

Debates concerning the choice of rhythm control versus rate control strategies are ongoing and should be made on an individual patient basis. Current ESC guidance sites are listed in box 2.

The time of AF onset, the patients’ haemodynamic status and the severity of symptoms, are important in guiding the most appropriate initial treatment strategies and subsequent long-term goals.¹⁷ For example, in asymptomatic elderly patients, rate control strategy are often preferable due to lower cost, fewer side effects and reduced hospital admissions.^17,18 Whereas direct-current cardioversion may be the best option in haemodynamically unstable patients in an acute setting.

A commonly held belief is that converting AF into sinus rhythm is a superior strategy compared to rate control alone. However, several large clinical trials comparing rate versus rhythm control have shown no difference in symptom relief, cardiovascular outcome or survival.^18-23

Some studies have actually suggested inferior clinical outcomes in the rhythm control groups including increased rates of hospitalisation, adverse medication effects and increased mortality.^24,25

In the RECORDAF registry, superior outcomes were shown in the rhythm control group in patients under 65 years. However, this might be explained by the delay of progression to permanent AF and therefore, less adverse outcomes associated with it.²⁶ At present, for asymptomatic patients in permanent AF without hemodynamic compromise, rate rather than rhythm control is the preferred treatment option.

Most clinicians aim for a resting heart rate between 60-80 bpm and 90-115 bpm during moderate exercise.¹⁸ Beta-blockers, nondihydropyridine calcium channel blockers, and digoxin are the common pharmacologic agents used for rate control. In severely compromised patients, IV medications such as metoprolol, labetalol, or diltiazem are useful as they can be titrated, and can rapidly slow down atrioventricular node conduction.^1,21 Beta-blockers are the preferred initial AV blocking agent after myocardial infarction and in those with congestive heart failure (CHF).^27-29

Carvedilol is less effective at controlling rate compared to metoprolol, due to its less potent beta-adrenergic blocking effects.³⁰ Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, should be avoided in CHF populations due to their negative inotropic effects.³¹ They may however be useful for patients who have chronic pulmonary and bronchospastic disease.^32,33 In patients with increased sympathetic tone such as decompensated heart failure, digoxin is less effective, as it works through enhancement of vagal tone.^34-36 However, digoxin in combination with carvedilol is superior to either carvedilol or digoxin monotherpy in the management of AF in a CHF population.²⁸

Digoxin in atrial fibrillation

The use of digoxin in both AF and heart failure settings remains controversial. In the Digitalis investigation group (DIG) study, it had no effect on overall mortality but reduced the overall number of hospitalisations and the combined outcome of death or hospitalisation due to worsening heart failure.³⁷ There was also an association between digoxin withdrawal and increased in hospitalisation rate and decreased left ventricle ejection fraction (LVEF).^38,39 However, recent results from a subsection analysis of the Atrial Fibrillation Follow-up Investigations of Rhythm Management (AFFIRM) study, suggest a significant association between digoxin and all-cause mortality, cardiovascular mortality and arrthymatic deaths in the CHF setting.

Similar findings were seen in all-cause mortality, arrhythmic deaths but not cardiovascular mortality in non-CHF patients.^18,40 These findings are difficult to interpret and may be an overestimate, due to potentially unmeasured confounders, and a suggestion that prescription of digoxin tends to be for patients with a worse prognosis.

They are however, important to bear in mind when choosing a rate controlling medication. A subsequent study into AF and one year mortality has also suggested that digoxin is an independent risk factor for mortality in patients without CHF.⁴¹

Antiarrhythmic medications, by prolonging the atrial refractory wavelength and action potential duration, inhibit the formation of wavelets responsible for AF.⁴² The presence of structural heart disease, ease of administration, tolerability and side effects are all important factors when considering which antiarrhythmic medications to use.⁴³

Without antiarrhythmic agents, one year AF recurrence rate is about 75%.⁴⁴ Use of antiarrhythmic medication is often limited by side effects, which can be divided into cardiac effects eg. proarrthythmias; and extra cardiac effects eg. thyroid dysfunction with amiodarone. Class Ia, Ic and III are commonly used antiarrhythmic medications in AF and are discussed below.  Figure 1 outlines the ESC 2012 recommendations for antiarrthythmic drug choice.

Class 1a drugs

Quinidine is one of the oldest antiarrhythmic agents. Though it is proven to restore sinus rhythm,⁴⁵ its significant side effect profile (including cinchonism, haematological disorders and  polymorphic ventricular tachycardia) means it is rarely used.

Class 1c drugs (flecainide and propafenone)

The agents are first line in patients without structural heart disease,⁴⁶ but contradicted in those with coronary artery disease.⁴⁷

Class 3 drugs (sotalol and dofetilide)

These are both safe in patients with coronary artery disease.¹⁹ In one study, dofetilide was significantly more effective in restoring and maintaining sinus rhythm in AF and heart failure settings.⁴² However, it is renally excreted and needs in hospital initiation and dose adjustment according to QTc, therefore is often not a practical option.¹⁹ Sotalol is also renal excreted, though can be used at a reduced dose in those with eGFRs of over 10, and can be initiated as an out-patient. It has non-specific beta adrenergic receptor blocker property, and therefore, it should be used with caution in patients with bronchospasm.

Amiodarone

Although classified as Class III agent, amiodarone also displays non-competitive alpha and beta adrenoreceptor blockage and calcium channel blockage.^48,49 Of all the approved antiarrrhythmics, amiodarone has the greatest potential to maintain sinus rhythm.^45,50 It is safe in patients with structural heart disease and heart failure.⁵¹ Amiodarone can be administered both intravenously and orally. Due to its lipophilic feature, it is extensively distributed in the tissue.⁵² Its long half-life means loading of the medication is necessary in order to achieve the therapeutic levels rapidly.  The main drawback of amiodarone is its extensive side effect profile which includes thyroid disease and pulmonary fibrosis.

Dronedarone

Dronedarone is a derivative of amiodarone. It does not have an iodine molecule and as a result, has less iodine related toxicity.⁵³ It is less lipophilic and has a shorter half life.⁵⁴ Several studies have shown that dronedarone is superior to placebo in terms of maintaining sinus rhythm and controlling ventricular rate during AF recurrences, though inferior to amiodarone.^55,56 The ATHENA trial showed that dronedarone reduces the incidence of hospitalisation due to cardiovascular events or death in medium risk patients with AF.⁵⁷ Post-hoc analysis demonstrated a reduction in stroke risk in patients receiving dronedarone, which was independent of underlying antithrombotic therapy.⁵⁸ However, in the subsequent PALLAS study (stopped early due to safety concerns) it was associated with doubling of mortality among dronedarone treated patients, nearly double the risk of heart failure and more than double the risk of stroke.⁵⁹ Further studies in those with moderate to severe CHF showed an early increase in mortality and a significant rise in creatinine in the dronaderone group.⁶⁰

The Medicines and Healthcare Products Regulatory Agency (MHRA)⁶¹ has provided guidance regarding dronedarone use which include:

• Its contra-indication in permanent atrial fibrillation, heart failure and previous history of amiodarone related liver or lung toxicity
• Regular serum creatinine measurements before and during treatment, if serum creatinine continues to rise, discontinue medication
• Regular liver function tests and discontinuation if alanine transaminase levels are elevated greater or equal to 3x upper limit of normal.

In patients with AF who do not respond to or are intolerant to antiarrhythmic and atrioventricular (AV) blocking agents, catheter ablation should be considered.¹ Targeting the area around the pulmonary vein usually provides satisfactory termination of paroxysmal AF.^62-63 However, outcomes are less favorable in persistent AF.^64-65 In patients with refractory AF, ablation of the AV Junction with permanent pacemaker insertion improves symptoms and quality of life,^63,66 though does not alter long-term survival.⁶⁷ In refractory AF patients with significant LV systolic dysfunction, it is preferable to have biventricular pacing post atrioventricular nodal ablation: this helps control symptoms as well as improving exercise duration, ejection fraction and functional capacity.⁶⁸

Although catheter ablation has become more popular in the past decade, it is a complex interventional procedure and requires skilled operators. Patients may need a pacemaker and there is an ongoing thromboembolic risk on this population group. Recurrences of symptomatic and asymptomatic arrhythmia are common.⁶⁹ As a result, current guidelines recommend catheter ablation is reserved for young patients with paroxysmal AF and minimal structural heart disease who have remained symptomatic after antiarrhythmic drug therapy. For those with structural heart disease, catheter ablation is reserved for those who are refractory or intolerant to antiarrhythmic medications. Complex, ablation procedures may required in those with persistent AF.¹

AF is the commonest cardiac arrhythmia, its prevalence increasing with age. It is by no means a benign condition and is associated with significant morbidity and mortality. AF significantly increases the risk of stroke and heart failure and carries significant medical, social and economic burden. Opportunistic screening is effective in detecting AF and should be carried out for all those over 65 years. Current evidence suggests that in the majority patients with persistent or permanent AF, who are haemodynamically stable, a rate control (rather that rhythm control) strategy is preferable.

Conflict of interest: none declared

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Authors

• Lisa Manning
• Manda Lam
• Kashif Musarrat
• Martin Fotherby